Patent application title: Indoleamine 2,3-Dioxygenase-2
Inventors:
George C. Prendergast (Penn Valley, PA, US)
George C. Prendergast (Penn Valley, PA, US)
Lankenau Institute For Medical Research
Richard Metz (Pennington, NJ, US)
Assignees:
Lankenau Institute For Medical Research
IPC8 Class: AC12N900FI
USPC Class:
800 18
Class name: Transgenic nonhuman animal (e.g., mollusks, etc.) mammal mouse
Publication date: 2013-08-29
Patent application number: 20130227719
Abstract:
The nucleotide and amino acid sequences of indoleamine 2,3-dioxygenase-2
(IDO2) and methods of use thereof are provided.Claims:
1. An isolated indoleamine 2,3-dioxygenase-2 (IDO2) protein comprising an
amino acid sequence which has at least 80% identity with SEQ ID NO: 1.
2. (canceled)
3. The isolated IDO2 protein of claim 1, where said amino acid sequence is SEQ ID NO: 1.
4. (canceled)
5. (canceled)
6. A method for identifying a compound which modulates IDO2 activity comprising: a) contacting the IDO2 protein of claim 1 with a test compound; and b) determining tryptophan catabolism activity of the IDO2 protein; wherein a change in the tryptophan catabolism activity in the presence of the test compound compared to the tryptophan catabolism activity in the absence of the test compound indicates that the test compound can modulate IDO2 activity.
7. The method of claim 6, wherein said IDO2 protein of step a) is expressed in a cell.
8. The method of claim 6, wherein IDO2 activity is assessed by measuring liver inhibitory protein (LIP).
9. (canceled)
10. An isolated splice variant of the IDO2 protein of claim 1.
11. An isolated nucleic acid molecule encoding the IDO2 splice variant of claim 10.
12. A transgenic mouse harboring homozygous null mutations in its endogenous IDO2 gene.
13. The isolated IDO2 protein of claim 1, wherein said amino acid sequence has at least 85% identity with SEQ ID NO: 1.
14. The isolated IDO2 protein of claim 1, wherein said amino acid sequence has at least 90% identity with SEQ ID NO: 1.
15. The isolated IDO2 protein of claim 1, wherein said amino acid sequence has at least 95% identity with SEQ ID NO: 1.
16. The isolated IDO2 protein of claim 1, wherein said amino acid sequence has at least 97% identity with SEQ ID NO: 1.
17. The isolated IDO2 protein of claim 1, wherein said amino acid sequence has at least 99% identity with SEQ ID NO: 1.
Description:
[0001] This application is a continuation-in-part of PCT/US2007/069271,
filed on May 18, 2007, which claims priority under 35 U.S.C. §119(e)
to U.S. Provisional Patent Application No. 60/801,255, filed on May 18,
2006, U.S. Provisional Patent Application No. 60/886,815, filed on Jan.
26, 2007, and U.S. Provisional Patent Application No. 60/914,472, filed
on Apr. 27, 2007. The foregoing applications are incorporated by
reference herein.
FIELD OF THE INVENTION
[0003] This invention relates generally to the fields of cellular metabolism, oncology, and immunology. Specifically, the invention provides the nucleotide and amino acid sequence of indoleamine 2,3-dioxygenase-2 (IDO2) and methods of use thereof.
BACKGROUND OF THE INVENTION
[0004] Tumors, virus-infected cells, and diseased cells characteristically express atypical, potentially immunoreactive antigens. Accumulating evidence suggests that the failure of the immune system to mount an effective response against progressively growing tumors or virally infected cells is not due to a lack of recognizable antigens. Immunosuppression is poorly understood and mechanisms by which cells escape immune surveillance have been poorly explored. Recently, it has been shown that cytotoxic T cells become tolerized by a reduction in local concentrations of tryptophan that are elicited by indoleamine 2,3-dioxygenase-1 (IDO1) activity.
[0005] IDO1 is an oxidoreductase that catalyzes the rate-limiting step in tryptophan catabolism. This enzyme is structurally distinct from tryptophan dioxygenase (TDO), which is responsible for dietary tryptophan catabolism in the liver. IDO1 is an IFN-γ target gene that has been suggested to play a role in immunomodulation (Mellor and Munn (1999) Immunol. Today, 20:469-473). Elevation of IDO1 activity depletes the levels of tryptophan in local cellular environments. Induction of IDO1 in antigen-presenting cells, where IDO1 is regulated by IFN-γ, blocks the activation of T cells, which are especially sensitive to tryptophan depletion. T cells must undergo 1-2 rounds of cell division to become activated, but in response to tryptophan depletion they arrest in G1 instead. In this way, IDO1 has been proposed to inhibit the TH1 responses that promote cytotoxic T cell development.
[0006] IDO1 has been proposed to modulate gene expression. This modulation is proposed to occur through a pathway involving GCN2, whose activation has been shown to lead to altered gene expression. The proposed pathway involves the following steps. First, IDO1 activity results in the metabolism of tryptophan. Second, the deprivation of tryptophan leads to tRNAs being uncharged. The presence of uncharged tRNAs results in the activation of GCN2 kinase and a general response pathway for amino acid starvation. Third, the active GCN2 kinase phosphorylates serine 52 of the alpha subunit of eukaryotic initiation factor 2 (eIF2α), which is known to be an important translation control mechanism. The regulation of eIF2α activity is governed by the phosphorylation of serine 52. Currently, there are at least three known kinases, i.e., IFN-inducible dsRNA-dependent protein kinase, heme-regulated repressor, and general control (GCN2), which can phosphorylate serine 52 in eIF2α. The phosphorylation of serine 52 in eIF2α prevents the GDP-GTP exchange activity of eIF2α resulting in the suppression of protein synthesis.
[0007] GCN2 has been shown to be important for IDO1-dependent responses since a GCN2 knock-out animal phenocopies the IDO1 knock-out animal.
[0008] The role of IDO1 in immunosuppression has been demonstrated by the ability of 1-methyl-tryptophan (1MT), a specific and bioactive IDO1 inhibitor (Cady and Sono (1991) Arch. Biochem. Biophys. 291:326-333), to elicit MHC-restricted and T cell-mediated rejection of allogeneic mouse concepti (Mellor et al. (2001) Nat. Immunol. 2:64-68; Munn et al. (1998) Science. 281: 1191-93). This effect is consistent with the high levels of IDO1 expression in placental trophoblast cells (Sedlmayr et al. (2002) Mol. Hum. Reprod. 8:385-391).
[0009] Significantly, IDO1 activity has been shown to be elevated frequently in human tumors and/or in cancer patients (Yasui et al. (1986) Proc. Natl. Acad. Sci. USA. 83:6622-26; Taylor and Feng (1991) FASEB J. 5:2516-22). Since IDO1 can modulate immune responses, one logical implication is that IDO1 elevation in cancer may promote tumor immunosuppression (Mellor and Munn (1999) Immunol. Today, 20:469-473; Munn et al. (1999) J. Exp. Med. 189:1363-72; Munn et al. (1998) Science. 281:1191-93). This possibility is supported by the observation that many cancers, including breast cancer, are characterized by a loss of beneficial immune functions that can limit malignant development. For example, TH1 responses (of which IFN-γ production is a hallmark) that promote the production of cytotoxic T cells are suppressed during cancer progression. A resultant hypothesis from this data was that if IDO1 drives cancer progression by blunting T cell activation, then IDO1 inhibition in animals should blunt tumor growth by reversing IDO1-mediated immunosuppression.
[0010] Notably, there are two stereoisomers of the IDO1 inhibitor 1MT, e.g., D-1MT and L-1MT. L-1MT inhibits IDO1 and exhibits a characteristic pattern of antitumor activities. In contrast, D-1MT shares the same in vivo properties, but does not inhibit IDO1 itself. One explanation for these results is that D-1MT inhibits an enzyme that is related to, but distinct from IDO1. However, no enzymes related to IDO1 have been identified.
SUMMARY OF THE INVENTION
[0011] In accordance with the present invention nucleic acid molecules encoding indoleamine 2,3-dioxygenase-2 (IDO2) and isoforms, splice variants, and mutants thereof are provided. In another embodiment of the instant invention, primers, probes, antisense molecules, and siRNAs for detection and regulation of IDO2 are provided.
[0012] Another aspect of the invention includes amino acid sequences of IDO2. Additionally, antibodies immunologically specific for IDO2 are encompassed by this invention.
[0013] In yet another embodiment of the instant invention, methods are provided for the screening of compounds for their ability to the modulate activities of IDO2. The screening methods can be performed in vitro or in host cells, or in animals transgenic for IDO2 expression.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIGS. 1A and 1B provide amino acid sequences of isoforms of IDO2 (SEQ ID NO: 1 and SEQ ID NO: 2, respectively). FIG. 1C provides a schematic of the IDO2 genome organization based on GenBank Accession No. NW--923907.1 when the IDO2 isoform comprises 10 coding exons and about 1227 coding bases.
[0015] FIGS. 2A and 2B provide amino acid sequences of mouse IDO2 isoforms (SEQ ID NO: 3 and SEQ ID NO: 4, respectively).
[0016] FIG. 3A provides a sequence alignment of the amino acid sequences of a human IDO2 (top strand; amino acids 30-416 of SEQ ID NO: 1 shown) and a human IDO1 (bottom strand; amino acids 13-400 of SEQ ID NO: 5). The underlined residues indicate the conserved histidine and aspartic acid residues necessary for heme binding. # indicates identical and + indicates similar amino acids. FIG. 3B provides the amino acid sequence of human IDO1 (GenBank Accession No AAH27882.1; SEQ ID NO: 5). FIG. 3c provides a sequence alignment of the amino acid sequence of a human IDO2 (SEQ ID NO: 2) and the amino acid sequence of a mouse IDO2 (SEQ ID NO: 4). + indicates similar amino acids. FIGS. 3D-3G provide an amino acid and nucleotide alignment of a murine IDO2 (amino acid, SEQ ID NO: 4; nucleotide, SEQ ID NO: 13) and a murine IDO1 (amino acid, SEQ ID NO: 6; nucleotide, SEQ ID NO: 7). The underlined region indicate exon boundaries.
[0017] FIG. 4A is a nucleotide sequence of human IDO2 (SEQ ID NO: 8) which encodes SEQ ID NO: 1. The nucleotide sequence in capital letters (SEQ ID NO: 9) is the sequence encoding the human IDO2 protein. FIG. 4B is a nucleotide sequence of mouse IDO2 (SEQ ID NO: 10) which encodes SEQ ID NO: 3. The nucleotide sequence in capital letters (SEQ ID NO: 11) is the sequence encoding the mouse IDO2 protein. FIGS. 4C and 4D are nucleotide sequences (SEQ ID NO: 12 and SEQ ID NO: 13, respectively) encoding human and murine IDO2 proteins, respectively. Underlined nucleotides indicate the first nucleotide of a new exon.
[0018] FIG. 5 provides a Western blot of murine IDO1 and IDO2 expression in T-REx®-293 cells. U is untreated cells, D is doxycycline treated cells, and DT refers to doxycycline and tryptophan treated cells.
[0019] FIG. 6 provides graphs of the growth of T-Rex® cells with no vector (center panel), pcDNA4TO-muIDO1 (left panel) or pcDNA4TO-muIDO2 (right panel). Cells were grown in media alone or in the presence of doxycycline, tryptophan, or both doxycycline and tryptophan.
[0020] FIG. 7 provides graphs demonstrating the ability of IDO1 and IDO2 expressing 293 cells to metabolize tryptophan. A kynurenine assay was conducted to determine the ability of IDO1 and IDO2 expressing cells to metabolize tryptophan. The expression of IDO1 or IDO2 was induced by the presence of doxycycline. The cells were also exposed to increasing amounts of tryptophan.
[0021] FIG. 8A provides a graph demonstrating the inhibition of IDO1 by methyl thiohydantione (MTH). T-Rex cells or IDO1 expressing T-Rex cells (C10) were treated with doxycycline in the presence of increasing concentrations of DMSO (carrier) or a known IDO1 inhibitor (MTH). The cells were maintained in growth media plus supplements for 5 days, after which the media was harvested and subjected to analysis for the presence of kynurenine. FIG. 8B provides a graph demonstrating that IDO2 metabolizes tryptophan and can be inhibited by 1-methyl-D-tryptophan (1M-D-T). IDO2 expressing T-Rex cells were treated with doxycycline in the presence of increasing concentrations of DMSO (carrier) or the D, L and mixed DL racemic isomers of 1-methyl-tryptophan, (1M-D-T, 1M-L-T and 1M-LD-T, respectively). The cells were maintained in growth media plus supplements for 5 days after which the media was harvested and subjected to analysis for the presence of kynurenine.
[0022] FIG. 9A is a Western blot demonstrating that IDO1 and tryptophan deprivation stimulates the expression of the LIP isoforms of NFIL-6. T-REx® cells (control) and T-REx® cells expressing IDO1 were either uninduced or induced with doxycycline in the presence or absence of added tryptophan (100 μM). FIG. 9B is a Western blot demonstrating that IDO2, regardless of tryptophan levels, stimulates the expression of the LIP isoforms of NFIL-6. T-REx® cells (control) and T-REx® cells expressing IDO2 were either uninduced or induced with doxycycline in the presence or absence of added tryptophan. Cells were also optionally treated with the D, L and mixed DL racemic isomers of 1-methyl-tryptophan, (1M-D-T, 1M-L-T and 1M-LD-T, respectively). FIG. 9c is a Western blot demonstrating that IDO2 expression results in the phosphorylation of elF2α. T-REx® cells expressing IDO2 were either uninduced or induced with doxycycline in the presence or absence of added tryptophan.
[0023] FIGS. 10A-10Q provide a genomic sequence of murine IDO2 (SEQ ID NO: 14) with select restriction enzyme sites and intron/exon boundaries included.
[0024] FIGS. 11A-11U provide a genomic sequence of human IDO2 (SEQ ID NO: 15) with select restriction enzyme sites and intron/exon boundaries included.
[0025] FIGS. 12A (SEQ ID NOs: 30-43, top to bottom) and 12B (SEQ ID NOs: 44-59, top to bottom) provide a schematic of IDO2 nucleic acid molecules and IDO2 primers for murine and human IDO2, respectively. FIG. 12C provides IDO1 primers and cloning primers (SEQ ID NOs: 60-82, top to bottom).
[0026] FIG. 13 provides a schematic of the locations of the introns and exons of IDO2 including exon 1a.
[0027] FIG. 14 provides a nucleotide sequence (SEQ ID NO: 20) of IDO2 which comprises 11 exons and encodes SEQ ID NO: 1. Asterisks depict the exon junctions.
[0028] FIGS. 15A-15Y is a genomic sequence of human IDO2 (SEQ ID NO: 21) with select restriction enzyme sites and intron/exon boundaries included.
[0029] FIGS. 16A-16G provide a nucleotide sequence alignment of a human IDO2 (SEQ ID NO: 12) with IDO2 splice variants and mutants: IDO2 Δ3/4/6 (SEQ ID NO: 22), IDO2 Δ8 (SEQ ID NO: 23), IDO2 Δ6/8 (SEQ ID NO: 24), IDO2 Δ4/5 (SEQ ID NO: 25), IDO2 R235W (SEQ ID NO: 26), IDO2 Y332stop (SEQ ID NO: 27), and a splice variant yielding an alternative exon 8 (SEQ ID NO: 29). SEQ ID NO: 28 is the amino acid sequence. Exon boundaries are indicated and the encoded amino acids are also provided.
[0030] FIG. 17 is a graph of the kynurenine activity of various IDO2 splice variants or mutants alone or co-expressed with IDO2, IDO1, or empty vector (Puc).
[0031] FIGS. 18A and 18B are images of Western blots of cellular lysates of 293 cells expressing the following: 1: no IDOs, 2: mouse IDO2 (WT), 3: human IDO2 (WT), 4: mouse IDO1/IDO2, 5: mouse IDO2, 6: mouse IDO2/1 chimera, 7: human IDO1/mouse IDO2, 8: human IDO2 (R-W), 9: mouse IDO2 (R-W), 10: hu8man IDO2 (Y-*), 11: human IDO1. The Western blot in FIG. 18A was probed with an anti-IDO1 polyclonal sera (1:200) and the Western blot in FIG. 18B was probed with an anti-muIDO2 monoclonal antibody (MAb 7.4.6; 1:100).
[0032] FIG. 19A is a schematic of human IDO2 mRNA and the location of the primers used for RT-PCR. FIG. 19B provides images of the RT-PCR assays performed on total RNA from the indicated tissues. The primers used in the RT-PCR are indicated at the right of the panels and GAPDH is provided as a control. FIG. 19C is an image of an agarose gel demonstrating the presence of various IDO2 isoforms in human placenta.
[0033] FIGS. 20A (SEQ ID NOs: 83-122, top to bottom) and 20B (SEQ ID NOs: 124-147, top to bottom) provide target sequences and siRNA sequences for human and mouse IDO2, respectively.
[0034] FIG. 21 is a schematic of a target vector strategy for the construction of a conditional IDO2 knockout mice strain. Removal of exons 9 and 10 in the IDO2 gene happens upon crossing with a transgenic Cre mouse expressing Cre recombinase under the control of tissue specific promoters.
[0035] FIG. 22 is a schematic of a screening strategy for IDO-2 knockin mice upon removal of the selection marker NeoR.
[0036] FIG. 23A is a schematic of vector pVLmuIDO2. FIGS. 23B-23I provide the sequence of vector pVLmuIDO2 (SEQ ID NO: 162).
[0037] FIG. 24A is a schematic of vector pVLhuIDO2. FIGS. 24B-24I provide the sequence of vector pVLhuIDO2 (SEQ ID NO: 163).
[0038] FIGS. 25A and 25B are graphs of the inhibition studies of varying amounts of D-1-methyl-tryptophan and L-1-methyl-tryptophan on IDO1 and IDO2 whole cell lysates, respectively.
DETAILED DESCRIPTION OF THE INVENTION
[0039] The involvement of IDO1 in immune suppression, particularly the suppression of T cell immunity, has been well documented. As stated hereinabove, there is evidence to suggest that a previously unidentified enzyme related to IDO1 is also involved in immune suppression. Indeed, L-1MT has been shown to be effective at inhibiting IDO1 activity and tumor progression, but the stereoisomer D-1MT does not significantly inhibit IDO1 activity yet retains antitumor properties. Further, at least one IDO1 antisera has been generated which recognizes, in addition to IDO1, a differently regulated protein with a slightly larger apparent molecular weight as determined by Western blot.
[0040] In accordance with the instant invention, a novel homolog of IDO has been identified and named indoleamine 2,3-dioxygenase-2 (IDO2, also referred to as indoleamine 2,3-dioxygenase-like-1 (INDOL1) and IDO-NT). Amino acid sequences of human and mouse IDO2 are provided herein (see, e.g., FIGS. 1 and 2, respectively). Nucleotide sequences of human and mouse IDO2 are also provided (see, e.g., FIGS. 4A and 4B, respectively). Notably, IDO2 has approximately 45% sequence identity with human IDO1 (FIG. 3A).
[0041] Significantly, IDO2 shares the structural features of IDO1 that are known to be essential for heme binding and tryptophan catabolic activity. Indeed, the histidine and aspartic acid residues required for heme binding are conserved between IDO1 and IDO2 (see FIG. 3A).
[0042] Various isoforms, splice variants, and mutant IDO2 nucleic acids and proteins are provided. One isoform of IDO2 is also slightly larger than IDO1 (420 amino acids versus 403 amino acids). This size difference may account for the larger species sometimes seen in Western blots with antisera directed to IDO1. Indeed, portions of the sequence of the IDO1 peptide used to generate the antisera are conserved in IDO2. Based on these facts, it appears that certain IDO1 antisera are capable of cross-reacting with IDO2.
[0043] The 5' untranslated region of the IDO2 gene comprising the promoter elements, has a high degree of homology with the consensus sequences for the key immune regulatory transcription factors STAT1 and IRF-7. Significantly, IRF-7 is the master regulator of dendritic cells which present antigen to T cells and control T cell activation versus anergy. This similarity in the 5' regulatory region to the consensus sequence of these immune regulatory transcription factors suggests that IDO2 plays a role in the regulation of the immune response. Indeed, in silico analysis (e.g., an electronic Northern based on serial analysis of gene expression (SAGE)) determined that the highest expression of IDO2 would be in dendritic cells, where IDO1 is also known to be expressed, and pre-dendritic cells (such as JAWS II cells).
[0044] IDO2 nucleic acid molecules and proteins may be useful in the diagnosis and prognosis of immune modulation, like IDO1. IDO2 may also be used in the methods described by U.S. Pat. Nos. 6,451,840 and 6,482,416 for IDO1. Furthermore, as described hereinbelow, IDO2 is a candidate therapeutic target for diseases and disorders associated with immune modulation and/or protein misfolding such as cancer, viral infections, and other pathological conditions.
[0045] The activation of GCN2 translation control pathway alters the expression of the transcription factor Nuclear Factor IL6 (NFIL6; also known in the literature as C/EBPβ/IL6DBP/TCF5). The CCAAT-enhancer binding protein beta (C/EBPβ) is a basic leucine zipper (bZIP) transcription factor selectively expressed during differentiation of liver, adipose tissue, blood cells, and endocrine pancreas. C/BBPβ encodes four isoforms arising from the differential initiation of translation at four different in-frame AUGs, thereby producing the 40 kDa, 35 kDa, 20 kDa and 8.5 kDa C/EBPβ isoforms. The Lap and LIP isoforms of NF-IL6 have a variety of pleiotropic activities and are involved in regulation cell function, cell growth, and immune response. Lap-1 and Lap-2 have an antiproliferative effect, regulate cell cycle control and cytokine expression, and are pro-inflammatory. LIP is a dominant negative isoform. Therefore, the altered expression of LIP is a relevant biomarker for IDO1 and IDO2 activity in any cell expressing NF-IL6.
[0046] IDO1 expression leads to the increase in LIP (also called liver inhibitory protein) which is a dominant negative regulator of Lap1/2 activities, since it lacks certain activation and regulatory domains on LAPS (Liver activation proteins) and can form heterodimers with the LAP proteins, thereby altering their activity. By inference, it may be concluded that the activation of LIP is dependent on the deprivation of tryptophan, the activation of the GCN2 pathway and the increase in LIP production, which in turn results in altered gene expression and cell function. The data described herein support this model since the addition of exogenous tryptophan, even when IDO1 is highly expressed, blocks the production of LIP and activation of the GCN2 pathway.
[0047] IDO2 expression also leads to the activation of GCN2 kinase and increased LIP production. However the activation of the GCN2-LIP pathway is not inhibited by the addition of exogenous tryptophan. Therefore, it may be concluded that the mechanism of action for IDO2 is not tryptophan deprivation but rather the direct activation of the GCN2 kinase-LIP pathway. This is may be due to the generation of uncharged tryptophan tRNAs directly, the charging of tRNAs with kynurenine, or some other effect on the GCN2-LIP pathway.
[0048] It is also demonstrated herein that IDO2 activity can be inhibited by 1-methyl-D-tryptophan (1M-D-T) which blocks the activation of GCN2 kinase and subsequent altered LIP expression.
[0049] The activation of IDO2, like IDO1, has distinct and important properties for the regulation of immune responses. It is known that IDO1 exerts its activity locally by depriving the local cell environment of tryptophan, activating the GCN2 pathway, and suppressing T-cell activation and other immune activities. IDO2 directly activates the GCN2 pathway and exerts its activity globally and systemically in any cell in which it is expressed, including immune T cells and antigen presenting cells. IDO2 may also impact cell activities at distal locations as the altered expression of LIP/LAP is known to affect the expression of soluble growth factors and cytokines that can impact cell responses, like immune activation. One such scenario would be the activation of IDO2 in an antigen presenting cell (APC), such as a dendritic cell, which converts the APC in the presence of antigen to a tolerogenic cell that suppresses the immune response to a particular antigen.
I. Definitions
[0050] The term "IDO inhibitor" refers to an agent capable of inhibiting the activity of indoleamine 2,3-dioxygenase (IDO) (such as IDO1 and IDO2) and thereby reversing IDO-mediated immunosuppression. An IDO inhibitor may be a competitive, noncompetitive, or irreversible IDO inhibitor. "A competitive IDO inhibitor" is a compound that reversibly inhibits IDO enzyme activity at the catalytic site (including, without limitation, 1-methyl-tryptophan); "a noncompetitive IDO Inhibitor" is a compound that reversibly inhibits IDO enzyme activity at a non-catalytic site (including, without limitation, norharman); and "an irreversible IDO inhibitor" is a compound that irreversibly destroys IDO enzyme activity by forming a covalent bond with the enzyme (including, without limitation, cyclopropyl/aziridinyl tryptophan derivatives). IDO inhibitors include, without limitation, 1-methyl-DL-tryptophan (1MT; Sigma-Aldrich; St. Louis, Mo.), β-(3-benzofuranyl)-DL-alanine (Sigma-Aldrich), beta-(3-benzo(b)thienyl)-DL-alanine (Sigma-Aldrich), 6-nitro-L-tryptophan (Sigma-Aldrich), indole 3-carbinol (LKT Laboratories; St. Paul, Minn.), 3,3'-diindolylmethane (LKT Laboratories), epigallocatechin gallate (LKT Laboratories), 5-Br-4-Cl-indoxyl 1,3-diacetate (Sigma-Aldrich), 9-vinylcarbazole (Sigma-Aldrich), acemetacin (Sigma-Aldrich), 5-bromo-DL-tryptophan (Sigma-Aldrich), 5-bromoindoxyl diacetate (Sigma-Aldrich), phenyl-TH-DL-trp (3-(N-phenyl-thiohydantoin)-indole) (Sigma-Aldrich), propenyl-TH-DL-trp (3-(N-allyl-thiohydantoin)-indole) (Asinex; Moscow, Russia), methyl-TH-DL-trp (3-(N-methyl-thiohydantoin)-indole) (Sigma-Aldrich), brassinin (LKT Laboratories), 5-methyl-brassinin (Mehta, et al. (1994) Anticancer Res., 14:1209-1213); 3,3'-diindolylmethane (DIM; LKT Laboratories), indole-3-carbinol (I3C; LKT Laboratories), and the IDO inhibitors provided in U.S. patent application Ser. No. 10/550,444 and U.S. Provisional Application 60/730,706. IDO inhibitors may selectively or preferentially inhibit IDO1 (an "IDO1 inhibitor") and/or IDO2 (an "IDO2 inhibitor"). IDO inhibitors include, without limitation, nucleic acid molecules (e.g., siRNA, antisense oligonucleotides), peptides, chemical compounds, and antibodies, or biologically active fragments thereof.
[0051] "Pharmaceutically acceptable" indicates approval by a regulatory agency of the Federal government or a state government. "Pharmaceutically acceptable" agents may be listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
[0052] A "carrier" refers to, for example, a diluent, adjuvant, excipient, auxiliary agent or vehicle with which an active agent of the present invention is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.
[0053] "Nucleic acid" or a "nucleic acid molecule" as used herein refers to any DNA or RNA molecule, either single or double stranded and, if single stranded, the molecule of its complementary sequence in either linear or circular form. In discussing nucleic acid molecules, a sequence or structure of a particular nucleic acid molecule may be described herein according to the normal convention of providing the sequence in the 5' to 3' direction. With reference to nucleic acids of the invention, the term "isolated nucleic acid" is sometimes used. This term, when applied to DNA, refers to a DNA molecule that is separated from sequences with which it is immediately contiguous in the naturally occurring genome of the organism in which it originated. For example, an "isolated nucleic acid" may comprise a DNA molecule inserted into a vector, such as a plasmid or virus vector, or integrated into the genomic DNA of a prokaryotic or eukaryotic cell or host organism.
[0054] When applied to RNA, the term "isolated nucleic acid" refers primarily to an RNA molecule encoded by an isolated DNA molecule as defined above. Alternatively, the term may refer to an RNA molecule that has been sufficiently separated from other nucleic acids with which it would be associated in its natural state (i.e., in cells or tissues). An "isolated nucleic acid" (either DNA or RNA) may further represent a molecule produced directly by biological or synthetic means and separated from other components present during its production.
[0055] A "replicon" is any genetic element, for example, a plasmid, cosmid, bacmid, plastid, phage or virus, which is capable of replication largely under its own control. A replicon may be either RNA or DNA and may be single or double stranded. Generally, a "viral replicon" is a replicon which contains the complete genome of the virus. A "sub-genomic replicon" refers to a viral replicon that contains something less than the full viral genome, but is still capable of replicating itself. For example, a sub-genomic replicon may contain most of the genes encoding for the non-structural proteins of the virus, but not most of the genes encoding for the structural proteins.
[0056] A "vector" is a replicon, such as a plasmid, cosmid, bacmid, phage or virus, to which another genetic sequence or element (either DNA or RNA) may be attached so as to bring about the replication of the attached sequence or element.
[0057] An "expression operon" refers to a nucleic acid segment that may possess transcriptional and translational control sequences, such as promoters, enhancers, translational start signals (e.g., ATG or AUG codons), polyadenylation signals, terminators, and the like, and which facilitate the expression of a polypeptide coding sequence in a host cell or organism.
[0058] The terms "percent similarity," "percent identity" and "percent homology," when referring to a particular sequence, are used as set forth in the University of Wisconsin GCG software program.
[0059] The term "substantially pure" refers to a preparation comprising at least 50-60% by weight of a given material (e.g., nucleic acid, oligonucleotide, protein, etc.). More preferably, the preparation comprises at least 75% by weight, and most preferably 90-95% by weight of the given compound. Purity is measured by methods appropriate for the given compound (e.g. chromatographic methods, agarose or polyacrylamide gel electrophoresis, HPLC analysis, and the like).
[0060] The term "oligonucleotides" as used herein refers to sequences, primers and probes of the present invention, and is defined as a nucleic acid molecule comprised of two or more ribo- or deoxyribonucleotides, preferably more than three. The exact size of the oligonucleotide will depend on various factors and on the particular application and use of the oligonucleotide.
[0061] The term "primer" as used herein refers to an oligonucleotide, either RNA or DNA, either single-stranded or double-stranded, either derived from a biological system, generated by restriction enzyme digestion, or produced synthetically which, when placed in the proper environment, is able to functionally act as an initiator of template-dependent nucleic acid synthesis. When presented with an appropriate nucleic acid template, suitable nucleoside triphosphate precursors of nucleic acids, a polymerase enzyme, suitable cofactors and conditions such as appropriate temperature and pH, the primer may be extended at its 3' terminus by the addition of nucleotides by the action of a polymerase or similar activity to yield a primer extension product. The primer may vary in length depending on the particular conditions and requirement of the application. For example, in diagnostic applications, the oligonucleotide primer is typically 15-25 or more nucleotides in length. The primer must be of sufficient complementarity to the desired template to prime the synthesis of the desired extension product, that is, to be able to anneal with the desired template strand in a manner sufficient to provide the 3' hydroxyl moiety of the primer in appropriate juxtaposition for use in the initiation of synthesis by a polymerase or similar enzyme. It is not required that the primer sequence represent an exact complement of the desired template. For example, a non-complementary nucleotide sequence may be attached to the 5' end of an otherwise complementary primer. Alternatively, non-complementary bases may be interspersed within the oligonucleotide primer sequence, provided that the primer sequence has sufficient complementarity with the sequence of the desired template strand to functionally provide a template-primer complex for the synthesis of the extension product.
[0062] The term "probe" as used herein refers to an oligonucleotide, polynucleotide or nucleic acid, either RNA or DNA, whether occurring naturally as in a purified restriction enzyme digest or produced synthetically, which is capable of annealing with or specifically hybridizing to a nucleic acid with sequences complementary to the probe. A probe may be either single-stranded or double-stranded. The exact length of the probe will depend upon many factors, including temperature, source of probe and use of the method. For example, for diagnostic applications, depending on the complexity of the target sequence, the oligonucleotide probe typically contains 15-25 or more nucleotides, although it may contain fewer nucleotides. The probes herein are selected to be complementary to different strands of a particular target nucleic acid sequence. This means that the probes must be sufficiently complementary so as to be able to "specifically hybridize" or anneal with their respective target strands under a set of pre-determined conditions. Therefore, the probe sequence need not reflect the exact complementary sequence of the target. For example, a non-complementary nucleotide fragment may be attached to the 5' or 3' end of the probe, with the remainder of the probe sequence being complementary to the target strand. Alternatively, non-complementary bases or longer sequences can be interspersed into the probe, provided that the probe sequence has sufficient complementarity with the sequence of the target nucleic acid to anneal therewith specifically.
[0063] Polymerase chain reaction (PCR) has been described in U.S. Pat. Nos. 4,683,195, 4,800,195, and 4,965,188, the entire disclosures of which are incorporated by reference herein.
[0064] With respect to single stranded nucleic acids, particularly oligonucleotides, the term "specifically hybridizing" refers to the association between two single-stranded nucleotide molecules of sufficiently complementary sequence to permit such hybridization under pre-determined conditions generally used in the art (sometimes termed "substantially complementary"). In particular, the term refers to hybridization of an oligonucleotide with a substantially complementary sequence contained within a single-stranded DNA molecule of the invention, to the substantial exclusion of hybridization of the oligonucleotide with single-stranded nucleic acids of non-complementary sequence. Appropriate conditions enabling specific hybridization of single stranded nucleic acid molecules of varying complementarity are well known in the art.
[0065] For instance, one common formula for calculating the stringency conditions required to achieve hybridization between nucleic acid molecules of a specified sequence homology is set forth below (Sambrook et al., 1989, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press):
Tm=81.5° C.+16.6 Log [Na+]+0.41(%G+C)-0.63(%formamide)-600/#bp in duplex
[0066] As an illustration of the above formula, using [Na+]=[0.368] and 50% formamide, with GC content of 42% and an average probe size of 200 bases, the Tm is 57° C. The Tm of a DNA duplex decreases by 1-1.5° C. with every 1% decrease in homology. Thus, targets with greater than about 75% sequence identity would be observed using a hybridization temperature of 42° C.
[0067] The stringency of the hybridization and wash depend primarily on the salt concentration and temperature of the solutions. In general, to maximize the rate of annealing of the probe with its target, the hybridization is usually carried out at salt and temperature conditions that are 20-25° C. below the calculated Tm of the hybrid. Wash conditions should be as stringent as possible for the degree of identity of the probe for the target. In general, wash conditions are selected to be approximately 12-20° C. below the Tm of the hybrid. In regards to the nucleic acids of the current invention, a moderate stringency hybridization is defined as hybridization in 6×SSC, 5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNA at 42° C., and washed in 2×SSC and 0.5% SDS at 55° C. for 15 minutes. A high stringency hybridization is defined as hybridization in 6×SSC, 5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNA at 42° C., and washed in 1×SSC and 0.5% SDS at 65° C. for 15 minutes. A very high stringency hybridization is defined as hybridization in 6×SSC, 5×Denhardt's solution, 0.5% SDS and 100 μg/ml denatured salmon sperm DNA at 42° C., and washed in 0.1×SSC and 0.5% SDS at 65° C. for 15 minutes.
[0068] The term "isolated protein" or "isolated and purified protein" is sometimes used herein. This term refers primarily to a protein produced by expression of an isolated nucleic acid molecule of the invention. Alternatively, this term may refer to a protein that has been sufficiently separated from other proteins with which it would naturally be associated, so as to exist in "substantially pure" form. "Isolated" is not meant to exclude artificial or synthetic mixtures with other compounds or materials, or the presence of impurities that do not interfere with the fundamental activity, and that may be present, for example, due to incomplete purification, or the addition of stabilizers.
[0069] The term "gene" refers to a nucleic acid comprising an open reading frame encoding a polypeptide, including both exon and (optionally) intron sequences. The nucleic acid may also optionally include non-coding sequences such as promoter or enhancer sequences. The term "intron" refers to a DNA sequence present in a given gene that is not translated into protein, is generally found between exons, and is "spliced out" during processing of the mRNA transcript. As used herein, the term "exon" refers to a nucleic acid sequence found in genomic DNA that is predicted and/or experimentally confirmed to contribute contiguous sequence to a mature (e.g., spliced) mRNA transcript and/or is translated into protein.
[0070] As used herein, the phrase "splice variants" refers to RNA molecules initially transcribed from the same genomic DNA sequence but which have undergone alternative RNA splicing. Alternative RNA splicing occurs when a primary RNA transcript undergoes splicing, generally for the removal of introns, which results in the production of more than one mRNA molecule, which may encode different amino acid sequences. The term splice variant may also refer to the proteins encoded by the above RNA molecules. As used herein, the phrase "alternative splicing" includes all types of RNA processing that lead to expression of plural protein isoforms from a single gene. As such, the phrase "splice variant" embraces mRNAs transcribed from a given gene that, however processed, collectively encode plural protein isoforms. For example, and by way of illustration only, splice variants can include exon insertions, exon extensions, exon truncations, exon deletions, alternatives in the 5' untranslated region and alternatives in the 3' untranslated region.
[0071] The phrase "consisting essentially of" when referring to a particular nucleotide or amino acid means a sequence having the properties of a given SEQ ID NO. For example, when used in reference to an amino acid sequence, the phrase includes the sequence per se and molecular modifications that would not affect the basic and novel characteristics of the sequence.
[0072] The term "promoters" or "promoter" as used herein can refer to a DNA sequence that is located adjacent to a DNA sequence that encodes a recombinant product. A promoter is preferably linked operatively to an adjacent DNA sequence. A promoter typically increases an amount of recombinant product expressed from a DNA sequence as compared to an amount of the expressed recombinant product when no promoter exists. A promoter from one organism can be utilized to enhance recombinant product expression from a DNA sequence that originates from another organism. For example, a vertebrate promoter may be used for the expression of jellyfish GFP in vertebrates. In addition, one promoter element can increase an amount of recombinant products expressed for multiple DNA sequences attached in tandem. Hence, one promoter element can enhance the expression of one or more recombinant products. Multiple promoter elements are well-known to persons of ordinary skill in the art.
[0073] The term "enhancers" or "enhancer" as used herein can refer to a DNA sequence that is located adjacent to the DNA sequence that encodes a recombinant product. Enhancer elements are typically located upstream of a promoter element or can be located downstream of or within a coding DNA sequence (e.g., a DNA sequence transcribed or translated into a recombinant product or products). Hence, an enhancer element can be located 100 base pairs, 200 base pairs, or 300 or more base pairs upstream or downstream of a DNA sequence that encodes recombinant product. Enhancer elements can increase an amount of recombinant product expressed from a DNA sequence above increased expression afforded by a promoter element. Multiple enhancer elements are readily available to persons of ordinary skill in the art.
[0074] The terms "transfected" and "transfection" as used herein refer to methods of delivering exogenous DNA into a cell. These methods involve a variety of techniques, such as treating cells with high concentrations of salt, an electric field, liposomes, polycationic micelles, or detergent, to render a host cell outer membrane or wall permeable to nucleic acid molecules of interest. These specified methods are not limiting and the invention relates to any transformation technique well known to a person of ordinary skill in the art.
[0075] An "antibody" or "antibody molecule" is any immunoglobulin, including antibodies and fragments thereof, that binds to a specific antigen. The term includes polyclonal, monoclonal, chimeric, single domain (Dab) and bispecific antibodies. As used herein, antibody or antibody molecule contemplates recombinantly generated intact immunoglobulin molecules and immunologically active portions of an immunoglobulin molecule such as, without limitation: Fab, Fab', F(ab')2, F(v), scFv, scFv2, scFv-Fc, minibody, diabody, tetrabody, single variable domain (e.g., variable heavy domain, variable light domain), bispecific, Affibody® molecules (Affibody, Bromma, Sweden), and peptabodies (Terskikh et al. (1997) PNAS 94:1663-1668).
[0076] Chemotherapeutic agents are compounds that exhibit anticancer activity and/or are detrimental to a cell (e.g., a toxin). Suitable chemotherapeutic agents include, but are not limited to: toxins (e.g., saporin, ricin, abrin, ethidium bromide, diptheria toxin, Pseudomonas exotoxin, and others listed above); alkylating agents (e.g., nitrogen mustards such as chlorambucil, cyclophosphamide, isofamide, mechlorethamine, melphalan, and uracil mustard; aziridines such as thiotepa; methanesulphonate esters such as busulfan; nitroso ureas such as carmustine, lomustine, and streptozocin; platinum complexes such as cisplatin and carboplatin; bioreductive alkylators such as mitomycin, procarbazine, dacarbazine and altretamine); DNA strand-breakage agents (e.g., bleomycin); topoisomerase II inhibitors (e.g., amsacrine, dactinomycin, daunorubicin, idarubicin, mitoxantrone, doxorubicin, etoposide, and teniposide); DNA minor groove binding agents (e.g., plicamydin); antimetabolites (e.g., folate antagonists such as methotrexate and trimetrexate; pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, and floxuridine; purine antagonists such as mercaptopurine, 6-thioguanine, fludarabine, pentostatin; asparginase; and ribonucleotide reductase inhibitors such as hydroxyurea); tubulin interactive agents (e.g., vincristine, vinblastine, and paclitaxel (Taxol)); hormonal agents (e.g., estrogens; conjugated estrogens; ethinyl estradiol; diethylstilbesterol; chlortrianisen; idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and megestrol; and androgens such as testosterone, testosterone propionate, fluoxymesterone, and methyltestosterone); adrenal corticosteroids (e.g., prednisone, dexamethasone, methylprednisolone, and prednisolone); leutinizing hormone releasing agents or gonadotropin-releasing hormone antagonists (e.g., leuprolide acetate and goserelin acetate); and antihormonal antigens (e.g., tamoxifen, antiandrogen agents such as flutamide; and antiadrenal agents such as mitotane and aminoglutethimide). In a particular embodiment, the chemotherapeutic agent is selected from the group consisting of: placitaxel (Taxol®), cisplatin, docetaxol, carboplatin, vincristine, vinblastine, methotrexate, cyclophosphamide, CPT-11, 5-fluorouracil (5-FU), gemcitabine, estramustine, carmustine, adriamycin (doxorubicin), etoposide, arsenic trioxide, irinotecan, and epothilone derivatives.
[0077] "Natural allelic variants", "mutants" and "derivatives" of particular sequences of nucleic acids refer to nucleic acid sequences that are closely related to a particular sequence but which may possess, either naturally or by design, changes in sequence or structure. By closely related, it is meant that at least about 75%, but often, more than 90%, of the nucleotides of the sequence match over the defined length of the nucleic acid sequence referred to using a specific SEQ ID NO. Changes or differences in nucleotide sequence between closely related nucleic acid sequences may represent nucleotide changes in the sequence that arise during the course of normal replication or duplication in nature of the particular nucleic acid sequence. Other changes may be specifically designed and introduced into the sequence for specific purposes, such as to change an amino acid codon or sequence in a regulatory region of the nucleic acid. Such specific changes may be made in vitro using a variety of mutagenesis techniques or produced in a host organism placed under particular selection conditions that induce or select for the changes. Such sequence variants generated specifically may be referred to as "mutants" or "derivatives" of the original sequence.
II. Nucleic Acid Molecules
[0078] Nucleic acid molecules encoding the IDO2 proteins of the invention may be prepared by two general methods: (1) synthesis from appropriate nucleotide triphosphates and (2) isolation and/or amplification from biological sources. These methods utilize protocols well known in the art. The availability of nucleotide sequence information, such as the sequences provided herein, enables preparation of an isolated nucleic acid molecule of the invention by oligonucleotide synthesis. Synthetic oligonucleotides may be prepared by the phosphoramidite method employed in the Applied Biosystems 38A DNA Synthesizer or similar devices. The resultant construct may be purified according to methods known in the art, such as high performance liquid chromatography (HPLC). Long, double-stranded polynucleotides may be synthesized in stages, due to any size limitations inherent in the oligonucleotide synthetic methods.
[0079] Nucleic acid sequences encoding the IDO2 proteins of the invention may be isolated from appropriate biological sources using methods known in the art. In one embodiment, a cDNA clone is isolated from a cDNA expression library, preferably of human origin. In an alternative embodiment, utilizing the sequence information provided by the cDNA sequence, genomic clones encoding altered IDO2 proteins may be isolated. Additionally, cDNA or genomic clones having homology with human and mouse IDO2 may be isolated from other species using oligonucleotide probes corresponding to predetermined sequences within the human and mouse IDO2 encoding nucleic acids.
[0080] The present invention also encompasses splice variants of IDO2. FIGS. 1C and 13 provide a schematic of the locations of the introns and exons of IDO2. Generally, IDO2 comprises 10 or 11 exons depending on whether exon 1a is included. The genomic region is about 73234 basepairs from the start codon ATG to the stop codon TAG with about 1266 coding bases. FIG. 14 provides a nucleotide sequence of IDO2 comprising all exons.
[0081] Exemplary nucleotide sequences encoding human IDO2 are SEQ ID NOs: 8, 9, 12, 15, 20, and 21 and exemplary nucleotide sequences encoding mouse IDO2 are SEQ ID NOs: 10, 11, 13, and 14. The nucleotide sequence of certain splice variants and mutants are also provided in SEQ ID NOs: 22-25. An IDO2 nucleotide sequence may have 75%, 80%, 85%, 90%, 95%, 97%, or 99% homology with any of these nucleic acid molecules.
[0082] The instant invention also encompasses IDO2 nucleic acid molecules which lack at least one of the 11 exons depicted in FIGS. 13 and 15A-15Y. For example, the IDO2 nucleic acid molecule may lack any one of the eleven exons (e.g., IDO2 Δ1a, IDO2 Δ1, IDO2 Δ2, IDO2 Δ3, IDO2 Δ4, IDO2 Δ5, IDO2 Δ6, IDO2 Δ7, IDO2 Δ8, IDO2 Δ9, and IDO2 Δ10). The nucleic acid molecule may also lack 2, 3, 4, 5, 6, 7, 8, 9, or 10 exons, wherein the exons are either consecutive or nonconsecutive. In a particular embodiment, the IDO2 splice variants are selected from the group consisting of: IDO2 Δ1a, IDO2 Δ3/4/6, IDO2 Δ8, IDO2 Δ6/8, and IDO2 Δ4/5.
[0083] The instant invention also encompasses allelic variants and mutants of IDO2. Natural allelic variants of the instant invention include, without limitation, IDO2 R235W and IDO2 Y332stop.
[0084] In accordance with the present invention, nucleic acids having the appropriate level of sequence homology with a nucleic acid molecule encoding IDO2 may be identified by using hybridization and washing conditions of appropriate stringency.
[0085] Nucleic acids of the present invention may be maintained as DNA in any convenient vector. IDO2 encoding nucleic acid molecules of the invention include cDNA, genomic DNA, RNA, and fragments thereof which may be single- or double-stranded. Thus, this invention provides oligonucleotides having sequences capable of hybridizing with at least one sequence of a nucleic acid molecule of the present invention.
[0086] Also encompassed in the scope of the present invention are oligonucleotide probes which specifically hybridize with the IDO2 nucleic acid molecules of the invention. Primers capable of specifically amplifying IDO2 encoding nucleic acids described herein are also contemplated herein. As mentioned previously, such oligonucleotides are useful as probes and primers for detecting, isolating or amplifying altered IDO2 genes.
[0087] It will be appreciated by persons skilled in the art that variants (e.g., allelic variants) of IDO2 sequences exist, for example, in the human population, and must be taken into account when designing and/or utilizing oligonucleotides of the invention. Accordingly, it is within the scope of the present invention to encompass such variants, with respect to the IDO2 sequences disclosed herein or the oligonucleotides targeted to specific locations on the respective genes or RNA transcripts. Accordingly, the term "natural allelic variants" is used herein to refer to various specific nucleotide sequences of the invention and variants thereof that would occur in a human population. The usage of different wobble codons and genetic polymorphisms which give rise to conservative or neutral amino acid substitutions in the encoded protein are examples of such variants. Such variants would not demonstrate altered IDO2 activity or protein levels. Additionally, the term "substantially complementary" refers to oligonucleotide sequences that may not be perfectly matched to a target sequence, but such mismatches do not materially affect the ability of the oligonucleotide to hybridize with its target sequence under the conditions described.
[0088] The present invention also encompasses antisense nucleic acid molecules which may be targeted to translation initiation sites and/or splice sites to inhibit the expression of IDO2. Such antisense molecules are typically between about 15 and about 30 nucleotides in length and often span the translational start site of mRNA molecules. Antisense constructs may also be generated which contain the entire IDO2 sequence in reverse orientation. Antisense oligonucleotides targeted to any known nucleotide sequence can be prepared by oligonucleotide synthesis according to standard methods.
[0089] Small interfering RNA (siRNA) molecules designed to inhibit expression of IDO2 are also encompassed in the instant invention. Typically, siRNA molecules are double-stranded RNA molecules between about 12 and 30 nucleotides in length, more typically about 21 nucleotides in length (see Ausubel et al.). Exemplary siRNAs for human and mouse IDO2 are provided in FIGS. 20A and 20B, respectively.
[0090] Several methods of modifying oligodeoxyribo-nucleotides are known in the art. For example, methylphosphonate oligonucleotide analogs may be synthesized wherein the negative charge on the inter-nucleotide phosphate bridge is eliminated by replacing the negatively charged phosphate oxygen with a methyl group. See Uhlmann et al., Chemical Review, 90: 544-584 (1990). Another common modification, which is utilized in a preferred embodiment of the present invention, is the synthesis of oligodeoxyribonucleotide phosphorothioates. In these analogs, one of the phosphate oxygen atoms not involved in the phosphate bridge is replaced by a sulphur atom, resulting in the negative charge being distributed asymmetrically and located mainly on the sulphur atoms. When compared to unmodified oligonucleotides, oligonucleotide phosphorothioates are improved with respect to stability to nucleases, retention of solubility in water and stability to base-catalyzed hydrolysis. See Uhlmann et al., supra at 548-50; Cohen, J. S. (ed.) Oligodeoxynucleotides: Antisense Inhibitors of Gene Expression, CRC Press, Inc., Boca Raton, Fla. (1989).
[0091] Other modifications of oligodeoxyribonucleotides to produce stable, membrane permeable oligonucleotide analogs are commonly known in the art. For a review of such methods, see generally, Uhlmann et al., supra, and Cohen, supra which also describe methods for synthesis of such molecules. In addition, modified oligoribonucleotides may be utilized in the present invention. However, oligodeoxyribonucleotides are preferred due to their enhanced stability, ease of manufacture and the variety of methods available for analog synthesis.
[0092] Still other modifications of the oligonucleotides may include coupling sequences that code for RNase H to the antisense oligonucleotide. This enzyme (RNase H) will then hydrolyze the hybrid formed by the oligonucleotide and the specific targeted mRNA. Alkylating derivatives of oligonucleotides and derivatives containing lipophilic groups can also be used. Alkylating derivatives form covalent bonds with the mRNA, thereby inhibiting their ability to translate proteins. Lipophilic derivatives of oligonucleotides will increase their membrane permeability, thus enhancing penetration into tissue. Besides targeting the mRNAs, other antisense molecules can target the DNA, forming triple DNA helixes (DNA triplexes). Another strategy is to administer sense DNA strands which will bind to specific regulator cis or trans active protein elements on the DNA molecule.
[0093] Deoxynucleotide dithioates (phosphorodithioate DNA) may also be utilized in this invention. These compounds which have nucleoside-OPS2O nucleoside linkages, are phosphorus achiral, anionic and are similar to natural DNA. They form duplexes with unmodified complementary DNA. They also activate RNase H and are resistant to nucleases, making them potentially useful as therapeutic agents. One such compound has been shown to inhibit HIV-1 reverse transcriptase (Caruthers et al., INSERM/NIH Conference on Antisense Oligonucleotides and Ribonuclease H, Arcachon, France 1992).
[0094] In accordance with the present invention, antisense oligonucleotides and siRNA may be produced by expression of DNA sequences cloned into plasmid or retroviral vectors. Using standard methodology known to those skilled in the art, it is possible to maintain the antisense RNA-encoding DNA in any convenient cloning vector (see Ausubel et al., eds. Current Protocols in Molecular Biology, John Wiley and Sons, Inc., (2005)).
[0095] Various genetic regulatory control elements may be incorporated into antisense RNA-encoding expression vectors to facilitate propagation in both eukaryotic and prokaryotic cells. Different promoters may be utilized to drive expression of the antisense sequences, the cytomegalovirus immediate early promoter being preferred as it promotes a high level of expression of downstream sequences. Polyadenylation signal sequences are also utilized to promote mRNA stability. Sequences preferred for use in the invention include, but are not limited to, bovine growth hormone polyadenylation signal sequences or thymidine kinase polyadenylation signal sequences. Antibiotic resistance markers are also included in these vectors to enable selection of transformed cells. These may include, for example, genes that confer hygromycin, neomycin or ampicillin resistance.
[0096] Cells and transgenic animals comprising a nucleic acid encoding IDO2 are also encompassed by the instant invention. The term "transgenic animal" is intended to include any non-human animal, preferably vertebrate, in which one or more of the cells of the animal contain heterologous/exogenous nucleic acid encoding IDO2, optionally from a different species. IDO1 encoding nucleic acids may also be inserted. Non-human animals include without limitation, rodents, mice, rats, non-human primates, sheep, dog, cow, amphibians, zebrafish, reptiles, and the like. In a preferred embodiment, the animal is a mouse. In another embodiment, the transgenic animal comprising a heterologous nucleic acid encoding IDO2 has modulated (e.g., increased) susceptibility to cancer and/or infection by microbes (e.g., viruses, bacteria, pathogens) compared to a wild-type mouse. In another embodiment, these transgenic animals exhibit at least one of increased LIP production, decrease in LAPS, decreased activation of GCN2, decreased elf2-α phosphorylation, and modulation of production of pro-inflammatory cytokines.
[0097] IDO2 knockout animals are also encompassed by the instant invention. Modifications and/or deletions may render the naturally occurring gene nonfunctional, thereby producing a "knock out" transgenic animal (e.g., IDO2.sup.-/-). In other words, the transgenic mice comprise homozygous null mutations in the endogenous IDO2 gene. The transgenic animal of the instant invention may comprise a genome comprising a disruption of an endogenous IDO2 gene, wherein the IDO2 gene disruption leads to the failure to express IDO2 and/or a functional IDO2 (e.g., an IDO2 which lacks tryptophan catabolism activity and/or heme binding). The disruption of the endogenous IDO2 can be obtained through the disruption (e.g., insertion of a nucleic acid sequence (e.g., selectable marker) or deletion (e.g., all or part)) of at least one exon. In a particular embodiment, exon 1 is disrupted. In another embodiment, exon 9 and/or 10 is disrupted. Knock-in animals are also encompassed in the present invention as transgenic IDO2 animals. In one preferred embodiment, the IDO2 gene or exons of IDO2 gene are flanked by site specific recombinase recognition sequences such as Cre/LoxP. These mice are conditional knock-out of IDO2 since the portion of the IDO2 gene flanked by the loxP sequences can be excised in vivo upon exposure to the site-specific recombinase Cre, provided into the genome of the offspring by crossing the knock-in IDO2 mouse with a transgenic mouse carrying the Cre recombinase under the control of a tissue-specific or inducible promoter.
[0098] The transgenic mouse may also comprise a knockout of the endogenous IDO1 gene. In a particular embodiment, the transgenic animal is devoid of IDO2 activity. In another embodiment, the transgenic animal has undetectable levels of IDO2. In yet another embodiment, the transgenic animal is fertile and transmits the homozygous null mutations to its offspring. In still another embodiment, the IDO2 knockout animal has modulated (e.g., decreased) susceptibility to cancer and/or infection by microbes (e.g., virus, bacteria, fungus, parasite, pathogen) compared to a wild-type animal. In another embodiment, the IDO2 knockout animals exhibit at least one of decreased LIP production, increase in LAPs, increased activation of GCN2, increased elf2-α phosphorylation, and modulation of production of pro-inflammatory cytokines.
[0099] Transgenic animals of the instant invention may be useful for the establishment of a nonhuman model for diseases involving improper expression and/or regulation of IDO2. The transgenic animals may also be useful as in vivo models for drug screening studies for certain human diseases, and for eventual treatment of disorders or diseases associated with IDO2, such as, without limitation, diseases that have an autoimmune component, diseases associated with improper IDO1 and/or IDO2 expression and/or regulation, and the like. In a particular embodiment, the course of microbial infection in mice devoid of IDO2 activity (i.e., knockout) or comprising a heterologous/exogenous nucleic acid encoding IDO2 may be assessed by a) inoculating the transgenic mouse with a microbe; b) inoculating a wild type mouse with the same microbe; and c) determining whether the course of infection in the transgenic mice is altered to that observed in the wild-type mice, thereby determining whether mice devoid of IDO2 or expressing heterologous/exogenous IDO2 are more/less/equally susceptible to infection by the microbe. In yet another embodiment, the susceptibility to cancer instead of a microbe can be determined by the above method.
III. Proteins
[0100] IDO2 proteins of the present invention may be prepared in a variety of ways, according to known methods. The proteins may be purified from appropriate sources, e.g., transformed bacterial or animal cultured cells or tissues, by immunoaffinity purification. The availability of nucleic acid molecules encoding IDO2 protein enables production of the protein using in vitro expression methods and cell-free expression systems known in the art. In vitro transcription and translation systems are commercially available, e.g., from Promega Biotech (Madison, Wis.) or Gibco-BRL (Gaithersburg, Md.).
[0101] Alternatively, larger quantities of IDO2 protein may be produced by expression in a suitable prokaryotic or eukaryotic system. For example, part or all of a DNA molecule encoding for IDO2 may be inserted into a plasmid vector adapted for expression in a bacterial cell, such as E. coli. Such vectors comprise the regulatory elements necessary for expression of the DNA in the host cell positioned in such a manner as to permit expression of the DNA in the host cell. Such regulatory elements required for expression include promoter sequences, transcription initiation sequences and, optionally, enhancer sequences.
[0102] IDO2 protein produced by gene expression in a recombinant prokaryotic or eukaryotic system may be purified according to methods known in the art. A commercially available expression/secretion system can be used, whereby the recombinant protein is expressed and thereafter secreted from the host cell, and readily purified from the surrounding medium. If expression/secretion vectors are not used, an alternative approach involves purifying the recombinant protein by affinity separation, such as by immunological interaction with antibodies that bind specifically to the recombinant protein or nickel columns for isolation of recombinant proteins tagged with 6-8 histidine residues at their N-terminus or C-terminus. Alternative tags may comprise the FLAG epitope or the hemagglutinin epitope. Such methods are commonly used by skilled practitioners.
[0103] IDO2 protein of the invention, prepared by the aforementioned methods, may be analyzed according to standard procedures. For example, such protein may be subjected to amino acid sequence analysis, according to known methods.
[0104] The instant invention encompasses the amino acid sequences encoded by the nucleic acid molecules described herein. Exemplary amino acid sequences of human IDO2 are SEQ ID NO: 1, 2, and 29 and exemplary amino acid sequences of murine IDO2 are SEQ ID NO: 3 and 4. An IDO2 amino acid sequence may have 75%, 80%, 85%, 90%, 95%, 97%, or 99% homology with these sequences.
IV. Antibodies
[0105] The present invention also encompasses antibodies capable of immunospecifically binding to proteins of the invention. Specifically, the antibodies may specifically bind to IDO2 to the exclusion of IDO1. Alternatively, antibodies can be generated which recognize both IDO2 and IDO1. The antibodies may also be generated to bind IDO2 splice variants and mutants of the instant invention either in addition to IDO2 and/or IDO1 or to the exclusion of other IDO2 proteins. Polyclonal antibodies directed toward IDO2 protein and variants thereof may be prepared according to standard methods. In a particular embodiment, monoclonal antibodies are prepared, which react immunospecifically with the various epitopes of the IDO2 protein. Monoclonal antibodies may be prepared according to general methods known in the art. For example, polyclonal and monoclonal antibodies may be prepared as described in Current Protocols in Molecular Biology, Ausubel et al. eds. Antibodies may be prepared by chemical cross-linking, hybrid hybridoma techniques and/or by expression of recombinant antibody fragments expressed in host cells, such as bacteria or yeast cells. The antibody molecules may then be isolated and purified from the expression system. The antibodies optionally comprise a purification tag by which the antibody can be purified.
[0106] The purity of the antibody molecules of the invention may be assessed using standard methods known to those of skill in the art, including, but not limited to, ELISA, immunohistochemistry, ion-exchange chromatography, affinity chromatography, immobilized metal affinity chromatography (IMAC), size exclusion chromatography, polyacrylamide gel electrophoresis (PAGE), western blotting, surface plasmon resonance and mass spectroscopy.
[0107] Polyclonal or monoclonal antibodies that immunospecifically interact with IDO2 proteins can be utilized for identifying and purifying such proteins. For example, antibodies may be utilized for affinity separation of proteins with which they immunospecifically interact. Antibodies may also be used to immunoprecipitate proteins from a sample containing a mixture of proteins and other biological molecules.
[0108] Additionally, target-specific antibodies, optionally selected by a functional assay, may be isolated. The crystal structure may then be obtained for the antibody. This structure yields a pharmacore upon which subsequent drug design can be based. Alternatively, the protein crystallography may be bypassed altogether by generating anti-idiotypic antibodies (anti-ids) to a functional, pharmacologically active antibody. As a mirror image of a mirror image, the binding site of the anti-ids would be expected to be an analog of the original molecule. The anti-id could then be used to identify and isolate peptides from banks of chemically or biologically produced banks of peptides. Selected peptides would then act as the pharmacore.
V. Therapeutic Uses
[0109] The present invention also encompasses methods for tumor suppression. Specifically, a therapeutically effective amount of at least one IDO2 inhibitor (optionally one which does not inhibit IDO1) can be administered to a patient, in need thereof, for the treatment of cancer. Cancers that may be treated using the present protocol include, but are not limited to: prostate cancers, colorectum, pancreas, cervix, stomach, endometrium, brain, liver, bladder, ovary, testis, head, neck, skin (including melanoma and basal carcinoma), mesothelial lining, white blood cell (including lymphoma and leukemia) esophagus, breast, muscle, connective tissue, lung (including small-cell lung carcinoma and non-small-cell carcinoma), adrenal gland, thyroid, kidney, or bone; glioblastoma, mesothelioma, renal cell carcinoma, gastric carcinoma, sarcoma, choriocarcinoma, cutaneous basocellular carcinoma, and testicular seminoma.
[0110] The at least one IDO2 inhibitor (optionally one which does not inhibit IDO1) may also be administered in combination with at least one signal transduction inhibitor (STI), as described, in the context of IDO inhibitors, in PCT/US04/05155 and PCT/US04/05154 and U.S. patent application Ser. Nos. 10/550,444 and 10/551,151, with at least one chemotherapeutic agent, and/or at least one immunomodulator, as described in U.S. patent application Ser. Nos. 10/550,444 and 10/551,151.
[0111] The present invention also encompasses pharmaceutical compositions comprising at least one of the IDO2 inhibitor(s) (optionally one which does not inhibit IDO1) in a pharmaceutically acceptable carrier. Such a pharmaceutical composition may be administered, in a therapeutically effective amount, to a patient in need thereof for the treatment of cancer. The pharmaceutical compositions may further comprise at least one STI, at least one chemotherapeutic agent, and/or at least one immunomodulator.
[0112] The present invention also encompasses methods for the treatment of chronic viral infections (see U.S. patent application Ser. Nos. 10/550,444 and 10/551,151). Specifically, a therapeutically effective amount of at least one IDO2 inhibitor (optionally one which does not inhibit IDO1) can be administered to a patient having a chronic viral infection. Additionally, at least one chemotherapeutic agent and/or at least one antiviral agent may be co-administered with the at least one IDO2 inhibitor.
[0113] Chronic viral infections that may be treated using the present combinatorial treatment include, but are not limited to, diseases caused by: hepatitis C virus (HCV), human papilloma virus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella zoster virus, coxsackie virus, and human immunodeficiency virus (HIV). Notably, parasitic infections (e.g. malaria) may also be treated by the above methods wherein compounds known to treat the parasitic conditions may also be co-administered.
[0114] Suitable antiviral agents include, without limitation: acyclovir; gangcyclovir; foscarnet; ribavirin; and antiretrovirals such as, for example, nucleoside analogue reverse transcriptase inhibitors (e.g., azidothymidine (AZT), ddI, ddC, 3TC, d4T), non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, nevirapine), nucleotide analogue reverse transcriptase inhibitors, and protease inhibitors.
[0115] The present invention also encompasses pharmaceutical compositions comprising at least one of the IDO2 inhibitor (optionally one which does not inhibit IDO1) in a pharmaceutically acceptable carrier for the treatment of chronic viral infections. Such a pharmaceutical composition may be administered, in a therapeutically effective amount, to a patient in need thereof for the treatment of a chronic viral infection. The pharmaceutical compositions may further comprise at least one chemotherapeutic agent and/or at least one antiviral agent.
[0116] The pharmaceutical compositions of the present invention can be administered by any suitable route, for example, by injection, by oral, pulmonary, nasal or other modes of administration. In general, pharmaceutical compositions of the present invention, comprise, among other things, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. Such compositions can include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol). The compositions can be incorporated into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., or into liposomes. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of components of a pharmaceutical composition of the present invention. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712 which are herein incorporated by reference. The pharmaceutical composition of the present invention can be prepared, for example, in liquid form, or can be in dried powder form (e.g., lyophilized).
[0117] In yet another embodiment, the pharmaceutical compositions of the present invention can be delivered in a controlled release system, such as using an intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In a particular embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. (1987) 14:201; Buchwald et al., Surgery (1980) 88:507; Saudek et al., N. Engl. J. Med. (1989) 321:574). In another embodiment, polymeric materials may be employed (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Press: Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley: New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. (1983) 23:61; see also Levy et al., Science (1985) 228:190; During et al., Ann. Neurol. (1989) 25:351; Howard et al., J. Neurosurg. (1989) 71:105). In yet another embodiment, a controlled release system can be placed in proximity of the target tissues of the animal, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, (1984) vol. 2, pp. 115-138). In particular, a controlled release device can be introduced into an animal in proximity to the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer (Science (1990) 249:1527-1533).
[0118] IDO2 may also be used to tolerize the immune system for a desired antigen. The IDO2 may be delivered as a nucleic acid molecule and/or a protein, optionally in a pharmaceutically acceptable carrier. The IDO2 may be administered to antigen presenting cells with the desired antigen in vivo or in vitro. For example, the antigen presenting cells, optionally obtained from the patient to be treated, can be treated ex vivo and then administered to the patient. These methods may be used to treat, for example, diabetes, lupus, Myastenia Gravis, Crohn's disease, and other autoimmune disorders.
[0119] IDO2 inhibitors as described hereinabove may also be used to alter the immune system to become active against a particular antigen. The antigen may be "foreign", e.g., viral, bacterial, and tumor specific antigens. Alternatively, the antigen may be a "self" antigen, e.g., amyloid, scrappie prions, and other misfolded proteins. The administration of the IDO2 inhibitors to patients would helpful in treating disorders/diseases associated with the particular antigen. The IDO2 inhibitors may be administered to APCs in vivo, in vitro, or ex vivo. The APCs may be loaded with the antigen of interest.
[0120] IDO2 and IDO2 inhibitors may also be administered to patients in need thereof to modulate the production of pro-inflammatory cytokines (e.g., IL6, TNFα, CD14, IL-1β, IL-8, IL-12, MCP1, m-CSF, G-CSF, and iNOS). IDO2 inhibitors would decrease LIP production, thereby leading to an apparent increase in LAPs, which regulate pro-inflammatory cytokines. IDO2, administered as a nucleic acid molecule and/or protein, or agents which augment IDO2 expression levels or activity would increase LIP activity, thereby causing a decrease in LAP activities.
[0121] IDO2 may also be involved in the production of proteins possessing a modified tryptophan amino acid. Specifically, IDO2 may generate kynurenine tRNAs in place of tryptophan tRNAs. As such, kynurenine may be incorporated into a peptide. The ability to incorporate a modified amino acid into a protein implicates IDO2 as an epigenetic post transcriptional modifier of gene function. The modifications by IDO2 may relate not only to normal biological function but also encompass modifications which affect disease states. For example, modified or misfolded proteins due to the incorporation of IDO2 altered amino acids may be causative factors in several diseases or disorders including, without limitation, cancer, immune disease, Alzheimer's, prion disorders, metabolic disorders, cardiovascular disease, Parkinson's, Huntington's, age-related disorders, and neurological disorders. Indeed, it has been previously demonstrated that the nitrosylation of tryptophan in beta amyloid results in the misfolding of the protein and abnormal amyloid production. Similarly, the incorporation of kynurenine into a protein may provide a "normal" biological role in altering protein function. However, under chronic conditions brought about by over-expression or over-activity of IDO2 (such as a chronic inflammation), the incorporation kynurenine may lead to "abnormal" gene products and/or expression which could alter critical factors controlling cell growth, differentiation, and function. Accordingly, the administration of IDO2 inhibitors to patients having disorders or diseases associated with proteins altered by IDO2 may be therapeutic. In order to determine if IDO2 inhibition would be therapeutic for a particular disease, the proteins associated with the disease may be screened for the presence of kynurenine and/or screened to determine if the protein is misfolded.
[0122] In addition to the IDO2 inhibitors described hereinabove, the splice variants and mutants of the instant invention may be employed to inhibit IDO2 and/or IDO1 activity in a subject. As described hereinbelow in Example 2, IDO2 splice variants and mutants (e.g., natural allelic variants R235W and Y332stop) can inhibit the activity of IDO2. Accordingly, IDO2 splice variants and mutants and/or nucleic acid molecules encoding the IDO2 splice variants and mutants may be administered to a subject in accordance with the methods described hereinabove as an IDO2 inhibitor.
VI. Screening Methods
[0123] The biochemistry of IDO has been well established, the enzyme having first been isolated in 1963 (Higuchi, K., et al. (1963) Federation Proc. 22:243 (abstr.); Shimizu, T., et al. (1978) J. Biol. Chem. 253:4700-6). IDO is a monomeric, heme-containing oxidoreductase with a molecular weight of approximately 41 kDa. To maintain the active ferrous form during in vitro catalysis, the enzyme requires methylene blue in combination with either superoxide or a reductant such as ascorbic acid. In vivo, it is suggested that a flavin or tetrahydrobiopterin may fulfill the role of the methylene blue dye and that there is likely to be a specific site for noncompetitive IDO inhibitors. Active enzyme can be produced by expressing the cloned, His-tagged version of the mammalian gene in bacteria (Littlejohn, T. K., et al. (2000) Prot. Exp. Purif. 19:22-29). This provides a convenient source of enzyme for biochemical analysis. A conventional biochemical assay for IDO activity based on spectaphotometric measurement of the production of kynurenine (the hydrolysis product of N-formyl-kynurenine) from tryptophan (Daubener, W., et al. (1994) J. Immunol. Methods 168:39-47) may be used as the read-out for both the enzymatic and cell-based assays. An enzymatic assay provides a facile, high-throughput screen for identifying compounds with IDO inhibitory activity. This assay may also be used to determine Ki values for specific compounds, which is important for the development of SAR (structure activity relationship) around the different compound series. A cell-based assay can confirm the IDO inhibitory activity of identified compounds and address the initial issue of bioavailability--the ability of compounds to inhibit intracellular IDO. Specificity for IDO inhibition may be examined in the cell-based assay by comparing against the other known tryptophan catabolizing enzyme tryptophan dioxygenase (TDO, also referred to in the literature as TD02).
[0124] Because of the homology between IDO1 and IDO2, methods employed for screening for inhibitors of IDO1 activity may be employed for screening compounds which modulate IDO2 activity of the IDO2 proteins described herein. Indeed, as demonstrated hereinbelow, IDO2 can produce kynurenine from tryptophan, thereby allowing the above enzyme assays to be employed with IDO2. Inhibitors may be specific for IDO2 or may effectively inhibit both IDO1 and IDO2. For example, D-1MT does not inhibit IDO1, but is an inhibitor of IDO2 activity. IDO inhibitors, as described hereinabove, may also be screened for their ability to inhibit IDO2. While the above describes the screening of compounds to identify inhibitors of IDO2, the screening assays can be employed to screen for modulators of IDO2 activity, e.g., for compounds that increase IDO2 expression levels or activity and/or compounds which decrease IDO2 activity.
[0125] In accordance with the present invention, the nucleotide sequences of both human and mouse IDO2 have been determined. For biochemical studies, IDO2 protein, optionally tagged with a purification tag which allows the isolation of the protein, may be expressed and isolated from an expression system. For example, C-terminal His-tagged IDO2 protein may be produced in E. coli using the IPTG-inducible pET5a vector system and isolated over a nickel column. The yield of the partially purified protein can be verified by gel electrophoresis and the concentration estimated by comparison to protein standards. To assay IDO2 enzymatic activity, a 96-well plate spectraphotometric assay for kynurenine production may be run following published procedures (Littlejohn, T. K., et al. (2000) Prot. Exp. Purif. 19:22-29; Takikawa, O., et al. (1988) J. Biol. Chem. 263:2041-8; see also U.S. patent application Ser. Nos. 10/550,444 and 10/551,151).
[0126] With regard to cell-based assays, cells, e.g., COS-1 cells and 293 cells, may be transfected (e.g., transiently transfected) with a plasmid expressing IDO2 (see Munn et al. (1999) J. Exp. Med. 189:1363-1372 for an exemplary method). Optionally, a companion set of cells is transfected with a TDO or IDO expressing plasmid. After transfection, the cells are contacted with the test compound. Subsequently, the supernatant can be spectraphotometrically assayed for kynurenine as described for the enzyme assay.
[0127] The following examples are provided to illustrate various embodiments of the present invention. The examples are illustrative and are not intended to limit the invention in any way.
Example 1
Reagents
[0128] Blasticidin (Invitrogen; Carlsbad, Calif.) was prepared as a 1000× solution at 5 mg/mL in sterile water and stored in 500 μL aliquots frozen at -20° C. Zeocin (Zeo; Invitrogen) was prepared as 100 mg/mL aliquots and stored frozen at -20° C.
[0129] Doxycycline (Dox; Sigma, St. Louis, Mo.) was prepared as a 20 mg/mL master stock in ethanol and stored frozen at -20° C. The working 100× stock (2 μg/mL) was prepared by diluting the master stock 1:10,000 in growth media. The working stock was stored in 500 μL aliquots and stored frozen and in the dark at -20° C.
[0130] 1-Methyl-D-Tryptophan (1M-D-T; Sigma-Aldrich Cat #45283) was solubilized in DMSO/0.1 N HCL as a 100 mM stock solution and stored in 100 μL aliquots at -20° C. 1-Methyl-L-Tryptophan (1M-L-T; Sigma-Aldrich Cat #447439) was solubilized in DMSO/0.1 N HCL as a 100 mM stock solution and stored in 100 μL aliquots at -20° C. 1-Methyl-DL-Tryptophan (1M-DL-T; Sigma-Aldrich Cat #860646) was solubilized in DMSO/0.1 N HCL as a 100 mM stock solution and stored in 100 μL aliquots at -20° C. 5-(indol-3-methyl)-3-methyl-2-thio-Hydantoin (MTH; Sigma-Aldrich Cat # M6006) was solubilized in DMSO as a 100 mM stock solution and stored in 100 μL aliquots at -20° C. L-Tryptophan (Tryp; Sigma-Aldrich Cat # T0254) was solubilized in DMSO as a 100 mM stock solution and stored in 100 μL aliquots frozen at -20° C.
[0131] Dulbecco's Modified Eagle Medium (DMEM) was obtained from Mediatech, Inc. (Herndon, Va.; Cat#10-013-CV).
Alpha minimum essential medium (α-MEM) was obtained from Invitrogen and contains ribonucleosides and deoxynucleosides/4 mM glutamax/1 mM sodium pyruvate and was stored at 4° C. Trypsin EDTA (1×) was obtained from Mediatech (Cat #25-053-CI) 10 mL aliquots were stored frozen at -20° C. until use. Fetal bovine serum (FBS) was obtained from Hyclone (Logan, Utah; Cat # SV30014.03) and 50 mL aliquots were stored frozen at -20° C. until use. Penicillin/streptomycin 100× (Pen/Strep) was obtained from Mediatech (Cat#30-002-C) which contained 10,000 I.U. Penicillin/mL and 10,000 μg/mL Streptomycin. L-Glutamine (L-glut) was obtained from Mediatech (Cat #25-005-CV) as a 200 mM solution (29.23 mg/mL with 8.5 g/L NaCl). Optimem was obtained from Invitrogen (Cat #31985-062) and stored in 10 mL aliquots at 4° C.
[0132] Antibodies to the phosphorylated eIF2α (anti-eIF2α-P (ser52)) were affinity purified. Rabbit polyclonal antibodies raised against the short amino acid sequence containing the phosphorylated Ser-52 (Santa Cruz Biotechnology, Santa Cruz, Calif., sc-12412). For Western blotting, anti-eIF2α-P was diluted at 1:200 in blocking buffer (PBS/0.1% tween-20, 3% w/v non-fat dry milk, phosphatase inhibitor cocktail (Calbiochem, La Jolla, Calif., Cat #524625)).
[0133] Antibodies to the c-terminal region of C/EBPβ were affinity purified rabbit polyclonal antibodies raised against a peptide corresponding to the C-terminus of C/EBPβ of rat origin (Santa Cruz Biotechnology, sc-150). For Western blotting anti-C/EBPβ was diluted at 1:200 in blocking buffer (PBS/0.1% tween-20, 3% w/v non-fat dry milk).
[0134] Anti-V5-Horse radish peroxidase (HRP) conjugated antibody was purchased from Invitrogen and stored at 4° C. For Western blotting anti-V5-HRP was diluted at 1:5000 in blocking buffer (PBS/0.1% tween-20, 3% w/v non-fat dry milk). Affinity purified goat anti-rabbit IgG antibody and affinity purified horse anti-mouse IgG antibody conjugated to HRP (Cell Signaling technologies, Danvers, Mass., cat #7074 and #7076, respectively) were typically diluted 1:1000 in blocking buffer (PBS/0.1% tween-20, 3% w/v non-fat dry milk).
[0135] GM-CSF was stored frozen at -20° C. as a 1000× solution (5 mg/mL). Interferon-γ (IFN-γ), IL-10, and lipopolysaccharide (LPS) were stored frozen at -20° C. as a 1000× solution.
Methods
Western Analysis:
[0136] Cell lysates were prepared as follows: Cells were removed from the dish by scrapping or pipetting in PBS and collected by centrifugation (2000 rpm/5 minutes). The supernatant was discarded and the cell pellet was lysed in RIPA buffer [50 mM Tris-HCl pH 7.4/150 mM NaCl/1% Triton x-100/1% Sodium deoxycholate/0.1% SDS] plus a protease inhibitor cocktail (Calbiochem Cat #539134). Typically 5×105 cells were resuspended in 200 μL of RIPA buffer. Cells lysates were vortexed and incubated on ice or frozen at -20° C. until use. Prior to use lysates were clarified by centrifugation (10,000 rpm/15 minutes) and heat denatured at 95° C. in SDS/sample buffer (100 mM Tris/25% glycerol/2% SDS/0.01% bromophenol blue/25 mM DTT). Proteins were separated by PAGE using NuPAGE® Gels (Invitrogen) and transferred at 100 Volts on to Immobilon-NC Nitrocellulose membranes (Millipore, Billerica, Mass., Cat # HAHY00010) in transfer buffer (25 mM Tris pH 8.3/192 mM glycine/20% methanol). The protein containing membranes were typically blocked at room temperature for 1 hour in blocking buffer (PBS/0.1% tween-20, 3% w/v non-fat dry milk). Primary antibody was added to the blot in blocking buffer at the suggested dilution, incubated by shaking at room temperature for 1 hour or at 4° C. for 12-18 hours and washed 5-6 times in PBS/0.1% Tween. For secondary antibody applications, the secondary antibody containing HRP was added in blocking buffer at the appropriate dilution, incubated by shaking at room temperature for 1 hour, and washed 5-6 times in PBS/0.1% Tween. The western membranes were developed by Chemiluminescence using SuperSignal® West Pico substrate (Pierce, Rockford, Ill., Cat #34078), exposed to autography film for an appropriate period of time (3 seconds to 18 hours), and developed.
Kynurenine Detection Assay:
[0137] This assay measures the product of the indoleamine 2,3-dioxygenase conversion of L-tryptophan to N-formyl-kynurenine by acid hydrolysis to kynurenine, which is measured indirectly though the absorbance (480 nm) of imine produced by the reaction of the aromatic amino group of klynurenine with p-dimethylaminobenzaldehyde (Ehrlich's reagent) as described by Takikawa et al. (J. Biol. Chem. (1988) 263:2041-2048). Typically, 200 μL of media from the test sample is combined with 12.5 μL of 30% TCA and incubated at 50° C. for 30 minutes. Evaporation was avoided by sealing the rim of the plate or tubes with parafilm. Samples are clarified by centrifugation for 10 minutes at 3-10K rpm. 100 μL of the supernatant was removed to a fresh well in an assay plate and mixed with 100 μL of fresh Ehrlich's reagent (2% p-dimethylaminobenzaldehyde w/v with glacial acetic acid). The plates were incubated for 10-30 minutes at room temperature and the absorbance was read at 490 nm. Typically, assays were performed in triplicate and the data analyzed using Excel software program (Microsoft). Background/control samples were typically derived from media from uninduced cells or cells that lack IDO1/2 expression vectors. Typically, control values were averaged and subtracted from the sample values.
Surforhodamine B Colorimeter Assay:
[0138] This assay is used to assess cell density and is based on the measurement of cellular protein content and performed as described Vichai and Kirtikara (Nature Protocols (2006) 1:1112). For a 96 well dish, sample wells were maintained in 200 μL of media and fixed by adding 100 μL of cold 10% (wt/v) TCA to each well and the plates were incubated at 4° C. for at least 1 hour. The supernatant may be removed and saved for Kynurenine detection assay. The plates are then washed four times by dipping the plate slowly into a 2 liter beaker of tap water. The wash is removed by gently flicking or blotting the plate. The water in the 2 liter beaker is changed after each wash. Any excess water was blotted and the plates were air dried. Plates can be stored indefinitely at room temperature at this stage. For analysis, 100 μL of 0.057% (wt/v) Surforhodamine B (SRB)/1% acetic acid (v/v) solution was added and the plates incubated at room temperature for 30 minutes. Plates were then rinsed four times in 1% acetic acid by dipping in a 2 L beaker of wash solution, as performed with the first wash. The plates were then allowed to air dry in an exhaust hood. Sample wells were then developed by adding 200 μL of 10 mM Tris base (pH 10.5), incubating at room temperature for 30 minutes with gentle shaking, and measuring the optical density (O.D.) at 510 nm. Typically samples were performed in triplicate and the data analyzed using Excel software program (Microsoft).
Cell Culture:
[0139] 293-T-REx® cells (Invitrogen) constitutively express a tet operator repressor protein and were maintained in DMEM/10% FBS/1× Pen/Strep/2 mM L-glut/blasticidin (5 ng/mL) at 37° C. with a 5% CO2 in air atmosphere and typically split prior to confluency. Cells were passaged by splitting the culture 1/10- by removing media by aspiration, washing 1× with PBS, incubating with 0.25% trypsin/EDTA until the cells detach, disbursing the cells in fresh growth media, and plating at 1/10 dilutions in fresh growth media. For long term cryopreservation, cells are detached from the plate as described above, collected by centrifugation, resuspended in freeze medium (growth medium/10% DMSO), stored in 1.8 mL cryopreservation vials (˜2-5×106 cells per vial) in liquid nitrogen vapor storage tanks.
[0140] JawsII (ATCC CRL-11904) is an immortalized mouse dendritic cell line derived from the bone marrow of p53 knock-out Blk/6 mouse (U.S. Pat. No. 5,648,219). Cells were maintained in DMEM/10% FBS supplemented with GM-CSF at 5 ng/mL and grown at 37° C. with a 5% CO2 in air atmosphere. For maintenance floating cells are removed by pipetting. Detached cells were removed by rinsing in 0.25% trypsin/EDTA and pooled with the floating cells. Cells were collected by centrifugation (1000 rpm 1 minute) and resuspended in fresh media, and subcultured at a 1:2 ratio. For long term cryopreservation, floating and adherent cells were detached and pooled from the plate as described above, collected by centrifugation, resuspended in freeze medium (growth medium/5% DMSO), stored in 1.8 mL cryopreservation vials (˜2-5×106 cells per vial) in liquid nitrogen vapor storage tanks.
Transfection:
[0141] Typically, T-REx® cells were transfected by lipofection whereby complexes are formed by mixing 1.6 μg of circular plasmid and 4 μL Lipofectamine 2000 (Invitrogen) in a final volume of 400 μL Optimem, as per protocol. These complexes were then added directly to expanding cultures of cells for a total of 6 to 20 hours. After 24-48 hours, cells were either split and placed in media and selection antibiotic (typically 100 ug/mL Zeo) or induced with Dox for transient expression.
RNA Preparation:
[0142] Total RNA was prepared from tissue and cultured cells using PureLink® Micro-to-Midi Total RNA Purification System (Invitrogen, Cat #12183-018). For RNA preparation from tissue, the tissue (˜10 mg) was cut into small pieces and mixed with 500 μL of kit lysis buffer and passaged through a 21 G needle in lysis buffer several times until the lysate was well homogenized. Then the lystae was passaged over the spin homogenizer column (Invitrogen). The supernatants were then processed as standard lysates. Briefly 1 volume of 70% Ethanol was added to the lysates, mixed well by vortexing, and loaded on to the RNA spin column, as described. Following the first wash, the samples were treated with RNase-free Dnase-I on the column as described in the protocol. The RNA was eluted in nuclease-free water and immediately stored at -80° C. The concentration of RNA was determined spectrophotometrically (O.D. at 260 nm).
Reverse Transcription:
[0143] c-DNA was prepared from total RNA that was reverse transcribed using ThermoScript® RT-PCR system (Invitrogen) according to the manufacturer's protocol. Briefly, 1-2 μL of RNA ranging from 0.01 to 1 μg of total RNA was mixed with either a specific reverse strand primer (10 pm) or a random hexamer (50 ng), 1 mM dNTP, 1× cDNA synthesis buffer, 20 mM DTT/40 U RNaseOUT®, and 15 units of ThermoScript® RT in a 20 μL volume. Reaction conditions varied, but typically the reaction was heated to 55° C. for 2 minutes and incubated at 52° C. for the specific primer for 60 minutes and terminated by heating at 85° C. for 5 minutes. For random priming the reactions were incubated at 25° C. for 20 minutes and then 50 minutes at 50° C.
PCR:
[0144] Double stranded molecules were generated by PCR amplification under the appropriate cycling conditions (typically, 2 minute denaturation at 95° C.; followed by 30 cycles of 30 seconds at 95° C. (denaturation); 30 seconds at 55° C. (annealing); and 30 seconds at 72° C. (extension); and a final 2 minute extension at 72° C.). Typically, 50 μL reaction mixes contained template DNA (0.2-100 ng), 10 pmoles of each primer flanking the target sequence, 0.2 mM of each dNTPs, appropriate MgCl2 concentrations (1-2.5 mM), and 3-4 units of Taq Polymerase. For cloning, PCR products were typically purified using a commercially available PCR product clean-up procedure (Promega or Qiagen) and eluted in sterile dH2O.
Results
[0145] The complete open reading frames (ORF) of the murine and human IDO2 mRNA have been delineated and confirmed by sequence analysis by RT-PCR. The exons corresponding to the ORF have been mapped by comparison to the genomic sequence in the GenBank and Celera Databases.
[0146] Both IDO1 and IDO2 are present on chromosome 8. The distance between the coding regions varies between the sequences available for human and mouse. In the mouse, the distance between the last exon of IDO1 and the first exon of IDO2 is about 4500 bases. The distance between the two genes, as determined from the available human genomic region, is about 20,000 bases.
[0147] Amino acid sequences of human and murine IDO2 are provided in FIGS. 1 and 2, respectively. Coding regions of human and murine IDO2 are provided in FIGS. 4A and 4B, respectively. FIGS. 3A, 3C, and 3D provide sequence alignments of human IDO1 and IDO2 amino acid sequences, human and murine IDO2 amino acid sequences, and murine IDO1 and IDO2 nucleotide and amino acid sequences, respectively.
[0148] The complete coding regions of murine IDO1 and IDO2 were cloned in-frame with the V5/His TAG coding region in pcDNA4/TO (Invitrogen) which contains a regulatory region that is repressed by the tetracyclin regulated repressor (TetR). The complete coding regions of IDO1 and IDO2 were generated using gene specific primers [IDO2 5'KpnATG (TCCGGTACCATGGAGCCTCAAAGTCAG, SEQ ID NO: 16) and IDO1 5'KpnATG (ATCCGGTACCATGGCACTCAGTAAAATA, SEQ ID NO: 17)] and 3' primers that were gene specific and removed the termination codon [IDO2minstop (TGTCCTGGTGCTAAGGGTCAAGACAATTCT, SEQ ID NO: 18) and IDO1 minus stop (TGAGTTGGCCTAAGGGTCAAGACAATTCT, SEQ ID NO: 19)]. The IDO1 and 2 coding regions where then cloned in-frame with the V5/His carboxyl terminal Tag in the pcDNA4 TO vector (Invitrogen).
[0149] Murine IDO1 and IDO2 were expressed as fusions with a C-terminal V5 epitope. Both were detected by Western blot analysis in T-REx®-293 cells following the addition of doxycycline (2 μg/mL) or doxycycline combined with tryptophan (100 μM) (FIG. 5). Little or no IDO1 or IDO2 was detected in the absence of doxycycline. IDO2 migrates slightly faster (apparent lower molecule weight) than IDO1. Both proteins were detected using an HRP-conjugated antibody to the V5 C-terminal tag (Invitrogen). Bound antibody was detected by chemiluminescence (SuperSignal® West Pico, Pierce).
[0150] The growth characteristics of T-REx® expressing IDO1 and IDO2 were also examined. FIG. 6 shows that growth curves of the T-REx® cells with no vector (center panel), pcDNA4TO-muIDO1 (left panel) or pcDNA4TO-muIDO2 (right panel). Cells were grown unsupplemented (media alone), or in the presence of doxycycline (Dox-20 ng/mL), tryptophan (Tryp-100 μM) or both doxycycline and tryptophan (Dox/Tryp). All cells grew normally in the absence of doxycycline (media alone) or in the presence of additional Tryptophan (100 μM). In the presence of doxycycline (20 ng/mL) the IDO1 expressing cells grow less well due to deprivation of tryptophan from the media. IDO1 expressing cells in the presence of doxycycline and tryptophan grew well until day 8-10. IDO2 expressing cells consistently grew better in the presence of doxycycline and tryptophan. For IDO2 containing cells, no significant changes in cell growth was observed following doxycycline or tryptophan additions alone. Similarly the growth characteristic of T-REx® cells with no vector was unaffected by the doxycycline, tryptophan or dox/tryp treatments.
[0151] The ability of IDO1 and IDO2 expressing 293 cells to metabolize tryptophan was also studied (FIG. 7). The kynurenine assay indicates that tryptophan is metabolized in IDO1 and IDO2 expressing cells. The assay was performed in triplicate on media harvested 72 hours in the absence of induction (no doxycycline) or following induction with doxycycline (20 ng/mL). Cells were also exposed to increasing amounts of supplemental tryptophan to the media (0 to 1000 μM). Significantly higher levels of kynurenine were detected in both IDO1 and IDO2 expressing cells when the tryptophan levels were higher than media alone. No significant kynurenine was detected in IDO2 expressing cells in the absence of supplemental tryptophan. These data suggest that IDO1 and IDO2 possess indoleamine dioxygenase activity. However the activity of IDO2 is far lower than that of IDO1 (note the abs scale is different between IDO1 and IDO2 experiments). Taken together these data suggest the IDO2, although possessing weak indoleamine dioxygenase activity, may have a different and preferred substrate than IDO1. Potential substrates of IDO2 include, without limitation, hydroxyl tryptophan, serotonin, melatonin, indoleacrylate, methyl-tryptamine, and indole-3-propanoate. Alternatively, IDO2 may require a co-factor for its full activation that is different that that present for IDO1.
[0152] IDO1 expressing 293 cells metabolize tryptophan and can be inhibited by methyl thiohydantione (MTH). T-REx® cells or IDO1 expressing T-REx® cells were treated with doxycycline in the presence of increasing concentrations of DMSO (carrier) or known IDO1 inhibitor (MTH). The cells were maintained in growth media plus supplements for 5 days, after which the media was harvested and subjected to analysis for the presence of kynurenine. The decrease in kynurenine production in the IDO1 expressing cells was observed in a dose dependent manner while no changes in kynurenne were observed in DMSO only treated cells (FIG. 8A). The control T-REx® cells (no vector) do not produce any detectable kynurenine. The presence of inhibitor was not toxic to the cells. These data demonstrate the ability to use this cell based assay to assess indoleamine dioxygenase activity of IDO1 by using a known IDO1 inhibitor.
[0153] IDO2 expressing 293 cells metabolize tryptophan and can be inhibited by 1-methyl-D-tryptophan (1M-D-T). IDO2 expressing T-REx® cells were treated with doxycycline in the presence of increasing concentrations of DMSO (carrier) or a variety of potential inhibitors, including the D, L and mixed DL racemic isomers of 1 methyl-tryptophan, (1M-D-T, 1M-L-T and 1M-LD-T, respectively) (FIG. 8B). The cells were maintained in growth media plus supplements for 5 days, after which the media was harvested and subjected to analysis for the presence of kynurenine. The decrease in kynurenine production in the IDO2 expressing cells was observed only with 1M-D-T in a dose dependent manner while no changes in kynurenine levels was observed in DMSO only treated cells or the other inhibitors. The control T-REx® cells (no vector) do not produce any detectable kynurenine and were used as background absorbance values which were subtracted from the experimentally obtained values. The presence of inhibitor was not toxic to the cells.
[0154] FIG. 9A demonstrates that IDO1 induces LIP expression. IDO1 is expressed in these cells when stimulated by doxycycline. When doxycycline is added to these cells, LIP is expressed (72 hours after stimulation). However, in the presence of exogenously added tryptophan (100 μM) the expression of LIP is eliminated; even when IDO1 is expressed. These data demonstrate that the LIP activation occurs via tryptophan deprivation, GCN2 activation, and differential LIP synthesis.
[0155] FIG. 9B demonstrates that the same activation of LIP occurs following IDO2 activation, but it is not inhibited by excess tryptophan. These data show that IDO2 activates the same pathway leading to LIP activation but that this pathway is not dependent on tryptophan deprivation. Also this data shows that the IDO2 activation of LIP is inhibited by the D isoform and, to a lesser extent, the L isoform of 1 methyl tryptophan. The selectivity for the D isoform to inhibit IDO2's activation of LIP demonstrates that IDO2 and IDO1 activities can be distinguished pharmacologically.
[0156] FIG. 9c provides a Western blot demonstrating that, like IDO2's activation of LIP expression, IDO2 also activates the GCN2 kinase leading to elf2-α phosphorylation (the protein target of GCN2). This activity is dependent of IDO2 expression which is not inhibited by excess tryptophan. These data suggest that IDO2 functions within this pathway but the activation of GCN2 kinase, phosphorylation of elf2-alpha, and LIP expression is not dependent on tryptophan deprivation. Unlike IDO1, which activates GCN2 kinase pathway through the deprivation of tryptophan and can be relieved by exogenous tryptophan, the IDO2 mechanism of action is different and can not be relieved by exogenous tryptophan. Therefore, IDO2 functions more directly in activating the GCN2 pathway, perhaps by acting on the tryptophanyl-tRNA directly.
[0157] FIGS. 12A-12C provide schematics of murine and human IDO2 as well as primers which can be employed to amplify regions of IDO2.
Example 2
[0158] Human IDO2 cDNAs were cloned from RNA isolated from normal human liver. Splice variants were identified which lead to alternative reading frames and/or early termination of the primary sequence of IDO2. These splice variants are IDO2 Δ3/4/6, IDO2 Δ8, IDO2 Δ6/8, and IDO2 Δ4/5. FIG. 16 provides the nucleotide sequences of these splice variants. Vectors comprising the splice variants were transiently transfected into 293 (T-Rex®) cells and a kynurenine detection assay was performed as described hereinabove to determine the presence of indole dioxygenase activity with the expressed IDO2 splice variants. As seen in FIG. 17, the tested splice variants did not possess detectable indole dioxygenase activity.
[0159] Two prominent single nucleotide polymorphisms (SNP) were also cloned. These two SNPs are not linked (i.e., they are not on the same allele) and are differentially represented in various populations as indicated by the SNP database. The R235W SNP encoded in exon 8 alters the arginine (R) present at amino acid position 235 to a tryptophan (W). The SNP at amino acid position 332 intoduces a stop codon at Tyrosine 332 (Y332stop). Both SNPs render the IDO2 molecule inactive when assayed for the production of kynurenine following a transient transfection assay as described hereinabove. As such these SNPs may be important indicators/markers for the propensity or resistance to certain disease states.
[0160] Additionally, as seen in FIGS. 15A-15Y and 16, an alternative splice site exists in exon 8 of IDO2, leading to an alternate sequence for exon 8.
[0161] When the alternatively spliced variants are co-expressed with either wild-type IDO1 or IDO2 lower, the indole dioxygenase activity, as assessed by the kynurenine detection assay, is reduced compared to wild-type IDO1 or IDO2 alone, even though IDO1 or IDO2 protein levels are the same in each reaction (see FIG. 17). These data indicate that an RNA or peptide product of the truncated IDO2 and/or alternatively spliced IDO2 may function to inhibit IDO1 and IDO2 activity. Such interactions may be dependent on direct or indirect protein-protein interactions between the truncated product and the full length IDO1 and IDO2 peptides. Alternatively the spliced variants may inhibit co-factor activity and the normal activation of IDO1/2 enzyme via changes in the oxidative state of the Fe component of coordinated Heme group. Nevertheless the negative interaction of these splice variants suggests the utility of a compound or peptide whose interaction with the splice variants or full length IDO1 or IDO2 will block the negative and inhibitory interactions resulting in increased IDO1 or IDO2 activity. Applications for such a compound or peptide include diseases that have an autoimmune component.
Example 3
[0162] Monoclonal antibodies specific to mouse IDO2 were generated using standard techniques. FIG. 18 provides images of Western blots which demonstrate the species and IDO-isoform specificity of the generated monoclonal antibodies. Mouse or human IDO1 and/or IDO2 were expressed in 293 (T-REX) cells. Additionally, the R235W (R-W) and Y332stop (Y-*) isoforms of human and mouse IDO2 were also expressed in 293 (T-REX) cells. As seen in FIG. 18B, monoclonal antibodies derived from hybridoma clones (7.4.6, 7.4.9 and 8.8.6) are specific to mouse IDO2 protein and do not recognize the human or mouse IDO1 proteins (shown reacting with rabbit polyclonal sera directed to both human and mouse IDO1). FIG. 18A demonstrates the reactivity of an IDO1 polyclonal sera which recognizes both human and mouse IDO1.
Example 4
[0163] The tissue specific expression of human IDO2 was determined using T-PCR. A human tissue panel of total RNA (Ambion, Austin, Tex.) was analyzed by RT-PCR. The RT reaction utilized oligo-dt priming followed by the specific amplification using primers specific to different regions of the IDO2 mRNA (FIG. 19A). Primer F1 recognized a region in the 5' untranslated region of the mRNA. Transcripts containing this region of the gene (exon 1a) are detected only in the placenta and brain (FIG. 19B). In contrast, primers specific to the 3' end of the gene (primers spanning exons 9-10) demonstrated a broader pattern of expression. The presence of splice variants can be detected in both the placenta (FIG. 19C) and brain tissue. Without being bound by theory, this data suggests that there may be alternative promoters initiating at exon 1a and at exon 1, as exon 1 is more widely expressed than exon 1a. Primers F2-R2 were used because exons 9 and 10 are present in all splice variants detected so far.
Example 5
[0164] The present example describes the generation of an indoleamine 2,3-dioxygenase-2 (IDO-2) gene conditional knockout allele in mice using homologous recombination in mouse embryonic stem cells and subsequent blastocyst injection of the appropriate targeted ES cells.
[0165] The mouse IDO-2 gene is located on chromosome 8, only 6 kb downstream from the IDO gene. The fact that the two genes are so close together makes it less desirable to attempt to knock out IDO-2 function by eliminating the first exons. As described herein, IDO-2 is organized into ten exons. Exons 9 and 10 play a crucial role for the enzyme function. As such, a conditional allele that upon recombination will eliminate only these two exons was created.
[0166] RP23-339B16 BAC clone (which contains both IDO and IDO2 genes) was used for generating the homologous arms and the conditional KO region for the gene targeting vector, as well as the southern probes for screening targeted events. The recombination targeting vector (FIG. 21) will result in the Cre-dependent deletion of exons 9 and 10. Exons 9 and 10 were chosen because the analogous structural domain of IDO1 constitutes the major catalytic domain of the enzyme. Similarly in vitro mutagenesis studies on IDO2 demonstrate that this region is required for enzymatic activity.
[0167] As demonstrated in FIG. 21, the unconditional knock-out was generated using a positive (Neo) and negative (dipteria toxin A; DTA) selection approach, whereby the DNA construct possesses a DTA expression cassette distal from the homologous arms to negatively select for non-homologous recombination and a neomycin positive selection cassette flanked by the sites for the FLP recombinase. In addition, the targeting vector has two Lox-P sites for the Cre recombinase each flanking exons 9 and 10, which allows for the Cre-dependent excision of exons 9 and 10. Embryonic stem (ES) cells (C57/B16) were electroporated with the targeting construct and the surviving NeoR transfected clones were screened by Southern analysis to identify ES cells carrying targeted IDO2 alleles. Six of the ES cell clones containing the recombinant targeted conditional allele were electroporated with Flp recombinase-expressing plasmid to eliminate the neo cassette. Two positive FLP treated Neo.sup.(-) clones expanded for further analysis using long-range PCR and Southern analysis. Selected clones with normal karyotypes were either injected into blastocysts (to generate a conditional IDO2-knockout chimeric embryo) or electroporated with CRE recombinase to remove exons 9 and 10. Four CRE treated ES cell clones were identified to possess the proper exon 9/10 deletion using PCR analysis, expanded, and injected into blastocysts (to generate an IDO2 knockout chimeric mouse embryo).
[0168] The 5' homologous arm (4.5 kb), 3' homologous arm (3.5 kb) and conditional KO region (1.7 kb) were generated by PCR. The fragments were cloned in the LoxFtNwCD or (for sequencing purposes) PCR 4.0 vectors and confirmed by restriction digestion and end-sequencing.
[0169] The final vector was obtained by standard molecular cloning. Aside from the homologous arms, the final vector also contains loxP sequences flanking the conditional KO region (0.25 kb), Frt sequences flanking the Neo expression cassette (for positive selection of the ES cells), and a DTA expression cassette (for negative expression of the ES cells). The final vector was confirmed by both restriction digestion and end sequencing analysis. NotI was used for linearizing the final vector prior to electroporation.
[0170] The 5' and 3' external probes were generated by PCR and were tested by genomic Southern analysis for screening of the ES cells. The probes were cloned in the pCR4.0 backbone and confirmed by sequencing. A screening strategy for mIDO-2 knockouts is provided in FIG. 22.
[0171] The offspring of the chimera pups for the conditional and unconditional IDO2 knockout animals were born, analyzed for germline transmission of the modified IDO2 alleles, and subsequently bred to homozygosity.
[0172] As indicated hereinabove, the homologous arms were generated by PCR. The 5'-arm was cloned into LoxFtNwCD in NotI/KpnI sites, upstream from loxP site. The template was BAC clone RP23-339B16 and the primers used were:
TABLE-US-00001 LDI_IDO2_5'F: Tm 57.8 (SEQ ID NO: 148) actggcggccgcATGCCGAATCTATTACCATTACTGCC LDI_IDO2_5'R: Tm 60.4 (SEQ ID NO: 149) actgggtaccACACCTTCATAGACCAGCCCCACA
The E9/E10 CKO region was cloned in BsiWI/SalI sites, upstream from FRT site. The template was BAC clone RP23-339B16 and the primers used were:
TABLE-US-00002 LDI_IDO2_INSF: Tm 60.4 (SEQ ID NO: 150) actgcgtacgcatatgTGTGGGGCTGGTCTATGAAGGTGT LDI_IDO2_INSR: Tm 52.8 (SEQ ID NO: 151) actggtcgacGGGATATAGCACAAGAACAGCTAAG
The 3' arm was cloned in LoxFtNwCD in AscI/XmaI sites. BAC clone RP23-339B16 was used as the template and the primers used were:
TABLE-US-00003 LDI_IDO2_3'F: Tm 52.8 (SEQ ID NO: 152) actgggcgcgccCTTAGCTGTTCTTGTGCTATATCCC LDI_IDO2_3'R: Tm 56.8 (SE ID NO: 153) actgcccgggGGTGTCTGTGAGATTTTGAGAATAGTCC
[0173] The 5' and 3' arms and the CKO region were end sequenced. The sequence of the 5' end of the 5' arm was determined to be:
TABLE-US-00004 (SEQ ID NO: 154) ATGCCGAATCTATTACCATTACTGCCAAGTCCCATTGGGAGAAAAACTA AAGTGTGCATTCGTGCATGTGTGCGTGTACGTGTGTGTCTAGAACTGAA AATTTTATTTCCTTGCAAGTATCAGACTAGAGTTTTCCTGGCCTGCTAG GTCCTCTGTTGCCTCTCCCCACCATGTCCCCAATTTGACTCCTGACACA GCACTGGCACTTGGCATTTTTCTAGAATTACACATTTTCCTGACTTTTC TCTTGACTACCGCCAGAGGAAATTTCTCTTAAAGGGGCTCCTGTGGCTG TGCTCAATCTAGTCGGATGAGTCAGGGAAATTCCCACATTAAAGCTAAA CTGATCAGTGGCCTTAATCCCATCTGAAAAGTCCTCCTGCCCTGTCCTG TAATAAATATATCATGGTGACCGGAACAGCTCATAGTATTAAGAGTCCT AGGAATTCGGTTGGGAACCTTGGGGAGCTATTTTTAGAATCCTACCCTC CAGTGTCTTTCAAAGGAATCATTTCTACTTCCTCTTGGCAGAGACTTGA TAAGAACCAGAAGGGGACTTTGTTTGCATCGACATAAGTTCCGGGCAAT GACACTTTTTATCTGGTATTTGGCATAAAGGCCATCCCTCCACTTCAAA TGCTGAGACTGTTTACTGTGCCGCTAAGTGGCTGTACAAGATCCTAAAT GTAGCTGTAGTTTCAACAAACATCTGGATTGTTGGGAGTTTCCAGTAGA CTTCTCTTTAAAATGTCAGCCTCGCTATTCTGCATCTATCCCGAGTTTC TCATTTGCTTCTTTAAAACACAGTTTTATTTAAGAGTGGATGTCCTGTG GAAATGAGATGTATTCCCTCCAGTTCCCAGCC.
The sequence of the 3' end of 5' arm was determined to be:
TABLE-US-00005 (SEQ ID NO: 155) TGAGTGTATGCTCGTGTATGTATGTGAGCACTGCAGGTGTCTGCATGGT GTGCCATGGTGCTCCACTGGGCTTCATGCTGTGCTCCCCTAGGCTTCAG TCAAGTCAAGACTAGGTCAAGTCATGGAGGGTAAACAGAAGAGAGAGAG AGCAGAAAATGAGGGACACAGGAAGGGTAGAGGGGGAAAGAGAGGGTTG TGAAGCTCACGCGTGATCAGGAGCCCCAGGCTTTCTTCTTCCAGCCGCC CATAGGCTCTGGTGCCCACAACATTGGTTACAACCCCGCTCTCCATCAT CATGCTTGTCATCACTGCTGTGACAAACCGCTTAATAATGGTTCTCACG GAACATTAAAAGCCAAGCCAAGTTTAACACCTCGAACATTTCCAAGTGT TATGGGGAATAACAGTTAAGTGTCTGGGTGTGCTTGTGTGTAATTGGGA ATCTGTAGTGGTGGGGTTACCAGTGTCAGGCCACAGTGTTTGTGATGAG CAGAGGGGTCGGGGTCTTTCTCAGATCCCTTATCTTGTCCTGTCAATGG TGGTGATGTAATAGGTGCACGCCTGTGACAGAGCTGTTTAAAGCATTGT AAGACCAATGAGTAAAGTTCCTACCCTTGCTTCTCCTTTAAGTGAGGCA GAAAAAGGCTCCACCATGACGTGGTGTAAAGATGAAGTCAATCTAATAC TTCCTTGGATACTCTAGCAAGCTTCATTCACACTTTTTATTTCTTCCTC TTCCTCTTCCTCTTCCTCTTCCTCTTCCTCTTCCTCTTCCCCTCCTCCT CTTCCTCCTCCTCTTCCTCCTCCTCTTCCTCCTCCTCCTCTTCCTCCTT CTCCTCTTCCTCCTCCCCCTCCCCTTCCCCTGTGCTCCTCATTATTATT ATTATTGCTCCTGTCTAGGTGGAAGGACAATCCAGCCATGCCTGTGGGG CTGGTCTATGAAGGTGT.
The sequence of the 5' end of CKO region (E9) was determined to be:
TABLE-US-00006 (SEQ ID NO: 156) GGTACCAAAGGCCGCAATGGCCAAACCTGCAGGAAGTACCAGAGCTCCC TAGGTTCTAGAACCGGTGACGTCAAGCTCGAATAACTTCGTATAATGTA TGCTATACGAAGTTATCCTGCAGGTCGATCGAGACCGTACGCTATGTGT GGGGCTGGTCTATGAAGGTGTTGCCACAGAGCCTCTGAAGTACTCTGGA GGAAGTGCAGCCCAGAGCTCCGTGCTTCATGCCTTCGATGAGTTCCTGG GCATTGAGCATTGCAAGGAAAGTGGTGAGCAGCAGTCTGATCTCACCTA TGCTTTGATGGGACAGCGAGGTAGACTAGGGAGACATCTCTAGCAACTG ATAAAGACGGGTGTAAATGAAAATGTCCTGAAGTTTATCCTTGCCTAAG CCAGCAGGCAGCTGTGTGCATGTGCCCTCTCTTACACTGAGTTAGTCAG TATTGGGGCATCGGATCTTATTAGGGTCTTCCAACAGTCCTGTGACCTG GGTTGTTCACTGTCCTGTTGGCTGGGGTCTTTTATCCGCAGATTCCCCT TTCTACAATGAGGTGATAATGTCACATTGAAAGGCCAGTCTGGAGCAGC AAGTGATAGTGCTGAACTTCTCTGCTAAAGCCTTTCCCATGAAATGGCC CAGCCTCCCACTGAATCTATGTGGACCAGGCGAGGGAGCCCATCGCTTT GAAGCCTTTAAAAT.
The sequence of the CKO region (E10) was determined to be:
TABLE-US-00007 (SEQ ID NO: 157) CAGAAATGAACATTTGAGCATTTGGCAGCTATAACAAAAGCCCGACAAG GCTGAGGGAGAGCCCTATCAAGCATTTCTGGTACCTGAGTGTTTGGAAC AGTGGGCAAACCCTCCCAAATGTCTGCCTCGAGCTAACGTATTTCTCCC GGCTGTTTCTTTCAGTTGGCTTTCTACACAGAATGAGGGACTACATGCC GCCTTCCCATAAGGCTTTCCTGGAAGATCTCCACGTAGCTCCTTCTCTG AGAGACTACATACTGGCCTCTGGTCCTGGGGACTGCCTGATGGCCTATA ACCAGTGTGTGGAGGCCCTGGGAGAGCTGCGCAGTTACCACATCAATGT CGTGGCCAGATACATTATCTCCGCTGCCACCAGGGCCAGGAGCAGGGGG CTAACTAATCCCTCACCCCATGCCTTGGAAGACAGGGGCACTGGGGGTA CTGCCATGCTGAGCTTCTTGAAGAGTGTCAGGGAGAAGACCATGGAGGC CCTCCTGTGTCCTGGTGCTTAGCAGTCATGTCCTGCACCCTAACACTTA GATGTTCTCATCCTGCATCCCAGCGTTAGAGGTTCACATCCTGCATCCT AGTGCTTAGCTGTTCTTGTGCTATATCCCGTCGACGAAGTTCCTATACT TTCTAGAGAATAGGAACTTCGGATCCACGATTCGAGGGCCCCTGCAGGT CAATTCTACCGGGTAGGGGAGGCGCTTTTCCCAAGGCAGTCTGGAGCAT GCGCTTTANCAGCCCCGCTGGGCACTTGGCGCTACACAAGTGGCCTCTG GCCTCGCACACATTCCACA.
The sequence of the 5' end of 3' arm was determined to be:
TABLE-US-00008 (SEQ ID NO: 158) ATCCCAGCGCTTAGCAGTCATGTCCTGCATCCTAGTGCTTAGCATTTTA TATCCAGCATCTTAGTGCTTAGAGATTCACATCCTGCATCCTAGAGCTT AGCATTTTATATCCAGCATCCTTGTGCGTATCAGCTATGTTTTGTATCC TGCTTAGCAGTTAACATCCTGCATCCTAGTACTTATCTGTTCTCATCCT GCATCCTAGAGCTTAGCAGTCAGGTCCCGTGGGAGCAAGAACCAGGGTC TGAGCTCTGTCTGAGCCCAAGCATGGCTTTACTGCTTTGTTAATTGTGG CTCCCACCTCCACCCCACCCCAGCCAGTTTGCTTGCTAGAAGCCTTTCT GCACTGCCTAATCCCCCTGCCTCACAGCAGAGAGCTGCAGCCATGACCT CCTCATTCAGTATTAGGTGGACAAGTCGGAGATACCCAAACTCAATTTT AAAAGAATCAAGTTGCTTTTGGGGCATGTTACTTCATCTTTTCTTACCC TGGGCCTCTATGACCTCCTCATTCAGTATTAGGTGGACAAGTCGGAGAT ACCCAAACTCAATTTTAAAAGAATCAAGTTGCTTTT.
The sequence of the 3' end of 3' arm was determined to be:
TABLE-US-00009 (SEQ ID NO: 159) AGCTCTAAGAGAAGGAATACAGCTTGGGACAGAGTTTGTTTTGAAGTGG GGTTCAGGTGCATTTCCTGGGTGTGTCCCTCATTTGGGGGTGTTAGGAG GCAGACAATGCTAAGGGCATGGTTTGATATGGTAGACTGACCATCCTGG GGTCCCTTCAGCTTGTGACACTCGCTGTACTGCTGGACTCTGCTGAGCC CTTTGAAGCCAGGACTCCTCCTCTGCTGCAGGAGTGCAGTGTCCTTCTT GCTGTATGAAGCTGGGACAATGCTCTTTGGCCTTCATACTGGACATCCC ATTGAGAAGCTTGTCACTCTGTAGAGAATAGACATCGCCCCCTTGTGGT TGTGAGGCTGCCCAGGACTTACTGCGGGGGGGGGGGGGGCATGTTGTCC AGCATAAGGAGAGAAGACCCCACTGCATGCTGCTGGGAAAAGGAAAGTA ACGTTCAGAGTAGTTTCTACTGGCTGCCTGCGCTCTCACGCCTGTAAGA ACAAACGTCCTAATGTCTGCATGTGGAGGAAGGAGCCAGGGGTGCTTAG GGTGCTGTTGGTCCCACCAATGTACTACTCATCTGGAAGACCTTGTCTT GGTTTTCTTGCCACTGGGACAAAGTGGGATTGGGTATCAGTCTCCCCAT GTCGGGCAAATGTACTTGAACAAGCAGCATGGTGGACCAGACATGGGAC TATTCTCAAAATCTCACAGACACCCCCGGGGGGCATGTTACTTCATCTT TTCTTACCCTGGGCCTCT.
[0174] The sequence of the 5' probe (SEQ ID NO: 160) is:
TABLE-US-00010 CTAGGGAGTCAGGAAGTCACACTGGTGAAGAGTGGGGGTGTGGGATGAC CACACTGAGGAGTCACACTTGAGGAAGGGGGGTGGCCACACTGAGGAGT GTCTGAAAGCATTGAGACTGTACATCTCAGGTTATCAGGGCTTCAGAGA AAACAGACAGGGAGAAGAGACAAGAACTGGATTCTGTGCGCAAAGGGGG AAAAGCAAGCAGATGTGAAGGGTGTGCTGTTAGAGTTTATCTAAAGATG TTTCTTTCAGAAATAAAGAGATATAAGCTTTAATTTGGATGAAATAAAT GTGGTCTAATTTCCCAGAATGTAGAGGAACTCACTAATGTAGCAAGATT GGCCTTTCAAAGCAGACCAAAGACATTGAGAATTAAGATAGCTATGATG GCGTGCTTCCTTAGGTGGAAGTCCTATATGGAATCCCATACTCCCCAAA TGTGACTGGTCG.
[0175] The sequence of the 3' probe (SEQ ID NO: 161) is:
TABLE-US-00011 AGGCAGGAGGGTCAGGAGTTCAAGGCCAGCCTAGTATACATGCAACAGT GTCTCAAAAATCAAAACAGAGAGGAGGGCAGGAAAGGAGAAGGGAGCCA GGGAGAGAAGGGAAGAGGAAGGGAGGGAGGGGGAAATGGAGGGAGGGGG AGATGGAGGGAGGGGGAGATGGAGGGAGGGGGAGATGGAGGGAGGGGGA GATGGAGGGAGGGGGAGATGGAGGGAGGGGGATGGGAAAGAGGGTTTAC AGCCCTGGTTTATCTTGAACAGAATCCTTACTTTGTCCCTCAGAGTGAC AGGACTGAAAAGATTGTCCCAGGATTTTGGCTGCAAAGCAAGGTCCACT CAGAGACCACAGAGCTCG.
Example 6
Production of Recombinant IDO2 Using Baculovirus Expression Vectors
[0176] The recombinant transfer vectors (pVLmuIDO2, pVLhuIDO2; FIGS. 23 and 24, respectively) containing the complete coding regions of murine and human IDO2, respectively, were derived from eukaryotic expression vectors, pcDNAmuIDO2 and pcDNAhuIDO2. The KpnI/NheI insert fragments containing the complete ORF of pcDNAmuIDO2 and huIDO2 were cloned into KpnI/NheI digested pVL1392 recombination vector that was modified to contain KpnI, XbaI, NheI, SpeI multiple cloning sites at the original KpnI site (See FIGS. 23 and 24). The resulting vectors were analyzed by gel electrophoresis to verify the size and integrity of the inserted genes and inserted coding regions were also analyzed by standard diodeoxynucleotide automated sequencing (Macrogen, Inc., Rockville, Md.).
[0177] Approximately 2 μg of each purified recombination transfer vector, pVLmuIDO2 and pVLhuIDO2, was mixed with 0.5 μg of Baculogold linearized baculovirus DNA (Pharmingen, BD Biosciences, Franklin Lakes, N.J.) and added to 6 μL of Cell fectin (Invitrogen, Carlsbad, Calif.) in a total volume of 200 μL sf900II serum free medium (sf900II-SFM). The solution was incubated at room temperature for 30 minutes, supplemented with 800 μL of sf900II SFM (Gibco-BRL, Carlsbad, Calif.), mixed and added to 1×106 cells of the Spodoptera frugiperda cell line, Sf9, in a 6 well plate. Cells were incubated at 28° C. for 4 hours after which the media was replaced with 2 mL sf900II-SFM 5% FCS. Supernatants containing the recombinant baculovirus (recBV) were harvested after six days and stored at 4° C. indefinitely.
[0178] "High Five" cells (Invitrogen) were plated at 1×105 per well (24 well dish) in 0.5 mL "Express Five" medium (Invitrogen) and incubated at 28° C. for 24 hours. Media was replaced with 0.5 mL of media containing varying dilutions of recBVs containing the muIDO2 and huIDO2 ORFs. Typically 3, 10, 30 and 100 μL of a 1/100 dilution of the recBV viral stock were used. After 24 hours the cells were microscopically examined for signs of infection such as cell rounding, detachment and failure to divide. Optimal titers are established when 100% of the cells show signs of infection.
[0179] After 48 hours the media was removed and the cells collected and lysed in 400 μL of RIPA buffer, clarified by centrifugations and supplemented with Laemmli SDS PAGE running buffer. Briefly the lysates were heated to 80° C. for 10 minutes and 4 μL of material was subjected to SDS polyacrylamide gel electrophoresis (10% SDS-PAGE, Invitrogen) and either Coomassie blue stained or transferred to nitrocellulose membrane for Western analysis. For Western analysis, SDS-PAGE gel blots were typically blocked 1 hour at room temperature in PBS/0.1% Tween 20 and 3% nonfat dry milk, incubated with primary and secondary antibodies. Typically membranes are incubated for 1 hour at room temperature in blocking buffer, and then incubated with affinity purified rabbit anti-IDO2 antibody diluted at 1:5000 in blocking buffer. Membranes were washed at room temperature 3-5 times for 10 minutes each in washing buffer (PBS, 0.1% tween), after which the membrane was incubated with HRP-conjugated goat-anti-rabbit antibody (Santa Cruz) in blocking buffer for 1 hour at room temperature, followed by five 10 minutes washes in washing buffer. The membrane was prepared for exposure to X-ray film using a chemiluminescence method with SuperSignal® West Pico chemiluminescent substrate (Pierce cat. no. 34078, Rockford, Ill.). The highest dilution that gave the maximum amount of protein productions was used.
[0180] High five cells grown in Express Five-SFM media were plated at 2×107 cells per T175 flask in 30 mL of media. After four hours the media was removed and recBV was added at 5-10 infectious units per cell in 6 mL of media. The flask was rocked every 10-15 minutes to ensure infection of every cell over the period of 1 hour, after which an additional 15 mL of media was added. After 24 hours the media in each flask was supplemented with tryptophan (final 100 μM) and hemin (5 μM final). After 64 hours, the infected cells were dislodged by the addition of glass beads. The cell suspension was separated from the glass beads by pipetting and pelleted by centrifugation (3,000 rpm 5 minutes). The cell pellet was either frozen or processed immediately.
[0181] The cell pellet, containing approximately 1.8×108 cells, was resuspended in 40 mL 50 mM tris pH 8.8 and sonicated, 4×10 second pulses, on ice. The suspension was adjusted to 50 mM NaCl, 1% octylglucoside, vortexed, and clarified by centrifugation, 20 minutes at 13,000 rpm, at 4° C. The supernatant was passed over a DEAE-Sephacel column equilibrated in Tris pH 8.8, 50 mM NaCl, 1 mM EDTA (EQ buffer). The column was washed with 10 column volumes of equilibration buffer. The IDO2 proteins were eluted with 50 mM Tris pH 8.8, 0.5 M NaCl, 1 mM EDTA.
[0182] The eluted fractions were subjected to SDS-PAGE analysis followed by staining with Coomassie brilliant blue R-250. Peak IDO2 containing fractions were combined and dialyzed against EQ buffer. The dialysate was applied to a Mono Q column using the AKTAPurifier 100 fast protein liquid chromatography (FPLC) system. The column was equilibrated in EQ buffer and eluted using a linear gradient of EQ buffer with increasing NaCl 50 mM to 1 M. Elution profile was established by dual spectroscopic measurements at 280 nm and 403 nm and SDS PAGE followed by staining with Coomassie brilliant blue R-250 and/or Western analysis. The 404/280 absorbance ratio was approximately 1.8-2.0. Peak IDO2 eluates were contained in the 400-500 mM NaCl fractions. An additional peak containing IDO2 was also observed eluting at 250 nM NaCl which may contain mostly dimeric forms of the muIDO2 protein. Indeed, the early eluting peak contained IDO2 dimers as determined by a non-heat denatured sample analyzed by SDS-PAGE, whereby an 120 kDa band can be seen in samples not reduced or heated, while upon heating the larger bands resolves into a single major protein band at ˜55 kDa. Both mIDO2 containing peaks were pooled and concentrated approximated 5 fold by centrifugal filtration (Amicon Ultra-4, Billerica, Mass.).
[0183] The concentrated material was applied to a gel filtration column, Superdex® 200 (GE Healthcare, Piscataway, N.J.), equilibrated in EQ buffer. Fractions were collected and analyzed by SDS-PAGE/Coomassie staining and confirmed by Western analysis. IDO2 containing fractions were pooled and concentrated to approximately 2 μg/μL by centrifugal filtration (Amicon Ultra-4). The purified protein material exhibited 404-280 nM ratios of 1.5 to 1.8.
[0184] IDO2 activity was measured as the amount of kynurenine formed from L-tryptophan. The standard assay conditions consisted of a mixture containing 50 mM Pipes pH 6.5, between 50 and 600 nM of rmuIDO2 or rhuIDO2 (where 100 nM of rIDO2 is approximately 5.5 μg protein per mL reaction), 200 U catalase (0.2 mg/mL, sp act. ˜1000 U/mg), 200 μM L-tryptophan, 10 μM methylene blue and 20 mM ascorbic acid. The mixture was incubated at various times ranging from 15 minutes to 4 hours at 37° C. before the reaction was stopped by adding trichloroacetic acid (TCA) to 3% final. The samples were then heated to 50-60° C. for 30 minutes to convert N-formyl-kynureneine to kynurenine, clarified by centrifugation, and supernatants (100 μL) were removed to a new dish, mixed with 100 μL Ehrlich's reagent (2% p-dimethylaminobenzaldehyde w/v in glacial acetic acid), and incubated 10-30 minutes at room temperature. Absorbance at 490 nm was determined on a plate reader and the data collected and analyzed using Excel software (Microsoft). Typically, samples were analyzed in triplicate and control values were typically averaged and subtracted from sample values. Enzyme activity was estimated based on the conversion of tryptophan to kynurenine using linear regression analysis based on an absorbance standard curve derived from assay measurements on known amounts of kynurenine. Inhibitions studies were performed whereby varying amounts (0-100 μM) of D or L stereoisomers of 1-methyl tryptophan (D-1MT or L-1MT) or MTH-trp and demonstrate that the purified recIDO2 proteins are inhibited by D-1MT (FIG. 25).
Example 7
[0185] Polyclonal rabbit anti-murine and anti-human IDO2 was prepared. Antisera were raised against a mixture of murine and human GST-IDO2 fusion protein. Antisera were screened for reactivity against the immunizing antigen by ELISA and western, and samples with high titer were purified by affinity chromatography. Specifically, antiserum was pre-absorbed to protein column containing GST. Since IDO2 and IDO1 possess conserved amino acid domains, the GST-unbound serum was passed over an IDO1-His-tagged peptide column. The unbound material was then affinity purified on an antigen specific peptide column containing human and mouse His-tagged IDO2. The resulting antibody was analyzed and determined to be IDO2 specific with no cross-reactivity with IDO1.
[0186] While certain of the preferred embodiments of the present invention have been described and specifically exemplified above, it is not intended that the invention be limited to such embodiments. Various modifications may be made thereto without departing from the scope and spirit of the present invention, as set forth in the following claims.
[0187] Several publications and patent documents are cited in the foregoing specification in order to more fully describe the state of the art to which this invention pertains. The disclosure of each of these citations is incorporated by reference herein.
Sequence CWU
1
1
1631420PRTHomo Sapiens 1Met Leu His Phe His Tyr Tyr Asp Thr Ser Asn Lys
Ile Met Glu Pro1 5 10 15
His Arg Pro Asn Val Lys Thr Ala Val Pro Leu Ser Leu Glu Ser Tyr
20 25 30 His Ile Ser Glu
Glu Tyr Gly Phe Leu Leu Pro Asp Ser Leu Lys Glu 35
40 45 Leu Pro Asp His Tyr Arg Pro Trp Met
Glu Ile Ala Asn Lys Leu Pro 50 55 60
Gln Leu Ile Asp Ala His Gln Leu Gln Ala His Val Asp Lys
Met Pro65 70 75 80
Leu Leu Ser Cys Gln Phe Leu Lys Gly His Arg Glu Gln Arg Leu Ala
85 90 95 His Leu Val Leu Ser
Phe Leu Thr Met Gly Tyr Val Trp Gln Glu Gly 100
105 110 Glu Ala Gln Pro Ala Glu Val Leu Pro Arg
Asn Leu Ala Leu Pro Phe 115 120
125 Val Glu Val Ser Arg Asn Leu Gly Leu Pro Pro Ile Leu Val
His Ser 130 135 140
Asp Leu Val Leu Thr Asn Trp Thr Lys Lys Asp Pro Asp Gly Asn Leu145
150 155 160 Glu Ile Gly Asn Leu
Glu Thr Ile Ile Ser Phe Pro Gly Gly Glu Ser 165
170 175 Leu His Gly Phe Ile Leu Val Thr Ala Leu
Val Glu Lys Glu Ala Val 180 185
190 Pro Gly Ile Lys Ala Leu Val Gln Ala Thr Asn Ala Ile Leu Gln
Pro 195 200 205 Asn
Gln Glu Ala Leu Leu Gln Ala Leu Gln Arg Leu Arg Leu Ser Ile 210
215 220 Gln Asp Ile Thr Lys Thr
Leu Gly Gln Met His Asp Tyr Val Asp Pro225 230
235 240 Asp Ile Phe Tyr Ala Gly Ile Arg Ile Phe Leu
Ser Gly Trp Lys Asp 245 250
255 Asn Pro Ala Met Pro Ala Gly Leu Met Tyr Glu Gly Val Ser Gln Glu
260 265 270 Pro Leu Lys
Tyr Ser Gly Gly Ser Ala Ala Gln Ser Thr Val Leu His 275
280 285 Ala Phe Asp Glu Phe Leu Gly Ile
Arg His Ser Lys Glu Ser Gly Asp 290 295
300 Phe Leu Tyr Arg Met Arg Asp Tyr Met Pro Pro Ser His
Lys Ala Phe305 310 315
320 Ile Glu Asp Ile His Ser Ala Pro Ser Leu Arg Asp Tyr Ile Leu Ser
325 330 335 Ser Gly Gln Asp
His Leu Leu Thr Ala Tyr Asn Gln Cys Val Gln Ala 340
345 350 Leu Ala Glu Leu Arg Ser Tyr His Ile
Thr Met Val Thr Lys Tyr Leu 355 360
365 Ile Thr Ala Ala Ala Lys Ala Lys His Gly Lys Pro Asn His
Leu Pro 370 375 380
Gly Pro Pro Gln Ala Leu Lys Asp Arg Gly Thr Gly Gly Thr Ala Val385
390 395 400 Met Ser Phe Leu Lys
Ser Val Arg Asp Lys Thr Leu Glu Ser Ile Leu 405
410 415 His Pro Arg Gly 420
2405PRTHomo Sapiens 2Met Glu Pro His Arg Pro Asn Val Lys Thr Ala Val Pro
Leu Ser Leu1 5 10 15
Glu Ser Tyr His Ile Ser Glu Glu Tyr Gly Phe Leu Leu Pro Asp Ser
20 25 30 Leu Lys Glu Leu Pro
Asp His Tyr Arg Pro Trp Met Glu Ile Ala Asn 35 40
45 Lys Leu Pro Gln Leu Ile Asp Ala His Gln
Leu Gln Ala His Val Asp 50 55 60
Lys Met Pro Leu Leu Ser Cys Gln Phe Leu Lys Gly His Arg Glu
Gln65 70 75 80 Arg
Leu Ala His Leu Val Leu Ser Phe Leu Thr Met Gly Tyr Val Trp
85 90 95 Gln Glu Gly Glu Ala Gln
Pro Ala Glu Val Leu Pro Arg Asn Leu Ala 100
105 110 Leu Pro Phe Val Glu Val Ser Arg Asn Leu
Gly Leu Pro Pro Ile Leu 115 120
125 Val His Ser Asp Leu Val Leu Thr Asn Trp Thr Lys Lys Asp
Pro Asp 130 135 140
Gly Phe Leu Glu Ile Gly Asn Leu Glu Thr Ile Ile Ser Phe Pro Gly145
150 155 160 Gly Glu Ser Leu His
Gly Phe Ile Leu Val Thr Ala Leu Val Glu Lys 165
170 175 Glu Ala Val Pro Gly Ile Lys Ala Leu Val
Gln Ala Thr Asn Ala Ile 180 185
190 Leu Gln Pro Asn Gln Glu Ala Leu Leu Gln Ala Leu Gln Arg Leu
Arg 195 200 205 Leu
Ser Ile Gln Asp Ile Thr Lys Thr Leu Gly Gln Met His Asp Tyr 210
215 220 Val Asp Pro Asp Ile Phe
Tyr Ala Gly Ile Arg Ile Phe Leu Ser Gly225 230
235 240 Trp Lys Asp Asn Pro Ala Met Pro Ala Gly Leu
Met Tyr Glu Gly Val 245 250
255 Ser Gln Glu Pro Leu Lys Tyr Ser Gly Gly Ser Ala Ala Gln Ser Thr
260 265 270 Val Leu His
Ala Phe Asp Glu Phe Leu Gly Ile Arg His Ser Lys Glu 275
280 285 Ser Gly Asp Phe Leu Tyr Arg Met
Arg Asp Tyr Met Pro Pro Ser His 290 295
300 Lys Ala Phe Ile Glu Asp Ile His Ser Ala Pro Ser Leu
Arg Asp Tyr305 310 315
320 Ile Leu Ser Ser Gly Gln Asp His Leu Leu Thr Ala Tyr Asn Gln Cys
325 330 335 Val Gln Ala Leu
Ala Glu Leu Arg Ser Tyr His Ile Thr Met Val Thr 340
345 350 Lys Tyr Leu Ile Thr Ala Ala Ala Lys
Ala Lys His Gly Lys Pro Asn 355 360
365 His Leu Pro Gly Pro Pro Gln Ala Leu Lys Asp Arg Gly Thr
Gly Gly 370 375 380
Thr Ala Val Met Ser Phe Leu Lys Ser Val Arg Asp Lys Thr Leu Glu385
390 395 400 Ser Ile Leu His Pro
405 3398PRTMus musculus 3Met Thr Leu Glu Val Pro Leu Ser
Leu Gly Arg Tyr His Ile Ser Glu1 5 10
15 Glu Tyr Gly Phe Leu Leu Pro Asn Pro Leu Glu Ala Leu
Pro Asp His 20 25 30
Tyr Lys Pro Trp Met Glu Ile Ala Leu Arg Leu Pro His Leu Ile Glu
35 40 45 Asn Arg Gln Leu
Arg Ala His Val Tyr Arg Met Pro Leu Leu Asp Cys 50 55
60 Arg Phe Leu Lys Ser Tyr Arg Glu Gln
Arg Leu Ala His Met Ala Leu65 70 75
80 Ala Ala Ile Thr Met Gly Phe Val Trp Gln Glu Gly Glu Gly
Gln Pro 85 90 95
Gln Lys Val Leu Pro Arg Ser Leu Ala Ile Pro Phe Val Glu Val Ser
100 105 110 Arg Asn Leu Gly Leu
Pro Pro Ile Leu Val His Ser Asp Leu Val Leu 115
120 125 Thr Asn Trp Thr Lys Arg Asn Pro Glu
Gly Pro Leu Glu Ile Ser Asn 130 135
140 Leu Glu Thr Ile Ile Ser Phe Pro Gly Gly Glu Ser Leu
Arg Gly Phe145 150 155
160 Ile Leu Val Thr Val Leu Val Glu Lys Ala Ala Val Pro Gly Leu Lys
165 170 175 Ala Leu Val Gln
Gly Met Glu Ala Ile Arg Gln His Ser Gln Asp Thr 180
185 190 Leu Leu Glu Ala Leu Gln Gln Leu Arg
Leu Ser Ile Gln Asp Ile Thr 195 200
205 Arg Ala Leu Ala Gln Met His Asp Tyr Val Asp Pro Asp Ile
Phe Tyr 210 215 220
Ser Val Ile Arg Ile Phe Leu Ser Gly Trp Lys Asp Asn Pro Ala Met225
230 235 240 Pro Val Gly Leu Val
Tyr Glu Gly Ala Ala Thr Glu Pro Leu Lys Tyr 245
250 255 Ser Gly Gly Ser Ala Ala Gln Ser Ser Val
Leu His Ala Phe Asp Glu 260 265
270 Phe Leu Gly Ile Glu His Cys Lys Glu Ser Val Gly Phe Leu His
Arg 275 280 285 Met
Arg Asp Tyr Met Pro Pro Ser His Lys Ala Phe Leu Glu Asp Leu 290
295 300 His Val Ala Pro Ser Leu
Arg Asp Tyr Ile Leu Ala Ser Gly Pro Gly305 310
315 320 Asp Cys Leu Met Ala Tyr Asn Gln Cys Val Glu
Ala Leu Gly Glu Leu 325 330
335 Arg Ser Tyr His Ile Asn Val Val Ala Arg Tyr Ile Ile Ser Ala Ala
340 345 350 Thr Arg Ala
Arg Ser Arg Gly Leu Thr Asn Pro Ser Pro His Ala Leu 355
360 365 Glu Asp Arg Gly Thr Gly Gly Thr
Ala Met Leu Ser Phe Leu Lys Ser 370 375
380 Val Arg Glu Lys Thr Met Glu Ala Leu Leu Cys Pro Gly
Ala385 390 395 4403PRTMus
musculus 4Met Glu Pro Gln Ser Gln Ser Met Thr Leu Glu Val Pro Leu Ser
Leu1 5 10 15 Gly
Arg Tyr His Ile Ser Glu Glu Tyr Gly Phe Leu Leu Pro Asn Pro 20
25 30 Leu Glu Ala Leu Pro Asp
His Tyr Lys Pro Trp Met Glu Ile Ala Leu 35 40
45 Arg Leu Pro His Leu Ile Glu Asn Arg Gln Leu
Arg Ala His Val Tyr 50 55 60
Arg Met Pro Leu Leu Asp Cys Arg Phe Leu Lys Ser Tyr Arg Glu
Gln65 70 75 80 Arg
Leu Ala His Met Ala Leu Ala Ala Ile Thr Met Gly Phe Val Trp
85 90 95 Gln Glu Gly Glu Gly Gln
Pro Gln Lys Val Leu Pro Arg Ser Leu Ala 100
105 110 Ile Pro Phe Val Glu Val Ser Arg Asn Leu
Gly Leu Pro Pro Ile Leu 115 120
125 Val His Ser Asp Leu Val Leu Thr Asn Trp Thr Lys Arg Asn
Pro Glu 130 135 140
Gly Pro Leu Glu Ile Ser Asn Leu Glu Thr Ile Ile Ser Phe Pro Gly145
150 155 160 Gly Glu Ser Leu Arg
Gly Phe Ile Leu Val Thr Val Leu Val Glu Lys 165
170 175 Ala Ala Val Pro Gly Leu Lys Ala Leu Val
Gln Gly Met Glu Ala Ile 180 185
190 Arg Gln His Ser Gln Asp Thr Leu Leu Glu Ala Leu Gln Gln Leu
Arg 195 200 205 Leu
Ser Ile Gln Asp Ile Thr Arg Ala Leu Ala Gln Met His Asp Tyr 210
215 220 Val Asp Pro Asp Ile Phe
Tyr Ser Val Ile Arg Ile Phe Leu Ser Gly225 230
235 240 Trp Lys Asp Asn Pro Ala Met Pro Val Gly Leu
Val Tyr Glu Gly Ala 245 250
255 Ala Thr Glu Pro Leu Lys Tyr Ser Gly Gly Ser Ala Ala Gln Ser Ser
260 265 270 Val Leu His
Ala Phe Asp Glu Phe Leu Gly Ile Glu His Cys Lys Glu 275
280 285 Ser Val Gly Phe Leu His Arg Met
Arg Asp Tyr Met Pro Pro Ser His 290 295
300 Lys Ala Phe Leu Glu Asp Leu His Val Ala Pro Ser Leu
Arg Asp Tyr305 310 315
320 Ile Leu Ala Ser Gly Pro Gly Asp Cys Leu Met Ala Tyr Asn Gln Cys
325 330 335 Val Glu Ala Leu
Gly Glu Leu Arg Ser Tyr His Ile Asn Val Val Ala 340
345 350 Arg Tyr Ile Ile Ser Ala Ala Thr Arg
Ala Arg Ser Arg Gly Leu Thr 355 360
365 Asn Pro Ser Pro His Ala Leu Glu Asp Arg Gly Thr Gly Gly
Thr Ala 370 375 380
Met Leu Ser Phe Leu Lys Ser Val Arg Glu Lys Thr Met Glu Ala Leu385
390 395 400 Leu Cys
Pro5403PRTHomo Sapiens 5Met Ala His Ala Met Glu Asn Ser Trp Thr Ile Ser
Lys Glu Tyr His1 5 10 15
Ile Asp Glu Glu Val Gly Phe Ala Leu Pro Asn Pro Gln Glu Asn Leu
20 25 30 Pro Asp Phe Tyr
Asn Asp Trp Met Phe Ile Ala Lys His Leu Pro Asp 35
40 45 Leu Ile Glu Ser Gly Gln Leu Arg Glu
Arg Val Glu Lys Leu Asn Met 50 55 60
Leu Ser Ile Asp His Leu Thr Asp His Lys Ser Gln Arg Leu
Ala Arg65 70 75 80
Leu Val Leu Gly Cys Ile Thr Met Ala Tyr Val Trp Gly Lys Gly His
85 90 95 Gly Asp Val Arg Lys
Val Leu Pro Arg Asn Ile Ala Val Pro Tyr Cys 100
105 110 Gln Leu Ser Lys Lys Leu Glu Leu Pro Pro
Ile Leu Val Tyr Ala Asp 115 120
125 Cys Val Leu Ala Asn Trp Lys Lys Lys Asp Pro Asn Lys Pro
Leu Thr 130 135 140
Tyr Glu Asn Met Asp Val Leu Phe Ser Phe Arg Asp Gly Asp Cys Ser145
150 155 160 Lys Gly Phe Phe Leu
Val Ser Leu Leu Val Glu Ile Ala Ala Ala Ser 165
170 175 Ala Ile Lys Val Ile Pro Thr Val Phe Lys
Ala Met Gln Met Gln Glu 180 185
190 Arg Asp Thr Leu Leu Lys Ala Leu Leu Glu Ile Ala Ser Cys Leu
Glu 195 200 205 Lys
Ala Leu Gln Val Phe His Gln Ile His Asp His Val Asn Pro Lys 210
215 220 Ala Phe Phe Ser Val Leu
Arg Ile Tyr Leu Ser Gly Trp Lys Gly Asn225 230
235 240 Pro Gln Leu Ser Asp Gly Leu Val Tyr Glu Gly
Phe Trp Glu Asp Pro 245 250
255 Lys Glu Phe Ala Gly Gly Ser Ala Gly Gln Ser Ser Val Phe Gln Cys
260 265 270 Phe Asp Val
Leu Leu Gly Ile Gln Gln Thr Ala Gly Gly Gly His Ala 275
280 285 Ala Gln Phe Leu Gln Asp Met Arg
Arg Tyr Met Pro Pro Ala His Arg 290 295
300 Asn Phe Leu Cys Ser Leu Glu Ser Asn Pro Ser Val Arg
Glu Phe Val305 310 315
320 Leu Ser Lys Gly Asp Ala Gly Leu Arg Glu Ala Tyr Asp Ala Cys Val
325 330 335 Lys Ala Leu Val
Ser Leu Arg Ser Tyr His Leu Gln Ile Val Thr Lys 340
345 350 Tyr Ile Leu Ile Pro Ala Ser Gln Gln
Pro Lys Glu Asn Lys Thr Ser 355 360
365 Glu Asp Pro Ser Lys Leu Glu Ala Lys Gly Thr Gly Gly Thr
Asp Leu 370 375 380
Met Asn Phe Leu Lys Thr Val Arg Ser Thr Thr Glu Lys Ser Leu Leu385
390 395 400 Lys Glu
Gly6407PRTMus musculus 6Met Ala Leu Ser Lys Ile Ser Pro Thr Glu Gly Ser
Arg Arg Ile Leu1 5 10 15
Glu Asp His His Ile Asp Glu Asp Val Gly Phe Ala Leu Pro His Pro
20 25 30 Leu Val Glu Leu
Pro Asp Ala Tyr Ser Pro Trp Val Leu Val Ala Arg 35
40 45 Asn Leu Pro Val Leu Ile Glu Asn Gly
Gln Leu Arg Glu Glu Val Glu 50 55 60
Lys Leu Pro Thr Leu Ser Thr Asp Gly Leu Arg Gly His Arg
Leu Gln65 70 75 80
Arg Leu Ala His Leu Ala Leu Gly Tyr Ile Thr Met Ala Tyr Val Trp
85 90 95 Asn Arg Gly Asp Asp
Asp Val Arg Lys Val Leu Pro Arg Asn Ile Ala 100
105 110 Val Pro Tyr Cys Glu Leu Ser Glu Lys Leu
Gly Leu Pro Pro Ile Leu 115 120
125 Ser Tyr Ala Asp Cys Val Leu Ala Asn Trp Lys Lys Lys Asp
Pro Asn 130 135 140
Gly Pro Met Thr Tyr Glu Asn Met Asp Ile Leu Phe Ser Phe Pro Gly145
150 155 160 Gly Asp Cys Asp Lys
Gly Phe Phe Leu Val Ser Leu Leu Val Glu Ile 165
170 175 Ala Ala Ser Pro Ala Ile Lys Ala Ile Pro
Thr Val Ser Ser Ala Val 180 185
190 Glu Arg Gln Asp Leu Lys Ala Leu Glu Lys Ala Leu His Asp Ile
Ala 195 200 205 Thr
Ser Leu Glu Lys Ala Lys Glu Ile Phe Lys Arg Met Arg Asp Phe 210
215 220 Val Asp Pro Asp Thr Phe
Phe His Val Leu Arg Ile Tyr Leu Ser Gly225 230
235 240 Trp Lys Cys Ser Ser Lys Leu Pro Glu Gly Leu
Leu Tyr Glu Gly Val 245 250
255 Trp Asp Thr Pro Lys Met Phe Ser Gly Gly Ser Ala Gly Gln Ser Ser
260 265 270 Ile Phe Gln
Ser Leu Asp Val Leu Leu Gly Ile Lys His Glu Ala Gly 275
280 285 Lys Glu Ser Pro Ala Glu Phe Leu
Gln Glu Met Arg Glu Tyr Met Pro 290 295
300 Pro Ala His Arg Asn Phe Leu Phe Phe Leu Glu Ser Ala
Pro Pro Val305 310 315
320 Arg Glu Phe Val Ile Ser Arg His Asn Glu Asp Leu Thr Lys Ala Tyr
325 330 335 Asn Glu Cys Val
Asn Gly Leu Val Ser Val Arg Lys Phe His Leu Ala 340
345 350 Ile Val Asp Thr Tyr Ile Met Lys Pro
Ser Lys Lys Lys Pro Thr Asp 355 360
365 Gly Asp Lys Ser Glu Glu Pro Ser Asn Val Glu Ser Arg Gly
Thr Gly 370 375 380
Gly Thr Asn Pro Met Thr Phe Leu Arg Ser Val Lys Asp Thr Thr Glu385
390 395 400 Lys Ala Leu Leu Ser
Trp Pro 405 71224DNAMus musculus 7atggcactca
gtaaaatatc tcctacagaa ggttctagaa ggatccttga agaccaccac 60atagatgaag
atgtgggctt tgctctacca catccactgg tggagctgcc cgacgcatac 120agcccctggg
tccttgtggc tagaaatctg cctgtgctga ttgagaacgg gcagcttcga 180gaagaagttg
aaaagctgcc cacactgagc acggacggac tgagaggaca caggttacag 240cgcctggcac
acctggccct ggggtacatc accatggcgt atgtgtggaa ccgaggggat 300gacgatgttc
gaaaggtgct gccccgcaat attgctgttc cctactgcga gctctcagag 360aagttgggcc
tgcctcctat tctgtcttat gcagactgtg tcctggcaaa ctggaagaaa 420aaggacccca
atgggcccat gacatacgag aacatggaca ttctgttctc atttcctggt 480ggggactgcg
acaagggctt cttcctcgtc tctctattgg tggaaatcgc agcttctcct 540gcaatcaaag
caatccccac tgtatccagt gcagtagagc gtcaagacct gaaagcattg 600gaaaaggcac
tgcacgacat agctaccagt ctggagaaag ccaaggaaat ttttaagagg 660atgcgtgact
ttgtggaccc agacacgttt ttccacgttc tccgcatata tctgtctggc 720tggaaatgca
gctccaagct gccagaaggt ctgctgtatg agggggtctg ggacacccca 780aaaatgtttt
cagggggcag tgcaggccag agcagcatct tccagagtct tgatgtcctt 840ctgggaataa
aacacgaggc tggcaaagaa tctcctgcag aattcctcca ggaaatgaga 900gagtacatgc
ctccagccca ccggaacttc cttttcttct tagagtcagc tcccccagtc 960cgtgagtttg
tcatttcaag acacaatgaa gacttgacga aagcttataa cgagtgtgtg 1020aatggtctgg
tctctgtgag aaagttccac ctcgcaatag tagatactta cattatgaaa 1080ccttcgaaga
agaagcccac tgatggcgac aagtcggaag agccctcaaa tgtggaaagc 1140agagggactg
ggggtacgaa tcccatgact ttcctaagga gtgtgaaaga tacaaccgag 1200aaagctcttc
tgagttggcc ttag 122482279DNAHomo
Sapiens 8agtccagatg atagttaaga aagcagtaag aatacagaga gtccacaatg
agatgaaaat 60gcactgccag ttgaaacatc ctcctacact ggagctttat aaatatttta
aagacaagga 120ttggattaga tttgacatta gaaatgtacc ataatacaga aggcaatgga
cacctaaaga 180acagaatgaa aaccttctta ggaaatgaag cttgacactt cacccaccag
gccaccacaa 240gaatgttgca ttttcattat tatgatactt caaacaaaat aatggagccc
cacagaccga 300atgtgaagac agcagtgcca ttgtctttgg aaagctatca catatctgaa
gagtatggct 360ttcttcttcc agattctctg aaagaacttc cagatcatta taggccttgg
atggaaattg 420ccaacaaact tcctcaattg attgatgctc accagcttca agctcatgtg
gacaagatgc 480ccctgctgag ctgccagttc ctgaagggtc accgggagca gcgcctggcc
cacctggtcc 540tgagcttcct caccatgggt tatgtctggc aggaaggaga ggcgcagcct
gcagaggtcc 600tgccaaggaa tcttgccctt ccatttgtcg aagtctccag gaacttgggg
ctccctccta 660tcctggtcca ctcagacttg gtgctgacga actggaccaa aaaagatcca
gacgggaacc 720tggagaccat catctcattt cctgggggag agagcctgca tggttttata
ctggtgactg 780ctttggtaga gaaagaagca gtgcctggga taaaggctct tgttcaggcc
acgaatgcta 840tcttgcagcc caaccaggag gccctgctcc aagccctgca gcgactgaga
ctgtctattc 900aggacatcac caaaacctta ggacagatgc atgattatgt agatccagac
atattttatg 960caggcatccg gatctttctc tctggatgga aagacaaccc agcaatgcct
gcagggctga 1020tgtatgaagg agtttcccaa gagcccctga aatactccgg cgggagtgca
gctcagagca 1080cagtgcttca tgcctttgat gagttcttag gcattcgtca tagcaaggaa
agtggtgact 1140ttctgtacag aatgagggat tacatgcctc cttcccataa ggccttcata
gaagacatcc 1200actcagcacc ttccctgagg gactacatcc tgtcatctgg acaggaccac
ttgctgacag 1260cttataacca gtgtgtgcag gccctggcag agctgcggag ctatcacatc
accatggtca 1320ccaaatacct catcacagct gcagccaagg caaagcatgg gaagccaaac
catctcccag 1380ggcctcctca ggctttaaaa gacaggggca caggtggaac cgcagttatg
agctttctta 1440agagtgtcag ggataagacc ttggagtcaa tccttcaccc acgtggttga
gaggctgccc 1500tctccccagc aatgcagagc ccccatggag ggcaggtggg cctggagaat
gagggtcagg 1560gttctgcctg ggatcatcca ggaaggatct cagccctatt catgtttctg
ctctacagag 1620cactatattc tccttgttga gagctgttgg cttcacaaag gagagttgat
gtggccaagc 1680ctttccctcc ctacctgatc actgcttaac ggcatgtata atggatactt
cctcatgcag 1740aacccccaga ggagtgactg tatgccattc tctttgccaa gtaatagaaa
accaatctaa 1800atgtcaaaaa tcagataaaa ttgcctgggg atacattact tgttgatttt
cttaaaaaac 1860aaattcactt aacaattcat taagttcata ctgagcactg cctccaagat
taaaaccagg 1920atttctgtgg tcccagacca gccctcttct ccctgaatgt gttgagttgg
tggcaggagg 1980ttggaaatgc tccagtggag atgggaagat agaggatgct gacaataagg
acttggaagt 2040cactagtgtg aaaatgagca gttaatgata tgggaacgga tgagactttc
cacgtggtac 2100ctagatttgc aaattctatt gtaatgcctt tatttttaga agaattattc
tctcttctta 2160ctctgaaaat ctgtatttgt aaaatgaatg aatggatcct atataagtaa
ataagaaaac 2220tgggaataag tagtaaatca atgtgtttag tgtgcaaata aatgtaaatg
cttttattg 227991245DNAHomo Sapiens 9atgttgcatt ttcattatta tgatacttca
aacaaaataa tggagcccca cagaccgaat 60gtgaagacag cagtgccatt gtctttggaa
agctatcaca tatctgaaga gtatggcttt 120cttcttccag attctctgaa agaacttcca
gatcattata ggccttggat ggaaattgcc 180aacaaacttc ctcaattgat tgatgctcac
cagcttcaag ctcatgtgga caagatgccc 240ctgctgagct gccagttcct gaagggtcac
cgggagcagc gcctggccca cctggtcctg 300agcttcctca ccatgggtta tgtctggcag
gaaggagagg cgcagcctgc agaggtcctg 360ccaaggaatc ttgcccttcc atttgtcgaa
gtctccagga acttggggct ccctcctatc 420ctggtccact cagacttggt gctgacgaac
tggaccaaaa aagatccaga cgggaacctg 480gagaccatca tctcatttcc tgggggagag
agcctgcatg gttttatact ggtgactgct 540ttggtagaga aagaagcagt gcctgggata
aaggctcttg ttcaggccac gaatgctatc 600ttgcagccca accaggaggc cctgctccaa
gccctgcagc gactgagact gtctattcag 660gacatcacca aaaccttagg acagatgcat
gattatgtag atccagacat attttatgca 720ggcatccgga tctttctctc tggatggaaa
gacaacccag caatgcctgc agggctgatg 780tatgaaggag tttcccaaga gcccctgaaa
tactccggcg ggagtgcagc tcagagcaca 840gtgcttcatg cctttgatga gttcttaggc
attcgtcata gcaaggaaag tggtgacttt 900ctgtacagaa tgagggatta catgcctcct
tcccataagg ccttcataga agacatccac 960tcagcacctt ccctgaggga ctacatcctg
tcatctggac aggaccactt gctgacagct 1020tataaccagt gtgtgcaggc cctggcagag
ctgcggagct atcacatcac catggtcacc 1080aaatacctca tcacagctgc agccaaggca
aagcatggga agccaaacca tctcccaggg 1140cctcctcagg ctttaaaaga caggggcaca
ggtggaaccg cagttatgag ctttcttaag 1200agtgtcaggg ataagacctt ggagtcaatc
cttcacccac gtggt 1245102464DNAMus musculus 10cgcacaagta
caaccacaca gaagacacag ctggaaagct ccctggcctg ggcattcctc 60tggggcagag
acctcacgcg aaaatatgga gcctcaaagt cagagcatga cgctggaggt 120gccgttgtcc
ttggggagat accacatttc tgaggaatat ggctttctcc ttccaaatcc 180tctggaagca
cttccagatc attacaagcc ttggatggaa attgccctca gacttcctca 240cttaatcgag
aaccgccagc tccgagctca cgtgtacagg atgcctctcc tggactgcag 300attcctaaag
agttaccgtg agcagcgcct ggcacacatg gcgctggccg ctatcaccat 360gggattcgtc
tggcaggagg gggaaggcca accccaaaag gtgctgccaa gatctcttgc 420cattcctttt
gttgaggtat ccaggaactt gggactcccg cctatcctgg tccactctga 480cctggtgctg
acaaactgga ccaaaaggaa cccagaagga ccgttggaaa tcagtaacct 540ggaaaccatc
atctcatttc cggggggaga gagcctgcgg ggcttcatcc tagtgacagt 600cttggtggag
aaggcagcag tgcccggcct taaggccctg gttcagggaa tggaggccat 660tcggcaacac
agtcaggaca ccctgctaga agccctgcag cagctgagac tctccatcca 720ggatatcacc
agagccttgg cccaaatgca tgattatgtg gacccagaca tattttactc 780ggtcatccgg
atcttcctct ctgggtggaa ggacaatcca gccatgcctg tggggctggt 840ctatgaaggt
gctgccacag agcctctgaa gtactctgga ggaagtgcag cccagagctc 900cgtgcttcat
gccttcgatg agttcctggg cattgagcat tgcaaggaaa gtgttggctt 960tctacacaga
atgagggact acatgccgcc ttcccataag gctttcctgg aagatctcca 1020cgtagctcct
tctctgagag actacatact ggcctctggt cctggggact gcctgatggc 1080ctataaccag
tgtgtggagg ccctgggaga gctgcgcagt taccacatca atgtcgtggc 1140cagatacatt
atctccgctg ccaccagggc caggagcagg gggctaacta atccctcacc 1200ccatgccttg
gaagacaggg gcactggggg tactgccatg ctgagcttct tgaagagtgt 1260cagggagaag
accatggagg ccctcctgtg tcctggtgct tagcagtcat gtcctgcacc 1320ctaacactta
gatgttctca tcctgcatcc cagcgttaga ggttcacatc ctgcatccta 1380gtgcttagct
gttcttgtgc tatatcccag cgcttagcag tcatgtcctg catcctagtg 1440cttagcattt
tatatccagc attttagtgc ttagagattc acatcctgca tcctagagct 1500tagcatttta
tatccagcat ccttgtgcgt atcagctatg ttttgtatcc tgcttagcag 1560ttaacatcct
gcatcctagt acttatctgt tctcatcctg catcctagag cttagcagtc 1620aggtcccgtg
ggagcaagaa ccagggtctg agctctgtct gagcccaagc atggctttac 1680tgctttgtta
attgtggctc ccacctccac cccaccccag ccagtttgct tgctagaagc 1740ctttctgcac
tgcctaatcc ccctgcctca cagcagagag ctgcagccat gacctcctca 1800ttcagtatta
ggtggacaag tcggagatac ccaaactcaa ttttaaaaga atcaagttgc 1860ttttggggca
tgttacttca tcttttctta ccctgggcct cttcccttct tccctacctc 1920cctcgtccct
tagtctttca cccctctctc tttctccttt tgtcaccctc cccctcccct 1980gcttactctc
ttttcccttc ccccctctcc tcatccctcc ttcctttctt ccttcccttt 2040ttgtctgtga
agcaccaggt ctgatgggcc tcaaactgtg atcttcctgt ctcacccttc 2100aaaggttatg
tgtatgtgac gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgttc 2160gtttcttttg
tttttcccta gtggagatga cacccaaaga tttgcacata ccaggcaatt 2220gctccaccac
ctgactacag tcccagctct ctgtattcct gaaggaaagt cttgatgagt 2280tgcctaggct
ggtattgagc tctttagccc aggcaggcct tagtctgagt agctgggatg 2340tacagggatg
agccactgag ccatgctgct gctgctaacg atgatgacga tgatgatgat 2400gaagattatg
ataactacag tcactgcaat aatgacggca aagataatga aaaaaaaaaa 2460aaaa
2464111194DNAMus
musculus 11atgacgctgg aggtgccgtt gtccttgggg agataccaca tttctgagga
atatggcttt 60ctccttccaa atcctctgga agcacttcca gatcattaca agccttggat
ggaaattgcc 120ctcagacttc ctcacttaat cgagaaccgc cagctccgag ctcacgtgta
caggatgcct 180ctcctggact gcagattcct aaagagttac cgtgagcagc gcctggcaca
catggcgctg 240gccgctatca ccatgggatt cgtctggcag gagggggaag gccaacccca
aaaggtgctg 300ccaagatctc ttgccattcc ttttgttgag gtatccagga acttgggact
cccgcctatc 360ctggtccact ctgacctggt gctgacaaac tggaccaaaa ggaacccaga
aggaccgttg 420gaaatcagta acctggaaac catcatctca tttccggggg gagagagcct
gcggggcttc 480atcctagtga cagtcttggt ggagaaggca gcagtgcccg gccttaaggc
cctggttcag 540ggaatggagg ccattcggca acacagtcag gacaccctgc tagaagccct
gcagcagctg 600agactctcca tccaggatat caccagagcc ttggcccaaa tgcatgatta
tgtggaccca 660gacatatttt actcggtcat ccggatcttc ctctctgggt ggaaggacaa
tccagccatg 720cctgtggggc tggtctatga aggtgctgcc acagagcctc tgaagtactc
tggaggaagt 780gcagcccaga gctccgtgct tcatgccttc gatgagttcc tgggcattga
gcattgcaag 840gaaagtgttg gctttctaca cagaatgagg gactacatgc cgccttccca
taaggctttc 900ctggaagatc tccacgtagc tccttctctg agagactaca tactggcctc
tggtcctggg 960gactgcctga tggcctataa ccagtgtgtg gaggccctgg gagagctgcg
cagttaccac 1020atcaatgtcg tggccagata cattatctcc gctgccacca gggccaggag
cagggggcta 1080actaatccct caccccatgc cttggaagac aggggcactg ggggtactgc
catgctgagc 1140ttcttgaaga gtgtcaggga gaagaccatg gaggccctcc tgtgtcctgg
tgct 1194121227DNAHomo sapiens 12atggagcccc acagaccgaa tgtgaagaca
gcagtgccat tgtctttgga aagctatcac 60atatctgaag agtatggctt tcttcttcca
gattctctga aagaacttcc agatcattat 120aggccttgga tggaaattgc caacaaactt
cctcaattga ttgatgctca ccagcttcaa 180gctcatgtgg acaagatgcc cctgctgagc
tgccagttcc tgaagggtca ccgggagcag 240cgcctggccc acctggtcct gagcttcctc
accatgggtt atgtctggca ggaaggagag 300gcgcagcctg cagaggtcct gccaaggaat
cttgcccttc catttgtcga agtctccagg 360aacttggggc tccctcctat cctggtccac
tcagacttgg tgctgacgaa ctggaccaaa 420aaagatccag acgggttcct ggaaattggg
aacctggaga ccatcatctc atttcctggg 480ggagagagcc tgcatggttt tatactggtg
actgctttgg tagagaaaga agcagtgcct 540gggataaagg ctcttgttca ggccacgaat
gctatcttgc agcccaacca ggaggccctg 600ctccaagccc tgcagcgact gagactgtct
attcaggaca tcaccaaaac cttaggacag 660atgcatgatt atgtagatcc agacatattt
tatgcaggca tccggatctt tctctctggg 720tggaaagaca acccagcaat gcctgcaggg
ctgatgtatg aaggagtttc ccaagagccc 780ctgaaatact ccggcgggag tgcagctcag
agcacagtgc ttcatgcctt tgatgagttc 840ttaggcattc gtcatagcaa ggaaagtggt
gactttctgt acagaatgag ggattacatg 900cctccttccc ataaggcctt catagaagac
atccactcag caccttccct gagggactac 960atcctgtcat ctggacagga ccacttgctg
acagcttata accagtgtgt gcaggccctg 1020gcagagctgc ggagctatca catcaccatg
gtcaccaaat acctcatcac agctgcagcc 1080aaggcaaagc atgggaagcc aaaccatctc
ccagggcctc ctcaggcttt aaaagacagg 1140ggcacaggtg gaaccgcagt tatgagcttt
cttaagagtg tcagggataa gaccttggag 1200tcaatccttc acccacgtgg ttaggat
1227131218DNAMus musculus 13atggagcctc
aaagtcagag catgacgctg gaggtgccgt tgtccttggg gagataccac 60atttctgagg
aatatggctt tctccttcca aatcctctgg aagcacttcc agatcattac 120aagccttgga
tggaaattgc cctcagactt cctcacttaa tcgagaaccg ccagctccga 180gctcacgtgt
acaggatgcc tctcctggac tgcagattcc taaagagtta ccgtgagcag 240cgcctggcac
acatggcgct ggccgctatc accatgggat tcgtctggca ggagggggaa 300ggccaacccc
aaaaggtgct gccaagatct cttgccattc cttttgttga ggtatccagg 360aacttgggac
tcccgcctat cctggtccac tctgacctgg tgctgacaaa ctggaccaaa 420aggaacccag
aaggaccgtt ggaaatcagt aacctggaaa ccatcatctc atttccgggg 480ggagagagcc
tgcggggctt catcctagtg acagtcttgg tggagaaggc agcagtgccc 540ggccttaagg
ccctggttca gggaatggag gccattcggc aacacagtca ggacaccctg 600ctagaagccc
tgcagcagct gagactctcc atccaggata tcaccagagc cttggcccaa 660atgcatgatt
atgtggaccc agacatattt tactcggtca tccggatctt cctctctggg 720tggaaggaca
atccagccat gcctgtgggg ctggtctatg aaggtgttgc cacagagcct 780ctgaagtact
ctggaggaag tgcagcccag agctccgtgc ttcatgcctt cgatgagttc 840ctgggcattg
agcattgcaa ggaaagtgtt ggctttctac acagaatgag ggactacatg 900ccgccttccc
ataaggcttt cctggaagat ctccacgtag ctccttctct gagagactac 960atactggcct
ctggtcctgg ggactgcctg atggcctata accagtgtgt ggaggccctg 1020ggagagctgc
gcagttacca catcaatgtc gtggccagat acattatctc cgctgccacc 1080agggccagga
gcagggggct aactaatccc tcaccccatg ccttggaaga caggggcact 1140gggggtactg
ccatgctgag cttcttgaag agtgtcaggg agaagaccat ggaggccctc 1200ctgtgtcctg
gtgcttag
12181452386DNAMus musculus 14tagttagaag gcagctcgtt tccagacaga tcatgccggg
ccagcacagt tccacgagga 60gcgatttttt tggatggggg aagaaagtga agaagaggag
aaagaggaaa agggggtgaa 120gggtcgcggt ctcagtcttt tatttgtgcc atgacataga
tgccaggtaa tgaatgatga 180atgatgcgca caggtgaagc ataggcctgc ctggagtgta
tggtggttgc catggcaaca 240gacccaagag ggtccttgtc gcttagggat gatgtcatag
ctggattccg aggctggttg 300taaagcagtt tctgatgcta acaatacata tatatgtaat
gataacaaag aaaaagaggc 360catgaatttg aaaggaagga aagaagttag gaaggaagga
aggaaggaag gaaggaagga 420aggaaggaag gaaggaagga aggaaggaag gaaggaaaga
agatgggaat ttggagagat 480gaaagggaag aatgatataa atacatttta atttcagcaa
ataaatacat tttcaaagat 540aaaaagccaa taaagagaaa ccctgtctcg aaaaaacaac
aacaaaccaa aaacaaacaa 600acaaacaagc caataaaact gactcctagt ttagtcattt
tgatacactg tcagaatccc 660tcaggaacca aactcatgtt gagtatggat ctgcacagcc
atagctgaga gttaagttcg 720tgtctcccac tttgtccctg gatttaacag cccctttctc
atactttatg aatgagaagg 780gaaagggggt gggggcttct cttggagtca gcattttaat
tcctaatctt cattgttgac 840ttactacttg gctttctttc agaataaatt tgcggccatc
ctggagttca acctcagggc 900aaggttctcc cctaccgctg aagcaccgca caagtacaac
cacacagaag acacagctgg 960aaagctccct ggcctgggca ttcctctggg gcagagacct
cacgcgaaaa tatggagcct 1020caaagtcaga gcatgacgct ggaggtgccg ttgtccttgg
ggagatacca catttctgag 1080gaatatggct ttctccttcc aaatcctctg gtaaggattg
gcttgtcctg gtcagcacat 1140gtgtctggat tgttagtctt taccttatgt ggttattgga
aggttcggta taagtcacca 1200gctggaggaa gagtgggaat acagtcctgt gagtcccgga
agagcagagg caactgctac 1260tggggacagc acaaagccag tggtcccctc cccccagccc
ccaaagtttc cttaaatcta 1320tggtagttag cactgactaa tcagaagcaa aggtgctatc
agagaggaga gactggatgg 1380agacatgccc taaggacaat tagaacccta taactacagc
aaagagtgga catgcacaca 1440accacatggt gtgacacaga ataatggagt ggccccactg
tatatccact ctgctttgga 1500gacaggttcg ccatgcatcc cagacctaag cagccaaagg
gcttagcctt ctgtgttgat 1560gcaaaccagt ttatcttact tgctggtgac agcagagata
atgggagacc tgcaatgttt 1620ttagagccag taagaagatt agatgttatc gggaatttcc
gatactcgtg aggaatgttg 1680gaaaacaagc aggcctgact ttcagtccaa ctgcacagca
gtctctagta tacctgctct 1740tgttaagtgt agtctgggct tgggagacat atgccggcaa
agtgctagtg gcaaagccca 1800tgcttttggc atcttttaaa aactgaccgt acctaaggga
gggtgaaggc cactgagtta 1860aaagtccagg gacccgatgt tgcagtcgcg gtaactgctg
atcagcacca actcacctag 1920ttcctctctt acttgtgatt aaaaatatca gggtctcaaa
cacctatcac agtgagactc 1980ttgttgtttt gaaacagaga atattgattt atgtagccca
ggctggccac ttgcctccac 2040ttccttactg ctgggaccat agctgaactc ccacagcaga
tccttttgtg ttgaacggta 2100ctggagggat ctaattgaag agaactaagt tctccacaga
aagatgtcag ctacgacatc 2160ggtcatagac atctgcaagc tgtccaggtt aggggttagt
cattagaacc agggccagat 2220ctcacagctt gaatcaagcc aggccttcct gctgctctct
cacggacagt taggaagcag 2280actgtactct gacatgatag cttgcagccg acggctcccg
gctcctctgt gctccttgtc 2340acgcaggccc tgctataaac taaagtgtct gacatgactt
cctggtgcct cgtaaagtta 2400ttaaaagtca gatttctcct ttgttctcgg aattggttcg
agagccctca ggggatttgc 2460tgagggtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg
tgtattctaa gagtgcttcc 2520ctaaaagggt cctctgtact gtcaacggat ctttcatagt
ctctctctcc ctgtctccct 2580gtctctctgt ctttctgtct ctctgtctct ctctgtttct
gtctttctgt ctctgtctgt 2640ctgtctgtct gtctatctct gtgtgtgtgt gtgtattttg
aaggtaggag gatctgagcc 2700tgaactacac acagctagat cctgtgactc tgtctcaaaa
cagagacaca atcaaactct 2760caactaatcg aaacaccaca aggcacactc cattctgggt
gtgtggtctc agtccagcgt 2820attcccatcc ttccaagttt acaggagagg aagggctgat
ggcagataca cccttgtcat 2880tactgggcat gtgtcctgag tttggaaaga gaacactgcc
aagcagggga acgaatatca 2940gggcaggcca tagctctggg gctttctggg ctgctttcct
ctttgtaaat actgggacca 3000ggcagacata cagataagac acaatagcaa catcaagttt
cccccctatt tgttagaaag 3060gttctatggt atggtgtgat ggatgggtac cccttaaaag
aggtccctag tgctgttcac 3120acagaaagga aatattccct gtcccaccca gctactcatt
tatagcccag taatttcaat 3180atgattcttt ctgtttcaat tttctttcat tcaagtgatg
gttttcaatg tcttttttgt 3240taaaggaaga ggaagaaacc ttgactagga tcaggtcctg
gctgctccaa aggtcaagac 3300agactcagtt cgacttcact ggacaaacag tcctgcaact
ttacactggt tgggaaagaa 3360cagtgggttt ggcccagtcc agtgccctag ggcatagcca
agacctgttc ttcttgggcc 3420aagggcaagt ggtaggtggc agaccttccc catctctttc
agaaagtctc acttaagaaa 3480acctagctgg ctagcaagtt caagggtata aattacccta
tccagctgtt tctatcaatt 3540caaagacttc caatttttag tgtctctatg gaactttgct
cctcgaatct gtaaaaatac 3600cacaagaatt ctttgctaag acatctgtcc tctgtgtata
tttgggagga caagacatct 3660ttttcagatg aagaatgtga ggaaatcagt ttgcaggaga
ggaggcagtt aagaggaggc 3720agcaagaggc tggcctgcag cagagctatg accccaagtg
ccaggcccac tctgaaaatt 3780gatttaacac ccttcctaaa cacaatgtga ctgctacttg
agtcatttcc tctcacagca 3840ctaagggcag ggcaggttag agcagtgggt cctgggctgt
ggggtgagac ctttagggga 3900gtttcaacaa acaatccaga tgccagagcc ccaccctgtt
tattcagact ctagacccaa 3960gagctgtacg ctgggaaggc cagataggga gaacaagcca
gagaatgcca gacagggagc 4020acaagccagc aaagtcagcc gtgaaggtgc cacggccaat
agagactcct aagtgcgaaa 4080ataaataaac tgatgacatg cccactccat gcttaagggg
aaagtagatc agagagggag 4140agagagagag agagagagag gcacccagag gcagaggcct
ctggacgatt ccgtagtaga 4200tagagaaagc agactgaaga tggccaccag actggacatg
gccaaggcta cctgggagga 4260aaggaagaac aacagaagtc agagaataga gaaaacctag
tgagagaagc aggaaggggt 4320tgggggggtg gatggagaga agttagcaat gacagcaggg
ttctaagaag aaagagttgg 4380ggaggggaga tcctgtgagc tggagggagt ggagtgagtg
gaggggaaga gctgagaagg 4440gacagatgct agcaggggct ttgagatgta cagcaggtac
ttgtgatagg tgactggagg 4500ccactggtga ccacatgtcc cttctgcaag aggtaaggga
aaacattcct ttaggtagag 4560ggaaaccagt gtcacaagtc cctgaggaaa gctggctttt
tatctaaccc ccagaaatcc 4620tcctgtagtc caggtgaagc tcatttctgg acatacagac
tgccttttgg agtttgggga 4680actggagttt cctttggacc tgacagtcag gagacgttgc
acatgtaacg taggggtaga 4740cacaagactg acaggaatgg caatgagaga ggacaacctc
cagggaaaaa ccaacatgtc 4800ccttctcatt cagaaattct aagcacttgg ttgaagcatt
gggccacagc tggagagaag 4860accggatagg aaattaattg ccacggacat ctgtattttt
cagataagac aaaaaggaag 4920aggtctaaca ttgtcctgaa atatgaggtt gccactgatg
atctctggac acatcagact 4980agtcagatag gggacttgaa acacaatgaa tccagagtct
gtagtagaga caaagaggcc 5040agattgcaaa atggttaatc ttgatcaagg ctggaaaatg
tgtatggaaa taagagagac 5100tgtaatatct taagaatggg gtttgtcctt gtgccagtat
taaagaacaa caacaaaaaa 5160aaaaaaaaaa gaaaaagaaa aagaaagaaa gaaagaaaga
gagaaagaaa gaaagagaaa 5220aagaaaaatg gaggaaagtc atggggaaac aggtaatcag
gcttgaatta aaaaaataaa 5280aaaataaaat aaaaagttaa aggacttgac tagtcccagg
tttctgcaca gatgaattaa 5340aaaatgaaaa gaaaagaaaa gaaaagaaaa gaaaagaaag
ggaaaaaaag aaaaaaagaa 5400aggaaaaaaa aaggaaagag aaaaacaaaa gacaggaaaa
gaagggagga aggaagaaga 5460gaaagaaaga aagacagaca gaaagagaga gagaaaggaa
ggaagaaagg aagagagaaa 5520gaaagaaaga aagaaagaaa gaaagaaaga aagaaaggaa
ggaaggagga aggaaggaag 5580gaaagaaaga aaagaaaaga aaagaaaaga aaagaaaaga
aaagaaatga aaagaaaaga 5640aaagaaaaga aaagaaaaga aaagaaaaga aaagaaaaga
aaagagagga aggaagacag 5700aggaaagggc ctggctgctt gtaggtactg tagcccggga
gatcatagcc agaggcaagg 5760acagctaggg aaatccagag tggtcatgac cgtgaaccac
ttgaggagag ggaagagaaa 5820agggcagccc agcccccagg ctagagaagt ttagggttgg
ggcagggttt gtcagccagt 5880gggtctttgt aactcccgag aacttgtagg cggctttgat
atgctaagta ggcacctcag 5940cctttcctct tgggtttgaa acccagaagg cctcagcaag
tgggacaagc caagcccaac 6000ttggaaagca gagttttaaa gggtgaaaca accaaccaaa
aaggttcact ctcttctagc 6060aagacgctta tgctgcaaag agacttaaga caatccggga
gcaaggacag gacacacgct 6120gaggatggga tgctaaatca gccctggaaa atacgtgtct
aatacaggag gctctcgccc 6180aagatctatt ggtttcctag cacagccgta aaatggctag
ctattttaga acagtaacca 6240gttctctgaa ctccatgcca gcctgtcccc aagtttccag
ccctctgctt caaacacttc 6300ttccaaccct tccaccctca atttcccaac agtcttctta
aacaattcct tctccccatt 6360ctcccaagac tagccactcc aaacggtaac aaccatatct
tccataccaa ctgccttctc 6420ttctccctct gctagcccaa tcccccctcc ttccctgact
cagctggctc ttttatactc 6480tatccagttc ctagtcatcc aagaagcaac caatgcttag
ggtcataggg tcaagccttt 6540gtaacagcta aaagttctta aagaggccag ttgactcgca
actggagacc ctttattact 6600tatttatttt tatgtctatg agtacactgt agctgtcttc
agacacacac cagaaaaggg 6660catcagatcc cattacaggg ttgtgagcca ccatgtggtt
gctgggaatt gaactcagga 6720cctatggaag agcaatcagg gctcttaacc ccgccgagct
catctggaga ccctttaaag 6780ggccaggagc ccaagataaa tcacattaca gttacatatg
acccaaactc aggtgagcta 6840gaccagtgaa gacttagact gatttctgga attaaggcac
tgggcctgca gcacttccct 6900ccaaagcctg cagtgcagaa tctgcccagg cctttcccag
gctccggtag cttcaacagc 6960ttcctggcta ctagctcctg gcatctttcc accccttcct
tatatggcct tctgctgctc 7020agtgtcttct cccctgatgc cttttcttct tcttttctta
caaggatgct gctcattggt 7080ttttaagacc caagctaatc ccagataatc tcatcagtaa
agagccctct ccaaatagta 7140tcacatactt agttcctaag gggacaactt atttgtgttc
taagacttgg ggcaaagtat 7200gagcagatgg tgcaatctta ggaatgctga ctgaaagaac
tgtcttgtcc ctagattccc 7260aaacctgatc tgtcaggaat gaatggggga aaaaagccca
ggacaatgac aggcaagagt 7320gtaaaatatc agtggtcgcc aaggggcttc gggacataaa
ttcagtgagt gagtgcattc 7380ttaccacgta tgaagaccat gccaaacaca gacataaata
acgaaaatta aagattaaaa 7440gtaaataaat tggccagatg tcatggcaaa tgcctgcatt
cctagcaact agcagaagca 7500ggaaggtatc aagttctagg cctgcctgta acactgaaca
catatgagac cagcctgaga 7560tatgtagaca aacaaaacaa aacaaaacga aagaccattg
atcaatcaat aacataaacg 7620ttcaggaaac acaggccaca caatcaggga ggctttgcct
ttgtttaggg gctgggtttt 7680tttttatatt ttcctttcct tgttcttctt cttgtttgtt
tgctttttgt ttgtttgttt 7740gcttgcttgc ttgcttttgt tttttcaaga cagggtttct
ccgtgtaggc atctctggct 7800atcctggaac tcattctgta gataaggctg tctttgaact
cagagatctg cttgcctctg 7860ccttcttaag gccgggacta aaggtgtgca cagtcactgc
cacctacctg ctgtttcttt 7920atcccctgca ttagtcaccc tcccacaccc gccagagctc
tgggatagag actctgtgtt 7980agggaatgga gcctacagct tccatcaggt gctatgtttt
aattcacatt ttctattcct 8040cttttctcat ttgtctgggg tgattctttt ggacaaaaaa
aaatgttatc ttttataatt 8100actaattagg atacaaacgt taaaatatat ctataatgta
ctcttgtata tcattcataa 8160tacctatttc gtattatact tccttatagt atatagcata
ttttgataac aaggtcacga 8220ggtcccaggc ctggaaccaa ctttttccta tgtaattggt
tgaagttact gacaccgtag 8280tagacttagc cctctggaaa cagcctttgg caatgaattt
gactctgttt cagacaacca 8340tcactttcct ggaaacggcc tctggcccat tcattacata
tttcttgccc atctgtgaca 8400cgctctgggt acaatcagca tgactcacta agagggtgtt
cccgtttgct tctggtttct 8460gtgagaaaac aaacaaaagc aactctggga ggcaagggtt
tattcagatt ataagtccct 8520gtcacagtca atcgctgagg gatgccaggt caagagctca
agcagggccc tggatgcagg 8580aagcagaaat cagagaaatg atgctctgtg gcttcctctc
aattcacacc tcccgggacc 8640acctgcctag ggatggcccc acccatagtg ggctggacct
ccctccatca atcactaatc 8700aagaaaacac cccacagatt tgtctacagg ccgatctggt
agagacaatt tctcagtgaa 8760ggctccttct gacttaatgt caagttggca aaaactaaca
ggcacagatg ggaaccagtc 8820ataacagtgc tctgtacagt tctcccattg ctctttagaa
tggtctcaca tggcctctca 8880caatgctcac acagcttctc ctgggaattt aatgcccctt
gcttcaactt ctctttgctg 8940tgccatgatg ctagcctttc ctatgtccaa tcccccaccc
acatccactg aggttcttgt 9000agactagaac cttccacatg agacagacta ccttaaccct
tgtcttaggg gtaggctggc 9060agggttacta tttctataaa acatactttc aattccattt
taacgtttca tatgtattat 9120atatatttat attatcaatg tagtgatgct aaatagacaa
acagatgact taagtcttaa 9180tgatgatcct ataagaattc ctaaaatata tctgtggtta
ttaagctctt ttatagtggg 9240acagccatta agtccttttc taattgtcaa aactgcaatg
agaactctgc cagtctccca 9300agtgtctcta gttaattgct attagatcgt aaccagactt
tctcctactc agagcacatt 9360ccaagcggtt gtaagacaat cagtcaaagt ttataaaaag
ggacaattta tatatatcct 9420gctaggacag aagataaaat attggctggt tttgtcgata
ctaagcttca ctaataactt 9480agttatggtt tgaacccttc agtgaacagg gtgatggatg
ttgagcagga tttttactcc 9540tcatggatat gcatgtaaac tttctctgtt gtaaacttat
atatcaattt atgatttgat 9600ttttgtgtgt gaacttgtga tgaactttgt aacatgtgat
cattctgaaa gatgtataag 9660tactaaggac aaagagatga gaggcagata gagttgaatc
cccccccccc ccccccaaga 9720atcaatcatt tcccttccta gaatttttgc tcctgtagag
aatttttcac tttccccact 9780taggatcttt ctgcctttcc ccttagttag ctttcgtagg
aaacttttta caacttagta 9840ataaatgcta taatcatttt tcgaagtgtc cccttttctt
cctgtgactt ccgactagca 9900ggccgaaagt tagagtggaa cagcttctgc tgagatagtg
cgaaggctat ctactttatc 9960ctttgctgtt tgaggaagat gtgctaagtg ccagagactg
cagtttctgg cctccgagga 10020acacagaagg caggtcagct acagtagcat cgagaagaac
ccaacaagaa agaagagctc 10080catgccaggg ctggcagcat tcctatgttt tatgtaatat
ttactgctga gcaggggata 10140atatctgaca tcatatgtta cttatacatt tttgttgatt
aaaaactata ataatcatcc 10200cttctcagca cccacagaaa accaaggcat gtggatctct
gtgagcttgg ggccagcctg 10260gttcacatgg tgagttccag gtcagctggt gttacataac
atgaccttgt ctcaaaaata 10320taataataat aacaataata atacaatatt atatatttta
taataaataa taacaatcac 10380tagtattaaa ataaaaataa aagaaaatat aaaatcatgc
ttgttaaata ttgctttata 10440ggacattatt tgactgtctt ttaacctggc aaatacccat
cagcattctt tctcaaaact 10500cagtaccact cgaggcctcc ttgacccact gtctcggtta
ttcagcacta atgatctaag 10560tgtatttttg gcacacagtt catattgtag acagcacttt
gtaatttttt tcttttatgt 10620ttactttttt tttttaactt ggataaataa gtataggcca
ggacatttat ctgtaaaaag 10680aaaggatgtg tattggaaag tttctatgag ctttgtgtca
gaaggggttt ggcctggcca 10740ctgaccacat gtgctaggga gggagagtta acctcccctc
tccccatggg gagccttagc 10800tgtttattct gttgctgtgg taagatgtcc tggtaagcaa
cagaggcagg gagggagggg 10860tttgtttggg ttcacagttc agcagaagcc acaggtggcc
tgaccttaag gcatctggcc 10920ttgtcgcacc cacacccaga gccacgggga tcttagctgc
cgttctcatc gttccatagt 10980ctagggtcta ggcccatgta atgatgccac ccacagccat
cctaactaga caaacaacca 11040ctcagagctg tgcccagagg ctcacctctc agtcattcca
gaccccgtta aacagacggc 11100cagtactaac tgttacactt tctgtatttc agtgtgggaa
gaacaaaaga gaagcctcat 11160ggcacaaaca cccaccgatt aagacaagca tcagcatgaa
gactagaaac aatattaaac 11220aatattaaaa gtgactttgg gaagagggga aatttttaag
tatgatttaa gaccagaaaa 11280cgagtgagat gtggtttgtt tcattattcc attaggaaca
gctatttaaa atacacataa 11340aggacaccat acctgggata tatactgggt tttagtctgg
actaaaggat gacacttggt 11400ttttaaacaa aggaaaaatt gagtgactaa agcttatgaa
aattgaactt gcagaaatct 11460aaaaatttaa atctagaata gtaacaaatt gatatcatca
attcgggagt tacatagatc 11520acctaacaaa ccacattggg acctcctaag tgttatcatt
ttagacaaga gggtaagaat 11580cggggtactc tttcgtctac tttagagagt tcatgctttt
ttgaatgccc tgttagcaat 11640gttgatccag aagactacat catcttcttc tttatgaatt
gggaagccag caacaaagca 11700actgagtagc aaaggcttat tcttggctaa gaataggaga
catgagaaac aaactcacaa 11760gttcactccg cgatctgttg tggttatagg cataggatca
aggagttgag tgggaaggag 11820aggctagtaa tcaggggaca tattgttact gggagacatg
ttcaagtatt tcctaagact 11880aggtggagat ttcccaggaa atccatcaat atatcttttt
caactatttt aaaaacttca 11940ctcatttatt ttagtatgtg tgtgaaaaag agacagagat
atatagagag agaaaggggg 12000agggagggag aaggagacgg ggaaagaaag acagggagat
agagagacag agaaaaaaga 12060cagagggagg aatgggtaga gggaaaggga gagagagaag
agggtcagag agaggggggg 12120agagagagaa agaaaagggg gggaggggaa aagggagaga
gaaatagaga cagagaggga 12180gggagggaaa gaagaaggaa agggggaggg ggagggggag
agagagaaag acacacacac 12240acacacacac acacacacac acacacacac acacacgggg
gtggggggag agagaatgct 12300gatgtcatag tgtgccactg gagatcagtg gacaactgtc
tcaggaacta gttctctcct 12360gccaccttgt gggatgcagg atgaccttag atcctacctg
ctggctagcc tacctttccc 12420atcttttatg gatctttctt gtcagaaacg aatgactgtg
atgttactga ggttggttgg 12480catggagcat gcaatgtagg tgttatattg tgaaggtaga
ggtgtttagc agtcactccg 12540gcacttatct gagacccaaa taattctggc caacctacct
gaagagcaac ctctggccta 12600tactatcttg ttataaaagg aaatcagatt aaagccagga
agacattctc taggctaact 12660aggaagactt ctctctcctg ccctctacac tgaaacattc
ctctttaaaa aaattatgtg 12720tctttggaat tattattatt agtattagta gtagtatttt
ggttgctatt gttgcacatg 12780ttaagcaatg agctaacatt tcccatcatg cctaccatca
tataaatgtt aggtttgagt 12840tcggggctaa gcagaccaca tttccatgtc atcttacagg
tacttgcagg cccaccatag 12900aacagttgta gaactctgac aaacttccag agctccgctg
aacttcagaa aatactgaat 12960cccagaggtc ccacaagtct ctatcctcct ctctgcagaa
ccctcagagc tgattctggg 13020cttcctggtg ctacacggaa atataaaaca acccgtctga
atgtatcaga caaattccct 13080agataaccag acggtagaga gcaatggcta agtcacatcc
cccagggatg ggggaacctc 13140actaattaat taaatggtaa atgtggtagg tacatgtacg
aactgacatc aaagaagatg 13200catgctgtct aaccagaaac ttgcctggtg ctactgtctc
tagtatgata aatttaaatc 13260tgacagttag gagtaaccaa tataattctg tactttcttc
agtctctaga gcagagactc 13320tcaacctgtg gtttgagacc ccctttggag cttgcatatc
agagattttg catagccaat 13380atttacacta ttatttgtaa cttgtaacaa ctttacagtt
atgaagtagc aacaaaataa 13440ctttatggtt gcgggggggg gggggtcacc acaacatgag
gaactgtatt aaagagttgc 13500acacggtatt aggaagggtg agaccccgtg ctatagagga
aaggctggaa agtcaaatgg 13560tttttacatg agttgtagtg ctgcctaaga ggagtgttta
gcaatcttct gggtaagact 13620caaagagacc cagaagccta gcaatacccg tggtagaggt
gtcacctcct actcaaatgg 13680gttgtaaaac acctttcaaa ctgctctcct ctcttctgga
ttactggcaa gccttggtcc 13740ctgtctgtgg ttgtcagact caggctgtgt caatcactta
gcggatggat aactggctac 13800agagctccac cagaaggtca gcttccgtat gtctggggtg
aggaccagga gcctgtgggt 13860tgaatcgttc ccaagggata aaagtactgt ggacgctgag
tgcactcgga tgctttgtgg 13920ttgcgtttgt ctgttgagct tacagcagtc catgcatgag
acattggaaa caaagagctg 13980cagccttcct ctgggatcta aggggaaaga atagactgca
gcctagagtc ttggttctca 14040gaaatgaact gtttaaggtt tctcacgtaa gctaggaagg
cagagcccag ctaggtttca 14100tttaattatg atgggattcc ttatttaggt accaaagaag
gaaaaggctc ctctggtgat 14160ggttagtgac agcttctttt ctgggtccca gccaatcaag
ggggcatctg agttctacag 14220actttaagtg cgtgattttt ctatttcaaa gtaaacacga
gatattctag cccagcattt 14280gagtcactat gttcaaatat attctaaaat gcccagatca
caccagcgag attaagtaag 14340ttggcagttc acagatacat caacatgaat ctatctttct
ttctttcttt ctttctttct 14400ttctttcttt ctttctttct ttctttcttt cattcattat
ctatttatct gcctacctat 14460catctatcta cctacctagc tatctagcta tgtctatctt
ccagtccgta aatctatctc 14520tgtgcatcta tctatctatc tatctatcta tctatctatc
tatctatcta tctatctatc 14580tatctatctt tcattatcta tttatctgtc tacctatcat
ctatctacct acctagctat 14640ctagctatgt ctatcttcca gtctgtaaat ctatctctgt
gcatctatct atctatctat 14700ctatctatct ctatcattta tcaaccatct ttctatccat
catccatctc tctctctctc 14760atatctctct catatatata catatgcata tgtatacgag
atcctttctc ctgaggaagg 14820agtcaagatt cacagtccta ggcaagtgct gtactcctgg
gcaatagggc agcctttgct 14880tttattctta gtctttctct tgatgccaac caaatgcgta
tcagcttcaa ttctgctctc 14940ttcagctgtg tacctgcagc tgtttcctgg agaaaatgac
accatcaacc atttctctcc 15000aggacaaagg ctgggtgggc tgggaggggt gcgggtggag
tgagtgcagg acaggagacc 15060aaaggctgaa ccagatgacg gtcttgccca gaacgcctcc
acccgtccag aactacagcc 15120gctgctcccc atgcagtttg actctgaaag tataacaacg
taaaaacaga attctaggcc 15180tttaggccca ggcttgagaa tgtggccttt gtaaaggtat
gctaatcata aaagagatag 15240cgacattcct ctacccaccc gcttcctggg ttcaaagagt
gctcattcaa agaaagtcac 15300cctgaggatt accagaacct gcaatgcaaa tgtgctattg
ttagaggctc ttagaagctg 15360tcttgagagt taacacttac caggtattcc ttgtgactct
tgtaacttta cacttccttg 15420tgactcttaa ctggtatctt tggtatcttc caacaatgcc
ctccccactt ccttgagttt 15480cggtttcttc ctttaaatac ccccttaccc agctactcgg
ggtgccacgg tcctctaccc 15540ctgcgtggtg tatgaccatg ggcccgagag cgcttttgaa
taaaaatcct cttgcaattt 15600gcagcaagac ccgtttcttg tgggtgattt tggggtgtcg
cctctcctga gtcagaacgt 15660gggggagccc tcacattgtg ggtctttcaa ctcgaggctt
ccagttcgtc ctgagttact 15720ttagagtcaa agaaagaaaa gggaagatta aatgaagttc
aaaacctcca cagcgtatgg 15780caagatgttg gaaatactag ggatgcaagt caaccaggag
ttttagccca gaatcacagg 15840agatctagat gttcatgacc ccgaccccca ccccctaaac
ccaacttcca cccccacccc 15900cgccacccca acagcaacaa gaagtgacac gtgggtctcc
tgttgatctc tgcctctcca 15960gagctggact ttcaagtgtc ctggcttatt actgtccctc
tgtgttgtca catttgctca 16020gggtcagctc tcctctcctc ttcccggttc ttagcataac
gcttattcct ctctgtagtc 16080tcacagcctg atctttaccc ccagtgagct gagaaactgg
atccatggga agctaagccc 16140ctcacttctg catctgccag gatgcatctc cttctccgct
cctcttcttc ctcatgcctt 16200gctgcctctg tgtcccccgc ccccctcttc ttcccagtgt
tcctcttcca gcagcagacc 16260atgaactcca tactgctctt atccctagaa gacctctgta
aaagcaggtt ccctttcatt 16320gatgtctctc ctaaaaagtc catcacatcg ccccacactt
ccccagcaca ggaccatttg 16380gacttagctt ccaagatcct gttctcagtt tcaatagcaa
aggtgtagag aaactggcat 16440gaacctcttt gtgttgcttt gtctctaagg gatggccttc
ttttaactct tgccttggac 16500tgggctcagt gggccctcct caatccgtgc gaatcagagg
acagatgggc gccgtagagt 16560cggcgagtga caaacagaaa cggcggcgag tgtgtagaat
ctgagtgtat ttttacaaag 16620tgaacaccag tcttatatag tacagaaaat aaagggatag
gatgtcacag caggcaaagt 16680acattgaagt tacctgacac aaaacaaagt aatgacttca
aaaggacttt caggaaccag 16740gtaatagtta cagtaaagat aaaacagctc tgcttagggt
cagctaagga caggtaagga 16800tttcacaccc tactcacaat ttgtgctact cctttgaacc
ttgtgaaagc tagcaccagg 16860gagttctgct ctagcagacc ttctcatgaa taatgcaata
ccacaaaccc cctatttcct 16920aggacttgat aaattctttc atgagtataa cttggctgtt
cttttaagta tctgtgggga 16980agctccattt gtcagaagaa ttcaccaact tgcttctaat
atgcaatgta gcctgctata 17040cctggctgta caagattcct gtctcagtgg gattctctaa
ctctttcatg gtaaacccac 17100ctattagcta ggccatggtg tattcccttg tttgggttag
acttggctac tgtcctaagt 17160cctaagtaat caccctgcag accagccctg agctattcta
gctctgttct ttgtaatgcc 17220taattagttt caccatttct actagaagta aatttgaatg
ttactgaata ggtaacattc 17280tcactgaatt tctactgaat tccaagctcg tcggcttcaa
gaattttcta ggacgttgga 17340acactggtgg aggcttacct atgttaaaat tcaaccttta
aaggcactta taataaaaca 17400atactaaaag agagcatgtg catccatata ccagactaac
acggggatag ggtatgagta 17460tacaggttat gagaatgcca aggttctagg aggttgagtt
tccttgaaac tctttgcctc 17520catgagtgct tccaggcctc tcggcctgtc aagcagactt
cactggagtg ggtatagcaa 17580actctgtatc gatgcccttg atcttctgat tattgccttt
cataaaatta tcttacattt 17640tgactgccat atggtctttc tctatggctc attgaacccc
gagagtgttc tttttatctg 17700tgccagtgga gtcagttcct gtgcctacct tgtaaatatc
cccagtgtgc taatctaggc 17760tttccttggt gtttcggttt gcataacctt aagaagcact
ggccacactc tgtgctttct 17820cttttagtga cttctgagtc acacttcttg gcacatcatt
tgaatttcta cagaagtgga 17880agctgaattg attgagaact agctttttgc ctactctgat
ctctacttgc atttcctgta 17940tgtgctctga cccattgcat ggctgctctg ttcataaaca
cggtcatggt tttcacccca 18000tttcttcata actcagaggc cctatgggct ccatccatgt
tttgtgtaca attttttatt 18060tttttatttt attttatttt ggtttttcga gacagggttt
ctctgtgtag tcctggctgt 18120cctggaactc actctgtaga ccaggctggc ctccaactca
gaaatctgcc tgcctctgcc 18180tcccaagtgc tgggattaaa ggcgcgcttg accaccgccc
tgcttcctgt acattttctg 18240aaaggccaaa tcaccttctt ttgcaacgca tacagctttc
cgctgagatc gcccaggtct 18300gttgcttgtt ttcagaagct gacacagaca atgggagtgg
aggagtttca gtacaagtcg 18360attcatagag atagatgcag cctaactggg cagcccaagc
cttcaattgc agctatgctg 18420gaggctgaag cagggggacc tcaaggtcaa cggcagcctg
agaaactcac agagactgtc 18480tcaaaataaa aaatatatat ataaaataaa actatacact
tgactcttat ctacaatgta 18540gtacgtggga ggaggctgag gtcgaagact gtgagtttga
tcagcctggg ctacatagca 18600aacatctgcc tcaaaagact ggaaatacaa aactaaaagt
gaagaaaaga gaagccacgt 18660tcagacttca aaaccaggct ccattgtcat gtttctggga
ctattcccta tccattccca 18720gagtagactg acagaattag cccccacccc ttctcgagcg
tctcaagccc acacctgagc 18780atagagcatg tgatttacat ggggatccat ttttcctcca
cttctcccct cccgtgttat 18840atgatcggag cctaaggtct gtaaccttgt cagctgcgtg
tccgtgtggc tagtctagcc 18900taaggccagg cttgccggaa gttctcttgg cacacctggg
ttgacttgac ttctcctgaa 18960gagcattcca aagctgctct ctgtaaaatt ctcagctgtt
tctatttgaa atgcaggaag 19020cacttccaga tcattacaag ccttggatgg aaattgccct
cagacttcct cacttaatcg 19080agaaccgcca gctccgagct cacgtgtaca gggtacgtcg
atttgttctt tgcttcatgc 19140tcctcctctc cccacccgtt ccgtctccat atccctttcc
ttctcagctc tctgggagtg 19200aaacggttga cctggcagtg ggaaccgact gtcaccactg
aggctttcag caaacctgtc 19260ttccttagtg cgcacaaaca gcacctgaga tgtgtcaagt
cctcatcgtg tttgtgcaaa 19320agacgatgat agatgagact tgaaaataaa ttctggggaa
acgaggaaga cacacattgg 19380agattggtgg gagccgcttg gcctgcttct gtaaaagcct
gcctgtcagg cagagtcaag 19440ccaggggctg aatgttctgt taatctcgga ggaaggaaca
cggaggaata gaggcctctg 19500gatgagtaca gatatcagat atacatcagc cgctgtctct
gctggcttgt gactttgctt 19560cccgtgatac tacagagtat ataaagcctt agagaattaa
actcaaggct gctgcagcac 19620tgactggata gccttcccgg tttttaagct ttgtttctga
gtcttctttt ccatctctcc 19680tacaatcctc actcacccct cagaagacct gttcaacttt
gtactggcag gaccggcagg 19740ggagatgctc agtggacttg tcccaagtca cgtggtcact
gctctgcttc ctctgggcag 19800gtaccttgac cttagtgtgt tacatactag tcagatcaaa
tgtctttctg atttttaaac 19860tcagagtcag tcttggctat gtagaagaag tgaaatccat
agacaccaca ttagaatctg 19920catgcaccta agtatatgac gcacgtctgt gacagagcga
gcaatttccc tccaaaagga 19980ataagaaaaa tatgaccccc acagaagaca ttcttccatt
caggaatttt atagtaagtg 20040tgaaacggag agttggcctc agaatcttgc ttccttcttt
gagaaatgga tgaagttctc 20100atttaatggt tgtgagcatc aatggctttt gtaaggaccc
tccccctcct catcttcatc 20160tgtcacaagc acaccacaag atgtcagatg ttcaagcaag
gcgctccacc ctccaggacc 20220ttctttgctg atgcttaatg tccaattatg agttgatttt
taaaaatatt cattgaatga 20280tccttatagc atattcagaa atcaggacag gcagctggcc
ttggtaatac tctagataac 20340cccccctctg aaccccccac tgaggctgaa gaccatgtaa
gaaagtgcaa ctaaaggagt 20400taattgttgc acaaaactca cacaaagcct cacaaaggta
gtttgtacac gctgttgaca 20460cattacacta acaaaaacat cgaggggaaa aaagatggga
aacagtagaa gataataatt 20520aatggtgacc tatggcctac acacacacac acacacacac
acacacacac acacacacac 20580acacacacat gcacacatca ccacacacgt gtgtatgcat
atgctcacac atgtacaaac 20640atatatcacc acatatgtga cacacacata cacactcata
tcaccacaca catgtgtaca 20700cacatgcaca cacacacatc accacacaca tatgcataca
taggaacata tagtacacac 20760atatcaccac atagatggca cacacacact cacataccat
cacatatatg catgcatata 20820gacatgcaca cacatgcccc cccacacaaa cacacatata
tgtacaaaac ctatagtgaa 20880cacactaccc tgagtcaagc tatgagtttt aagaacatac
atactgtccc ccaaaactcg 20940tcacaaggtg ttttgtcctc aaagggaaag ctcctctcta
tctaactgat gtctagaacc 21000cacaaatatg ttagttgtgt accagagggg acggcgggtg
gttagttagt agagggtctc 21060ccacaaaccc atgtgtctgt cttcatccac catcttttac
actgatgaat gagttactag 21120ccagtaactc atgcagtgag gcaaagcagt tatgatggtt
ctgggtgaca agcaagtgaa 21180gagtattggt gaggatacta agcacgcgca tgcactttgc
tacaactagt ctgtcatgtg 21240aactgccatc tcacagaaac attcatacaa aaaaaagtgc
agatgaatat gcaaagctgt 21300ttgctgtagc cactttcata gcaacggtaa atacaatgta
acagaaatac aatgtaacag 21360aagacaggag agcagaagga gaagcccatg aatctccatt
cacaaatata tctgttacat 21420aaatgaaaag ggacagatat taagtggtca cgtaggcacc
tgcctgtatc cttccgccac 21480gctacacatc tttgctctgt agtttactga gcattaggaa
gttcgcgaca gtatctatat 21540gcagaattat tgaacctcta cttcaacaac atgtgcatgt
gagcttaata tttatagatg 21600atagaggtag aaatagacat atttactatc tgacagagtc
ctaacatgta gcccaggatg 21660gctttgaatt agacatcttc ctatctccgc ctccagagtg
ctggtatcag tcttcataaa 21720gacttctata tgaaaacaaa tgtcctgttt tctatgtatt
cgccttcgtg tcaaactata 21780cttttcaaga agttcaagaa gtgatgtcca caagaacctg
atgtgtgtca gaaacactca 21840gctccccagt gaagttggca ggagggctcg cctggttcag
agaagccttg cgtgctccct 21900gagttctgag aggagagtat cgaggttaat tctcccaggt
taaatacgca atcaaataat 21960gtcagggaga tgacgggtgt gtgtcgtcct cccagaccat
ctgtgactgt ttgagtaagc 22020aaaaggattg actaaaaagc tatcatttcc ttttcagtcc
ctacagtcac ttttgaatca 22080caggtatgtt taggaggtga ggccaacaat cctgaaatgt
gcagggactc tccagaaagc 22140agtcatcatc ccctggacct cgttccttta caccgaggcg
tcctggcttg taggtggcct 22200tcttcaacaa ctgaggggtg acaaggacaa agcctgagaa
gacacagcct agattgtgaa 22260gactttgaaa gatttttata ctgactgcat gctaaaatat
cttttatacg ttgactcaac 22320aaagtacatt atcagaacta attttacttc ttgtttgcct
taaaaaaaaa aaagtggctg 22380ctgaaagtat acgagatcct ttctcctgag gaaggagtca
agattcacag tcctaggcaa 22440gtgctgtact cctgggcaat agggcagcct ttgcttttat
tcttagtctt tctcttgatg 22500ccaaccaaat gcgtatcagc ttcaattctg ctctcttcag
ctgtgtacct gcagctgttt 22560cctggagaaa atgacaccat caaccatttc tctccaggac
aaaggctggg tgggctggga 22620ggggtgcggg tggagtgagt gcaggacagg agaccaaagg
ctgaaccaga tgacggtctt 22680gcccagaacg cctccacccg tccagaacta cagccgctgc
tccccatgca gtttgactct 22740gaaagtataa caacgtaaaa acagaattct aggcctttag
gcccaggctt gagaatgtgg 22800cctttgtaaa ggtatgctaa tcataaaaga gatagcgaca
ttcctctacc cacccgcttc 22860ctgggttcaa agagtgctca ttcaaagaaa gtcaccctga
ggattaccag aacctgcaat 22920gcaaatgtgc tattgttaga ggctcttaga agctgtcttg
agagttaaca cttaccaggt 22980attccttgtg actcttgtaa ctttacactt ccttgtgact
cttaactggt atctttggta 23040tcttccaaca atgccctccc cacttccttg agtttcggtt
tcttccttta aataccccct 23100tacccagcta ctcggggtgc cacggtcctc tacccctgcg
tggtgtatga ccatgggccc 23160gagagcgctt ttgaataaaa atcctcttgc aatttgcagc
aagacccgtt tcttgtgggt 23220gattttgggg tgtcgcctct cctgagtcag aacgtggggg
agccctcaca ttgtgggtct 23280ttcaactcga ggcttccagt tcgtcctgag ttactttaga
gtcaaagaaa gaaaagggaa 23340gattaaatga agttcaaaac ctccacagcg tatggcaaga
tgttggaaat actagggatg 23400caagtcaacc aggagtttta gcccagaatc acaggagatc
tagatgttca tgaccccgac 23460ccccaccccc taaacccaac ttccaccccc acccccgcca
ccccaacagc aacaagaagt 23520gacacgtggg tctcctgttg atctctgcct ctccagagct
ggactttcaa gtgtcctggc 23580ttattactgt ccctctgtgt tgtcacattt gctcagggtc
agctctcctc tcctcttccc 23640ggttcttagc ataacgctta ttcctctctg tagtctcaca
gcctgatctt tacccccagt 23700gagctgagaa actggatcca tgggaagcta agcccctcac
ttctgcatct gccaggatgc 23760atctccttct ccgctcctct tcttcctcat gccttgctgc
ctctgtgtcc cccgcccccc 23820tcttcttccc agtgttcctc ttccagcagc agaccatgaa
ctccatactg ctcttatccc 23880tagaagacct ctgtaaaagc aggttccctt tcattgatgt
ctctcctaaa aagtccatca 23940catcgcccca cacttcccca gcacaggacc atttggactt
agcttccaag atcctgttct 24000cagtttcaat agcaaaggtg tagagaaact ggcatgaacc
tctttgtgtt gctttgtctc 24060taagggatgg ccttctttta actcttgcct tggactgggc
tcagtgggcc ctcctcaatc 24120cgtgcgaatc agaggacaga tgggcgccgt agagtcggcg
agtgacaaac agaaacggcg 24180gcgagtgtgt agaatctgag tgtattttta caaagtgaac
accagtctta tatagtacag 24240aaaataaagg gataggatgt cacagcaggc aaagtacatt
gaagttacct gacacaaaac 24300aaagtaatga cttcaaaagg actttcagga accaggtaat
agttacagta aagataaaac 24360agctctgctt agggtcagct aaggacaggt aaggatttca
caccctactc acaatttgtg 24420ctactccttt gaaccttgtg aaagctagca ccagggagtt
ctgctctagc agaccttctc 24480atgaataatg caataccaca aaccccctat ttcctaggac
ttgataaatt ctttcatgag 24540tataacttgg ctgttctttt aagtatctgt ggggaagctc
catttgtcag aagaattcac 24600caacttgctt ctaatatgca atgtagcctg ctatacctgg
ctgtacaaga ttcctgtctc 24660agtgggattc tctaactctt tcatggtaaa cccacctatt
agctaggcca tggtgtattc 24720ccttgtttgg gttagacttg gctactgtcc taagtcctaa
gtaatcaccc tgcagaccag 24780ccctgagcta ttctagctct gttctttgta atgcctaatt
agtttcacca tttctactag 24840aagtaaattt gaatgttact gaataggtaa cattctcact
gaatttctac tgaattccaa 24900gctcgtcggc ttcaagaatt ttctaggacg ttggaacact
ggtggaggct tacctatgtt 24960aaaattcaac ctttaaaggc acttataata aaacaatact
aaaagagagc atgtgcatcc 25020atataccaga ctaacacggg gatagggtat gagtatacag
gttatgagaa tgccaaggtt 25080ctaggaggtt gagtttcctt gaaactcttt gcctccatga
gtgcttccag gcctctcggc 25140ctgtcaagca gacttcactg gagtgggtat agcaaactct
gtatcgatgc ccttgatctt 25200ctgattattg cctttcataa aattatctta cattttgact
gccatatggt ctttctctat 25260ggctcattga accccgagag tgttcttttt atctgtgcca
gtggagtcag ttcctgtgcc 25320taccttgtaa atatccccag tgtgctaatc taggctttcc
ttggtgtttc ggtttgcata 25380accttaagaa gcactggcca cactctgtgc tttctctttt
agtgacttct gagtcacact 25440tcttggcaca tcatttgaat ttctacagaa gtggaagctg
aattgattga gaactagctt 25500tttgcctact ctgatctcta cttgcatttc ctgtatgtgc
tctgacccat tgcatggctg 25560ctctgttcat aaacacggtc atggttttca ccccatttct
tcataactca gaggccctat 25620gggctccatc catgttttgt gtacaatttt ttattttttt
attttatttt attttggttt 25680ttcgagacag ggtttctctg tgtagtcctg gctgtcctgg
aactcactct gtagaccagg 25740ctggcctcca actcagaaat ctgcctgcct ctgcctccca
agtgctggga ttaaaggcgc 25800gcttgaccac cgccctgctt cctgtacatt ttctgaaagg
ccaaatcacc ttcttttgca 25860acgcatacag ctttccgctg agatcgccca ggtctgttgc
ttgttttcag aagctgacac 25920agacaatggg agtggaggag tttcagtaca agtcgattca
tagagataga tgcagcctaa 25980ctgggcagcc caagccttca attgcagcta tgctggaggc
tgaagcaggg ggacctcaag 26040gtcaacggca gcctgagaaa ctcacagaga ctgtctcaaa
ataaaaaata tatatataaa 26100ataaaactat acacttgact cttatctaca atgtagtacg
tgggaggagg ctgaggtcga 26160agactgtgag tttgatcagc ctgggctaca tagcaaacat
ctgcctcaaa agactggaaa 26220tacaaaacta aaagtgaaga aaagagaagc cacgttcaga
cttcaaaacc aggctccatt 26280gtcatgtttc tgggactatt ccctatccat tcccagagta
gactgacaga attagccccc 26340accccttctc gagcgtctca agcccacacc tgagcataga
gcatgtgatt tacatgggga 26400tccatttttc ctccacttct cccctcccgt gttatatgat
cggagcctaa ggtctgtaac 26460cttgtcagct gcgtgtccgt gtggctagtc tagcctaagg
ccaggcttgc cggaagttct 26520cttggcacac ctgggttgac ttgacttctc ctgaagagca
ttccaaagct gctctctgta 26580aaattctcag ctgtttctat ttgaaatgca ggaagcactt
ccagatcatt acaagccttg 26640gatggaaatt gccctcagac ttcctcactt aatcgagaac
cgccagctcc gagctcacgt 26700gtacagggta cgtcgatttg ttctttgctt catgctcctc
ctctccccac ccgttccgtc 26760tccatatccc tttccttctc agctctctgg gagtgaaacg
gttgacctgg cagtgggaac 26820cgactgtcac cactgaggct ttcagcaaac ctgtcttcct
tagtgcgcac aaacagcacc 26880tgagatgtgt caagtcctca tcgtgtttgt gcaaaagacg
atgatagatg agacttgaaa 26940ataaattctg gggaaacgag gaagacacac attggagatt
ggtgggagcc gcttggcctg 27000cttctgtaaa agcctgcctg tcaggcagag tcaagccagg
ggctgaatgt tctgttaatc 27060tcggaggaag gaacacggag gaatagaggc ctctggatga
gtacagatat cagatataca 27120tcagccgctg tctctgctgg cttgtgactt tgcttcccgt
gatactacag agtatataaa 27180gccttagaga attaaactca aggctgctgc agcactgact
ggatagcctt cccggttttt 27240aagctttgtt tctgagtctt cttttccatc tctcctacaa
tcctcactca cccctcagaa 27300gacctgttca actttgtact ggcaggaccg gcaggggaga
tgctcagtgg acttgtccca 27360agtcacgtgg tcactgctct gcttcctctg ggcaggtacc
ttgaccttag tgtgttacat 27420actagtcaga tcaaatgtct ttctgatttt taaactcaga
gtcagtcttg gctatgtaga 27480agaagtgaaa tccatagaca ccacattaga atctgcatgc
acctaagtat atgacgcacg 27540tctgtgacag agcgagcaat ttccctccaa aaggaataag
aaaaatatga cccccacaga 27600agacattctt ccattcagga attttatagt aagtgtgaaa
cggagagttg gcctcagaat 27660cttgcttcct tctttgagaa atggatgaag ttctcattta
atggttgtga gcatcaatgg 27720cttttgtaag gaccctcccc ctcctcatct tcatctgtca
caagcacacc acaagatgtc 27780agatgttcaa gcaaggcgct ccaccctcca ggaccttctt
tgctgatgct taatgtccaa 27840ttatgagttg atttttaaaa atattcattg aatgatcctt
atagcatatt cagaaatcag 27900gacaggcagc tggccttggt aatactctag ataacccccc
ctctgaaccc cccactgagg 27960ctgaagacca tgtaagaaag tgcaactaaa ggagttaatt
gttgcacaaa actcacacaa 28020agcctcacaa aggtagtttg tacacgctgt tgacacatta
cactaacaaa aacatcgagg 28080ggaaaaaaga tgggaaacag tagaagataa taattaatgg
tgacctatgg cctacacaca 28140cacacacaca cacacacaca cacacacaca cacacacaca
cacatgcaca catcaccaca 28200cacgtgtgta tgcatatgct cacacatgta caaacatata
tcaccacata tgtgacacac 28260acatacacac tcatatcacc acacacatgt gtacacacat
gcacacacac acatcaccac 28320acacatatgc atacatagga acatatagta cacacatatc
accacataga tggcacacac 28380acactcacat accatcacat atatgcatgc atatagacat
gcacacacat gcccccccac 28440acaaacacac atatatgtac aaaacctata gtgaacacac
taccctgagt caagctatga 28500gttttaagaa catacatact gtcccccaaa actcgtcaca
aggtgttttg tcctcaaagg 28560gaaagctcct ctctatctaa ctgatgtcta gaacccacaa
atatgttagt tgtgtaccag 28620aggggacggc gggtggttag ttagtagagg gtctcccaca
aacccatgtg tctgtcttca 28680tccaccatct tttacactga tgaatgagtt actagccagt
aactcatgca gtgaggcaaa 28740gcagttatga tggttctggg tgacaagcaa gtgaagagta
ttggtgagga tactaagcac 28800gcgcatgcac tttgctacaa ctagtctgtc atgtgaactg
ccatctcaca gaaacattca 28860tacaaaaaaa agtgcagatg aatatgcaaa gctgtttgct
gtagccactt tcatagcaac 28920ggtaaataca atgtaacaga aatacaatgt aacagaagac
aggagagcag aaggagaagc 28980ccatgaatct ccattcacaa atatatctgt tacataaatg
aaaagggaca gatattaagt 29040ggtcacgtag gcacctgcct gtatccttcc gccacgctac
acatctttgc tctgtagttt 29100actgagcatt aggaagttcg cgacagtatc tatatgcaga
attattgaac ctctacttca 29160acaacatgtg catgtgagct taatatttat agatgataga
ggtagaaata gacatattta 29220ctatctgaca gagtcctaac atgtagccca ggatggcttt
gaattagaca tcttcctatc 29280tccgcctcca gagtgctggt atcagtcttc ataaagactt
ctatatgaaa acaaatgtcc 29340tgttttctat gtattcgcct tcgtgtcaaa ctatactttt
caagaagttc aagaagtgat 29400gtccacaaga acctgatgtg tgtcagaaac actcagctcc
ccagtgaagt tggcaggagg 29460gctcgcctgg ttcagagaag ccttgcgtgc tccctgagtt
ctgagaggag agtatcgagg 29520ttaattctcc caggttaaat acgcaatcaa ataatgtcag
ggagatgacg ggtgtgtgtc 29580gtcctcccag accatctgtg actgtttgag taagcaaaag
gattgactaa aaagctatca 29640tttccttttc agtccctaca gtcacttttg aatcacaggt
atgtttagga ggtgaggcca 29700acaatcctga aatgtgcagg gactctccag aaagcagtca
tcatcccctg gacctcgttc 29760ctttacaccg aggcgtcctg gcttgtaggt ggccttcttc
aacaactgag gggtgacaag 29820gacaaagcct gagaagacac agcctagatt gtgaagactt
tgaaagattt ttatactgac 29880tgcatgctaa aatatctttt atacgttgac tcaacaaagt
acattatcag aactaatttt 29940acttcttgtt tgccttaaaa aaaaaaaagt ggctgctgaa
aattttcaaa gaaaacccgt 30000gactcattgc atgattctcg tgatcggggc tgtggtcaat
ccgcacgcag aactgcttca 30060atccttcttg attctgtgac ctccgagacg aaaattcctc
tttggttccc gcaggggtgt 30120ttagcctcaa atttcaagtc atcctcttcc ccctagcggc
cggaggagga agggctctgc 30180ataccccagc ccgcccctag gaagccaatg tccccagcgt
tttacaagtg gcgcatgccc 30240tctgaggcaa gcctgcggag caaagggagt gaagtggtgg
cgagagctga agagatgagc 30300aatgagccgg tggcagccag gcaggacagg gaagctggcg
tggtcggatt gtgtactgat 30360gctgtttttc agggtggccc tttccgtgtc accaggagct
gtggtttcca atggggatga 30420agtggggaca gagctgggtg gaaagccccg ccacctcatc
tggctgggct gtggttgttt 30480gagcatcaga gcaagcttta tatccagccg atccatggtt
tttgtggggg actttacatc 30540cctaacctca ctgggtctcg ctgcgttcaa aattttaata
cagttacagg gttcgagaag 30600ctgagggctt ccaggtatta catatctatt aatgctgctg
tgcgggcttg gagggaagaa 30660cttatctcgc cctcaatgct tactctgtga tcctcaaagc
aatagatgga gaccagtgta 30720tggcacaaac tgggcacatc ctaggccatg gaccccagga
cctggcacct cctctactgc 30780attcctctaa gagctggttt aagtgggtgt gcatgaagct
aatagctgca atagctgtgg 30840gaccctcaag tcacgggtcc tggtcctggt cctccaccgt
tgttttttgt tttttggttt 30900ttgtttttgt tttttgtttt ttgttttttt tttttggctt
tgttttgttt tgttttgttt 30960tgttttgttt tgttttgttt tttcagctgc taatcctttt
aatctcttga ctagatgcct 31020ctcctggact gcagattcct aaagagttac cgtgagcagc
gcctggcaca catggcgctg 31080gccgctatca ccatgggatt cgtctggcag gagggggaag
gccaacccca aaaggtgagg 31140agcaaggaga aatcaggctc tgctgaggtc cctgcacctg
gaattacgac accagctcca 31200ggttccgttg cctagtttcc aaaaatcagc ggaaggcaag
aaaagagggt tagatttttt 31260ttttccattt ttcttttctt ttctttttct tttttttttt
cttttgctac ggagctgatt 31320ttcttttaga ctaatgtcca ctttcaaaga ctccagccat
tccaataata tgtgaggagc 31380ttccttaggc cccaaggact cagaaaacac cctgcagaat
tttatacttc taaatacatt 31440ggttattatg actttcataa ttaccccatt gtacagacat
ctggggatct gtcccaagct 31500caaggccttt gtcccagagc agcctgggga cagttgggaa
agccagtttc tgagtccact 31560gaagtagcca tccttctcca gtacaacttg gacacttcct
tatttcctta ttctgcccag 31620ctgattgctg ctttagttta ttaacccttt gtctaactcc
ctccaataac tttctagttt 31680cagtctgtcc ctcagagcac aaaccctttc ttctctaccc
ctggaggaaa ctaatatttc 31740ttttgagtca tggtcttaca aagcagcccc aaaccagtct
agaacctgct ctcttgtcca 31800agttgttctc caacctgtga tcttcttgcc ccggccttcc
aaatgctggc attgcagtca 31860ctccaggcac gtgacaccct gtgcagttat gctcccagtc
agtgttggga tggaatccag 31920gacctgtgtg tgccgagtga atactttatc actcaacagg
acctccgttt tctcttcctt 31980tcccctaagt ttctctttcc cagaaatcaa ggtgttgaca
tcattccaga atgcgtgaga 32040agcccgaggt gtgcttcaag ggctcatctt acccacagag
aaacacttga gaccaagaag 32100caaggacagc acagagctcc tgttccttca gactctaaca
cgataccata ttgtatctca 32160tctaaaggac tcgagtgtct agggtctgct gttggaaagt
ttaaaaccca ggccagtgtg 32220acagaacctc ctgatgagtt ctgctgcata ggccccctaa
accaatctcc tgaattatga 32280gttagagagg aggaagcaat gtccagcccc caaggccatc
ccaggctcat cacccctcat 32340tttggaagtc ttccctgacc ttcccagtgg aagtgtctga
ctcacatctt cccattctcc 32400ccagccctga cttctgtgga tgcttggcag agctctacgc
cctgtaagct gtaactgttc 32460tctacctaaa gcacacctct tccctaactc ggaggaagaa
agaatggcag acacagatct 32520ttagactctt cagtcctggg ctggggagac gactcagtgg
gtaaattggg agcaagcagg 32580ccgagacact gaagctaaga ttcccacaac cagtgagaaa
actggcacag gcagcaggga 32640gcaagagaga ccctgtctca aacatggtgg aaggtgtcaa
ctggagtcca cacattcccc 32700ttggcatgaa tgtgcctaca tttacgtctg tctgtctgtc
tgtctgtctg tctctctgtg 32760tctctctcac acacacacac aaacagacag agagagacag
agacagggag aaatttctat 32820tttagaagga aaatgattgg ggggagggga acataaaaat
gttcttttgt tgttgttgtt 32880tgtttgtttg tttgtttgtt tttacacctc taccagtttg
gcctttccat ggccgggacc 32940tcatggacct gagcatctgc tctggactgt ggacagatag
agatctgtac tcaagggaca 33000ccccaaacgt tagtgggtga aagggtaggg ctatggacag
gggctttgca acctgaaggg 33060tccttggggc gtgagcgaga agcttgtgtt tcagtggagt
cctgaacggg tgttaggagg 33120ttgatgtcat accccaggtc ggaaccctag caaatcatgt
taagagtcag aagagacaaa 33180ggacggtcaa gggggggggg gtctgtcatt gagtgactac
ctgacgttat ggggcttgac 33240tcatgaggtg acacaaacat cagttctgca agctgaaatt
ctctgtcctc tttatccttt 33300ctggggtgcg ctctctatct ctctgtctct gtctctgtct
gtctgtctgt ctgtctgtct 33360gtctgtcttt ctcctatccc cccctctctc acacacacat
atacacacct ctgttttttt 33420ttatctatgt acatctttac ttctattttg catcatgtgc
atctagcctt gtatctatat 33480atagatcata tatattattt ataatctatc atccatctag
aaagcacttt accttgatag 33540ttcttagtct ttgatttaca ttaaacattt tggtgaaata
attctctttc tccttttctc 33600ctccttctcc tcctccttct ttctcctcct cttccttctc
ctcctttttc tcctgtctcc 33660tcttcttcct cctcttcctc ctcctcctct ttctcctgtc
tcctcttctt cctcctcttc 33720ctggtacagt ttccagaggt tctgtttatc atgtgcacag
tgtattccat ctctgggttt 33780tgcatctctt gaaatgtgtt ctcataacca gcattctcac
cgggtctctc ccatgaagca 33840tgtgtagggt ataggtgtgg aacattcaga gaattcgtgc
ttggtctcca ggtcgcttat 33900cacaggcaac cgtgatgatt ttctctgcca gtagaatata
ctaattgtct ggattcctgt 33960cctaaaggtg ctgccaagat ctcttgccat tccttttgtt
gaggtatcca ggaacttggg 34020actcccgcct atcctggtcc actctgacct ggtgctgaca
aactggacca aaaggaaccc 34080agaagggtaa ggagggaaag gattccttca gttagcagca
gattgagaaa agactcagga 34140cttgaactgt cttcgcagaa aagactcagg gtcttagggc
tgttttatag tgagctgtgt 34200gctcccattc atttaattta gggttccaat aaaagggaat
gcacacattt aaacctgaga 34260catttcttct tcctgggctc tcaggcacac tggcttgctg
cttccagtgc ccatctggat 34320ctcttaatca gactgtcagc ctccagctgt aataatgaca
ctgggctgtt ttttctcagc 34380atgttctgtg ttccattcaa gtcaggttag gatggggtgt
ctggaggtga tctctatggt 34440tctgaataaa tgatttcacg tgggtggaat tctgattcac
accatctatt ctgtctagtt 34500tacaccattc cacacttgtc ccgggcacaa aagcatctgt
ttattgactt ttcaacaaac 34560aaccaatcca tggaaacttc attttcacag ttgaatctgt
ctcaggcggt cgacgcaagg 34620cagcatttac ttttgttata aattaaaaca gcaaacaaga
agtccaggct ggacataaag 34680ggacctttct tggcatgctg gttgtaggta gccatgcagt
gctgaaagag atggttgaga 34740tctgctgtgg accctttcaa gagacccttc cttttaagaa
ctggggaggg ctcctcttat 34800ctacagtctg ctgagcctta gaacttcatg ctttctggga
tgatgatgtc atatgacgat 34860gatgtcatat gataatgtta catgatgtca tacgatgttg
atgttgtatg gtgatgctat 34920atgatgaatg gtatcatgat ggcatcatat gttgatgata
agcttgtttg tgactgggga 34980ctgaatgaac cttcacctgt gaggcaggag ctccacccct
gttttctatc cccagccctc 35040tcttcagcgt ttatttagat acagtttctc tcacaatgcc
aaagctgacc tgaaattcac 35100actgtagcat aagcagtccc tgacttggtg atccttagac
ctcctcagcc ccttgactat 35160ctgccactaa cagcatgcac aaccaggcct gacttggtct
ttgaccaatt atacagcaac 35220gaaaaactga tctgcattga aagctactaa atctaactta
gaattggagt aggtgagatg 35280ataaatatgt gcgcctggac tattgtgaag ctgggtttgt
gattcaaggg aaattgggag 35340atgaagtctt aagggaggtg acagggttga aaacaacccc
aggaaatgaa tgtcccatca 35400agtgaggtac agcacccaga gatgcaaatg caagcctgga
gctcccccac cgtatttctt 35460ctgagccatc atcttcctga gtcttttaag atgtctaccc
agggcttatt aagtgctttg 35520aagaaatgaa agaaatagaa gcaacacccc cccccacctc
cacccccacc acccaaacag 35580ttcagtattg agacaaagta gctcttaaca caagtcaaag
aacaacataa acagtatctt 35640cagaactcca gggggaacag cagggaaagc atggtgcctg
accagacgct gatgtaaggc 35700cactcctaac aggtgggtag gattagagta actgaagtgg
ggtctgcacc gagaggcagc 35760tagagagagg caagcaagaa tgtgtacata cacagacaca
cgacacgggc tgtcaagtga 35820gatctggttt ctgctgtcac ccagtggctc actgtccatc
ctaggtgggt cctgatccgt 35880acatgtgcca gggcattgca gatgagtgtg ggagcctggg
tacccgggac ctcaagaatt 35940atatctggtt actaactaag ttgttttctt tttttttttc
tttttctctt tgttatcacc 36000aataactatt atgcgaccag accgttggaa atcaggtaag
atgtgccttt agaaccaccc 36060actgttacct ttaaaggctt gtgataaagc aagagggtgg
catggtcagc tgtatggatg 36120gaatagcatc agctgtctat gaactcctga aaattcgaag
tgcattaaaa agtcaatagt 36180ccaagcagta gctctgatgg aggttagctt ctaggggtgc
agggattaat ttttcttaac 36240cacattttcc tgtatgtcca tgatttaaaa aaaaagtgta
gtgtaagaaa agaaaccgtg 36300gctctgtgaa aactggcaga gatttcttat ttctgaagaa
catcagcaaa aggccagaaa 36360caggcaggtc acagtgacag aagggtccct ttgtaatccc
ttcttacctg atgggctgga 36420gcccttgtga gtaggtgtgg tctatagtca taggctccac
cttccccggg gagcagagct 36480agcagaggag ccagagtcac atcctgcgct ctctctctct
ctctctctca cacacacaca 36540cacacacaca cacacacaca cacacacaca caccctcctc
agctctgtgg agcatacagg 36600tggatggcaa atattcccca ggctaacacc tctgctggac
cgaggagatg tgtgactcac 36660ctccgctttg ctgttttgag gtttgaggct gggctttgct
tatgtttgag atgctgggga 36720caacgcagat gtgtgcagat actcatctgg gttctgtatc
aggtcagatt tggctctgat 36780gggaagacag gacagcagca ggttgattag aaatgacctc
cctcctcctc ctcctcctct 36840tcttcttctt cttcttcttc ttcttcttct tcttcttctt
cttcttcttc ttcttcttct 36900tcttcttctt cttcttcttc ttcttcttct tcttcttctt
cttcttcttc ttccacacat 36960tatattctat ccacagtttc tcctccccta ctcctcccag
tcctcctctc acttctcctt 37020tccctagatc tactcctact tttccaaaaa aaaaaaaaaa
aaaaagcaag cctcctggag 37080ctatcctcca aacctgccct gacatagtta caaacagcag
cccctcattt caaggcttga 37140tgaggcaacc cactaggagg acaaggatcc aaagagcagg
caagagtcag agacactctt 37200ccactcccac tattcggagt tccacaggaa cacgaaacta
cacacaacca caacatatga 37260gcagacggcg taggtcacgc cgatgcaggt tctgtgattg
tcacttcagt ctctgtgagc 37320ccccatgagg tcggcttgtt tttgattccg tgggctgtgt
tctcctggcg ttctcaaccc 37380ctctgactac tgtagtctgt cctgcccctc ttctgtagcg
ttcctggagc tccacctact 37440gtttggatgt ggtaatgaca ggcttccggc cgcggttctg
tggcagcaat tcatccttgg 37500gttagaactc tagtcaggca cgcaggcaca cacccataat
ggtcatagtt ctcaggtcat 37560aggaatttgg ctctaactga tctgattttc ttcttttctt
ggtctcttcc tccagtaacc 37620tggaaaccat catctcattt ccggggggag agagcctgcg
gggcttcatc ctagtgacag 37680tcttggtgga gaaggcagca gtgcccggcc ttaaggtatc
ttcttactca cccggccctc 37740tccctatggt ggttttcccc acgtggacag acagaggcct
cctcctccta gggttgacga 37800tgaagagaca tatctgagtt ctagcctgtg gtgtcagtgc
ccttttagcc tggagtgaac 37860cgacttctcc gtctacaccc aggtaccaca cgctgagtgc
aacagacacc cactgcgcta 37920gctgttccac ttcatggacc tgcagaagct agagactcag
aggtcaaaaa gaaaaagact 37980gttttatgga aaggcagata aaggcatatc catgcatatc
tgtagggatg ccagagtaga 38040aacgactgtg atatgggaaa cccagaagga atgagaaagc
acttgtgttg aggctcttga 38100tgtcacaatt tacgctccag agatattcca gtagtgtggg
ctactccgtg gcgatctgca 38160tcccgcgggg gttttaataa aaaaagttac ttcgtagcac
ctcaactgag aacgtggatc 38220ttattcctag gccctggttc agggaatgga ggccattcgg
caacacagtc aggacaccct 38280gctagaagcc ctgcagcagc tgagactctc catccaggat
atcaccagag ccttggccca 38340aatgcatggt aagatactgg agcagcgtct ccagtggcct
ggacttgggc aggtcctacg 38400tggatgatgg tggtccatct ctccacaaga tggcgctagt
gttctatatt tagcgtaaag 38460cgtcccagtc agagaattgt tttttttttt ttttttccag
tcggcagaaa tatttttttt 38520agaatcgttc tttatagttt cgtgtggttg gggtagcttc
ccttctccag ggtccagata 38580cgactttggc atgctgatct cttaacgaag cctgggagat
tggatgggcc acaaggggga 38640atgttggtta tacaggttag gcttgctggc gggcagggct
gtcccgtggg ggcgtctgta 38700aggccctcaa gagtcatttg cttttcctct ctgaccatgt
tacaaatcca gaaagaccct 38760catgatccgc tgaaggaggt ccaaggaccc ggagagctcc
ccaattagac tccttccaag 38820ccatctgatc ctgagacaaa tttctctatg tgatgacttt
ttttcaaggt tttagaacta 38880gctgtattca cacacgtggc gaaggagaag gacacgtgtc
cacacttttc aaagatggca 38940acagtatcct ccacaccatc ccatgaagcc cttagtgtgg
gcacgccctc ctcgcgtctc 39000cggatggagg atatgtccta gcctctgaaa tacttgcagt
caaaataggg cactagtgag 39060gacagtttag tccagtgttc agtgagtttt catccccagt
gctgagacgc catgggaagg 39120gcagtgttcc tggcacacaa gcaggctgac aacagcctat
cagacaagga cacacagcta 39180aggggctaag ggctgtccga tgatccttac tcagtgtggc
actgaggagc ggaaacaggt 39240cgccaccacc ttgcctctat gcaggcacct tgccagcagt
acagagtcag caaggggagg 39300cgcttgccat actataacag ttaccataaa agagagatca
tgtttaaaaa caaaatcaaa 39360cgctggaagg cataggcagg gggtcgtgcg tgtccttggc
acggagtctg gtctgcatgg 39420gctgcttttg tgtgtgattc ggagagcgtg gctgggtgga
ttccctccac tcccaaaccc 39480ccaactagat tttaccaata accaatcact gtgtttagag
cccagcttca gcaagcatcc 39540tgggtttccc tcaggacatc cttccttcct tcccaggcat
gtagggtcca taaaaatgcc 39600ttttgtggac atcggaggcc cactgcgctg caagccaagt
ccccaggcct ttgcccagcc 39660taacatagtt gtacaaataa ggtttgttta atgccatttg
caagcaaaaa ttctccactg 39720aaatatggtc ccaggactgt tcgttagctc ttacgtaaga
aatgattcag gaagaacagg 39780ttggaaatat aatcccccat actttcttct gaagttttca
tcttttatac ttaagttctt 39840aactcatcta ttatcatctg catgtgctat gagatagcaa
atgaattcaa tctccctcct 39900gcaggtaacg tccacatggt ctctccttag atttggttaa
aggagcaggt tttctgcagt 39960ggcctctgct ctttcccttt gggtgtgtct ctctgctctg
ggtgccctta gtctcttctt 40020ccttttctct ggaaagttcc ctccctggtt ttcttcttca
ggggcctggc tgtctctcgg 40080gagccttagc aggaaccaca aaaagaaaca cagaaaccaa
accctcaaat ggggacttag 40140ttcaagctgc attaagtatg gattctgata ttatacgtgc
aatttctatc acggaaggaa 40200aacaggccaa gggactagaa gcagcataaa atattagtct
gcatttcctg atgacttctt 40260ctaactcatt tgtcacggtt gctgggtggt ctttatctgt
cacatgctgt cttgacacaa 40320ggacccctct ctggtataca ccttcattgg ctacccagtt
tccctgtgtg agaattcagc 40380atctgcattt tcatgcgcag ggttccttga gtttcttcca
aaggaaggca gatgcctaaa 40440ttctgtttta tcaacagtta tttgcattct tgtgtgtggc
aaacatatct ttttatttag 40500ttacttctgc gctgtttgtt tctaccttat agaatgaagc
aggtatttaa acgttaactt 40560ggaatccagc cctttggtaa actacattct tattgattac
agcagtaatt tacagggtta 40620gctgggtttc tatgcagaga tcttgttgct gagacgtatg
cttaggttca tcattaatta 40680tctttttctt aaaaataatt ttccctcaca taatatatcc
ttcccctttt ctcccctcag 40740tttctgccca ccttccctcc cacccagatc caccaccttc
tgtgttacac tggaaaacca 40800acaggcttct aaggggtaat aataaaataa agtaagagaa
aacaaaaact atcatgttaa 40860gttggacaag acaaacaaac agatggaaag gagcctggga
aaaggcacat gcacacacac 40920acacacacac acacacacac acacacacac caagagacaa
aaagtcagct gtaagtgcac 40980atgcatccac acactcagga taccacaaaa cactaaacca
gaaatcatag catatataca 41040aaggacctgt agggtaaaaa aaaaaaaaaa aaaaaaaaaa
aaaagtgtgt gtgtgtgtgt 41100gtgtgtgtgt gtgtgtgtgt gatagagaga gagagagaga
gatgggggga gggagaggga 41160gagggagagg gggagggagg agaaggagag ggagaggaag
agagggagga gagggagaga 41220gagggagaga gggagagggg gagggaggag aggaagagag
ggagagaggg agagggagga 41280gagagaggga gagagggaga gggggaggga ggagaaggag
agagagaggg aggagaggag 41340ggagggggag gggaggggga ggggaggggg aggggagggg
gagggggagg ggaggagaaa 41400cagacagaga gagacagaca cagagatatg agacagagag
acagatcctg tctagagcgc 41460tggcgagttt tatgtgaact cagcacatat agatcatcta
agaggagagc tcctcagtgc 41520agaagaggcc ctcatagggc agggctgtgc tcaagcctgt
ggggcatttt ctcaattagt 41580gattgatggg gaggacccag cccatcgtga gtggagccac
ccctgggctg gtggtccagg 41640tttctataag agagcaggct gagcaaccta tgaggatcaa
gccagtaagc agcgtccctc 41700cacggtctct gcatcagctc ctgcctccag gtgccatccc
tgttggcgtt cctgtcctga 41760gttcccttga ttaggaagca cggtgtggaa gcatacgatg
gataaatgct ttgttcctca 41820agttgcttgg gtcaggttgg tttttcacag tgatagcaac
cgtaaccaag acaacatgtg 41880aagtaaaata aaagataaaa ataagataca ctcttgaaaa
tggagggggt aggagtccct 41940gttgtgacat tatgagagac tgaacctcca aagacgccat
tttgtttgac ttctgctgca 42000gtctagtact ggacatgcag cctgccctaa gaggtgggga
ccaggagggg aagcagtgat 42060cgggatgtaa aatgaatgaa tgaatgagtg aatgaatgaa
tgaatgaatg aggaaaagag 42120tattttgttt tcccagtgag acttccttag agaaaactaa
atttttgttt tcaagtagct 42180gtcacttgga ggcagcatct gggtgagggg tgagtgctgt
gtccacttct cctctcagct 42240gtgaccctgt gtggtgcaga ccagtgaagg ccctgtgcat
gctgtgactt cgttgacctt 42300ggtgattgaa aaggccttgt tttcttggtg tccttcaccc
ccccccctcc gcccaactct 42360taatttctgt tttctctacc atatggttct ctgagcactg
aggggtgggg gttgatggaa 42420acatcaaaga ccatttataa ctgagtgttc cgaggtctct
cactctctgc acactgtctg 42480gctgtgggtc tctgcgtttg tttcctatct gctgcaggag
gaagcctgtc cgatggtgac 42540ggagcaaggc gctgatctct gagaacagca gaacatcatc
aagagtcatt gtgttgcgtt 42600ttgttttttg tttttgtttt tgtttttgtt ttaaagtcaa
tattatttag tttcccccct 42660aggtccctgg gctatctagt ttcagcatgt tggtcaccca
atcaatttcg ggcatgaatt 42720ccattgtgtg gagtgggact taagtcaaat cagacgtagc
ttagatgctt ctataaactt 42780tgtacaactg cactagcata tcttgcaaac aggataccat
tgtagaacaa agggtctgta 42840actggctata cacacacaca cacacacaca cacacacaca
cacacacaca catatatatt 42900atattatata ttatatatta attatatatt tatgaatcac
ttttgaaata tctaccgaat 42960atattttata ttttcatgta aattctattg tatctatcaa
catgatcact tggctttacc 43020tttaattcat taagttgtgt aaaatagtaa tgcatacaca
tcccacttcc tatgcaaagg 43080gctggatact gtacttaaca atctggagaa gaagcaaaca
tcaaagtcta ggggaggtcc 43140cagaaaacag gctagctcag gggacacagt cgcactggtg
aagaccaccc tggggagtca 43200caccctagaa gggagagtgt aaccatacta aggaatcaca
cttgaggaga ggtgagacta 43260ccctggggag tcacacctga gaagagaggg tgtgaccacc
ctagggagtc aggaagtcac 43320actggtgaag agtgggggtg tgggatgacc acactgagga
gtcacacttg aggaaggggg 43380gtggccacac tgaggagtgt ctgaaagcat tgagactgta
catctcaggt tatcagggct 43440tcagagaaaa cagacaggga gaagagacaa gaactggatt
ctgtgcgcaa agggggaaaa 43500gcaagcagat gtgaagggtg tgctgttaga gtttatctaa
agatgtttct ttcagaaata 43560aagagatata agctttaatt tggatgaaat aaatgtggtc
taatttccca gaatgtagag 43620gaactcacta atgtagcaag attggccttt caaagcagac
caaagacatt gagaattaag 43680atagctatga tggcgtgctt ccttaggtgg aagtcctata
tggaatccca tactccccaa 43740atgtgactgg tcggtgcagc ttggggctaa cagctctgtt
gacctgtggt gacccctgga 43800aagccctgtg ggatagagga actcctggat gtcagtcatt
tgctctgcct ctcttgtgaa 43860agcagtggtc tctgtttttc ttccttctct cggcttttca
tattctcttg catatcctgt 43920ttatttgaaa tgtttcttaa aggatgctca tagtctctca
ctggtggtgg tgaagtacaa 43980aaccctgctg cacagcaaac agagggggcc agcatacgga
acggattaac agccctatga 44040gagcccacac gctcttcaag agaacattcc atctgtattt
gctgctgcca ttctgggatc 44100tgcatacatc agataggagt gggaagccct gggaaaacag
cagggtccaa ggcacatgtg 44160gccaattgct ttttgcccat ggtaaagttc acatttgatt
gctttccaga ttatgtggac 44220ccagacatat tttactcggt catccggatc ttcctctctg
ggtaagtaca gcttaattgg 44280tttcctgctt gagacctgta gagttcccca gatttgtgcg
aggatagaca gacagaagct 44340tcctaaagta agaagtatag caagtgactc aagctggcaa
agtcaccacc tgggtccact 44400ctaggaggct ggaccccaaa atgatcagaa ggaaaaaggt
tccaacaaag ctgggaactt 44460aaatccaaaa ggggcaaaag gggctgtctt cagccaccag
agggagacca tggaccctct 44520gagaacccca acgtgatgac aggggcaaaa attaaagatg
ggagagagag tgggcaggga 44580gaatgtgggg aggagatgga agggagggta gaggagagaa
aggctggaaa atgatagcta 44640cttctttgtc ccttgacctt tgaggacata gcattcaggg
gacccatcag gagacaagag 44700tccaggctgt cacctgacag aaccatcaat gccttgatct
tagactccct ctccttcgga 44760gttgtgagaa atacagtatg attgatcata ttcagcttga
agtattttgc tatggtggta 44820gcaggtaccc ttgatttgtc tcacggctat acacttctct
gtctgtctgc ctacctcgca 44880tgccccctgc tccatcaagc acatgtcttc acccagttat
ttctaccttg acaagcttta 44940accaggttgc catccaattc accaaccaac agagccgatt
cacttttgaa cgtttgtgtc 45000ttgttgactt ggaggtgccg gtgatgttat cagaagcatc
caagctgtgc ctggagacag 45060caagagacag accagatgcc gaatctatta ccattactgc
caagtcccat tgggagaaaa 45120actaaagtgt gcattcgtgc atgtgtgcgt gtacgtgtgt
gtctagaact gaaaatttta 45180tttccttgca agtatcagac tagagttttc ctggcctgct
aggtcctctg ttgcctctcc 45240ccaccatgtc cccaatttga ctcctgacac agcactggca
cttggcattt ttctagaatt 45300acacattttc ctgacttttc tcttgactac cgccagagga
aatttctctt aaaggggctc 45360ctgtggctgt gctcaatcta gtcggatgag tcagggaaat
tcccacatta aagctaaact 45420gatcagtggc cttaatccca tctgaaaagt cctcctgccc
tgtcctgtaa taaatatatc 45480atggtgaccg gaacagctca tagtattaag agtcctagga
attcggttgg gaaccttggg 45540gagctatttt tagaatccta ccctccagtg tctttcaaag
gaatcatttc tacttcctct 45600tggcagagac ttgataagaa ccagaagggg actttgtttg
catcgacata agttccgggc 45660aatgacactt tttatctggt atttggcata aaggccatcc
ctccacttca aatgctgaga 45720ctgtttactg tgccgctaag tggctgtaca agatcctaaa
tgtagctgta gtttcaacaa 45780acatctggat tgttgggagt ttccagtaga cttctcttta
aaatgtcagc ctcgctattc 45840tgcatctatc ccgagtttct catttgcttc tttaaaacac
agttttattt aagagtggat 45900gtcctgtgga aatgagatgt attccctcca gttcccagcc
tgccacaggt ctcagagagg 45960ccaggaacgg ggggcccagg ttgctctgca gggaaacatc
gcctcatttt gttgtctgcc 46020ttaacttcct ctttccttgg gattgctaga aatacaccag
gagcaggtct aaaaataacc 46080ttaccgtaga ggccagaatt taaaatggcc ccatcccttt
acaaatggca gctcagccct 46140acgtggagaa agaggcagtt gtgtctccca gtgctgctgg
ggatggggtg taaaaacaga 46200cccaagttca tcatctgacc tcagagctgg tgttttctgc
atcaccttca gcatggctgg 46260ctttggcgaa ggcactccag cgagtgctga aaggacattg
cctgatgacg tccttggcat 46320ttgtcatatc tgatagatcc cttaagcact ggttgtgccg
tactgactga aaagctcttt 46380tctccttcct tccttccttc cttccttcct tccttccttc
cttccttcct tccaataaat 46440ccatagtgag ggcctaccac atcctagaca ccactgtatg
tgctggaaac agcagtaaag 46500aaaagcagtc acgtggtcct tgtggagcct gtgacttcag
gatggggaga aggtattgac 46560aaagcaaacc gaatcaaagc aaacatccaa cagtatgtgt
tacaactaga ggctgcatga 46620agcaatgccg ggtaggatgc gggctgctag ggagggacca
ctgggtgtgg tggctcaggt 46680atcttgttta ctgatatcta gaaataccac atccccagtg
atatgggaac agatgtcaca 46740ggcaatggag tgctctcaga agaagattcc tgttgtaaga
ggagggaaca gttcctgtga 46800caggaggagg gagcagacat gaagaataga cttagatgta
tgtgagaagg aggatgcctg 46860ccattgtgga ggactctcag tgtgggcagt gctgccttcc
tttctgagtg gcacagtcct 46920gtttggggct gcaggttgtc agtacccctc ctgagtgggg
tagggtggca gagaacaaga 46980ttacaaagaa agcatcagag gtggacccaa ggggaagatg
ccgagatgga gatgaatgtc 47040aaccatcttg aagatgaggg gagaggtgga gagtatacag
cctgtgggtc ctgacgcctg 47100tcacagagaa acagaaacat gtgcgtgccc ttggccgctc
tggacacaga ttgcagccca 47160tgtgctggtg tggaccaggt ccattatcca caccgtcgtc
atgtctgcaa catcacttgc 47220tcataaaata ccattctaca gtttctctag ccccgaactc
ttatatttgt ttttgggttg 47280ttcacaggcc tctttggatt ccattcaaat cctcgaacag
gtgcaagaag cagattcccc 47340tacagactag gggaactgag ggtcagaaag gctgtgcact
gtagctgaga gatgagagtg 47400gcagcaggca ttcttagcct ccagggttgc tagaacaata
aatagctggt gcttaccgaa 47460tgtctaatgt gctccagaca cctggcaaat agtatttgag
tcggatctta caatgaccca 47520taagctaagt atgaatgtca atgccaaaca tagctcttat
ctcaaaggaa taagagttag 47580tttattcttt ggccaaatat taatgcccag aaacacagat
tccagttgtc ccaaattaac 47640atgttccact ggggaaatga aggagttttc atagctcaag
ggcaaagcaa gttaccaatc 47700aaggggtttt ttgagaacac tggtgggggc cccaggcagg
caagttacag caaacaagaa 47760ctctgtacat agtcacatgc agacgggtag tggaagcctg
ttgtctacta ggtcaataca 47820ttccaaacca tcaaagatac tgggtcaggc aggacggagt
taaagatagc ccattgtcgt 47880ttgactctgg atcttcaaac tttccaactc tccacgatca
atcagttttg tagaatcttt 47940aacataggca tggcttcccc ctccctcctc ccacacaccc
cagcgccacc tggaacttca 48000gtttatacta acactactca gacaagggag ccaaggctct
gagaggtccc atgtgctaac 48060ccagggctag caaccaatgc acagtagagc ttagattctg
tatctgccca gaatagagac 48120cttgtcccac agtttgtgtg acgctccctt ctacctgtgt
atcctttctt cttctttctt 48180atgctgtatc tcttttctga acatgacttc ctcagttggt
taccattgaa attcactaat 48240cggttgactt taaacagcca ccaaatctgg caacctggcc
acttgctgtg ttggcagcct 48300cagagcagag tctggggaaa ggtctaggat gcaggtgggg
ggagctagcc tgaacacaag 48360gcttggattg acagggagca gaaacagcca tgtaaacctg
ctacttgccc tgtcaaccag 48420gggctggttt gcttgctggc aaaagaggtc aatgtgcttc
ttggcgaagg tagacatcta 48480tgggataaag aaaagtagac tgcaacttag agatgcatgt
gtgtgtgtgt gtgtgtgtgt 48540gtgtgtgtgt gtgtgttcct ggaatgctgg gggtctggga
acttagctca agtctttgat 48600tctttaggaa agaaggtaaa aattgcctgg tcctatctac
tgtcaagtgg tcggggtgag 48660agagtgagtg tatgctcgtg tatgtatgtg agcactgcag
gtgtctgcat ggtgtgccat 48720ggtgctccac tgggcttcat gctgtgctcc cctaggcttc
agtcaagtca agactaggtc 48780aagtcatgga gggtaaacag aagagagaga gagcagaaaa
tgagggacac aggaagggta 48840gagggggaaa gagagggttg tgaagctcac gcgtgatcag
gagccccagg ctttcttctt 48900ccagccgccc ataggctctg gtgcccacaa cattggttac
aaccccgctc tccatcatca 48960tgcttgtcat cactgctgtg acaaaccgct taataatggt
tctcacggaa cattaaaagc 49020caagccaagt ttaacacctc gaacatttcc aagtgttatg
gggaataaca gttaagtgtc 49080tgggtgtgct tgtgtgtaat tgggaatctg tagtggtggg
gttaccagtg tcaggccaca 49140gtgtttgtga tgagcagagg ggtcggggtc tttctcagat
cccttatctt gtcctgtcaa 49200tggtggtgat gtaataggtg cacgcctgtg acagagctgt
ttaaagcatt gtaagaccaa 49260tgagtaaagt tcctaccctt gcttctcctt taagtgaggc
agaaaaaggc tccaccatga 49320cgtggtgtaa agatgaagtc aatctaatac ttccttggat
actctagcaa gcttcattca 49380cactttttat ttcttcctct tcctcttcct cttcctcttc
ctcttcctct tcctcttccc 49440ctcctcctct tcctcctcct cttcctcctc ctcttcctcc
tcctcctctt cctccttctc 49500ctcttcctcc tccccctccc cttcccctgt gctcctcatt
attattatta ttgctcctgt 49560ctaggtggaa ggacaatcca gccatgcctg tggggctggt
ctatgaaggt gttgccacag 49620agcctctgaa gtactctgga ggaagtgcag cccagagctc
cgtgcttcat gccttcgatg 49680agttcctggg cattgagcat tgcaaggaaa gtggtgagca
gcagtctgat ctcacctatg 49740ctttgatggg acagcgaggt agactaggga gacatctcta
gcaactgata aagacgggtg 49800taaatgaaaa tgtcctgaag tttatccttg cctaagccag
caggcagctg tgtgcatgtg 49860ccctctctta cactgagtta gtcagtattg gggcatcgga
tcttattagg gtcttccaac 49920agtcctgtga cctgggttgt tcactgtcct gttggctggg
gtcttttatc cgcagattcc 49980cctttctaca atgaggtgat aatgtcacat tgaaaggcca
gtctggagca gcaagtgata 50040gtgctgaact tctctgctaa agcctttccc atgaaatggc
ccagcctccc actgaatcta 50100tgtggaccag gcgagggagc ccatcgcttt gaagccttta
aaatagttgt tattgatttt 50160tctggcagca tagagctatc ctttaatgac taccaaaaaa
aaaaatattg ctaccaaact 50220ttaatttgga tcagaaccaa aaagaattaa aactctctgg
cacgaacctg ttctctggaa 50280cagtcagggt tgtttctggg tttcagcatt tgattttagt
cactgactct caacaaccaa 50340ccaaccaaac aaacaaacaa acaaccaaac aaccaaacaa
caacaacaaa acctaaccca 50400aacaacaaca gttaaaggtg taatggtttt caagaaaaca
ctgagttttc agtgtttcgg 50460cttctctggg tttttactaa aatacctgct taccaatgtc
gtctctacgt gcacagtaac 50520ttccatttcc tgcccccctg cccgcccccc atttataagt
atctagcaaa cagaattcac 50580cagagtgttc tgtgtttgtg tgtgtgcgtg tagactcgtc
tcttagtcct cagcagggaa 50640taccacatca gtcatacaca cggagcagta gatttctgtc
caactttatt atctgagaga 50700tgtttgcttc tttttctccc ctgtgtctcc tgtcaacaac
cagaaatgaa catttgagca 50760tttggcagct ataacaaaag cccgacaagg ctgagggaga
gccctatcaa gcatttctgg 50820tacctgagtg tttggaacag tgggcaaacc ctcccaaatg
tctgcctcga gctaacgtat 50880ttctcccggc tgtttctttc agttggcttt ctacacagaa
tgagggacta catgccgcct 50940tcccataagg ctttcctgga agatctccac gtagctcctt
ctctgagaga ctacatactg 51000gcctctggtc ctggggactg cctgatggcc tataaccagt
gtgtggaggc cctgggagag 51060ctgcgcagtt accacatcaa tgtcgtggcc agatacatta
tctccgctgc caccagggcc 51120aggagcaggg ggctaactaa tccctcaccc catgccttgg
aagacagggg cactgggggt 51180actgccatgc tgagcttctt gaagagtgtc agggagaaga
ccatggaggc cctcctgtgt 51240cctggtgctt agcagtcatg tcctgcaccc taacacttag
atgttctcat cctgcatccc 51300agcgttagag gttcacatcc tgcatcctag tgcttagctg
ttcttgtgct atatcccagc 51360gcttagcagt catgtcctgc atcctagtgc ttagcatttt
atatccagca tcttagtgct 51420tagagattca catcctgcat cctagagctt agcattttat
atccagcatc cttgtgcgta 51480tcagctatgt tttgtatcct gcttagcagt taacatcctg
catcctagta cttatctgtt 51540ctcatcctgc atcctagagc ttagcagtca ggtcccgtgg
gagcaagaac cagggtctga 51600gctctgtctg agcccaagca tggctttact gctttgttaa
ttgtggctcc cacctccacc 51660ccaccccagc cagtttgctt gctagaagcc tttctgcact
gcctaatccc cctgcctcac 51720agcagagagc tgcagccatg acctcctcat tcagtattag
gtggacaagt cggagatacc 51780caaactcaat tttaaaagaa tcaagttgct tttggggcat
gttacttcat cttttcttac 51840cctgggcctc ttcccttctt ccctacctcc ctcgtccctt
agtctttcac ccctctctct 51900ttctcctttt gtcaccctcc ccctcccctg cttactctct
tttcccttcc cccctctcct 51960catccctcct tcctttcttc cttccctttt tgtctgtgaa
gcaccaggtc tgatgggcct 52020caaactgtga tcttcctgtc tcacccttca aaggttatgt
gtatgtgacg tgtgtgtgtg 52080tgtgtgtgtg tgtgtgtgtg tgtgtgtgtt cgtttctttt
gtttttccct agtggagatg 52140acacccaaag atttgcacat accaggcaat tgctccacca
cctgactaca gtcccagctc 52200tctgtattcc tgaaggaaag tcttgatgag ttgcctaggc
tggtattgag ctctttagcc 52260caggcaggcc ttagtctgag tagctgggat gtacagggat
gagccactga gccatgctgc 52320tgctgctaac gatgatgacg atgatgatga tgaagattat
gataactaca gtcactgcaa 52380taatga
523861561540DNAHomo sapiens 15ccaaaagttg tttggtagga
gagggttgag gctgggagag gtggctcatg cctgtaatcc 60cagcactttg ggaggccaag
gtgggtggat ctcctgaggt caggagttcc agaccagcct 120ggtcaacatg gtgaaacccc
atctctacta aaaatacaaa aaattggcgt ggtggtgggt 180gcctacaatc ccaattactt
gggagactga ggcaggataa tcgctcgaac ctgggaggca 240gaggttgcag tgagcagaga
tcgcgccact gcactcaagc ctaaccaaca ggggcaaaac 300tctaggacta gagctaaggt
atcaaaaaaa aaaaaaaaaa aaaaaagaag tagagtgttt 360aattaaataa tttgttcttg
ctgtaaaatg taaagtagat attcctcttc aaagactttc 420ctccccgtct aattaggaat
aaatagtaac ttctcttaga agcaaaattt attcaaagac 480ctgtgctaac attcttaaat
atctgctagc cacaataagg aaatcaatgt actttatgtt 540cttagctccc acaatttagc
ctaaatattt tccctggcat gtttatactg gtctaagcaa 600gcattaggtc atagcctgtt
cctcttcctt atttaaaagt gtttttacct ttctcagcgt 660tccacaagtt acttcctcct
tcctttgttc tcctctacct gtgcctcttt taaaaagttc 720taagttgcta gccaattggg
acaaatacag aatgtaaggt cccattccag ccaacggaaa 780ctggacacag cagtagggtg
gatgtgtcag gttataaatg accctgtctc ctttgtttgg 840tgtactctag tggcaaaact
gctggcaagt gtaccttttc tgcaggaagt aaaaatggcc 900ttactaaata aattaaattt
atgttcaagt gctatttctt tttttttttt tttcgagatg 960gaatttcact tttgttgccc
agcctggagt gcaatggcgc gatctcggct cactgcaacc 1020tccacctccc aggttcaagc
aattctcctg cctcagcctc ccgagtagct gggattacag 1080gcatgcgcca ccacgctcgg
ctaattttgt atttttagta gagatggggt ttctccatga 1140tgaggctggt ctcaaactcc
tgacctcagg tgatccgcct gccttggcct tccaaagtgc 1200cttggccttc caaagtggcg
tgagccactg cgcccagcct cgagtgctat ttctttacgg 1260cacggaagaa caaacatttc
aaacaatgct attaccaagt ttgttagtat ttattatctc 1320atttgctaaa cctaaaaaat
atatatcctt ctttaacgtg atcgaatatt tcaaaaagtt 1380attgtgttgt ttcttaaaat
aaatcaatca taatcctaga ctatgttact caaactacat 1440acaacacctt ctgagcttct
ggcaggccct tcctcccctc cctgctcacc acagatcact 1500ggaataattg tctgcatgta
acttctaatt ttgaagtggt tgtggtttat caaacctgga 1560acatggcact tccaagtaca
tgagctaagg tcacagtaag actcaagccc cttcaacaga 1620atacctggaa tttctctgtt
aaagattttc tcctttacct gactacatgt ttgtaatgca 1680gatccctcca ggagcgctta
cttataaact gtcctggatc actaacgcga cattttgatg 1740taaattagtt tatcttgacg
tgctaatggt agaaaaaaag agaacatgag gaaacttggg 1800tgctttcagg gctggtagga
aggattaaat ctttgcggca atttctgaga aggggaagga 1860aaccttgcta acaattttga
tagtttactc catttggctg gagtaactct gatccatttg 1920tcaaattcac gatggagcag
gtacctgtta gggtacaggt ttgataaacc acaaccacag 1980gtctatttca tttctccttt
tccaaagtgg aacaaatttg tctctggggt taaaactgct 2040tttctcatat tggtgtgtaa
gagaaaatga gggaatttct ttgagtttgt ttggtttgtc 2100tgtttgttta agcagcattt
tttaaataat ttactcagcc ctgtctcaga gaaagtccat 2160gatgatctgg aattcaacct
cagggaaaag ttctctcctg tgcctgagac actgcgcaac 2220taactggaac cgaaggatgg
aacctgggtg tttaatttat taggaacaat tgattcttca 2280gtgacacttt ccatgcagat
acttcaaaca aaataatgga gccccacaga ccgaatgtga 2340agacagcagt gccattgtct
ttggaaagct atcacatatc tgaagagtat ggctttcttc 2400ttccagattc tctggtaagg
atagagcctt ggtaaggata ggtcagaata tgtttcttga 2460gatgttggtt ggtttgtttt
ttaaaaatgt atgtgattat taagagacca atataaatat 2520caagttgttt acctgagaaa
gatgctacaa agagcataga ttatcattac tatcaaaaga 2580gaagtgacag ataccacaga
gaacaggtca aatggaacat tttttgtttc agtttctttt 2640gactagattg tcaggccaga
gaaattataa gcaaacctgt agttatcaag aaaaagcatg 2700aacttaaata taaataaaga
acaaatacag agcctcagca cctggaacat ggcacttcca 2760agtacatgag ctaaggtcac
agtaagactc aagccccttc aacagagtac ctggaatttc 2820tctgttaaag attttctcct
ttgcatgact acatgtttgt aatgcagatc cccccaggag 2880cgcttactta taaactgtcc
tggatcacta tcgcgacatt ttgatgtaaa ttagtttatc 2940ttgacttgct aatggtagaa
aaaaagagaa catgaggaaa cttgggtgct ttcagggctg 3000gtaggaagga ttaaatcttt
gtggcaattt ctgagaaggg gaaggaaacc ttgctaacaa 3060acaatacctc tttcttaatt
ctacttaggg ctcaaattgt aatgcaaatc tttttcatca 3120tttagccctt ataaacactg
tttttctcat ctggtgtggt ccaaggccta gaacattaaa 3180actatcaaag cttttacaga
ccatcaggtg tcatccccct ctttctacat ctgagctagc 3240tgaaatccag aggaaatgac
ttgctgaaag tcatgagtgg caaaagcaga actagttctg 3300cttataactc ttgactttta
gttattatta ttattaatta ttattattac atcctaaatg 3360agggccaagg ccactcagtt
aaaaatcgtg gggtccaggc caggtgcagt ggctcacgcc 3420tataatccca gcacttttgg
gaggccaagg caggtggatc acttgaggtt caggagttca 3480agaccaggtt gatcaacatg
gtgaaacccc gtctctacta aaaatacaaa aattggccag 3540gcgtggtggc acatgcctgt
agttccagct attggggagg ctgaggcagg agaatccttg 3600aacccaggag ggggaggttg
caatgagtgg agatcatgct gttgggaatg aagtttttgg 3660tgtcacagaa aaagaatgaa
catgggaaca aatgatctct cagcaaaagg acctttactt 3720tctgcagaaa gggtgctact
caatagctgt ccagccacga gagcacacca aacaaaggag 3780acagagttat ttataacctg
acgcatctac cctactgctg tgtccagctt ccattggctg 3840gaataggacc tcacatttta
cactttaccc aatcggctat tagtttaaaa cttttttaat 3900tggataaggg aacagaacaa
agaaagaaaa gcaagttgcc cagggatagt taaggaaaca 3960tctccatata aggaatggca
tgcactatgg gctggggctt ttctagttct gtacagacat 4020gccggagcaa gctacgacag
ctgatttgga cagccactaa tagtggctag caatcttata 4080gtaagaaatt gtgacttttt
ataatctttg aagaactttc ccatttctga cagtgccact 4140gcactccagc ctgggcaaca
agagcgaaac tcgtctcaaa acaaaacaaa acaaaacaaa 4200acaaaacaaa acagctctct
actcttggaa gcagcagagt ttttatcttc atttatatca 4260ctccggtaac actcagaagt
agacaagcct cagggtaggt attcagtaaa agcccactga 4320attccacact attctttaat
catagttaaa tggcaaatta ggctggaggg tgggggtgga 4380acctctccaa aattactgca
atgactgcaa catcggaccc caagattttt tttttttttt 4440ctgagataga atctctttct
atcgcccagg ctggagtgca gtggcactgt gagaaatggg 4500aatggaccgg actgtttcct
ctgacactgc cactaggttg accaagtgtc cctatttgtt 4560aggtactgga tggacgcctg
acatgcaaga ctctcagtgc taaatcagga aagtgctggg 4620acaattcgga tgagtcggtc
acgctaagtt gcacttaata gctcttgtga ctttgactga 4680attacaaaca tcccctgacc
ctcaattttc acatttactg gatggagatc tggtgccacc 4740tccactagat tgctatggag
aatgaatgtg aaagcatttt cataaatcca gtgtaaggac 4800cagaagccag tcttctgacc
ttgagccagt gcttgttaaa aactccactc tatacatcta 4860acccaattca ggaatatcct
gcctagttcc aaaggaagaa aagaccaaat tgctcttatt 4920gggattaaat gcgtacactg
agctgaggaa aaacagtatt acaaatgagc taaacatgac 4980gtagatccac agttgtagaa
ttcccctctt tgttctttcc tctttcataa ctacggaaac 5040agatgagaaa catttacggc
atcaggttct tgtgatgctc cctgcctgat atgctatggt 5100tttgttaatg gaatgtccat
tcctgagctt atgcagaaaa aagtcccttg ggaaagtggt 5160tttactgtgt tatgttcatt
ttccccatag ttctcaaaat gtacttcctt gtttcagttt 5220taattttctt tcattggtgt
gaccattttc aactgctccc tttctgggaa gaggtagcag 5280acggacattt tcatcaaaat
ctgccccagg ttgcttcaca gataaggagg gacccagcca 5340ctaaaatcac caggcagagt
gttgcaagag tagatagaga atcacaattg gctgccctgc 5400tcaaggggac accagatctt
actttcgttt agttgaaagg caagcgtcag agtcgggagg 5460ctgtaccttc atgtccagtg
gcctcacaga agttccttca gtatctcttt tagatgaaac 5520tcttttagaa gttccttcag
tatctctttt ggtttctcac tatagatagt tacttgaaca 5580tgtctgaaga aaacgtggtc
aagacagtga ataaaaaaaa ttctggtttt gggaagcagt 5640ctgacttagt ttcaaatatt
ctatcccact gtttctgtca atgttcaaac ctttccaagc 5700tccaacattt attgtggaaa
atgtgtgcct caccaactca tgcaaataaa tgtttcatgt 5760gccctacgtg tgtagagggg
gcatggatgt gtgtttttgg agggagggct aatttttctt 5820tagacatgga gaatacgagg
aaattagctt ggcatcaaga aggttacagc aggagacaag 5880agtgaagaga actgagagag
cccggaaatg aggctctgga gttcagattt tttttttttt 5940gagatggcgt cttgtacccc
aggttggagt gcaatggcaa aatctcagct cactgcaacc 6000tccgcctccc gggttcaagc
gattctcctg cctcagcctc ctgagtagct gggattacag 6060gcatgagcca ccatgcctgg
ctaattctgt agttttagta cagatggggt ttctccatgt 6120tggtcaggct ggtctcaaac
tcccaacctc aggtgatcca ccctccttgg cctcccaaag 6180ttcaaggatt acagccatga
accactgcgc ctggcctaat ttttgtattt ttagtagaga 6240cagggtttca ccatgttggt
caggctggtc ttgaactcct gacctcgtga tctgcccacc 6300tcagcctcat gaagtgctgg
gattacaggc atgagccaca gggccaggcc tggagttcag 6360atttaacaca tcctgtaaat
gacatgatgc atctgatatt tgaagagttt tcctcaaaga 6420atgttacatg caaggtggtt
tagagttgtt gtttccggct atatagcaaa agtacttggg 6480gagttttaaa aaatactgat
gccgaagctc cacctagaat agttcattca gaatctctag 6540cataattgac ctcagtactt
gaaatatgat tattataaat gttagtcaac tgctttttta 6600ggctctatga ctgatagaaa
tctttcactt ttatatcatc tccagttaat gagtcccata 6660aattgaaatc tagtgtttaa
atttttactt catatttatt tttactgatt gttttattat 6720tattattttt gagacagagt
ccgctttgtc gcccaggcta gagtgcagtg acgccatctc 6780ggctccctgc aacctccgcc
tcctgggttc aaacgattct cctgcctcag cctcctgagt 6840agctgggatt acaggagccc
accaccaacc acacccagct aatttttgta tttttagtag 6900acggggtttc gccatgttgg
ccaggctggt ctcgaacccc tgacctcaag tgatccaccc 6960gcctcggccc tctgtctcaa
aacaaaaaca aaaacaataa caaaactttt ctcttctacc 7020cgagatgttt aagtttaaat
cacaccattt gtacaaaaat tccctgtctt gtccttaaaa 7080ataatttgta atcactagct
agttttgaga tcgattgcca tctaaccgaa tgccatttgt 7140tctctctctc tagtttcaac
ttaataaccc tttctgcatt ttctattctt tcaaaatttt 7200tccggccatt ttattgtttc
tatttagtga aaatttattc actggtttct atgcctaagg 7260gcatttagga agttgcttag
gatacagacg tgataaaaag accagtgtaa aaactctcca 7320ctcctagaca ttatattcta
gtcctcatct cctgtcattt aagtcctcag tgattctatg 7380cacttttgct tttggtttgg
gcagatgctc tgagtttaat gtttctctga gatgaggacc 7440ccctattcaa ctcacaaatc
ccataaggag gcctctgtgc ctttgctggt gccccagaca 7500gggtgctgat gcttacttat
cttcaagatt gtgaagtcag atttaatagt atagtcgttt 7560gccagagctg ctgtaacagt
agccacaaac agttgggctt aaaataccac aaacaggagg 7620gcttaaatca cagaagttga
ttttctcaca gttcttgagg caggaagtcc aagatcaagg 7680tgtcgtggag ttggtttctt
ctgatgtctt gctccttggc ttgtagatgg cctccttatt 7740attgtgtcct cacatggtct
tttctccact atgcacaaat tccctatgtc tctctctctt 7800tttttttttt tttttttttt
ttgagacaga gttgcactct gtcacccagg ctggagtgca 7860gtggtgcaat ctcggctcac
tgcaaccttt gcctcccggg ttcaagcaat tctcctgcct 7920cagtctcctg aatagctggt
attacaggtg cgcaccacaa agcccagcta attttttgta 7980tttttagtag agatagggtt
tcgctatttt ggtcaggttg gttttgaact cctggcctca 8040agtgatccgc gcacctcggc
ctctcaaagt gctaggatta caggcataag ctactgtgcc 8100cagtctcccc ctgtctcttt
gtgtccaaat ttcctcttct ttagggacac caatcagatt 8160aaattggacc caccctaaag
gcctcatttc aatgtacctc cttcaagggc ctatctccaa 8220atacagttat atttttaggt
actagggcta gggcttcagc ataggaattt gggggagaca 8280caatttagca catagcagaa
aatataaggc caggaaaaaa tattctggca tgctagatgg 8340actcattaac aaatattaac
caatataaac caattaacaa atatttcttt aatatttgcc 8400tttttttttt tttttttttg
aaacagagtt tcactcttgt tgcctaggct ggagtgcagt 8460ggcacgttct tggctcactg
aaacctctgc ctcctgggtt caagtgattc tcctgcctca 8520tcctcccaag tagctgggat
tacaggtgcg ggccatcaca cccggcttat tttttgtatt 8580tttagtagag atggggtttc
actatgttgg ccaggctggt ctcgaacttc tgacctcagg 8640tgatccacct gccttggcat
ctgaaaatgc tggggttaca ggttgcctgg tgatttttaa 8700gaggaatgac tgagctctca
tgccaggtgg ggggagggga cagagaaagt tgaatactct 8760gacgatagcc atgatccata
gctctgaagc ttagactcga atctacccat cccgcaagga 8820agaaaacaaa gaaataaaaa
agaagaaaag aaatctccca atgtcaggtc ccaccctctt 8880tagaagtaat ttcagcaaaa
ctttgttgct attttggcat gtcctctact gtagtagctt 8940gtcaaaatac tgtccccaaa
cgttttctat atttctagat tttactgttt aatgtataat 9000aataatgttc taacattaaa
acgtaaccat agcaatgctc cgactcactt gatctttaaa 9060tatattgttg aactcaattt
tgtgacatct tcagaattgt ctttttgtat tcataaatag 9120caacagtgga tagttgcctt
ggttagtgtt attatttcaa ggattaatct ttaggttacg 9180ttttcttcat aagatgcatt
agatgacttt tttttttttt tttttgagac agagtcttgc 9240tctgttgctc agactggagt
gcagtggtgc agtctcagct cactgcaatc tccacctcct 9300ggctcaagag agtctctcga
ctcagcctcc tgagtagctg ggattacagg cacgcaccac 9360catgcctggc taatttttgt
atccttttta gtaaagacgg gatttcccca tgttggccag 9420gctgatctcc aactcctgac
ctcaagtgat ccatctggct tggcctccca aagtgctggg 9480attacaggca tgagccacca
cacgcagcca attagatgcc ttctcatgct tttctgtgtt 9540gtgaaacaga tcatctatcc
gttgatatag catagctctt cagactacag acattttagg 9600ctataagttt tgaattacat
tttctattcc ctttatgctt cttgttctag ttaggttttt 9660tatttctaaa taaaaatatg
aatttttgca atttcccaaa tgcgaactca actgaaattt 9720tcaagtgtat tagcaaaatt
tattcatagc agcctcttac atttcattaa gaattgattt 9780tttcttattc cctgttgaag
tttgtttata aaatatagta atagtaataa ctatatagaa 9840agtgttcact ttgtagtagg
ccctatgtta actttaacta cactttttaa atctaagcct 9900catagtagtc ttggatggat
gcggtggctc acgcctgtaa ccccagcact ttgggaggct 9960gaggcgggtg gatcacgatg
tcaggagttc aagaccagcc tggccaacat ggtgacactg 10020tctctactaa aaagacaaaa
atcagccgga cgtggtggta tacacctgta gtcccagcta 10080tttgggatgc tgagtcagga
gaattgcttg aacccaggtg gtggaggttg cagtgaaccg 10140agatcacaca agtgcactct
agcctggatg acagagtgag actccatctc aaaaaaaaaa 10200aaaaaaaaaa aaagagatca
ataaataaaa taaataaata atcctcacaa tagtcttcac 10260catttgcaaa tgatccattt
gacaataaat gaattcagca ctatcatgga aatatatttc 10320caagctgacc agttttctcc
atttccaccc cacttcaatc caccttcatg tagccctagg 10380actattgtct cctccccttg
tttccttatt tccattcctg ttcagctgta acacattctg 10440ttcatagcag tcaagtgatg
cttacaaatg gaaatcaggc tagaggtggt agttcacacc 10500tataattcca gcattttggg
aggctgaggc aggaggatca catgaggcca ggagtttgag 10560accagcctgg gcaacatagc
gagaccccat ctctacaaaa ataaaaaaga attagctgtg 10620catgatccta tgtgcctgtg
ttccagctac ttgggaggct gaggtgggaa gattgcttga 10680cccagggagt ttgaggctgc
aataagctat atttgtacca ctacactcca gtgtgggtga 10740cagagtgaga tcctgtctct
aaaaaacgta aaatgaaaat aaaaccttga tagtttgctc 10800tttaaaactc ttcctacagg
gcccctgtga tgctcacctg tctctagaag ggcatgtaat 10860agctctttct ccttcacttt
actttgatgc aatgtcagaa cagcttcttt ccatcaaaac 10920ttaaaccttt gatttcattt
aaaatcatct gcttcaaatt ctaatctttc tgatagttta 10980ggttctaatt tttctgatgt
taatattgtc acccaagttt cctgttcata tttacctggt 11040ttattttatt tttattttta
tttatgtatt tgagatggag tctagctctg tcacccaggc 11100tggagtgcag tggtgcgatc
tcagctcact gcaaccttcg cctcctgggt tcacgccatt 11160ctcctgcctc agcctcccga
gtagctggga ttacagggac ccgccaccat gcccggctca 11220ttttttgtat ttctactaga
gacgtggttt caccgtgtta gccaggatgg tcttgatctc 11280ctgacctcgt gatctgcccg
catcggcctc ctagagtgct gggattacag gcgtgagcca 11340ccgcgcccag actttatttt
attttttgag acgaagtctt gctctcttcc ccaggctgga 11400gtgcagtggc ttgatctcag
ctcactgcaa cctctgcctc ccaggttcag gcgattctcc 11460cgcctctgcc tcccaggttc
aggcgattct cccgcctcag cctcccgaac agctggggtt 11520acagatgcct gctaccacac
ccagctaatt tttttctttt tttggagaca gtctcactct 11580gtcgcccagg ctggagtgca
ctggcgtgat ctcagctcac tgcaacctcc gcctcctggg 11640ttcaagcgat tctcctgcat
caacctccta agtagctggg attacagacg tctgccacca 11700catcaaacta atttttgtat
ttttagtagc tgagattata ggctcgtgtc accacgcctg 11760gctaattttt gtatttttag
tagagacggg gtttcaccat gatggccagg ctcgtcttga 11820acctctgacc tcaagtgatc
tgcccatctc agcctcccaa agtgctggga ttacaggtgt 11880gagccactgg gcctggcacc
tggtttattt ttgtgcatgc ttttattttt aattttccta 11940tgctactttc ttagccaaaa
tttatactta atctaatcaa gcattaatct aacaaagagt 12000ttagtgttca tataaaatac
agttttacaa atctgttttt ctttaaatta taaatttgtt 12060aagaaaatta tccaaagaat
gatccagaaa caaaagaatg gctgtgtgtc ttttcaatat 12120catcctggag cattgtctca
accatctcac tttacggtga ctaaaacatc tagaggtttt 12180ccctttgttt tctgtacttc
ttagtattga ttaatactgt tgtgctactt cagtctgaag 12240ttccatgtta atctgtagat
tttttttttt ttttttgaga cagtgtctcg ctctgtcgcc 12300caggctggag tgcagtggtg
cgattggctc actgcaagct ctgcctccca ggttcaggcc 12360attctcctgc cttagcctcc
cgagtagctg ggactacagg tgcccgccac cacgctgggc 12420taattttttc tatttttttt
tttaggagag acggggtttc accgtgttag ccaggatggt 12480cttgatctcc tgacttcgtg
atctgcctac cttggcctcc caaagtgctg ggattacagg 12540cgtgagccac tgtgcccggc
tgttaatttg tagattttta tacagaaaag cagcaaaata 12600tttctgttga gtagaaaata
taactccaat gcttatgact gtattcctta taggacacta 12660actcattatg tgtctaacct
agcaatttta tgtcaacact attttctcaa acctctataa 12720actttggctg ggcacagtgg
gtcacacctg taatcttagc actttgagag gctgaggcag 12780gtggatcacc ttaggtcagg
agttcaagac aaggctggcc aacatggcaa aaccccatct 12840ctactaaaga tacaaaaaat
tagccaggca tggtgacatg cccctgtaat cccagctact 12900caggaggctg aggcaggaga
atctcttgaa ctcaggaggt ggagccaaga tcatgccact 12960gcattccagc ctgagcaata
gggtgaaact gtgcctcaaa atgaataaat aaaataaata 13020aataagtcag agattgtgaa
taggatgttg gatataccca agttatgaat taattaggag 13080cttgaaccca ggaggcagag
gttgcagtga gctgagatcg caccactgca ctttagcctg 13140agcgatagag tgaaactgtg
tctcaatcaa tcaatcaatc agagattgtg agtaggatgt 13200tggatgtacc caagttatga
attaattagg agcttgaacc caggtttgtc tcagatcctc 13260agggactgaa gacttccaag
tgaattatgg gtaatgtata ggtctatact actccaaatt 13320tacagttttc agacttccct
gggttctcat ggaccttcca tgtcatttct atgtttaggt 13380tgaggtccct ggtcttttct
cctctgtaat taatttcaca cccaccccta tctcaactca 13440cacaacttga tcttcactcc
catctgctaa gaaattgagt ccataaaaag tgaactcctt 13500taaactctag atcttctact
gctgcaagga cagacattcc attctggctc tctctctcct 13560cctttgcttc ttccagtcct
ttgctccttc tgcattctgt tactctcctc tctcctttgt 13620cttcaatctc tccctcttgc
aatagccaac tataaactgc tcaagcttct cattcttaaa 13680agatctctct gaaatgcaaa
ttccctactg ccttatggct ctccttcaaa agtaatctac 13740attttctcta ttttctaatt
cctcaacaca ctaacgtttg aaccctgctt ctatgaccct 13800gacctaaatt tctattaaat
gtacatagat aaactaatat atatttgtga cttcctaata 13860ttgttttgtt ttttaaagag
gtcaatctta ctttaactct gtaatgatgc ggttgacctt 13920ctgatgattc tctacttctg
tgaaatcctc tactgtcttg actttttaat taatttattt 13980ttttttgaga cggagtctcg
ctctgttgcc caggatggag tgcagtggca caatctcggc 14040tcactgcaag ctccacctcc
cgggttcatg ccattctcct gcctcagcct cccgagtagc 14100tgggactaca ggtgcccgcc
aacacgccca gctaattttt ttgtattttt agtagagacg 14160gggtttcacc gtgttagcca
ggatggtctt gatctcctga cctcgtgatc tgcctgcatt 14220ggcctcccaa agagttggga
ttataggcgt gagccaccgc acctggccct actgtcttga 14280cttttatagg gtcattctat
tcaagctcat tgagcgtctg tcactatgtt tttgatctgt 14340attgctggaa tcagttcctc
tatctgcctt gtgaatattc tccattgtgc taatctaggc 14400ttctcctttc atttttcata
ttccctcaca tggctttata cactcttgtg gttttaacca 14460caatataggg tttttactgt
agttatgctt tcaaattgta tacttctttt tttttttttt 14520ttttgaaatg gagtgttact
ctgttactcc agtctggagt gcagtggtac gatcttggct 14580cactgcaact ttcgcctccc
aggttcaagc gattctccta catcagcctc ccgagtagct 14640gggattacag gcatgtgcca
acacgcctgc ctaatttttt atttttagta gagacaggat 14700ttcaccatgt tggtcaagcc
cgtcacaaac tcctgacctt aggtgatccg ccctcctcgg 14760cctccccaag tgctgaaatt
acaggtatga gccatcgtgc ccagccccaa ttgtatgttt 14820ctaatatgac ttttctcctg
aactttaaac tgtgtatcca acttctcagc acagtcatat 14880cttttgattc cacaggtaat
ttaatgtcaa tatatttaaa aatgaattta ccacctttat 14940ccccactctt tgactttcac
ctgcatttct gtttcaattc ttgtttccat ccattcattt 15000gctcacctaa ttcataaaca
tggaaatcat cctcaattcc tcttcttctt agcccaaaaa 15060ttcaattgtg caggttatgc
actgagaaaa agagcctcag gttaggggga taaatcagag 15120attggtgaac tttttctgaa
gggccaaata ctaactgctt taagcttgct taccatatgg 15180tttatgttgc aactaccaac
tctcctgctg taatgtaaaa gcaaccatag atagcatgta 15240aacaaatgag acaggctggg
tgccaatgaa aattcacgaa aattaatgta gtttactgtc 15300ccttgggtga gagttggggg
tcactgaaat tcggactatg tcttacttgg ctaaaccaca 15360ggcctagagt gggccataaa
tggagctatt gggctagtga ttttcttgcc ttaagccccc 15420agccccaaat ttaataatca
catcatttta atttcatttt ccaagtgtat ctttaatata 15480tggcttctcc tttccaaatt
cactgtcatt acctaagttt agtccttgaa caatatttta 15540aaggcttcct tatctgactt
tatatcttaa agtcctacaa atttatcttc ctaaaattca 15600aatcaaacca tgtcaccaac
ttacagaaag ggaaaattca tatattctac acacagcaca 15660tttcatgtaa ctttctaggc
tcatctttca tcatcctttt gatgcaggat tttctgctcc 15720tcagctcagc gaaatccagg
atcttgtctc atgaccagga agaattaggc aggtggacat 15780agtgaagggt gaggatgacg
gaatttatta agcaaaaggg gagttctctg caaagagagg 15840ggtttcacca gcagtctccc
acctcacaat ggagcaccag gactttcaca cacaaactga 15900aaaggctagg ctcctcccca
gcataaggca tgaattcctg gtggttccac cagttttcct 15960actatgcatg tgggtgtgcc
caagcaaacc ataggtagta tcagaaaagg caacatttga 16020ttggttaaaa ggcattattc
acccaagcaa accataggta gtatcagaaa aggcaacatt 16080tgattggtta aaaggcatta
ttcagaaaga atcaatcggg aaagggtgag ccaatagggg 16140aagttctccc tctgggtcac
gggtttcatc tgggaccagg agtctggcct ttcagccttt 16200agactgtttt aggcttgaag
gtgggtttca cagggaccct tccctatctg cctaggcatc 16260tgtctgcctc ctgcctctat
cactttctct tgagttttat attttagcaa cactgagtca 16320tctttgtccc aggaagcacc
tacatctgtt tatctgctgt cccctctacc tttactacct 16380tcccttcttc acatttatac
ccagaaaagt cacttcccct ccaaaaattg ggatcaactg 16440tcatattttt atgaatattt
cactttaatt cctcacaaca gctgacagaa ttaactactt 16500cctcttcttt gcaagttatt
tggctcacac agatatcagt aattaaacat attttactgc 16560attggcatat atctgactaa
tgtgtttttc tcccgtacta ggcaatatgc tccttagtca 16620tctgtgtatc tgaggtgagc
acagggccta actagcatat ggtgcattct caatgttcgt 16680tcaactgcat tgacttgaat
tcccctgaag actgaaatgt gaaaatagct actctcggaa 16740gcccctttcc agagaggtct
aaaatattta catgtttcta ttttaaatgc agaaagaact 16800tccagatcat tataggcctt
ggatggaaat tgccaacaaa cttcctcaat tgattgatgc 16860tcaccagctt caagctcatg
tggacaaggt attcttctct tcaccccctc atcacattct 16920gttttcatca tcataccact
tttctttctt agccttgtgg aagtgtgtca attgtcctgg 16980gaaactgttc attaccattg
aacttatcag caaagctata tcttccttcc tgaaaaacag 17040aatgacccct tcgtaatctg
atacatgtgt tttcctaagg ttttcagagc cagcacaaaa 17100caatgcctga cacatgccaa
taactcacca aatgtttgtt taaagaagaa tctgggtggg 17160aatgataaac taactaatgg
acaaggtatc gcctaagaag gtcagcttgg aaattctcag 17220gttcctcatt ccatgtacgt
actcaaggct ctgttgttac tgagggggtc taacttgatt 17280ttgtcctagg tgttatagaa
tagttaaatg gagggaattt ctgaattata aaattggcca 17340tgggttctac aaaacatcca
ataagcctgt aaattccaca aaagtgttga ttaggctgat 17400acaaaggtaa ttgcagtttt
tgccattact tttaatgaca aaaaccacaa acacttttgt 17460accaacctaa tagctatgta
accctgaaaa agttactcaa ctctgtaatc ccatttcctt 17520atttataaaa tgagagaaac
tctggtctca cagtattgtt atgggaagta aatcactttc 17580aaagtggccc ttttgtagtt
cttgtcctat aatagcattc agtatacatt cattacttct 17640ctgtagtctc ttctccatct
gtcctaatct atcagtttgg agtaccacat aattgcggaa 17700gtccatgaaa agttttccgc
tctccaaaat ttccctttgc tgatggataa tatttaatgt 17760ctagaattac aaattctttt
taaaatactc attgaatgtt tgctttgtgc aaagcactag 17820aaccttgtaa aagatgagta
agggactggc ttcaatgtct gtgaagatag caaactaaac 17880agagtaattt ctttgcctga
tagataaaat gttgtgttga catgaccaaa gaaatccaaa 17940aataagaaaa aaactatctg
taaacacaga aaaatagaga aaagttccaa tgatggaata 18000aaaatttaaa ggattttttt
gaacgtatta agcaaatcat gtataaaatc cagaaataag 18060tttacaggac ccatgtcaag
gatttaacca aagcagaggg agatccccat gagtcccctt 18120ttcccatctc agaatagcag
agaagagaag caagggaagc ctggaacagt tggcaagagg 18180gcaggttaga attcagtttg
tgaattatga ggtcgtctgc cgtaggcatt taccaggctt 18240tatttgattt aactgccata
aaggaagaga aggacttgtt aaattggggc tcctcttagc 18300acagcattga aaccagtccc
tattccttct tggccttttg gctaaaattg agtgtgaaat 18360ctatcaccta acatttgtac
tgggtttagg ctgggtgtgg tggctcacgc ctgtaatcct 18420agcactttgg gaggccaagg
ctggcggatt gcctgagctc aggagttcga gaccagcctg 18480agaaacatgg tgaaaccatg
tctctactaa aaatagaaaa aattagcagg gtatggtggc 18540acatgcctgt agtcccagct
atttgggagg ctggggcaga agaatcactt gaacccagga 18600gacagaggtt gcagttagct
gagatcacac cactgaactc tagcctgggc cacagagtga 18660gactctgtct caaaaaacaa
aacaaaacaa acaaacaaat atatatatat taaaatacaa 18720atttttactg ggtttaatag
tgtcttccta gaagtcatgt tcatgcataa tctgtgaaag 18780tggtcttatt tggaaatagg
gtgtgtacag ttgtattcga gttaagctga ggtgatactg 18840gattaaattg tatatgatga
gtgtccttat aagaagagga aaaattaaac acaggaacat 18900agactcaagg gaaaacatca
cgtgaagatg gaggtagaat tggaatgatg cattgacaag 18960ccaagatgtg ccaaggattg
ctggcagtca ccaggagtta ggagacaggc atggaacaga 19020atggaacaaa ttctccctca
gaggctccag aagaaatcaa ccctattgat accttaattt 19080gggacttcta tcttccataa
ctgtggcaga gtacatttct gctattttaa gtcatgatgt 19140ttgtggtcat tagttatggc
agcgcataaa actaacacaa cactcttggt ctctatcgct 19200tctttttttt tttttttttt
ttgagacaga gtctcactct gtctcccagg ctggaatgca 19260gtggtgcaat cttggctcac
tgcaacctcc agctcccagg ttcaagcaat tctcctgcct 19320cagcctcctg agtagctggg
actacaggca cccgccacca tgcccatgta atttttgtat 19380ttgtagtaga gacggggttt
caccatattg gccaggctgg tctcgaactc ctaaccttgt 19440gatccaccag cctcagcctc
ccaaagccct gggattacag gcctgagcca ccatgcacgg 19500cctctatccc tactcttaat
tgcctggaaa atacctaaca aatgaaggcc agtttttaga 19560ctttaccacc aaaggctgaa
attgaaacag gaattgtttg tgagaagcaa acacaatagt 19620ttcgagagac tgaatcagtt
agcaatttcc tgtgagaggc aaatgtaata gtttctagaa 19680ccacagatgg agctataaca
aaaacatgtg ttctctggat cctttacttg ctacagacaa 19740cacaataagt gaatttacag
ctttgatctt acagtgcacc taagccaacc accttgtctt 19800agaatgtctc aacataccta
tctgtatctt gaaacaaaat atattaattg ccttagaccc 19860attcactcac atttcctagg
aagacatgat cagagggagc tatgcaagaa gaaatccagc 19920agaactctgg aaatacaata
agaaaatcca tattagacac taatcttaat aaaactaacc 19980ttcgttcatg aatttgaata
gacaaaatta ccaaataata tggaaaaaat gggcaactca 20040aaaagaagag ggtagcccac
ttggcattca ggaccaatgg cctccaataa ataagatgat 20100attagtgctt taaatatttt
atttagtgta tccagtatat tgccttccta aattaagtga 20160aagctgatat ataaaaagaa
ctattagaaa taaaaaacca cacacatccc agaactcctc 20220aatataaacc taacaaattc
agtaaaacat tgattgcaaa aaatatatat agtgacttag 20280ggacttcctt gataaatttc
ataaagcata aagaaaaatc aaagagtgca aaccatcaga 20340aaaatacaaa tatataaaaa
agagaaatac aggtgatcca aattcctttt aatggaatcc 20400cataagcaga tgggtggagg
aaaagtaaaa cttccaacat ataagcacaa aatttttaga 20460ccttaagaaa tatttgagtt
ttttatatca gaaagacagt gttggggtga gggttggggg 20520gcacatgtaa atactcagat
aaaattgtga attttctagg gtaaagaaat ctgcatattc 20580atagaaaaca aaaatgaaaa
atagtttatt tacagagtaa atacatacga ctgtttacct 20640gtaatgctaa atattaaaag
acagtttctt ttcttttttt tgagacagag tttcactctt 20700gtcgcccagg ctggagtgca
gtggtgctat atcgactcac tgcaacctct gcctctgggt 20760tcaagcaatt gtcctgcctc
agcttcccga gtagctggga ttacaggcac ccgccaccac 20820acccagctca tttttgtatt
tttattagag acggggtttc accatgttgg ccaggctggt 20880ctcaaactcc tgacctcagg
tgatccaccc gccttggcct cccaaagtgc tgggattaca 20940ggcgtgagcc accgtgctgg
cctaaaagac aatttcatac ctatttgtat ggctaatttt 21000ttaaaaatct ggccatatca
aaatactgaa gaggacgtat agcaatagag actttcattc 21060attgctggtt gaaatgcaaa
atggtacagc cagtttgaaa actagcttgg cagattctta 21120taaaatgaaa catagattta
ccatgcaact cagcaatggc attcctaagc atttatccaa 21180gtaaatggaa aatgtatgtt
cccagaaaaa aaatccatat atgaatgttt ataacagctt 21240tattcataat caccaaaaaa
aaaaaaaaat ctggaagaaa acaggatatc cttcaaccgg 21300ggaatgaata aaccaaatta
taataattgt aaattgtggg atggatagtg gaatagtatt 21360cagcgataca aatgattgag
caattaattt gtgcaatgac agggatgaac cttaaataca 21420tttacctaaa tgaaagatgt
caggcctata ttgtatgatt cttttcaaat gactttttag 21480aaagggcaaa actagaagga
ttaaatatag ctttatggtt actagagaca ggtaaggagt 21540gggtagttga ctgcaaaggt
aatatatagg ggaatgttta gcatgatgaa actgttttat 21600atggcactca ggtgatggat
atatggctct aggcactgaa aaacccatgg aattgtatgt 21660cacaaagaat ggactttcat
gtatgcaaat tttaaaaaat aaaccagaaa attgggagaa 21720tactaggatg gaatgcagac
tgtgataaat aaaactaact ggactctcag caaactaaca 21780caggaacaga acaccaaaca
ccgcatgttc ttacttataa gtgggagttg aacaatgaga 21840acacaaggac acagagaggg
gaacatcaca caccggggcc tgttgtgggg tggggggcta 21900ggggagggag agcattagga
caaataccta aagcatgagg ggcttaaaac ctagatgatg 21960ggttgacagg cgcagcaaac
caccatggca catgtataca tatgtaacaa accagcacat 22020tctgcacatg tatcccagaa
cttaaagcaa atttttaaaa aagtaaaaaa aaaaaaaaca 22080aacaacaaca cctaactgga
ctacaaatgc actatataac ttcgatgaag agagtgggga 22140gtagggaaag gaacggactt
aaattactcc agaaaatagt gttgtgttgt gactagaatc 22200tataaggctt acggtaaatg
aaactttaca ggatcactat actctaattg gtaaatcagt 22260ttttcatggg gtgcgggtga
acagttgtga aactgcttta catgtagtca tacctttgca 22320ttttgcagat atttcaattt
ttacaaattg aagattcgta gcaaccttgc atcaagcaag 22380tctgtcaacc ccatttttcc
aatagtgtgt acgcatttgg tgtctgtgtg tcatattttg 22440ataattataa caatagttaa
aactttttct ttactattac atctgttaca gtgatctgtg 22500atcagtgatc tttaatgtta
ctatcataat cgttttgaag gtgccataaa ctgtgcccct 22560ataagtcctg aaacttaatt
gataaatgta tgtgttctga ctgctccact gaccagccat 22620tgccccatct ctctccccct
cctcaggcct cctgatttcc tgagacataa taatattgaa 22680attaggccaa ttaataatcc
tacaatggcc tctaagtgtt caagtgaaag gagttgcatg 22740tctctcactt taaaaatcta
aaactagagg ctggtcatgg tggctcaggc ctctaatccc 22800agcactttgg gaagccaagg
cggggagatc acctgagttc aggacttcga gaccagcctg 22860gccaacatgg cgaaactctg
tcttgactaa aaatgcaaaa attagccagg catggtggtg 22920cacacctgta atcctagcta
ctcaggagac tgaggcagaa caatcgtttg aaccctggaa 22980atggaggttg cagtgagcct
agattgtgcg attgcactcc agccagggca acaagagtaa 23040aactccttct caaaaaaaaa
aaaaaaaata tctaaagcta gaaatgatta agcttggtga 23100gaaagtcatg tcaaaaccag
ataggcttaa agctgggcct cttttgccaa acagccaagc 23160tgggagtgca aaggaaaagc
ttttgaagaa aattaaaagt gctactccag tgaacatacg 23220aatgataaga aagcaaaaga
gccttattgc tggtatagag gaagtttgag tattttggat 23280agaagatcaa accagccaca
acttccctta aaccaaagcc taattcaaag aaaggcccta 23340attctcttca attctacaaa
gtctgagagg gctgaagaag ctgtagtaaa aaagttttaa 23400accagcagaa tctggttcat
gaagtatgag gctagaagcc atctccacaa cataaaagtg 23460caaggtgaag cagcaagtgc
tgatggagaa gctgcagcta attatccaga agatccagct 23520aaaatcatca atgaaggtgg
ctacatttat tttttatttt tgttatttat taatttattt 23580attttgagac aaagtcttgc
tctgtccccc aggctggagt gtggtggcat gatgttggct 23640cactgcaacc tccacctcct
aggttcaagc aattctcctg cctcagcctt cccagtacct 23700gggattacag gcatctgcca
caacgcctga ctaatttttg tatctttggt agagacgggg 23760tttcaccaca ttggccaggc
tggtcttgaa ctcctgacct caggtgatcc acccgccttg 23820gcctcccaaa gagctggatt
acaggcatga gccaccacgc ctggccagtg gctacattta 23880aaaataggtg ttcaatgcag
acaaaaccat cttttattgg aagaagattc caaccaggac 23940tttttttttt tttttttttt
tgagacagag tctcactctg tcgccaggct ggagtgcagt 24000gatgcgatct cagctcactg
caatctctgc ctcccgggtt caagtgtttc ccctgcctca 24060gcctcctgag tagctgggac
tacaggcacg tgccaccatg cccagctaat ttttgcagtt 24120ttagtagaga cggggtttca
ccatgttggc caagatggtc tctatctctg acctcgtgat 24180ccacccccct tggcctccca
aagtgctggg attacaggtg tgagccactg cgcccggccc 24240aggactttca tagttagaaa
aaagtcaatg cctagcttga aaggacaggc tgactctctt 24300gttaggggct agtgcagctg
gtgactttaa gttgaagcca gtgctcattt accattcctg 24360aaatcttagg gcccttacca
gctatgctaa atctactctg cctgtgctct gtaaacggac 24420aataaggcct ggatgatggc
atatctattt acagcatgct ttactgaata ctttaagctc 24480actgttgcga cctactgctc
agaaaaaaat attcctttca aaatattact gcttattaac 24540aatgcctctg gtcacccaag
agctctactg gagatataca ggaaataaat gttgttttca 24600tgtctgctaa cacatttgtt
ctgcaaccta tggatcaagg ggtcattttg gctttcaagt 24660cttattattt aagaactata
ctttgtaagg ctattcctga cacagataat gatccctctg 24720aagaatctgg gcaaagtcaa
atggaaacct ggaaaggatt cactattcta gatactatta 24780aaagcattca tgattcatgg
aggacgtcaa aataaaaaca ttaataggag tttgcaagaa 24840gtcaaccctc atggatgact
ttgaggggtt caagacttga gcagaggaag tcactggaga 24900tgtcgcagaa atagtatgag
aactaaaatt agaagtggaa tctgatttta taactgagtt 24960gctgcaatct tacgattgaa
cttttctttt cttttttttt tgagatgccc ctgctgagct 25020gccagttcct gaagggtcac
cgggagcagc gcctggccca cctggtcctg agcttcctca 25080ccatgggtta tgtctggcag
gaaggagagg cgcagcctgc agaggtgagg gccagagagc 25140agcttctcct gttacccggc
aggttacctg cgcctggagt aacgtgctcc ctgcttggtg 25200ctaccctgtt ttcctggaaa
atgggtactt tcttcttctc gatgggcatc agtttaagca 25260acgatgaagg gctcatttat
tatttattat tattattttt ttattttatt ttgagccagt 25320ctcactctgt cactcaggct
ggagggcagt ggggtgatct tggctcactg caacctcccc 25380ttccaggttc aagcaattct
cctgcctcag cctttcttgt agctgagact acaggcaccc 25440accaccacac ctggctaatt
tttgtatttt tagtagagat gggtttcacc atgttgccca 25500ggctggtctc gaactcttga
cctcaggtaa tctgcctgcc tgggcttccc acagtgctgg 25560gattataggc gtgagccact
gcgttcagcc tgaagggcca tttaaatgaa ggattttttt 25620attttaattt ttctgactaa
gagctaattt gttttttaaa ctggtagcta tttcttcctt 25680ttataagctt ttgaatgttt
gtttgtttgt ttttggcact ctcttccaag aatgtttgaa 25740gacctgcatt tgaaggcaga
ttgccttttt gctttaaaac agggttgcac catgttgccc 25800aggctggagt gcagtggtgc
aatcatagct cactgcagcc tcaactcctc ccaggctcaa 25860gcaaccctcc cacctcagcc
tcctgagaag ctggggctac cagcatgtac cgccacaccc 25920agctaatgtt aaaaattttt
tgtagagatg agggtcttgc tgttttgccc aggctgatct 25980taaactcctg gcctcaagtg
atcctcctgc ctttgcctcc tgtgctggga ttacaggcgt 26040gagccaccat gccgggcctg
aagacagact ctgagaattc ataaaaacct cacagcattt 26100tgtactctta tgtatataaa
ttatctaggt tgctcttcat aatcctgtaa agtaacaaga 26160gccataccgg cccattttac
aactgaaaag cacagacact tatttcctta atcaaggtca 26220gacagcaaat tagtggaaaa
gccaaggcca gaacccaggt cttctgattt tactagtgca 26280gccttctttc cccaggggac
acattgacat ttacaacact catctttatt ttttttttaa 26340tactgctttc tatccagcca
attattagtc tgtcttttaa taattcatcc aaatctcttc 26400tgaatcattg cataactttg
tacagtttcc acccacagtg tcttttactt ttatttttgg 26460aagtaactgt ttttaaaagt
tactgttatt tttaaaagtg tgccttcccc agaaatcagg 26520gagttaccca tgtcctagaa
ctccacggtg aagagaacag cctgtgccca tcgtgtttgc 26580ctgattgatc ctacctcttg
tctctcgggg aaacacagga gactcaggga agaggaaaag 26640tgtagagtca ttgcagcctt
gttatttgtc aatgcatctc ttttcttttt ctttttcttt 26700ttttgataca gagtttcact
cttgtcgccc aggctagagt gcagtggcgt gatctcggct 26760cactgcaacc tcggcttcct
gggtccaagg gattctcctg actcagtctc ctgagtagct 26820gggattacag gcacctgccg
ccacggccag ctaatttttt ttgtattttt agtagagacg 26880ggtttcacca cgttggccag
gctgatctcg aactcctgac ctcaggtgat ccacccacct 26940gagcctccca aagtgctgtg
attacaggca tgggccccag cacccggcca gtgcattgca 27000tttttttttt ttttttcgag
acggagtctc actctgtcac ccaggctgga gtgcagtggc 27060acgatcttgg ctcactgcaa
gctccgcctc ccaggttcac gccagtctcc tatctcagcc 27120tcccaagtaa ctgggactac
aggcgcccac cacaacgcct ggctaatttt tatattttta 27180gtaaagacgg cgtttcacca
tgttagccag gatggtctcg atctcttgac ctcgtgatct 27240gcccgccttc gcctcccaaa
gtgctgggat tacaggcgtg agccaccgtg cccggcgtgc 27300atttttaaaa gtgtgtctga
tgctgaaaag tttgaagtct aggcacgtcc cagtgggtcc 27360tctttatacc atcccctctg
caaaccatta tcctaaattg gggtttgggg gagagaagag 27420tgacagtgga aagaagtctc
cacctcccag ctgtgccctg gtagttccag gggacccgga 27480ggctccccac acccaccacc
ccgcctcaga tcacctttca ctttctttgt ttctcctccc 27540ttgacttttc agctcagaaa
gtacctggct ctccaatgcc ttctgaggaa agtttacccg 27600aggttcacat tgcaagactc
attaaagctc tttagtgttt tccacccgag aaaaaattca 27660agggaaaaat gaagacaaaa
gcagggcatt cttaatggat attttatctt aaggagaaat 27720gaaaatggag atggaagagg
gggcacaagg atggggtttg aatctagact cgttcagcct 27780ttacctccga tagagaacct
catacagctt ttctggactt ctggctgata aagagccgtg 27840gagggttcct tggataaaaa
aggttgaagg gggtctgtcc tgtggtggct tacttgaagg 27900tattactggg tttgacttat
ggagtaagag acggagtcag tttccccaca ggctgaggca 27960gtctgtcctc atgcttttct
agggcactgt ggtctcccag gctcatacct aggtgcacac 28020acaggtttct gcatctagct
ttgtatctct atgagtcggt caatcaataa atctatctat 28080catctgtcta ctgatctatc
atctatctat ctagctagct atcatctctc tatcatctat 28140ctatgtatct atcatctctc
tctatatatg tgtgtatata tatatatata tgtatatata 28200tatttctatc cttccatcta
cttacctatc tatcaaaatt tttttccgtt gataatattc 28260tcgggcccca gtttatgttt
aattgttttg gtaatgcctt tctttgcaca gtcagtttac 28320agaggttatt ttatattcta
tatgtatgtg tggtccagcg ttgtaatttt cacatatatt 28380gcaccgtgta ctcataagca
gtatttccac tgggtcatta acagaaagat atgtgtgcgg 28440catatgaatg tgcatcactc
aggtaattca agcttggttc ccagatcatt tctgtaccac 28500aggattgccg aaataaaaga
caaccatggt tatttcctct gctgcaagct ttctagaata 28560tgctatttgt ctggatttat
atctgaaagg tcctgccaag gaatcttgcc cttccatttg 28620tcgaagtctc caggaacttg
gggctccctc ctatcctggt ccactcagac ttggtgctga 28680cgaactggac caaaaaagat
ccagacgggt aaggaaggaa gagaatgctt tgaatttcca 28740taactttccc ccaggaaaca
cccaggcttt tttttataat tagggaagtt catatttatg 28800gtctgccgta tggttccaaa
gaaggggtga gcttgaccaa aaattcaaat atcacaggcc 28860ccagaagttt cctcttaatc
cattctgaac acattggctc agaccatttt gtcttgtttg 28920tttccacatg acgtgtgaat
ttctcaacct gaccttcaag ctcctgcaaa atcagctttt 28980atttgttctt tctcttcaaa
ctgtttattc cctaagatgc cctccattca tatcaggtta 29040aaaccagttg gctttgataa
gtaatcatta tataatgatc agaagagaat gattatggat 29100gaattcagag cagatgctcc
aggtgggttg gattgagaat ttgattaata attccatcta 29160ttccaccaaa gtcacatcat
tcctttgaca gttgggctgg gaataggggc atttgtctac 29220agaaggaata gcatgagatt
ttaacaaaca agaaattcaa caaacagaat tagacagatg 29280atctgagatg ttaaattttc
ctttcacctt aatttttgca gccaaattta tttcagctct 29340agatgaaaga gacagcactt
tcttttgtgg ctgactacaa cagctgaaga ttcactgagg 29400tttgatatga ggaagaactt
cctcagccat gggattgcca gaggcgatga tgggaatcta 29460cttaaaaggg ttacatattt
agtagacagc ctagatttta agactaattt atgtgccccg 29520gccgggcccg gtggctcacc
cctgtaatcc cggcactttg ggaggctgag gcaggtggat 29580catctgaggt caggagttga
agaccagcct ggccaacatg gtgaaacccc gtctctacta 29640aaaatacaaa aaaattagcc
gggcatggtg gcacatacct gtaatgccag ctgctcggga 29700ggctgaggca ggagaattgc
ttgaacgaag gaagtagagg ttgcagtgag cgaaatcatg 29760ccattgcact ccagcctagg
tgacaaactc tgtctcaaaa gaaaaaaaaa ttatgtgccc 29820cattggaaga agtgagattc
ggccatctca tctctctcgg gagctctgag ccctggagtt 29880ttatgttttc tgcaattatg
aattgtgatc cttgattaat tatgctttaa taataaaatg 29940ggtgactact gaaagctgct
gaatctgggt aagaatttgg atgaaaaaaa taatatatgt 30000gcgtaattta ttctgttcaa
ggtactgaat attgaataag ctggatttat tactcaaaga 30060gaaagacaga ataagagaag
gttgaaggga aaaatgactg tactagaatg gtagtcaaaa 30120atgcaacaac aggcaggtgc
agcggctcat gcctataatc ccagcacatt gggaggccca 30180ggtgggcagg tcacctgaga
tcaggagttt gagaccagcg tggccaacat ggccaaaccc 30240cctctctact aaaaatacaa
aaattagcca ggtgtggcag tgggtgcctg caatcccagc 30300tactcaggag gctgaggcag
gagaatcact tgaacctggg aggcagaggt tgcagtaagc 30360tgagactgca ccactgcact
ccagcctggg tgacagagtg agatcctatc tcaaaaacaa 30420acaaaacaaa acaaaacaat
aacaaaaaag ctattaatag cttcctaggg agtaagagtg 30480aagggctagt ttaattccag
agatgcggac acagtcctgg gtctcaccaa ttattctgct 30540tggtaattac cttttgaagc
cttttaatat gcctaacaca gagctaagtg ctatgaagaa 30600atgaaagaaa tagaagcaaa
gtactcccca tgtggttaaa taacaagaca ctacatgaca 30660aatgtcaaag agtgactcaa
acaatatgtc ctttagaatt tcagagaaat gacatcaatg 30720caggctttac aagtcagtaa
aaatcttggt gatgaggcag aacttgatgt aaggcaaatc 30780ctaaaagttg agtaggaatc
aactagctag aataaaatgt ggggttgtgg taaatacaaa 30840aatgtaagat gagtgaaata
acttatttat ttatttattt attttcagag acggagtctc 30900cctctgtctc ccaggctgga
gtgcagtggc atgatctcgg ctcactgcaa cctctgcctc 30960ctgggtttga gcaattctcc
tgcctcagcc tcctgagtag ctgggattgc aggcacctac 31020caccacaccc gactaatttt
tgtattttta gagagatggg gttttaccac gttggccagt 31080ctggtatcga atcctcgacc
tcataatcca cctgcctcag ccttccaaag tgctaggatt 31140acaggcatga gccactgtgc
ccagcctaat aatatattaa gatggccaca ggccaaatat 31200tctggggctg gaatgtgagt
ggaaatgtcg ctcacccttt atcacatagc accccatagt 31260ccagccacaa cttgcagaat
tcaaagtaag tgtggatgtg tgtgtgcctg cagtgccttg 31320cacacaagtg tgcatgcctg
tggacatgtg accctagaag ttattaatat atctggttta 31380caaactgaat tgttctttta
ttttttttct ctcttggtgg tcatcaataa ctgaaattgg 31440gctagattcc tggaaattgg
gtaagttctc agaaatcatt tacgcacttt agaatccagg 31500ccaaatttaa aatcttacaa
taaaacaaag aacaaagcat gctaaattat atgtataata 31560taatatcaac catataaaat
gcataaaaaa tatactagaa ggaaatgtgc ctaaaattca 31620cagtctaaaa tttaacagtg
attgcctctt ccttgtatag ataagggatt tttttttact 31680gtattttcca gtctgtacat
aataaaacaa gtaatgtgca atgcaaacaa aacaaaatga 31740aactttatca aatttcagta
actccttgaa gtttaatttt ttttttgaga ctgagtctta 31800gtctgttgcc caggttggag
tgcagtggtg tgatctcggc tcactgcaac ctctgcctct 31860gggttcaagg gattctcctg
cctcagcctc ccgagtacct gagattacag gcacccacca 31920ccacacctgg ctaatttttg
tatttttagt tgagacagcg tttcactata ttggccaggc 31980aggtcttgaa ctcctgacct
caggtgatcc acccgccttg gcctcccaaa gtgctgggat 32040tgcaggcgtg agccactgca
cccagttgaa gtttaatagt gtgaaaaaaa tatttctcat 32100ctcactatat cttctatggg
aggccagatt gcagattgtc tacagaaaaa tcccttcaaa 32160agaccttgtt attacataga
ctggagctca tggggcaggt ctggtccaca catccttagg 32220ctccgcttct cctggaaaac
aaaaatagcc tctgatccag tgttgcctct cccatcacca 32280aacctcagct tctatcgcca
aactcatcaa ataagagtgt ccagtagaaa aactgggcag 32340atgggggcac agaaggtgaa
gacatcattt cccaagctaa tgttgctgct ggaacaatgt 32400aagtcttgac tttgtcttgg
tttggtttgg tttgacattg gtttgttttt catctttgtc 32460tcatgcttaa aatgtgaagg
gcaaatatga tccttagagt taaggtttta ggttttgtag 32520atgttttact ccatttaaat
gacagcagat catttagaaa tgattcctct gtaacagcct 32580tccagatccc attcgattgt
acagcattga gatagataga tagatagata gatagataga 32640tagatagata gatagacgga
atttggccct gtgttcccac ccatatctca tgtcaaattg 32700taacccccac atgtcaggag
agggatccag tgggaggtga caggatcatg gggttggatt 32760tccccaatgc tattctcatg
atagtgagtt ctcacaatat ctcattatta ttattattat 32820tattattatt gcaacagagt
ctcactctat ctcccaggct ggagtgcagt ggtgtcatct 32880cggctctctg caacctcttg
cctcagtctc ttgcgtagct gggattacag gcatgccccg 32940ccatgcccag ctaatttttg
tatttttagt agagacggag tttcaccatg ttggccaggc 33000tgatctcgaa ctcctgacct
caggtaatct gcctacctcg ctctcccaaa gtgctggaat 33060tacaggcgtg agccactgtg
cctggccagt tctcacaaga tctgatggtt taaaagtgtg 33120gcacttcccc cacctcctgc
cgccatgtaa gatgcttgct tacccttcca ccatgattga 33180aaagtttcat gaggcctcct
agccatgctt cctggtaagc ctaaggatct ctgagtcaat 33240tacacctcgt ttctttataa
attacccagt ctcaggtatt tctttatagc agtgtaagaa 33300tgaactaata cacacataaa
cagattagag gcagcactgg cctgagttgt gaaactcttc 33360ccagcctggt cctgcgatta
gctggctata tgaccttgga caagctgctt tgcttctctg 33420ggccatggtt tcatacctgc
aaaaaaaaga gcatggactt ggctgttgcc tgggtctctc 33480tagccctgtg gagaatcagc
tacatctctt actaggaact tctcattcag ccagttattc 33540cactgcggag atggtccagg
accattaggg ccatgctaga cattgggagg ctgcctgtca 33600ggtgaacatg aaattgaact
tatctgttct ctttcctccc tgaatgttgc tgaaggtaga 33660tgcccatcct cagggctgtc
ttacggagag gagaaagttg tgcagtgatt ccaccctgca 33720gttatctaac tcggcaggga
actctgggca gtgagtactc acggtacagt ctccacacct 33780ctaatcatgt gctcctctcc
ttcccaagga acctggagac catcatctca tttcctgggg 33840gagagagcct gcatggtttt
atactggtga ctgctttggt agagaaagaa gcagtgcctg 33900ggataaaggt atcttctcac
ttgatagcac cttttctttt taaatgagct tgagctttac 33960ttcccactca gtgcctttcc
tgcagtggat ttctcaacac aaatgaacat agaccttgtc 34020ctgcttagtt caagtctgag
agaagagatc taagctctag gccaccatat ttgctccctt 34080ttctcaattc ctataaaact
cggaatggac cttttgtcca ttcaacaaac aggcattggt 34140ttgggcaatg ggaaattgga
tcgaacaaga cagacatttt cccagccctg acagaagctt 34200atgatggata cagtggatga
agatggatta acgtggatta caggtgtgag ccactgcacc 34260gggcctcaaa ctggaaattc
ttcaggagtc agacaggtat caggaaggct ggatagaaga 34320caaaagacag tgatgcagct
tgtgatcaac tacagcgtta atgccttgcc taaaaatatt 34380tcagttagat ttctgccttc
gctctgtcgc tcaggccaga gtgcaatggc gtggttttag 34440ctcactgcaa tctccacctc
ccaggttcaa gcaattctcc tccctcagcc tcctaagtag 34500tgcacgccac cacgcctggc
taatttttgt atttttagta gagacagggt ttcaccatgt 34560tggtcaggct ggcctcgaac
tcctgacctc gtgatctgct tgcctcagcc tcccaaagtg 34620ctgggattac aggtgtgagc
caccctgccc agccaacact acctcccttg ataagcatat 34680gttgagcacc tactggtcct
caatagggtg acccatttct gctatattat agcgctttct 34740ttctctctca gtagttaaac
tccatggtta ctttagttct catccatgtg tttagtccat 34800tagaagatac agagtcaaat
atcggccttc caagtgtagt tcagatgaag tagagactca 34860aggaagacaa ggaagtcttc
ccagcagagg ggattctaga gctgggggct ctgtagaatc 34920tgtctgtgta ttagtccatt
ttcacactgt tataaacata ctacctgaga ctgggtaatt 34980tataaaggaa agaagtttaa
ttgactcata gttctgcatg gatggggagg cctcaggaaa 35040cttacagcca tggaggaaag
tgaaggggaa gcaagaacct cttcacgagg cagcaggaga 35100gagagcaaag gggggagctg
ccaaacactt ttatacaatc agattttgtg aaaactctcc 35160ctcgtatcat gagaacagta
tgggagagcc cacccccata attcaatcac ctcccaccag 35220gtccctccat cagcctgtgg
ggattaccat ccaagatgag atttgggtgg ggacacagat 35280ttcaacacag atttaaatct
gactttatat gagagcttcg gagcaaggat gccccagttg 35340gagatgcagt agaactgatc
ataacgtgac aaatccgaga gaagaagagt aaaataatag 35400tactcaggcc cttgggaggt
gcaagaagta acagccagat gaaattccag aaacacttac 35460ctaggggtct gtctgggagg
tccccaggga gcttctggct gtcaggccaa ccccacagtg 35520gatctagctt aggacgttcc
caggaagctc tgacaaactg tccggtcctc ccctgggttc 35580caacagtatg aggcttactc
tgcctgcatg gactttaagg gagtgctaat aagttgtgta 35640catgcatctc atccctaggc
tcttgttcag gccacgaatg ctatcttgca gcccaaccag 35700gaggccctgc tccaagccct
gcagcgactg agactgtcta ttcaggacat caccaaaacc 35760ttaggacaga tgcatggtaa
gatgcttccg aagctcctga aggatccccc aggggtcctg 35820ggctctgctt aggggaagag
ggcctgggga ccaggcatgt cctgaagggg gtgataatac 35880attcatccac cagatgacgc
tggtggacta tctttgtttt aggttaaaca catattatct 35940tggagagcta ttgtcacagc
tttgtattct ccctctcctt tatattctcc cgtgattaag 36000atggtttccc ttctgcagtg
gccagatatt tcttaggcat gttgaggtct tgcctgaagc 36060ttgagaggag gggatgggat
gcacagtaat gttggtcgcg cgtgccccat cctgcagtgt 36120taggtactgc agagcaggtt
gtctacactc tgtaatgccc cttttattct aaccccctgt 36180gttggttcct gagatgtctg
accttggttt taagccttgt ctaatggatg gcctgtattc 36240cctttctgta gctagggcag
gctgatttgt caaaggtagg aaagttgtca gaatcaaaat 36300ggagtcactt gtgttgaata
aaaattttta aaccttgaca aatagagctg gggaaggcta 36360caaagagaga gctcccgtgt
ataaatgcct gataacaaaa tcttttccaa aggactgaaa 36420aaatcaccac cttgcacaaa
ggccatcaca accttacata cacaaaaaaa tacttacaca 36480acgacatctg cccagcaact
gcctttccaa cattggcctt gtgccaccct ttttattgat 36540gctcatagcc aaggttaatg
atctcaaaac agttacataa ttgtcctcat ttttccttta 36600aaaacctttg tcttccttta
tctttctgaa tacccacatg gtttattatg gcacatgtat 36660tcccattgca atgccctatt
ccagaataaa tatcagtttc cattagggag cctctccctg 36720ttaatctgct taacacaggc
atggtcagtt acggggccca accttcctgg accggttaca 36780tcttattctg gttactgcat
tcagtttcca acatctggga ggctcttcaa attcttctct 36840cagaggaatc tgaagaatgt
atgtgtttag gaggatgtga gagaggggtg tggtttctta 36900acaagagaat atcagagtct
aagtatcatt ttccctgaat cttgcttccc tgcaggaaag 36960aaagattctg ggaaaagaga
gtgtttacaa gaagcaggac tggagggagg gagaaagacg 37020ctaggtactg ccaagcttta
ttatcttgta ttaaaaaagt aaatataatt tgtcatccca 37080gcctctcagc actagtagaa
atctatctga agtcacagga ttaggtatta tccacttcct 37140ggttttatag tttatatttg
tattttctct atttccttga attttaattt taaagccctc 37200atgatcacat cagtaggtct
tctgccaaac agctccctta agttgtatgg tggctttgcc 37260aagctgaaat gagatgagat
gtgttttagc tttgccaaga aagcctgagt ccatcactta 37320ggatagcaag gctattaggg
agatagtgca ggtgtcttca gatcacatgg atgagcaaaa 37380ggaagcaatt ttggaagatt
atgagaaacc ttccaacagg tcccagtgta catagcagta 37440agatggtgca tgcagtgtct
aactgtcaca ggctttccta gggctcactt tcagactcac 37500ttcttttttt tttttttttt
ttttgtgaga tggagtctca ctctgtcact caggctggag 37560tgcagtggca cgatcttggc
tcactgcaag ctctgcctcc cgggttcaag cgattctctt 37620gcctcagtct ccctagtagc
tgggattata ggcatgcacc accatgccca gctaattttt 37680gtatttttag tagagatggg
gtttcgccat gttggccagg ctggtctcga actcctgacc 37740tcaggtgatc tgcctacctt
ggcctcccaa agtgctggga ttacagccgt gagccactgc 37800gcccagctca gactcacttt
ttaggcccag gccaacctgc tgtgttctcc tgctcagctt 37860ctgcaggagg tctcatcgtc
taaggaggtc ccagggctac cgcccttgtt ttctcaaaag 37920gcacattttc ccacacagac
ataatttcgt ttcagtgttt tactcctagt cacattcatc 37980tatatggaca aatagctgaa
tggattggac tgtgttttct aaagatggcc ccatgccatc 38040ctgcgcgctc ctccacagcg
tggcctgggc attcctttcg accaggggtg gactctgtgc 38100ccctacttgt gatgtacgtg
ttgccaatag aatgtagtat aggggatagc acagacttct 38160gaggcaagac tagaagaggt
gatgcaggtt taaccttgtg tcctgagcca ctaggtaaaa 38220agtccaccta ccctgagatc
actctgctgt gcaaacgaca caggcaaacc acatcaaaga 38280gccatgtggg ttctccagtt
ggcttctgcc caggagtgaa ggtgccctca gatggttcta 38340ggctcccatc ccaacttatg
tcctgtcttg aagtcttccc aactgaggca ccagccactg 38400tggagcagag tcaagccatt
gccatcttgt tctgcccaga ttccccatca acagaatata 38460gtggtttttt cacacctcta
tgtttggagt ggtttctatg cagcaatagt aaccacaaga 38520aataaagtta taaaaatagt
aacaaacact agaaactgca agatttaagg aatcacctga 38580atgctccagt cattgtctct
ggtttgtaat gataaacttt cttctgcgtg ataaatagag 38640cttggctgga ctttttccct
ctgcttccat tccccaaaat ggagcgtacc aaacaattgc 38700ttctttcaga gcccagcttt
agcaagagtc atgagctcta atcccttcat ccataaatac 38760ttcctttcca ggcacgtaga
gcccttcaca ctcagggctg agtagaaaat gcctgttgca 38820gactgcagtg gcgttttgga
gagccaccct cctggtacct gagtcactag tcctttgccc 38880agcttttctc agttttgtaa
agcgctcact tctgagtgga agacagaacc agcccggtct 38940attttcataa tctgccccca
taaggcagaa gtccacacgg tactggaaac ataaccatat 39000ctatgtcagt ctgccactgc
ctgccgcctg tcaaccgtgc gtgtctgcat ccagtccttc 39060tttggagctg ctttccagcg
actcagccag atctgagctt tctgactcat tggaaggtta 39120aactattttc agactttcaa
gtgttgagat tattaagaca tgtgtttttt tttttcttct 39180ttttttggca tgcttactga
tcgcccctgt tctctaggaa gtaatgttct tcttggaaaa 39240ggtgaaggat atttttctcc
ccaaaaagcc atggaaatgt ttgcctttat ttacttccaa 39300attaacagaa tttccagctt
ttgcttgacc catcggcgca ttggcagcgt taagaatttt 39360ttcttttagc agtaatgagg
agtcgaaggg tttcttccta accatttagt gtatgcattt 39420aaatcaggtt tctttttgag
taaattgggg ctaagctgta gtgtgaactt ctgctactgt 39480tcctttctca ttagttcact
tgatttcatg gaaggaattt tccatctcag cctgtgaact 39540tattttgtct aaactcaatt
ggaaagtaat taacactgag attcttcttt aataaattct 39600atatgataat aaaatcatac
aaacatctct ttatttttct ttttgaccta gaaaagatgt 39660tcacaggcca gacctggtgg
ctgaagcctg taatcccagc acactgagag gaagaggcgg 39720gtggatcaca tgaggtcagt
ccgagggcag ggtagccaac gtggtgaaac cccatctcta 39780gtaaaaacac aaaaattagc
tgggcatggt ggcacatgcc tgcaatccca gctactcagg 39840aggctgaggc aggagaatca
cttgaacctg ggagatggaa gttgcagtga gcctagatcc 39900tgccactgca ctccagcctg
ggcgacagag tgagactctg tccccaaaaa aataaataaa 39960taaaagatgt tcacaatata
ttgttaagtg aaaaaagcag gctacataac ttgcataata 40020tgagtgcatt ttaataaaaa
tatacatatt tagcaaaata aaaggacaaa tggtatttat 40080taaaatattt acgttgatta
tttcaacaca gaggatgata gttgattttg cttaatttct 40140tccctccttc ttttcaattt
gaattttcta taatgaagat tgtttctttt tctttctttc 40200tttttttttt ttgagatgga
gtttcgctct tgttgcccag gctggggtgc gatggcgcca 40260tctcggttca ccacaacctc
tgcgtcccag gtttaagtga ttcttctgcc tcagcctccc 40320tagtagctgg gattataggc
gtgtgccacc acacccggct gattttgtat ttttagtaga 40380gacgggcttt ctccatgttg
gtcaggctgg tctcgaactc ctgaccttag gtgatctgcc 40440cacctcagcc tcccaaagtg
ctgggattac aggcatgagc caccgcgcct ggactgatta 40500ttttttaaat agggttagaa
agtgaggaag ttactaaact ccgattagcc caaatatgcc 40560ccagtgggtc cttctggcag
agtaaatgtc tcggttcagc ctgaatctgg gaaattgttc 40620ctacggttca gcctgaatct
gggaaattgt tcctacctta taaactggag tatccttcag 40680aaatgacatt tactcaaact
tccttttagg cagactgcat aatagcaatt tttaatatta 40740accatttaaa aaaaaccttc
agattaatta acaccaaaag aataattggg aaaatacaac 40800tcctcacttt aaaaaagaaa
caaccaaagt aaatactaaa aaactatatg atgttatatt 40860atctaagctt agtttactgc
aaagatcaag agcacactac tagttgacgg cctctattca 40920cactgttcat agccctcgct
cgcttctcca gccattcact cactcatgca aaaggtctgt 40980acacacaatg atgcctgatg
gtataatagg aaccttaaca tttcaattaa aaggcaaaat 41040gaggacactt accatcagcc
tataaaatta ttcttattat tcttcttctt cttctcctcc 41100tcctcctcct cttcttcctt
cttcttcttc ttcttcttct ccttctcctt ctccttctcc 41160ttctccttct ccttctcctt
ctccttctcc ttcttcttct tcctcttctt cttcttcttc 41220ttcttctttt ttttttgaga
tggagtcttg ctctgttgcc caggctggag tgcagtggtg 41280tgatctcggc tcactgcaac
ctctgcctcc caggttcaag ctattctcct gcctcagcct 41340cccaagtaac tgggattaca
ggtgcatgcc accacgcccg gataattttt tgtattttta 41400ctagggatgg ggtttcacca
tgttggccag gctagtctct aactcctgac ctcaagtgat 41460ccacctgcct cggcctccca
aagtgctggg tgtgggcggc aagccaccca ggtgccaagg 41520caagagacag agggcacgag
ctgttccagt ataatgagga aaatatatag aataagaata 41580gttatactag aaatagatta
tagatatgat tacatatgaa tatcattctt cattagtttg 41640tagcactact ctttattcca
gtattataat aatctttgtt ctacaattat aacctaggaa 41700aaaccaggcc atacagagat
aggagctaaa gggacagggt gagaagtgac cagaagagtg 41760tgagccttct gttatgcccg
gacagggcca ctagagggct ccttggtcta gcggtaacgc 41820ccgcgtctgg gaagatgcct
gtcacctaac ggaccgtggt ctagcggtag cgtcagtgcc 41880tagaaaaggc actcttttta
aatatacttt ttatttttgt ttaatcttcc ctgatttcct 41940atagatctga gatatgtcat
gcttattttc attgctatct aaaaatctca ataaacttta 42000tacctaagag taaaaaaaaa
aaaaaagaaa agaaaaggcg ctcgttactt agccgaccgg 42060gaaagggagt ctccctttcc
ccgggggagt tagagaagac tctgctccac cacctcttgt 42120ggagggcctg acatgagtca
ggcctgcctg cagtcatctg gaggcctaac cgtctccctg 42180tgatgctgtg cttcagcggt
cacgctccta gtcctgaaca cctggctccg ccttttagat 42240agcagtagca gaattagtga
aagtactaaa agtctttgaa atgcagaagt aatggcgtaa 42300gctgtcacgt ctctctctcc
gcctcagctg ccaaacagag aagggtcccc tgtccagtgg 42360acacgtgact tgggtgacct
tacctgtcat tggagacgac tcatactcct taccctgccc 42420cttgccttgt atctaataaa
taacagctca atctggcatt tggggccact actggtctcc 42480gcatcttggt ggtagtggtc
ccccgggccc agccgtcttt tattctatct ctttgtcttg 42540tgtctttatt tctaccatct
cttgtctccg cacacgagga gaaaaaccca cagaccctgt 42600agggctggcc cctacagctg
ggaattacag gcatgagcca ccgcatccag ccagcctaaa 42660attcttctga aggataataa
tatagtactt gaagacacgg tttgaaaaaa atcatactaa 42720atgaaagggc accattttac
aagcactaga actacattaa acttaaatga attccaacac 42780tcttaataat gtaactcaaa
aacaagtcta gtgttaacaa aagctccaat aactaaaact 42840acattaacag gcacaatgaa
cattgtaaac gccgctaatt ggcaccaagt ttaatagggc 42900agacaatatt ttcttctgca
ttcacactta ctcagttaca ctgttgaaaa atgctgctgc 42960tcaagctatg aatgctttac
aaaagaaatc attttaataa atacagtaaa tgctaaaact 43020ctagctaaac tattatgcaa
gatatacaac caagacaaat acaaattcat aatacaagca 43080acttgcattc aaaatgaact
ctaccactat attttattaa aagggcagac tttatgaatt 43140aacccagctg cttcctgaat
tacaaaagtg gcatgactca atatgaaaat aagaaactgt 43200ctacaaattt ctgacagtaa
taaattgtaa tatacaatac atgcaggagt cttacggaag 43260aataaactct cctaggaaac
aaaaatattt tatactttta aaatccaaag taaaaaaaaa 43320agaaatcatt gccagatgcg
gtggctcatg cctgtaatcc aagcactttg ggaggccaag 43380gcaggatcgc ttgagcccag
gagtttgaga ccagcctggg caacatagca aaaccccatc 43440tctacaaaaa aatacaaaaa
ttagatggta atggtggtga gcgcctgtgg ttccagctac 43500ccaggaggct gaggtgggag
gatgcacctc aaggctgcaa tgagccaagg tcacaccatt 43560gtactgaagc ctggggacag
agtgagaccc tgtctcaata agtaaataaa taaatatctt 43620ttatgaaaaa gattctctag
tcagaattaa cacctcaact agccaaacat caggaagtta 43680cattacagct acttaataca
caaagggaca cattttcacc agtcgttgtc ttctgatatt 43740tctattccag aaacacacac
tctcacttcc ctacactccc catcccatca tttcttcaga 43800gcatggaaac agaatttgtt
gaacaccaga aatctcttgc tatggtggta cataagtcat 43860aacatttgtt gctgcccagc
agcaggtatg aagccggctg gtgactggct agcaaatgcc 43920tattctgtaa gctcctcact
tagcccatct gtagctctga cttctccacc aattcccttc 43980tctcctttca cagcctttct
gagtttctga gggataattt cagaggttcc atataactgt 44040caaagcctat ggtagacatg
gcaaagtgaa aatcctctcc actggccatt tctgtttctc 44100ttgggggcat ctttcacttg
cctcaggtgt tataaagctg atgaacacac gtacacgttg 44160tttaacactt tcttgggcat
ttcccatttg agatatggca tgtttcatta tcctagtgac 44220atgtgcaatc agaaaatgta
tattttgttc tctgcaactt tcttttgaaa aatgtatatt 44280tgaacaaaat atacattttt
tgtatcttca tgaccattca tgctgtcctc actgtcatca 44340tgaggctcta tataacataa
tgactcctcc agggcagtct tcggaaattc ccagtgcaga 44400agcacgtgtc atacagcagt
ccccattcat ctccagtgca gctctggctg gctcccatgt 44460ctgatcagct gtttggttgg
acagaaaatg actgcaaggg aatcagttcc agtgtgagct 44520ctgtttgcag aactcagact
cccctccctc ccatgttaat gctttttttc ttcttctttt 44580tttttttttt ttttttttga
cagagtctca ttctgtcacc caggctggag tgcaatgcta 44640tgatctcggc tcactacaac
ctgtgcctcc ccggttcaag caattctcgt gcctcaactt 44700cccgagtagc tgagattaca
ggtgcacacc accacacccc actaattttt ttgtattttt 44760agtagagacg gggttttgcc
atgttgccaa ggctggtgtc aaactcctga gctcaggaaa 44820tccaccttcc tcagcctccc
aaagtgctag gattacaggc gtgagccacc atgcccagcc 44880ccatgttaat gcttctaaag
tttgccctca cttctttaga aattccttca gtacatcctt 44940taagacttcc tctagtgagt
gtctgctggt ggtaaactct cccctctaaa agttgcttta 45000tttctcctca attcctgaag
gatatttttg ctagcagcta tattctttta gatgttgaac 45060atatcggtac aaaagcttct
ggtttccatg gttgctattg agatgttagc tgtcggttta 45120tctttctccc ctgactatgt
gtacctgttt ctctgtatct gtctactttt tgggttgctc 45180aatttattgg ccttgggctt
cattctgctg ctgctttttt tttttttttt tttttgagat 45240ggagtcttcc tctgttgccc
aggctggagt gcagtggtgc aatcttggct caatgcaacc 45300tctgcctctc ggttcaagcg
attctcctgc ctcagcctac cgagtagctg ggattacagg 45360cacctgccaa cacgccaggc
taatttttgt atttttagta gaaataggat ttcactatgt 45420tggccaggct ggtctcaaac
tcttgacttc aggtgatcca cccacctcag tctcccaaag 45480tgctaagatt acaggcctga
gccaccacgc ctggccacaa tttttaaact ttttattttt 45540acaggcacct gccaacatgc
acaactaatt tttgtatttt tagtagaaac aggatttcac 45600tgtgttggcc aggctggtct
caaactcttg acctcaggtc atccaccacc ttggtctccc 45660aaagtgctag gattacaggc
gggagccacc atgcctggcc aaaattgtta aactttttat 45720tttcttcctc aagaggatga
gaagaaaggt caattgtaag ctttagaagt cttgcccaat 45780agccaatctg agaatattct
ccgtaaacat tcaccagagg cagccagtga ccatgggata 45840cttttggtga gaggaattga
ttgctggggt caggaatggg aggaaagcat acttctcatt 45900agataccttg ttgaacttcg
taaattgtgt gccaaatgca tgtcttacct agacttcata 45960aattaatttc tttaaaaata
atcaaagaca attttttaaa gacttattta atttaaggtg 46020attataaaac atccagtata
ctttcactat taaaaaagta agtattcctg tctgggcttg 46080gtggatcaca cctgtaatcc
cagcactctg ggaggctgag gtggtcggat catgaggtca 46140agagattgag accatcctgg
ccaatatgat gaaaccatgt ctctcctaaa aatacaaaaa 46200ctagctgggc gtagtggcgt
gcctgtagtc ctagttactc aggaagctga ggcaggagaa 46260tcgcttgaac ccaggaggcg
gaggttgcag tgaactgaga tcgtgccact gcactccagt 46320gtggcaacag agtgagactc
catcttcaaa aaaaaaaaaa agtattccta aacagcatat 46380tatcatgata tattattttg
ttttgtaggg ttttgaacct tgtctaaaaa gaattaaaat 46440gtataaattt cttcctgcaa
tttccctatt tcactaaggg tcattcacat tggtcatata 46500gacatagcac attttcacca
ctatatagca gcattttgta caaatagact acaatttact 46560tattctgcac ttatttctgt
ttgtttgttt tgctatgaaa agcaatgtca ttacatatat 46620tcatgcccat agctacaagt
ttacatattt caggttttct gtagggtgga caccagggag 46680ttgaattgtt caacaggact
ttacattcat ctttagtttt attggccaac accaaattgt 46740tcttcacaat gtttgaacta
agttgaaatt ccacctcccc atcacattta gttttgtcaa 46800cttcatttct tcattcatta
attcattcat tcagtctttt gtttatttgt ttattgccag 46860tctgataggc gtatagtggt
gcttcatcat ggttttactt tgcatttctc tgattttctt 46920tttaaatttt taaaaaatta
tttttatgta gaaacaaggt ctcgctacat ggcccaggct 46980ggtcttgaac tcctggcttc
aaatgatcct cccacattgg cctttcaaag taccgagatt 47040gattataggc gtgtgccact
gtggccagct gatttccctg atttctgatg agttaacaat 47100ctcttctttc tctctctctc
tctctgtgta tacaggtact caccattcgt gcctattttc 47160tgtaaaatat gtggctttcc
tcattttttt tttttttttt tttttttgag gcagagtctc 47220gctctgttgc aggctagagt
gcagtggtgc gatcttggct caccacaacc tccacttcct 47280gggttcgagc aattctcctg
cctcagcctt cagagtagct gggactacag gcgtgcacca 47340ccatgcccag ctaatttttg
tatttttagt agagattggg tttcactatg ttggccagac 47400tggtctcaaa ctcctgactt
tgtgatctgc ccacctcagc ctcccaaagt gctgggatta 47460caggagtgag ccactgcgcc
cagccatctt tcctcatttt tatactaatt aggcttttat 47520cttacttgtt ttttttaatg
ttttttgtac actctgaagg ctgatttttg ttaattgtat 47580gtgttgcatt ttttatggtt
tgtcttatgc cttttgaaag taaaagttct taatttaaat 47640atagccaacc tgtaaatcat
ttgtgaaagt ctgtggttta agaggtcttg aataagaaat 47700tatcccatca tcataagtca
taaatacttt tttgttgttg ttgagacaga atctcatttt 47760gttgtccagg ctggagtgca
gtgggttgat ctcagctcac tgcaacctct gcctcctggg 47820ttcagcaatt ctcctgcctc
agcctcccaa gtagctgtga taataagcat gtgccaccac 47880accagtctaa tttttgtatt
tttagtggag acaggatttc atcatgttgg ccaggctggt 47940ctcaaactcc tgacttcaag
tgatccacct gtctcagcct cccaaagtgc tgggattata 48000ggtgtgaacc accatgcctg
gcccataaat acatttttat gtattttctt ctaaagttgt 48060tttgtctttc actttttagt
ttttaattca catataatta ctacttgcta cttataatta 48120tctgtaagta gtatgagatg
agaaataaat tctatttccc tcctatggat aagcacaaac 48180ctgcagtatt agcacagtct
tatgtcagat tttctaaaat gaatgggtgt gttttctagg 48240ctctctgttc tgtttcatta
tctgtctttt cctgcaacga tatcatctgc cttaaaaact 48300ctagccttgt ggtattcctc
attttcaagc agagcaaacc ccgtcacctt gcttttctcc 48360tccagcatcg cttgtgctat
cctggactaa gaccttcata tagactgtta gaatcatcta 48420gccaagttcc attttaaaaa
tctatgttgg agctgggcgc ggtggctcac gcctgtaatc 48480ccagcacttt gggaggctga
ggagggcaga tcacttgagg tcaggagttg gagaccagcc 48540tgatgaaacc ccgtctctac
taaaaataca aaaattagct ggacgttggg cacttgaatt 48600ctagctactc aggaggctga
ggcaggagaa tcgcttgaac ctggcaggcg gggggtgcag 48660tgagccgcga tcatgccact
gtactccagc ctgggtgaca gagtgaggct ccatctccaa 48720aaataaataa ataaataaaa
taaaatatct atgttggaaa ttttgtacaa attttattaa 48780atgtctacat taatttggag
aaaaatgact tgattttgat tatctattca atatttctgt 48840attatgaata aggcaaaaag
agaggcagag aatagcataa aataataact aaaattcctg 48900ggtaaaccac ctcaaatcat
ttcttcatat ggctcaatat tcttttgtga catggcctga 48960aatatatcca gacagagaac
tcttctcttc aatacatttc ttcttttagg tattcatatt 49020gagttttcct gtccatgaac
atggtataag agagtatatc ccttcgggag gccaaggtgg 49080gtggatcacc tgaggtcagg
agtttgagac gagcctggcc aacatggtaa agtcccatct 49140ctactaaaaa cccaagaatt
atccaggtgt ggtgacacat gcctgtagtc ccagctactc 49200aggatgctga agcaggagaa
ttgcttgaac caaggaggcg gaggttgcaa tgagccaagg 49260tcatgccatt gcactccagc
ctgggtgaag agcgagactc catctcaaaa aaaaaaaaaa 49320aaaaaaaaag aaaacgagaa
tatatccttt catttactag tttttcttca atttctttca 49380agataaaggg cttacctatc
ttctgcttta ttcatagtta cttgatattt ttgtttctaa 49440taaatatggt gtctgtctat
ttacctgcct cttacctgtt catttccagt ttcaaaaatg 49500atgttgatat ttgaatatta
accttaaatc tagcaccttg gtaaacacta ttattcattc 49560taataattat cagtagatta
tatgtgtttt ttatttataa atcatattgt ttgagtagca 49620tgctttgctt cttcatttat
aaaatttaca acttttattt ctttttaata atttttttct 49680tattctcctg gctaggactt
ctaacacagt attgagtgga agtgctgatc cttgtttagt 49740ttcacatttg aaaaaagatt
gcttttacta tttcactgtt aagtataata tgcaccatag 49800gctttctgtg gattcctttt
atccatttaa gaacatctct tattcctaat tagctgaagt 49860tttctgcatg tttgttttca
tcatgagtgg atttttttac atctattgaa atcattttac 49920atagaagata tttcacacct
attgaaatgg tcatttcact tttccttctt taatatgtta 49980agttgggcaa aatattaaag
tatcacctgt cattctgctt cagcaaaaag tagtagtgtc 50040ttagcagtat tggtgaaaag
acagcatcaa ataaaaaaga tgtagaagta ggacccagta 50100aaaatctagc gcatggggca
ttgtcacatg taagcagaca gaatgtgaca ccaccaagga 50160gcatctgaag ggctggaggc
tgaaggaaga catgagtcac ccaggctcat ggacacttca 50220gagaaattag ggagcaggaa
gaagaaatag gatcaaagac tacgtatgtt ggttggaaaa 50280ggaagctgat ggtatggaga
tgttattatt taggtctcac ataaaagatg tagataaata 50340ggtagatagg tagatagatg
atagatagag agatagatag ataaatacat agatagatag 50400atgataaata gatgttgtta
tttaggcctc acataaagat gtagacagat tagacagaca 50460gatgatagat agatagatag
atagatagat agatagatag atagacgata gatagataga 50520tagataatct cagaaacaga
gacacagtga tctcagtaag ataggcatat gccaggtgac 50580agaattcaga ggggtcccac
tacgtgaaaa caatagaaca accttcgaaa agaaatttag 50640tacaaataag agggcaggct
tccttacata caagttagta aactggaaga atcagttatc 50700ctcaaacatt ggaatagatc
aaaaatagtt gtttatatta atgaaggtag ctaaacatga 50760agctaagtga acctgtctct
gacctagtgt ggcaatccct gggcaaggga cacttgctcc 50820gctcttgtat ccttcactga
atattcagac tttcagttaa gcatcggtga atttagtttt 50880catctcttgt gaaaaccttg
agagaggtaa ttctctctgc ttttcttctt ttcccttcct 50940tcattttctc aaacattgcc
tgtttaaaat acgaaatttt aaaagatggc cttgttctct 51000tttttgttgt tattattaag
tacagagaaa ggaagaacca caaatagcaa agggcaacat 51060atggaatagt ttagaagttc
cgggagcacc catgagggca actgcagaag agaacattct 51120atcccccgtt gctgcagctt
tcattccagg tctccatgca tatcagatag ggaaggaact 51180ccgggacagc agcagggccc
atgcacatgt aaccaattgc tttctttgcc tgtagtaaag 51240ttcacatttt gattgcttct
ccagattatg tagatccaga catattttat gcaggcatcc 51300ggatctttct ctctgggtaa
gtatagttca gttgttttcc tgtgtgaagt ctctgtagca 51360ttgactgaat gtataagggg
acgaagagac agaagcttcc tagcgtaaga aacataccaa 51420gtgactcttg ctagggatcc
actctcaggt aaaagaagtg ggataccatc tgcacaacaa 51480ataacactga gggctaagta
tttcagttaa gagtgtttgt tcctaggcag ttcagatcca 51540tttatattca cttttcttag
aatcctagct caatgacaga agaagaaaaa cacagtatgt 51600cactcacaca gttctatcac
ttacatctac tttttcttct tgttattaag gcatgtagaa 51660ggctggggag tgtagtatag
agttggatag catcgaagct ttcttctaaa gttcctggaa 51720gagctacact gtggtttgaa
cgaatgtgtc cctccaaaat tcatatgtta aaacctaatt 51780gtgatggtga ggtattcgaa
ggtgggttct ctgggaggtg attatgtctc ctctgagagg 51840agaagacaat cccctgagtg
gaactaatgc ccttataaag gggctggagg gagttcactt 51900ggcccttttt gctccttttt
tcttccattc cttgtccctt ccactatgtg aggacacggg 51960agttgaggca ttaccttgga
cgtggagacc aggccctcac cagacactga acttgccagc 52020accttgatct tggacttccc
agcctccaga actgtgagaa atacatttct gttatgggta 52080gtccccaact caatacagtt
tgacttacca ttttttgact ttatgttggt gcaaaagcat 52140acatattcag tagaaactac
tttgagtacc catacaacca ttctgttttt cacatttggt 52200acagtattta ataaattcca
taacatattc aacatgttga cataaataag ctttgcgtta 52260ggtgattttg cccaactgtg
ggctaatgta agtgttctga gcacatttaa gggcagctag 52320gctaagctaa ggtgtttggt
aggtcagatg tattaaatgc attttttgtc ttatgatatt 52380ttcaacttac attgggttta
tcaggatgta acccactgtg aattaaggaa tatctgtatt 52440tacaaattac ccagtctaat
gtattttgtt gtagcaacag gaacaaacta aaacactacc 52500ccaaaccatt tttttcatat
tttctgagta ctcttctttt gtcacatggc ttgaaatttc 52560ttcacataga gaactctact
attattttat tttattttat tttattttat tttttgagac 52620agagtcttgc tcttttcacc
caggctggag tgcagtggtg ccatcttggc tcacggcaac 52680ctctgcctcc tggattcaaa
ctactctcct gcctcagcct cccgagtagc tgcgattaca 52740ggtggctgcc accaagcctg
gctaattctt gtatttttag tagagacgga gtattgccat 52800gttagtcagg ctggtctcga
actcctgacc tcaggtgatc tgcccacctt ggcctcccaa 52860aatgttggga ttacaggctt
gagccaccac gtctggctga taactctact tttagatact 52920ctctttgctt aaacaaatta
gccattcctt ccttgacatg ttttaatcag attgccttcc 52980tattaacttc ggaaattaag
agtttctgct atgtttttgt ttaattttta aacagtgaaa 53040aatgaaaggt ggaggcaatg
gctggatgag gtgaatatgt caaatagata tcatctagtg 53100ggccatctta ttaactagga
gacacctgaa gtgctatcaa tagaaataat ctgaagctgt 53160gtctggatac agcaagagac
atgcaaatgc taaaaatcta ctatattaca ttggtgcaag 53220gacagagtag caacacatac
taagtatttt ctccagattg ggtgtgtttg acgtgtgaag 53280cacttcaaac agagtccagc
ctgggaggga gtggggatgg aatcctcctt gtagagggta 53340cagagtggaa gcaagaaggt
ttccaagatt gagagtaatg ggtgtatggt ttatggggga 53400aagggaaaac aaaaagaagg
gtgcagaaat ggagctggga gtgtgtttta gtatttaggc 53460tttctctgta tacctttgat
aggattagaa aaagaaaaat ggaccatttt taaaaatttc 53520atgctaccac atagcaggct
tatactatag atgcagaaac agactgggat ttaggaagca 53580ccccaattct ggaaaatccc
tttttgcttc acattgctct ctaaatctgt atgttttccc 53640ttgttacgta acaatttacc
acaaatttag cagcttaaaa caatatgcat tcattgtttc 53700acaattctgt aagtcggaat
cataggcaag ctcaactgac ttttccattt agggtcgcaa 53760aaggccgaag tcaatttatc
tattgggctg ggctcttaac tgaagatctg gggaagaatt 53820cccttcaaaa ctcatttagg
ttgttgtcag aattcagtgt tttgtggttc tagaactgag 53880atctgtttcc ttgttggctg
tcagacagga gctgctctca gcttcttgag gcatccagta 53940ttccttatca tgtgtttttt
tttttccatc tcagcactgg cacttttttt tttttttttt 54000ttgagacaga gtcttgcttt
gtcacccagg ctggggtgca gtggcacgat ctcggctcac 54060cacaacctcc atctcccggg
ttcaagtgat tctcctgcct cagcctcccg agtagctggg 54120attacaggca cccgccacca
gcccggctga tttttgtatt tttcatagag atgtggtctc 54180accatgttgg ccaggctggt
cttgaactcc tgacctcaag tgatcctccc acttcagcct 54240cccaaagtgc tgagattaca
ggcatgagcc atcatgccca gccagcactg acaattctaa 54300tccttctagc actttgattc
cttctcacct ctccttctgc ctctagccag agaaaactct 54360ctgattttaa aggtcttatg
tgattagatt cagcttacct aggtaattca ggataactcc 54420ctatgtcaag gtcaactgat
taataacctt aattacacct gcaaagtccc ctttgccata 54480atatatcata ctgacagaca
tgctatagca taatactaat agttctaaga attatgataa 54540gaatcttgga aaaccatttt
tagaattata cctaccacag tatccttcaa gggataaatt 54600gattctactt cttctctatg
tcagaagcat ctgatgagga tgaactatat attctgaaat 54660ccccatgatt agatgtgtac
tagaaggtga ttttactttc attaaaataa attcggagtc 54720attgacacat tttatctttg
atttacataa atgcctccgc tctgtttctt accctcaaaa 54780tatttcccat gtagctaagt
ggccagtacc gaatcctaca tgcattaata agtgtagatg 54840gacaaaaata tctggattac
tgagaattcc cattagcatt gtctagaaaa atgtaaattt 54900gcttttttgt tcttgattta
tcctattttt gatttattat ttatatttat ttatttattt 54960atttattttt agatggaggt
ctcgctttgt cgcccaggct ggagcgcaat ggcgcaatct 55020tggctcactg caacctctgc
ctcccaggtt caagctttcc tcctgcctca gcctcccaag 55080tagctgggac tacaggcacc
tgccacagtg cccggctaat ttttgtattt tcagtagaga 55140cagggttttg ccctgtgggc
caggctgttc ttgaactcct gacctcaggt gatctgccca 55200ccttggtccc ccaaagtgct
gggattacag gcatgagcca ccacacctgg cctttttgct 55260tactttttaa aaacattttt
atttaggaga atggagatat ttcatatgta gatgacacat 55320attcattccc tttagttccc
acacacattc aatttcttga ggaagttagc ctttgcaaaa 55380aaaaaaaaat gatctcattt
ttttttcccc actaaaactt ctcattttct tggggttgct 55440agaaagttgc tacaagaaag
gctaaaaata attgtgccta cagatatttg aaaggaaaat 55500agttcctctt ttttcacagt
agcagcttgg acctgagaat gtatgggagc aataattggg 55560ctgctcaaag aaacacaatt
tcccttcctc agactagaat taccaaccta gagaacatga 55620gtttttaaag tagatgtgct
tcttttatct ttttggactt gtatgctggt gttttctctg 55680tcaccttcac tgtggaaatc
ctcttgaggg tgaggcactg aaagcagatt gattaatgtc 55740tcttggccat ttgagacatt
ggatggctct tttaagttgg ccacgttctt tcaagaacta 55800tgcttgggct acatattctg
gatatataat acatacttgt aggatgttat ttttaaatca 55860ttcatttatc acatatttag
tgagtgccta ccccatgtca gttctaggtg ctggaaatag 55920agcagtaaaa ccaaccctca
acttggcccc tctggagctt acatttcaat gcggtgggtg 55980gggggatgga caattaatac
acaagtaaat ctaataaaag cgtcatacaa tatacattac 56040aatggtaagc acaatgaaga
aatggaaagc tggatagaga gtattagaga ctgtcgaatg 56100tagtggccaa attttcctgt
ttattgtggt ccaagagtgc cacagccctc tatgacattt 56160gagcagacac ctggaggaag
tgagggagtg agccgccaag aaggaatggc aagtgcaata 56220accctgaggt gggagcgtgt
tggtcgtggt ggaagagctg caggaagcca gcagggccgc 56280aacactcagg ggagaataag
aaagagtgag gtgacagtag agaccggatc atgtagagct 56340ttgtcagctt cttttctgag
tgagatggac aacacggaca cgttttgaaa agaataacaa 56400tgtgatctgc cttcagttgc
aaatcatctc tgtattgact gagtaggaaa taaactccaa 56460gaataaagac ggaaacaggg
aaaatattta agaagcgatc attacaatcc agggtggtgg 56520cttgtactag ggtacaaggg
ctaaaggtgt tgagaaatgg tcagattctg gatatatact 56580gaaatcaaag ttgatggaaa
gatatgagtc aaagataatt tgcaggtttt ggggtcctgg 56640ttcactgaaa gaacagagac
atcatttact ccaatgagga agactatagg aggaacaggt 56700ttagcaaaga agaaaggaaa
tcaggagatc agtttgggga cacggtcata tcaagtaggc 56760agttggatgt atgggtctgg
aatatagggg agtggtctag ctatcagtgt aaatagcttt 56820ttacatttgt aaatagtcag
gatataggct tttctttttc tttttgtgag acacagtctt 56880gctctttcgc ccaaactgga
gtgcaatggc acaatctcag ctcactgcaa cctctgcctc 56940tgggttcaag cgatactcct
gcctcagcct cccgagtagc tgggactaca ggtgtgcacc 57000accataccag gctaattttt
gtgtttttaa tggaaatggg gtttcaccat gttgaccagg 57060ctggtgtcaa actcctgacc
tcaatcgatc tccccgcctg ggcctcccaa agtgctggga 57120ttacaggcat gagccacccc
atccagctgg gatatagttg ttttctaaat ctatgaggct 57180agagaagacc atttgggaat
tgagagcagt gagcagtcca cggactgacc ctttgagagt 57240gcaacattta gcagtactca
agatgggaag gagctagtga aaaagcccca aatgactaca 57300taagaccatc aaccagatta
caaagaaaga cccgaacatg tgtgcccata tatcacccaa 57360cagcagttat gtctttcatg
tttcttcccc ataaaatgtt gttcatcaac tttattagac 57420tagggtctta acattggaca
aatcacaaaa cctctctgga gcctatttta tttttcaaca 57480gctgtaggaa gcaaatacaa
attggaaatc taaggctcag aaagatttgt acaaagttac 57540acagtaatga aaggggagcc
gggattccca ctcactctaa agaatatgat aaaatggcta 57600gtattcactg aatgcttaac
atgttccagg ccctgggcag gtattatttt aattagttct 57660cacaataatc caataaggga
gatactaatt tactcagatg agaaagctga ggctcagaga 57720ggttaatgaa ctaagccaag
gctcactgtt aataaatagc aaaggtaaaa ttaaattcca 57780tatctgcttg agatagaggc
cttgctccta atagctgcag cctgtcaggg cctggcagca 57840gtaacctctc ctttcctctt
cccaccattc ccctgcactg ctttctgtac cgcatctctt 57900ttcagagtga tgttgcccca
attgcggagg ccactgtgct gtttatccag tgaaagctgt 57960agcacagcca acccaaagcg
tccccagtga aaacaacctg gctccttaca gcacttccag 58020cctcagagca gtatttgaaa
aatatcatga acagcaaaca cagcagtctg tctgtggctt 58080ttatatgtgt atatggtgtg
tgtgtatgtc ccttctcttg agcaaaataa cttttagaat 58140tatagaaaaa aaatgtgcaa
catcaatgtg gatctgctgt ttaaactcat aacagagaaa 58200gtagcttgtt tctggctata
ggaggaaaag acgatattcc ttagtaaaaa tggaaatcca 58260catatggggt tcttgtaaaa
atgaagatag aaaattgcaa gtttggggat caagttctgg 58320ttctatcatc ctttaacagt
atgaccctgg aaccttaatt gctttgagtc tttgttactt 58380tatctatgaa atgaagtatt
taaaaaaact ccaaaaatct gtcctgatgt acacacaaga 58440ggtcaaatga gaaaatgaat
gtgaagatgc tttataaact atacagcatg gtaggtgcaa 58500atgtgacatg aacttgtttt
ggacacatta taaagtcacc cccacaaact gtgattgttc 58560aagactatgc aaagtcagac
acaggaaaat aagtaaaaca gatggaggca taaagagggg 58620gaactcagag aaaacagtga
agaacaggaa tcaggaagac aaaggagagg aaaggtgggg 58680aggagaggag aaggaaaggg
ggaagggaat ggaggagagg agaacagctg cttcacagag 58740catggccggc agcccagtcc
cagcctttct gcatgtccct gacttcagcc tctggcgagg 58800cacaggctta ctctgtgctt
cctgctgtta ctcttcttat ccatccttat tatcaatacc 58860tgtggtcaac aaagtatttg
ataaaggcat cctcaaagtc aggtaacatc tgtacgttat 58920agattacaaa gttgagtaat
atccagaatt ggtagtttaa cgtgatgact tcttaacaat 58980tatcactgtt tcagggaagg
gcaaaggtgt gtgtgtgtgt gtgttcatct gtgtgtatct 59040gtgtatgtaa ttgtgggtgt
ttgtgtatat ttgtgaggct ctttacttgg cggagttaaa 59100aagtatctgc tcatcaaggt
tgagattagc aaaggaagtg aagatttttc cagagcccct 59160aaaatgtgcc ttttgaccaa
cactgaggac atctttataa ctgagtatgt gcaataaata 59220tgtcttggga cctgtgccac
aaattcctct ctaaatagcc tttacctctc tggaataacc 59280ctttagatga ggaagaaaag
ggctgtgatt ttatagcttg ttatgaagct ggagtgaaga 59340tgatgcttca gtacttaccc
tacaaagata cccccaatcc ctcaccctaa aattaccatt 59400gaaatcatgt tccctttctc
attcactctc agtttccatg tcagaaaata taccattacc 59460tccctgcacc cctttcatct
ctctcacttt tctcttgctt agatggaaag acaacccagc 59520aatgcctgca gggctgatgt
atgaaggagt ttcccaagag cccctgaaat actccggcgg 59580gagtgcagct cagagcacag
tgcttcatgc ctttgatgag ttcttaggca ttcgtcatag 59640caaggaaagt ggtaagtcag
acattttgtt ttcccttgag agtagaggga ggaagaggag 59700aggtgttttt tttttttcca
attgataaaa ccaaatataa attaaaatgt catgaagttt 59760atacttctct aagtcagcca
agaaactgca tgactgccaa tgtttttgtg tcaagccaat 59820taatattgga atatcagatg
tcagcttgat cttgggtttt acttccaaat cttaaaatgt 59880tgctctgttt ccaactgttc
actatcactt tggtttggat ctttagacac tagcttcctt 59940tttctgaaat gggggagaga
tgtggagttt gaaggctatg agtctgggcc agctggaaac 60000aggtctggga tcttccaaga
aagtccttcc ccacaaaatg gtgcaacttc tagccaaatc 60060tatttatacc agcagaggga
tctatcaccc tggaagcttg aaattgttca ttttcttacc 60120tgccaggatc aagttaagtt
tttaacagtt gcaaaaagac acttcatact atggagtttt 60180caagttggat tagaagaaaa
agaatcacca gaacttagtg tcgtagattc aagtcacttc 60240tctaaaactg tcataatttt
tcacggattt tggcatttgg tgacattaat ggttgattta 60300cttaccatgc ataatattaa
acccataacg aatttcctat aaatatctat tgatttgatt 60360tttaaatcac ttggcttcaa
gaggctatta ctaaaacagt gactcattct ttatcttttt 60420tgccttcacg ggctttatat
aactttctcc ttttcttgtg ctccctccaa aacaaagcac 60480tgagaaaaca aaattcacca
gagtattcag ctagtcagtt caagggtttg tgttctacat 60540ttgaagatat tccttatagc
agctaccaac gggatacttt gtttacattt gttgtgtagt 60600aaatatttat atattggcaa
acaaatctag ttccaactct gtcatctgag atgttcttac 60660tttgtttcct cttctccatc
tcctgtcaac tgttagaaat atacatttga gtacgtgaag 60720tctgcaaaca aaagggccaa
ggtagatttg agttagaaca ccagcaacag tttctggtgc 60780attcttgtct gaaaaagcag
agaagattgg gcaccgtggg tcatgcctgt aatcccaaaa 60840ttttggaagt ctgaggcagg
tggatcgctt gagcccagga gttcaagaca agcctgggca 60900acatagcaag aacccgtctc
tactaaaagg aatacaaaaa aatattagct gggtgtggtg 60960gcgcacacct gtagtttcag
ctactcagaa gactgaggtg ggaggatcac ttgaactcag 61020gggcagaggt ggcagtaagc
tgagatcaca ccactgcact ccagcctggg caacagagca 61080agatctcatc tagagaaaaa
aaaaataaaa aagaagaaga agcagacgag ctctgctata 61140tttccatgtg gagctatgac
gttatgctgt attgtttctt tcaggtgact ttctgtacag 61200aatgagggat tacatgcctc
cttcccataa ggccttcata gaagacatcc actcagcacc 61260ttccctgagg gactacatcc
tgtcatctgg acaggaccac ttgctgacag cttataacca 61320gtgtgtgcag gccctggcag
agctgcggag ctatcacatc accatggtca ccaaatacct 61380catcacagct gcagccaagg
caaagcatgg gaagccaaac catctcccag ggcctcctca 61440ggctttaaaa gacaggggca
caggtggaac cgcagttatg agctttctta agagtgtcag 61500ggataagacc ttggagtcaa
tccttcaccc acgtggttag 615401627DNAArtificial
SequencePrimer 16tccggtacca tggagcctca aagtcag
271728DNAArtificial SequencePrimer 17atccggtacc atggcactca
gtaaaata 281830DNAArtificial
SequencePrimer 18tgtcctggtg ctaagggtca agacaattct
301929DNAArtificial SequencePrimer 19tgagttggcc taagggtcaa
gacaattct 29201266DNAHomo sapiens
20atgttgcatt ttcattatta tgatacttca aacaaaataa tggagcccca cagaccgaat
60gtgaagacag cagtgccatt gtctttggaa agctatcaca tatctgaaga gtatggcttt
120cttcttccag attctctgaa agaacttcca gatcattata ggccttggat ggaaattgcc
180aacaaacttc ctcaattgat tgatgctcac cagcttcaag ctcatgtgga caagatgccc
240ctgctgagct gccagttcct gaagggtcac cgggagcagc gcctggccca cctggtcctg
300agcttcctca ccatgggtta tgtctggcag gaaggagagg cgcagcctgc agaggtcctg
360ccaaggaatc ttgcccttcc atttgtcgaa gtctccagga acttggggct ccctcctatc
420ctggtccact cagacttggt gctgacgaac tggaccaaaa aagatccaga cgggttcctg
480gaaattggga acctggagac catcatctca tttcctgggg gagagagcct gcatggtttt
540atactggtga ctgctttggt agagaaagaa gcagtgcctg ggataaaggc tcttgttcag
600gccacgaatg ctatcttgca gcccaaccag gaggccctgc tccaagccct gcagcgactg
660agactgtcta ttcaggacat caccaaaacc ttaggacaga tgcatgatta tgtagatcca
720gacatatttt atgcaggcat ccggatcttt ctctctgggt ggaaagacaa cccagcaatg
780cctgcagggc tgatgtatga aggagtttcc caagagcccc tgaaatactc cggcgggagt
840gcagctcaga gcacagtgct tcatgccttt gatgagttct taggcattcg tcatagcaag
900gaaagtggtg actttctgta cagaatgagg gattacatgc ctccttccca taaggccttc
960atagaagaca tccactcagc accttccctg agggactaca tcctgtcatc tggacaggac
1020cacttgctga cagcttataa ccagtgtgtg caggccctgg cagagctgcg gagctatcac
1080atcaccatgg tcaccaaata cctcatcaca gctgcagcca aggcaaagca tgggaagcca
1140aaccatctcc cagggcctcc tcaggcttta aaagacaggg gcacaggtgg aaccgcagtt
1200atgagctttc ttaagagtgt cagggataag accttggagt caatccttca cccacgtggt
1260taggat
12662173660DNAHomo sapiens 21ccctggcctt ggaagatgcc ctagagacgc tgaggtggtt
gtacttttgc cataggagtg 60gcagccagag aactgagccc aatgaatgca aaggctggtg
cctggaaata ttgtgacttt 120gccacagaaa gaagatggag aattttaaag ttggaaatct
gcctggtaag ggatcatttg 180ctggtgtctg caaagttgag tccatacaca ctggtttgga
aatttcagtc cagatgatag 240ttaagaaagc agtaagaata cagagagtcc acaatgagat
gaaaatgcac tgccagttga 300aacatcctcc tacactggag ctttataaat attttaaaga
caaggattgg attagatttg 360acattagaaa tgtaccataa tacagaaggc aatggacacc
taaagaacag aatgaaaacc 420ttcttaggaa atgaagcttg acacttcacc caccaggcca
ccacaagaat gttgcatttt 480cattattatg gtaagtacac tggtaacttc ttttctaacc
tcgtatgcat aatgtaaaca 540tcaagactga caatttgggg ctagcaactc aattggaaaa
tcactgttct ctattgtaaa 600attcctaatt atgtttccct agaaattgca aagtgcacat
gtacttgcat ttaatgtttg 660gtccatgggc tgaatgcttt gtgcattact tttctggttg
ttgttgttgt tgttgttgtt 720gttgttgttg ttgttgtttt gagacagagt ctcactctgt
tgccaggctg gagtgcagtg 780gcatgatctc ggctcactgc aacctctgcc tcccaggttc
aagcaattct tctgccacag 840ccttccaagt aactgggatt acaggcgctc accaccacac
cctgctaatt tttgtacttt 900tagtagagac ggggtttcac catgttggcc aggctggcct
caaactcctg acctcaagtg 960atccacctgc tttgacctcc caaaatgctg ggattacagg
catgagccac cttgcccagc 1020ctgtgcatta cttttgagga cacatttgac aatggcacag
tcaagaacac cacataaagt 1080agtattggca gattatgaaa tagcaattgt tttggaagac
agcaaaacct gaagtatttt 1140cagacatgta cattatgaag tattatacct tctttaacta
tgtgcaagtt aaaatcagtc 1200ataactgaaa atcaaaaggg caataatgaa catacttcat
ccagaagagg tatccacaaa 1260acttctgaaa gaggtcttag tatatccagg gatggagata
ttattacaat gtattatcca 1320aatgatggaa gttttctctt gctgatagaa tgcatccacc
tactaacatc agtaagtaca 1380ggtttaacaa tttaccagaa atgtactgga ggaaatatga
atatgcttcc agatttattc 1440tacctaaagg atctggctct attttacaag gtcatctatt
ttacaaggta ctgtagatgc 1500attttgatga aaaaaattac cctgctattg attttgaggt
ctggtattat gatagagcaa 1560aaactatcca aaagagattt aattcaagtc attgcaaaat
cttggaaaat gtgtgagaaa 1620tcttacacat ggaaaggagg aagtaaagat ggtagcttaa
acatgtgttc cactgtgaac 1680aattctctgc aaacccaccc ccaaaagtca aggaggctga
caggctgaag aaagaggctg 1740tcaaatctag tttctcagaa aaagaaaaat taatagggac
ttaagaacag aagccatata 1800tctgccctga gatgagctgg tggatcctca cactgttacc
cccagaccca gggcttatat 1860accacaggga aagacaattg cagtaatttg cttaacggca
ggatttacgg caagtacatg 1920ctcttaagag tagattaagt agtaacctta gaggcattcc
tagaactgga gttaatcaga 1980agtcaacaca gtggattagc atccaagatg gagttgcttt
agcctccaca aagagaaaat 2040gaagataaat ttggtccatg ctaattaggg ggtgttccat
ttgtttgaaa ctgaaatcta 2100taatttccaa agaagaaaat aaacgtggaa gtcgtccttc
ctttttggta tgcatagaca 2160atctggcagt gttaggcccc taaggcctta tcacctcctc
cttctgtggg tcaaacttta 2220cagtgagagg aaagacatct tttaaaagaa gaataatcat
gactagttta atcatgacta 2280gttcatcttc cctgcaatag atacccatat ttaacatacc
tattgtacaa agaatatgat 2340tgcacagcta caactttggg acaaactcct tttctgccgc
tttcaatgat cgtcttccaa 2400aatcagaaca gcttttgaat tttattttgt gaaaaatgtc
gtttgagtga cacagtaaac 2460tctgtggagc tctgtggata cagttgaatg atggctccca
gtttatcatg caggtgggat 2520tatattccaa cagttatgtt tcacagaaag gcaaaataac
caggtacgga aaaaatgaaa 2580aatttgcagc ttacatcaaa cagaaattgc agtgtctttc
atctctttaa agttttctaa 2640tcaaaattct agttttcatc aattaaaact ttatttaggt
agatacattt aataagtaac 2700tttttgttgg cttaaaggga atgaacttta tgtaatgtaa
ctgtctattt caggaagctt 2760ttctatgaga atttaaaact acaccaaaat atcttctttt
tttttttttt gagacaaggt 2820gtcacattgt ctctcaggct ggagtgcagt ggtgtgatcc
tagctcactg tagccttgaa 2880ttcctgggct caactgatcc tgctacctca accccccacg
tagctaggac tacaggcctg 2940caccaccaca tctggctaat tttttatatt tttgtagaga
aatggtctgg ctacgttgcc 3000caggctggtc ccaaactcct ggcctcaggt gatcctcctg
cgtcaacctc ccaaagtgtt 3060gggattacag gtgtgagcaa acctgccatc tcaaaacatg
tgtattttaa tgagacaaca 3120aagatcaagg gaactttagt ccttacaatg taatgatcaa
aaaagtgaaa tagataatca 3180acataacatt gcttgtagac catgcaaaca atcttattgc
atttgtatat ttgtaatgaa 3240ctgttttata ataacaaaat gtaaaatgtg tattttattt
gtccttttat tgttttccta 3300cttcttagac atgttaagaa ctatggaaaa agatatggga
gtttgtgaaa atttaaataa 3360ttcatattta tattacaaga aacagatatt agaatatgtt
tgttttatat ttcttttgta 3420gcagaatttt ctagccaggc attgtggctt acacctgtaa
ttccagcact ttgggaggct 3480gaggtgggac aatcacttaa gcccaagagt ttgaaatcag
tgagggcaac atagtgagac 3540tctatctcta caaaaaattc tctatctata tctatataaa
ggaattttgt gaggaaaact 3600atatattttg tatataaatg aattttatca ggaaatatat
ctgtaaatga attttataaa 3660atatagcatc actttatcct tgatttattt catttaataa
ttattttaaa gtaatatact 3720aataaactca ttttaaaaac tgctatgacc ataaaactat
tagagataac ataagagaaa 3780atctaggtga ccttgggttt ggagataact ttttatatat
aacaccaaag gcgcaatcaa 3840tgaaaaaaaa tgacaagctc tatatcacat atcaatatta
aaatgtgatc tgtgaaaggc 3900atcgtcaaga gaacaaaaag acaagccaca gactgggaga
aaatatttgc aaaagacata 3960tgtgataaaa gacaattatc aaaatataca aataattctt
aaaactcaaa aataagaaaa 4020tgaacaactc agttaaataa tgggcaaaag atctcaacag
aaaccccatc aaagaagaaa 4080cacagtggca agcatatgaa aatatgatct acatcatatg
ccattaggaa attgcaaatt 4140aaaacaatga gataccacta catttctaca ttggtgaaaa
ttccaagtac tgacagcact 4200ctcagtgctg gtgaggatat ggtgcagtag aaatccacac
tcatgccggg cacagtggct 4260catgcctgta atcccagcac tttgggaggc tgaggcgggt
ggatcaccag gtcaggagtt 4320tgagatcagc ctgaccaaca tggtgaaacc ccggctctac
taaaaataca aaaattagcc 4380cggtgtggtg gcgggcgcct gctactcggg agtctgaggc
aggagaatcg cttgaaccca 4440ggaggtggag gttgcagtga gccgagatgg cgccactgca
ctctagcctg ggcgacagag 4500caagactcca tctcaaaaaa aaaaaaaaaa aaaagaggcc
aggagtggtg gctcacacct 4560gtaatcccag cactttggga gactgaggta ggcggatcac
ttgaggtcag gagttggaga 4620ccagccttgc caacatgaca aaaccctgtc tctactaaaa
ccacaaaaat tagccaggag 4680tattggcaca tgcctgtagt cccagttact cgggaggctg
agacaggaga atttcttgaa 4740cccgggaggc ggaggctgca gtgagccgat atcgcaccac
tgtactccag cctgaacgac 4800agggcgagac tctgtctcaa aaaaaaaaaa aaaaaaaaaa
aaaaggaaag aaagaaagaa 4860agaaaaaaga aaattccgtg attgcagtct ttacgtattt
atttgttatt aagtacagta 4920aaataaagaa ggatagatgt catggaaaat gtcacgaaaa
taaaagagtt aaaaaaaaaa 4980aaaagtaggc tgcaatgcca gatgcctgaa aagttaatca
acgaaaggac ttaaatgtcc 5040ccattgaatt taggaacaaa gaagtaatta atgaactggg
caaaaacact caatgtacca 5100gcgttatcga tttagaaact gaaactaagt atatctgatg
ttgcttttag gaaacaagta 5160aatgaggtcc taaaaagtta aactgtgacc atattttctt
tcctttttct aatttctcct 5220tgggccattt ccaaaaagcc ctaatacccc gactgataga
aatggatacc ttgctgtgca 5280ctggtactac tgtgattcat ggaaagctga tcatgcaacc
caagacgcca aaattcccag 5340ccttactgtt acgaaagaaa gtttctaagc acaattgtct
ctagccaact tcctcttagt 5400aagaaagagg ccaggcaggg cttcatgcag ggtacagccc
tgagtttctt actgcgtggt 5460aagtttctgg ggctgggagt aaagcagcgt gaccgaaagc
agtacaaagt tctaccggac 5520acgcagatcc cggtcctaca aatatgaggt ccataatgag
actgagatat cattcatcca 5580acaaatattt attgaatacc aaacattggg cttacggcta
aaggaaaata caaagttgtg 5640ttggatatgg gttctgtttt caaggagctt ataatctaat
aggaaagatg aggttactac 5700attagtagca atcagaccag atagaactgg aagtgtgatg
taaatgaggt acagattgat 5760tgtagaattt tgcagaaaga aaacaattct gaagaaatgt
tcatggaagt attagcagtt 5820gagatgtatc ttaaaagata agtggggttc ctgttggaaa
cattcaaaac tctctcttct 5880agctatttta aaatacgcaa tatattatta actatggtca
ccttactgtg ctatagaaca 5940ctagaactta ttcctactat ctaactataa ttttgtaccc
actaaccaac ctctccctgt 6000ccctcctccc cctattcatc ccaccctctg gtaaccactg
ttctactctc tgcttcccaa 6060aacaaagaaa tgatcactgt ttcggtgatg gagatgtcaa
ttaccctgat ttgatcatta 6120cacattgcat acatgtatag aaatatcaca tgcaactctt
aagtatatac cattcttatg 6180taccaaatac aaataaaatt gaaaaaaaaa aaaaactttg
gctgggcgcg gtaggtcatg 6240ccagcacttt gggaggctga ggcaggcgga tcacctgagg
tcaggagttc cagaccagcc 6300tggccaacat ggtgaaaccc aatctcttct aaaaaataca
aaaattagct tggtgtggtg 6360gcaggggccc gtaatcccag ctactcagga ggctgaggca
ggagaaatgc ttgaacctgg 6420aaggcagagg ctacagtgag ccgagatcat gccactgcac
ttcagcctgg gtgacaaagc 6480aagactccat ctcaaaaaaa aaaaaaaaaa agcctcctga
gtaactggga ctacaggcat 6540gcgacaatac tcccggctct ctttttaaaa atgagaagta
gaagtagtgg tgactgtcaa 6600gaaagtattt tggaaaaata ctatgaataa ccagaccaaa
gaaaccaaat accagttgtt 6660tcaggagcag taaatcattt ttgagggctt gagcaaaggt
cttgctagaa aggtgcttag 6720gggtcagatt ttggacataa tgccaggcca agaaaatttg
cactttattt cattaacaat 6780gaggagctct tgaaagtttt attggcagga cctaagatag
ttacagaccc acaagtaaca 6840tgggtctaga ccttgggaac aagaaaagtc aagatcgagt
atgcagactt gggaaccgag 6900tataactaat ggttaagatt aaataaaaat acataagaac
actgagatag agaaatggct 6960cattaatgct gcaaatgtct gcatgtttag ggatgaaata
gaaaaagaag tcagaaaaat 7020acagttcaaa caataggaaa gaaaaccaga aatgcatgat
tctaagaaat gaatgggtgg 7080acatggtggc tcacatctgt aatcccagca ctttgggagg
ccgaggcaga aggatagcta 7140cagcccagga gttcaagacc acccagagca acacagcaaa
accccatctc tacaaaaaac 7200aaaaataaaa attagccaag catggtggta cacacctgta
gtcccagcta ctcactcaac 7260aggctgaggc agaaggatca cttgagccca ggaggtgaag
gatacagtaa gctatgattg 7320caccattgca ctccagcctg gctgagagaa tgagagcttg
tttccaaaaa taaaaaataa 7380gaaagaattt ttagaatgag aggaaaacaa catgaaacat
gagaaaaata acattccctg 7440ttatatggta ggtgcttcgc ttatagtttc tcattaattc
atcatgtaat gtctctggga 7500taaacattat ggatttcctg cagaaacaga agctcagaat
tttatgccag gtgttgaaag 7560gccatgtagc taatagatga tagaacacag actcacactc
tggtagtcct gagttaacag 7620tagaaaagtc ctgggctggg cgtggtggtt cacgcctgta
atcccagcat tttgggaggt 7680tgaggcaggc agatcaccag aggtcaggag tttgagacca
gcctggccaa catgactaaa 7740gcctgtctct accaaaacca caattaccca gcgtggtggc
gggcacttat agtaccaact 7800actcaggagg ctgaggcaga agaattgctt gaacctggga
ggtagaggtt tcagtgaggc 7860aagatcaagc cacggcactc cagcctgggt gacagaatga
gactctgtat aacaaacaaa 7920caaacaaaat cagtaagaaa gtcccagact aagaggcatc
aaatcaggat tctactccaa 7980ctctgatgcc agcttccagg aatacacttg ataagttgtt
tcattcccat aaatcttggg 8040tgattcgtgt ttaatgagag cattgaactg aatcatttat
tctatgactc agttctaata 8100tttcacaatt ctatggttgt ataatattac aggaaattct
tgagaaggtg cagagggaat 8160ggatgaaaaa aaccacatga ctaacataaa aaataatggg
gccatctttt catttgagat 8220tgaaggaaag aacgagagga caattaaaca tgcagagtct
gagaacttgc atttaggagg 8280cataagatgc tgaactgcaa aattggttag atattgggct
gaagagaatt gagaattttt 8340taataataaa aactcttggc agggcgcagt ggctcacgcc
tgtaatccca gcagtttggg 8400aggctgaggt gggtggatca cttgaggtca ggagtttgag
accagcgtga ctaacgtggg 8460gaaaccccgt ctttaagaaa aatgcaaaaa atattagctg
ggtgtggtgg tacaagcctg 8520taatcccagc tacttgagag gcttaggcag gaggatcacg
tgagcccagg aggtggaggt 8580tgcagtaagc cgagattgtg ccactgtact ccagtctgga
tgacagaggg acactatctc 8640aaaaaacaaa caaacactct taagaaatta ggtgtagaaa
gaatgttcct caataccata 8700aaggccatat gtaagaaacc tatagctggc cgggcgcggt
ggctcaagcc tgtaatccca 8760gcactctagg aggccgaggc gggcagatcg cgaggtcagg
agatcgagac catcctggct 8820aacacagtga aaccccgtct ctactaaaaa tacaaaaaat
tagccgggcg aggtggctgg 8880tgcctgtagt cccagctact cgggaggctg aggcaggaga
atggcgtgaa ccccgggggg 8940cggagcctgc agtgagctga gatcgcgcca ctgcactcca
gcctgggcga cagcgagact 9000ccatctcaaa aaaaaaaaaa aaaaaaaaaa ggaaacctat
agctaacatc atactgaatg 9060gtgaacagtt gaatgctttc gtctaagaac tggaacaaga
caagcacgcc aactctcacc 9120actcttactc aacatagtac tttaagtcct agccagagca
atcaaacagg ggaagtggat 9180aattgagaat ggctcgagag gtgctgtggc tcagtcctgt
tgtcctggca cagaaggagc 9240tgaggccagg cgttcaagaa tggctcctag atgtctcata
aggaaccata aatcaaacaa 9300ctttcaaaac tgaaacctgc gtgagaacgg ttgcattagt
taatctggga gcttcctgct 9360tttttttagc tttcatattt atcttagaga aagggaggaa
ggagagatgt gtatggatac 9420ataagcattc aaatacattt gtgtataatc ttatgaccag
aattcaggtc caatgaacaa 9480aaaggtaggg tcttcggaat ttccccagtg agatctatga
cctgaatatt attacgcaag 9540gatccacttt gggattacag gcgtgaacca ctacacccag
cccaggactt tcctgctgtt 9600aactcaggac taccacaatg tgagtctctg ttctgtaatg
cccaaccttg tttttactaa 9660ccccgctttt agactccccg ttttccttta atcacctagc
cttgtttcca cctgaattga 9720ctctccctta gctaagagag ccagacagac tccatcttgg
ctctttcact ggcagcccct 9780tcctcaagga cttagcttgt gcaagctgac tcccagcaca
tccaggaatg caattaactg 9840gtaagatact gtggcaagct atatccgcaa ttcacaggaa
ttcgtctgat tgataacgcc 9900caaagccccg agtctatcac cttgtaatag tcttaaagcc
cctgcacctg gaactgttta 9960ctttcctgta accatttatc cttttaactt tttgcctaat
ttatttctgt aaaattgttt 10020taactggacc cccctcccct ttctaaacca aagtataaaa
gaaaatctag tcccttcttt 10080ggggctgaga gaattttgag cgatagccgt ctctcggtcg
ctggctaata aaggattctt 10140aatttgtctg aaagtgtggc gtttttccaa ctcgttcagg
tacaacagtt ctagcatcta 10200ttagctatgt ggcctttcaa cacctggcat aaaattctga
acaatggctt ggaaattaag 10260ataccttagc tctagtcctt gctctgctaa taattaatag
agtgaaactg gacagggtta 10320ttcacatgtg tgtgcctcag tttactgtta actgaagaat
gacaaagttc ataaatttga 10380aaaggagagg tttcttatat ggggttgcaa cctgcagggt
ggccatgcta cagtctggga 10440agcattgcct ctggctggaa gccagaaaca ggcactttca
gggtcagaag aataagacag 10500agatttatgc tgaatggggt gaccaaatat acatattcaa
taggctatag gaggagttat 10560gaatatttat gaaaggagaa atgtgtacat gtgcaatttg
gcttcatgcc ccttcatggg 10620acctacattc aaaaaatggc agccttagca tgatctgagg
gaggatcttt cagccctctg 10680aggtcaaaag tgaaggagag gacaggaaac cctcactgtg
tgttctccgt aggggccaga 10740accactgcat gtttggtgaa cctggctggt tgttatgttg
aaactgcaaa agggagggat 10800aacagtcagg tgcttgtttg ataccagggg tagaggagac
tttcaaaagg gctggtttct 10860gtttagccct tagggaagaa tgtctaaaga gaattaccta
caagggtata acgaggagtg 10920tctgacattc catctagtaa tgaactagaa ctcagttttc
aagttaactc tgggaccctc 10980ttagccaaga agaggtccat tcagttggtt gaagagctta
ggatttcatt tatatctctc 11040atcactaatc tgcaaaagct ggtagtgaaa ccgcctttgc
aaaattatga ctgagacagc 11100gaaagagatc taacttaatc gattccgtct tgcttctaac
ctccaagctg tccttattca 11160ttcccgggca taggctgaac taactccggg agaagcttag
tttatagttt ttagtttaaa 11220acaaagatag taacagccct ttcccaaagc agacctcctt
cttgccttgg aactagactg 11280cctttagtgg gactaacatt agccacaaga ttagaaactg
tggcttagga gtcatacagc 11340tggaggctac aagattctga ctctccctaa actgctccta
agatcagtcc ttgagatatt 11400ttgcagaccc tgtacttgat ggatcaggtg gcaccaccca
gattgataaa gtggctcatc 11460tgatcttgtg gcccccaccc aggaactgac tcagcacaag
aagagagctt tgactctcta 11520tgatttcatc tctgacccgt cagcactcct ggctcgctgg
cctccctcag gccaccaagt 11580tgtccttaaa aactctgctc ccactgggcg gtggctcatg
cctgtaatcc cagcactttg 11640ggaggccaag gcaggcggat cacaaggtca ggagattgag
accatctggc taacatggta 11700aaccctgtct ctactaaaag tacaaaaaat tagctgggca
tggtggcacg cacctgtagt 11760cccagctact cgggaggctg aggcaggaga atcacttgaa
cctgggaggc agaggttaca 11820gtgagccgag atcatgccac tgcactccag cctgggcaac
agagtgagag acttcatctc 11880aaaaaaataa atagataaat aacctccgct ccctgaatga
atgctcccgg agactgattt 11940gaatcataat aaaactccag tctcccgcac agcctgctct
tcatgaatta ctctttctct 12000attgcaaatc ccctgtcttg ataaattggc tctgtctaga
cagtgggcaa ggtgacctca 12060ctgggcagtt acagtagtac ccacttcata agtgaaatca
cttatcttag tggtagggtc 12120ccaaaagttg tttggtagga gagggttgag gctgggagag
gtggctcatg cctgtaatcc 12180cagcactttg ggaggccaag gtgggtggat ctcctgaggt
caggagttcc agaccagcct 12240ggtcaacatg gtgaaacccc atctctacta aaaatacaaa
aaattggcgt ggtggtgggt 12300gcctacaatc ccaattactt gggagactga ggcaggataa
tcgctcgaac ctgggaggca 12360gaggttgcag tgagcagaga tcgcgccact gcactcaagc
ctaaccaaca ggggcaaaac 12420tctaggacta gagctaaggt atcaaaaaaa aaaaaaaaaa
aaaaaagaag tagagtgttt 12480aattaaataa tttgttcttg ctgtaaaatg taaagtagat
attcctcttc aaagactttc 12540ctccccgtct aattaggaat aaatagtaac ttctcttaga
agcaaaattt attcaaagac 12600ctgtgctaac attcttaaat atctgctagc cacaataagg
aaatcaatgt actttatgtt 12660cttagctccc acaatttagc ctaaatattt tccctggcat
gtttatactg gtctaagcaa 12720gcattaggtc atagcctgtt cctcttcctt atttaaaagt
gtttttacct ttctcagcgt 12780tccacaagtt acttcctcct tcctttgttc tcctctacct
gtgcctcttt taaaaagttc 12840taagttgcta gccaattggg acaaatacag aatgtaaggt
cccattccag ccaacggaaa 12900ctggacacag cagtagggtg gatgtgtcag gttataaatg
accctgtctc ctttgtttgg 12960tgtactctag tggcaaaact gctggcaagt gtaccttttc
tgcaggaagt aaaaatggcc 13020ttactaaata aattaaattt atgttcaagt gctatttctt
tttttttttt tttcgagatg 13080gaatttcact tttgttgccc agcctggagt gcaatggcgc
gatctcggct cactgcaacc 13140tccacctccc aggttcaagc aattctcctg cctcagcctc
ccgagtagct gggattacag 13200gcatgcgcca ccacgctcgg ctaattttgt atttttagta
gagatggggt ttctccatga 13260tgaggctggt ctcaaactcc tgacctcagg tgatccgcct
gccttggcct tccaaagtgc 13320cttggccttc caaagtggcg tgagccactg cgcccagcct
cgagtgctat ttctttacgg 13380cacggaagaa caaacatttc aaacaatgct attaccaagt
ttgttagtat ttattatctc 13440atttgctaaa cctaaaaaat atatatcctt ctttaacgtg
atcgaatatt tcaaaaagtt 13500attgtgttgt ttcttaaaat aaatcaatca taatcctaga
ctatgttact caaactacat 13560acaacacctt ctgagcttct ggcaggccct tcctcccctc
cctgctcacc acagatcact 13620ggaataattg tctgcatgta acttctaatt ttgaagtggt
tgtggtttat caaacctgga 13680acatggcact tccaagtaca tgagctaagg tcacagtaag
actcaagccc cttcaacaga 13740atacctggaa tttctctgtt aaagattttc tcctttacct
gactacatgt ttgtaatgca 13800gatccctcca ggagcgctta cttataaact gtcctggatc
actaacgcga cattttgatg 13860taaattagtt tatcttgacg tgctaatggt agaaaaaaag
agaacatgag gaaacttggg 13920tgctttcagg gctggtagga aggattaaat ctttgcggca
atttctgaga aggggaagga 13980aaccttgcta acaattttga tagtttactc catttggctg
gagtaactct gatccatttg 14040tcaaattcac gatggagcag gtacctgtta gggtacaggt
ttgataaacc acaaccacag 14100gtctatttca tttctccttt tccaaagtgg aacaaatttg
tctctggggt taaaactgct 14160tttctcatat tggtgtgtaa gagaaaatga gggaatttct
ttgagtttgt ttggtttgtc 14220tgtttgttta agcagcattt tttaaataat ttactcagcc
ctgtctcaga gaaagtccat 14280gatgatctgg aattcaacct cagggaaaag ttctctcctg
tgcctgagac actgcgcaac 14340taactggaac cgaaggatgg aacctgggtg tttaatttat
taggaacaat tgattcttca 14400gtgacacttt ccatgcagat acttcaaaca aaataatgga
gccccacaga ccgaatgtga 14460agacagcagt gccattgtct ttggaaagct atcacatatc
tgaagagtat ggctttcttc 14520ttccagattc tctggtaagg atagagcctt ggtaaggata
ggtcagaata tgtttcttga 14580gatgttggtt ggtttgtttt ttaaaaatgt atgtgattat
taagagacca atataaatat 14640caagttgttt acctgagaaa gatgctacaa agagcataga
ttatcattac tatcaaaaga 14700gaagtgacag ataccacaga gaacaggtca aatggaacat
tttttgtttc agtttctttt 14760gactagattg tcaggccaga gaaattataa gcaaacctgt
agttatcaag aaaaagcatg 14820aacttaaata taaataaaga acaaatacag agcctcagca
cctggaacat ggcacttcca 14880agtacatgag ctaaggtcac agtaagactc aagccccttc
aacagagtac ctggaatttc 14940tctgttaaag attttctcct ttgcatgact acatgtttgt
aatgcagatc cccccaggag 15000cgcttactta taaactgtcc tggatcacta tcgcgacatt
ttgatgtaaa ttagtttatc 15060ttgacttgct aatggtagaa aaaaagagaa catgaggaaa
cttgggtgct ttcagggctg 15120gtaggaagga ttaaatcttt gtggcaattt ctgagaaggg
gaaggaaacc ttgctaacaa 15180acaatacctc tttcttaatt ctacttaggg ctcaaattgt
aatgcaaatc tttttcatca 15240tttagccctt ataaacactg tttttctcat ctggtgtggt
ccaaggccta gaacattaaa 15300actatcaaag cttttacaga ccatcaggtg tcatccccct
ctttctacat ctgagctagc 15360tgaaatccag aggaaatgac ttgctgaaag tcatgagtgg
caaaagcaga actagttctg 15420cttataactc ttgactttta gttattatta ttattaatta
ttattattac atcctaaatg 15480agggccaagg ccactcagtt aaaaatcgtg gggtccaggc
caggtgcagt ggctcacgcc 15540tataatccca gcacttttgg gaggccaagg caggtggatc
acttgaggtt caggagttca 15600agaccaggtt gatcaacatg gtgaaacccc gtctctacta
aaaatacaaa aattggccag 15660gcgtggtggc acatgcctgt agttccagct attggggagg
ctgaggcagg agaatccttg 15720aacccaggag ggggaggttg caatgagtgg agatcatgct
gttgggaatg aagtttttgg 15780tgtcacagaa aaagaatgaa catgggaaca aatgatctct
cagcaaaagg acctttactt 15840tctgcagaaa gggtgctact caatagctgt ccagccacga
gagcacacca aacaaaggag 15900acagagttat ttataacctg acgcatctac cctactgctg
tgtccagctt ccattggctg 15960gaataggacc tcacatttta cactttaccc aatcggctat
tagtttaaaa cttttttaat 16020tggataaggg aacagaacaa agaaagaaaa gcaagttgcc
cagggatagt taaggaaaca 16080tctccatata aggaatggca tgcactatgg gctggggctt
ttctagttct gtacagacat 16140gccggagcaa gctacgacag ctgatttgga cagccactaa
tagtggctag caatcttata 16200gtaagaaatt gtgacttttt ataatctttg aagaactttc
ccatttctga cagtgccact 16260gcactccagc ctgggcaaca agagcgaaac tcgtctcaaa
acaaaacaaa acaaaacaaa 16320acaaaacaaa acagctctct actcttggaa gcagcagagt
ttttatcttc atttatatca 16380ctccggtaac actcagaagt agacaagcct cagggtaggt
attcagtaaa agcccactga 16440attccacact attctttaat catagttaaa tggcaaatta
ggctggaggg tgggggtgga 16500acctctccaa aattactgca atgactgcaa catcggaccc
caagattttt tttttttttt 16560ctgagataga atctctttct atcgcccagg ctggagtgca
gtggcactgt gagaaatggg 16620aatggaccgg actgtttcct ctgacactgc cactaggttg
accaagtgtc cctatttgtt 16680aggtactgga tggacgcctg acatgcaaga ctctcagtgc
taaatcagga aagtgctggg 16740acaattcgga tgagtcggtc acgctaagtt gcacttaata
gctcttgtga ctttgactga 16800attacaaaca tcccctgacc ctcaattttc acatttactg
gatggagatc tggtgccacc 16860tccactagat tgctatggag aatgaatgtg aaagcatttt
cataaatcca gtgtaaggac 16920cagaagccag tcttctgacc ttgagccagt gcttgttaaa
aactccactc tatacatcta 16980acccaattca ggaatatcct gcctagttcc aaaggaagaa
aagaccaaat tgctcttatt 17040gggattaaat gcgtacactg agctgaggaa aaacagtatt
acaaatgagc taaacatgac 17100gtagatccac agttgtagaa ttcccctctt tgttctttcc
tctttcataa ctacggaaac 17160agatgagaaa catttacggc atcaggttct tgtgatgctc
cctgcctgat atgctatggt 17220tttgttaatg gaatgtccat tcctgagctt atgcagaaaa
aagtcccttg ggaaagtggt 17280tttactgtgt tatgttcatt ttccccatag ttctcaaaat
gtacttcctt gtttcagttt 17340taattttctt tcattggtgt gaccattttc aactgctccc
tttctgggaa gaggtagcag 17400acggacattt tcatcaaaat ctgccccagg ttgcttcaca
gataaggagg gacccagcca 17460ctaaaatcac caggcagagt gttgcaagag tagatagaga
atcacaattg gctgccctgc 17520tcaaggggac accagatctt actttcgttt agttgaaagg
caagcgtcag agtcgggagg 17580ctgtaccttc atgtccagtg gcctcacaga agttccttca
gtatctcttt tagatgaaac 17640tcttttagaa gttccttcag tatctctttt ggtttctcac
tatagatagt tacttgaaca 17700tgtctgaaga aaacgtggtc aagacagtga ataaaaaaaa
ttctggtttt gggaagcagt 17760ctgacttagt ttcaaatatt ctatcccact gtttctgtca
atgttcaaac ctttccaagc 17820tccaacattt attgtggaaa atgtgtgcct caccaactca
tgcaaataaa tgtttcatgt 17880gccctacgtg tgtagagggg gcatggatgt gtgtttttgg
agggagggct aatttttctt 17940tagacatgga gaatacgagg aaattagctt ggcatcaaga
aggttacagc aggagacaag 18000agtgaagaga actgagagag cccggaaatg aggctctgga
gttcagattt tttttttttt 18060gagatggcgt cttgtacccc aggttggagt gcaatggcaa
aatctcagct cactgcaacc 18120tccgcctccc gggttcaagc gattctcctg cctcagcctc
ctgagtagct gggattacag 18180gcatgagcca ccatgcctgg ctaattctgt agttttagta
cagatggggt ttctccatgt 18240tggtcaggct ggtctcaaac tcccaacctc aggtgatcca
ccctccttgg cctcccaaag 18300ttcaaggatt acagccatga accactgcgc ctggcctaat
ttttgtattt ttagtagaga 18360cagggtttca ccatgttggt caggctggtc ttgaactcct
gacctcgtga tctgcccacc 18420tcagcctcat gaagtgctgg gattacaggc atgagccaca
gggccaggcc tggagttcag 18480atttaacaca tcctgtaaat gacatgatgc atctgatatt
tgaagagttt tcctcaaaga 18540atgttacatg caaggtggtt tagagttgtt gtttccggct
atatagcaaa agtacttggg 18600gagttttaaa aaatactgat gccgaagctc cacctagaat
agttcattca gaatctctag 18660cataattgac ctcagtactt gaaatatgat tattataaat
gttagtcaac tgctttttta 18720ggctctatga ctgatagaaa tctttcactt ttatatcatc
tccagttaat gagtcccata 18780aattgaaatc tagtgtttaa atttttactt catatttatt
tttactgatt gttttattat 18840tattattttt gagacagagt ccgctttgtc gcccaggcta
gagtgcagtg acgccatctc 18900ggctccctgc aacctccgcc tcctgggttc aaacgattct
cctgcctcag cctcctgagt 18960agctgggatt acaggagccc accaccaacc acacccagct
aatttttgta tttttagtag 19020acggggtttc gccatgttgg ccaggctggt ctcgaacccc
tgacctcaag tgatccaccc 19080gcctcggccc tctgtctcaa aacaaaaaca aaaacaataa
caaaactttt ctcttctacc 19140cgagatgttt aagtttaaat cacaccattt gtacaaaaat
tccctgtctt gtccttaaaa 19200ataatttgta atcactagct agttttgaga tcgattgcca
tctaaccgaa tgccatttgt 19260tctctctctc tagtttcaac ttaataaccc tttctgcatt
ttctattctt tcaaaatttt 19320tccggccatt ttattgtttc tatttagtga aaatttattc
actggtttct atgcctaagg 19380gcatttagga agttgcttag gatacagacg tgataaaaag
accagtgtaa aaactctcca 19440ctcctagaca ttatattcta gtcctcatct cctgtcattt
aagtcctcag tgattctatg 19500cacttttgct tttggtttgg gcagatgctc tgagtttaat
gtttctctga gatgaggacc 19560ccctattcaa ctcacaaatc ccataaggag gcctctgtgc
ctttgctggt gccccagaca 19620gggtgctgat gcttacttat cttcaagatt gtgaagtcag
atttaatagt atagtcgttt 19680gccagagctg ctgtaacagt agccacaaac agttgggctt
aaaataccac aaacaggagg 19740gcttaaatca cagaagttga ttttctcaca gttcttgagg
caggaagtcc aagatcaagg 19800tgtcgtggag ttggtttctt ctgatgtctt gctccttggc
ttgtagatgg cctccttatt 19860attgtgtcct cacatggtct tttctccact atgcacaaat
tccctatgtc tctctctctt 19920tttttttttt tttttttttt ttgagacaga gttgcactct
gtcacccagg ctggagtgca 19980gtggtgcaat ctcggctcac tgcaaccttt gcctcccggg
ttcaagcaat tctcctgcct 20040cagtctcctg aatagctggt attacaggtg cgcaccacaa
agcccagcta attttttgta 20100tttttagtag agatagggtt tcgctatttt ggtcaggttg
gttttgaact cctggcctca 20160agtgatccgc gcacctcggc ctctcaaagt gctaggatta
caggcataag ctactgtgcc 20220cagtctcccc ctgtctcttt gtgtccaaat ttcctcttct
ttagggacac caatcagatt 20280aaattggacc caccctaaag gcctcatttc aatgtacctc
cttcaagggc ctatctccaa 20340atacagttat atttttaggt actagggcta gggcttcagc
ataggaattt gggggagaca 20400caatttagca catagcagaa aatataaggc caggaaaaaa
tattctggca tgctagatgg 20460actcattaac aaatattaac caatataaac caattaacaa
atatttcttt aatatttgcc 20520tttttttttt tttttttttg aaacagagtt tcactcttgt
tgcctaggct ggagtgcagt 20580ggcacgttct tggctcactg aaacctctgc ctcctgggtt
caagtgattc tcctgcctca 20640tcctcccaag tagctgggat tacaggtgcg ggccatcaca
cccggcttat tttttgtatt 20700tttagtagag atggggtttc actatgttgg ccaggctggt
ctcgaacttc tgacctcagg 20760tgatccacct gccttggcat ctgaaaatgc tggggttaca
ggttgcctgg tgatttttaa 20820gaggaatgac tgagctctca tgccaggtgg ggggagggga
cagagaaagt tgaatactct 20880gacgatagcc atgatccata gctctgaagc ttagactcga
atctacccat cccgcaagga 20940agaaaacaaa gaaataaaaa agaagaaaag aaatctccca
atgtcaggtc ccaccctctt 21000tagaagtaat ttcagcaaaa ctttgttgct attttggcat
gtcctctact gtagtagctt 21060gtcaaaatac tgtccccaaa cgttttctat atttctagat
tttactgttt aatgtataat 21120aataatgttc taacattaaa acgtaaccat agcaatgctc
cgactcactt gatctttaaa 21180tatattgttg aactcaattt tgtgacatct tcagaattgt
ctttttgtat tcataaatag 21240caacagtgga tagttgcctt ggttagtgtt attatttcaa
ggattaatct ttaggttacg 21300ttttcttcat aagatgcatt agatgacttt tttttttttt
tttttgagac agagtcttgc 21360tctgttgctc agactggagt gcagtggtgc agtctcagct
cactgcaatc tccacctcct 21420ggctcaagag agtctctcga ctcagcctcc tgagtagctg
ggattacagg cacgcaccac 21480catgcctggc taatttttgt atccttttta gtaaagacgg
gatttcccca tgttggccag 21540gctgatctcc aactcctgac ctcaagtgat ccatctggct
tggcctccca aagtgctggg 21600attacaggca tgagccacca cacgcagcca attagatgcc
ttctcatgct tttctgtgtt 21660gtgaaacaga tcatctatcc gttgatatag catagctctt
cagactacag acattttagg 21720ctataagttt tgaattacat tttctattcc ctttatgctt
cttgttctag ttaggttttt 21780tatttctaaa taaaaatatg aatttttgca atttcccaaa
tgcgaactca actgaaattt 21840tcaagtgtat tagcaaaatt tattcatagc agcctcttac
atttcattaa gaattgattt 21900tttcttattc cctgttgaag tttgtttata aaatatagta
atagtaataa ctatatagaa 21960agtgttcact ttgtagtagg ccctatgtta actttaacta
cactttttaa atctaagcct 22020catagtagtc ttggatggat gcggtggctc acgcctgtaa
ccccagcact ttgggaggct 22080gaggcgggtg gatcacgatg tcaggagttc aagaccagcc
tggccaacat ggtgacactg 22140tctctactaa aaagacaaaa atcagccgga cgtggtggta
tacacctgta gtcccagcta 22200tttgggatgc tgagtcagga gaattgcttg aacccaggtg
gtggaggttg cagtgaaccg 22260agatcacaca agtgcactct agcctggatg acagagtgag
actccatctc aaaaaaaaaa 22320aaaaaaaaaa aaagagatca ataaataaaa taaataaata
atcctcacaa tagtcttcac 22380catttgcaaa tgatccattt gacaataaat gaattcagca
ctatcatgga aatatatttc 22440caagctgacc agttttctcc atttccaccc cacttcaatc
caccttcatg tagccctagg 22500actattgtct cctccccttg tttccttatt tccattcctg
ttcagctgta acacattctg 22560ttcatagcag tcaagtgatg cttacaaatg gaaatcaggc
tagaggtggt agttcacacc 22620tataattcca gcattttggg aggctgaggc aggaggatca
catgaggcca ggagtttgag 22680accagcctgg gcaacatagc gagaccccat ctctacaaaa
ataaaaaaga attagctgtg 22740catgatccta tgtgcctgtg ttccagctac ttgggaggct
gaggtgggaa gattgcttga 22800cccagggagt ttgaggctgc aataagctat atttgtacca
ctacactcca gtgtgggtga 22860cagagtgaga tcctgtctct aaaaaacgta aaatgaaaat
aaaaccttga tagtttgctc 22920tttaaaactc ttcctacagg gcccctgtga tgctcacctg
tctctagaag ggcatgtaat 22980agctctttct ccttcacttt actttgatgc aatgtcagaa
cagcttcttt ccatcaaaac 23040ttaaaccttt gatttcattt aaaatcatct gcttcaaatt
ctaatctttc tgatagttta 23100ggttctaatt tttctgatgt taatattgtc acccaagttt
cctgttcata tttacctggt 23160ttattttatt tttattttta tttatgtatt tgagatggag
tctagctctg tcacccaggc 23220tggagtgcag tggtgcgatc tcagctcact gcaaccttcg
cctcctgggt tcacgccatt 23280ctcctgcctc agcctcccga gtagctggga ttacagggac
ccgccaccat gcccggctca 23340ttttttgtat ttctactaga gacgtggttt caccgtgtta
gccaggatgg tcttgatctc 23400ctgacctcgt gatctgcccg catcggcctc ctagagtgct
gggattacag gcgtgagcca 23460ccgcgcccag actttatttt attttttgag acgaagtctt
gctctcttcc ccaggctgga 23520gtgcagtggc ttgatctcag ctcactgcaa cctctgcctc
ccaggttcag gcgattctcc 23580cgcctctgcc tcccaggttc aggcgattct cccgcctcag
cctcccgaac agctggggtt 23640acagatgcct gctaccacac ccagctaatt tttttctttt
tttggagaca gtctcactct 23700gtcgcccagg ctggagtgca ctggcgtgat ctcagctcac
tgcaacctcc gcctcctggg 23760ttcaagcgat tctcctgcat caacctccta agtagctggg
attacagacg tctgccacca 23820catcaaacta atttttgtat ttttagtagc tgagattata
ggctcgtgtc accacgcctg 23880gctaattttt gtatttttag tagagacggg gtttcaccat
gatggccagg ctcgtcttga 23940acctctgacc tcaagtgatc tgcccatctc agcctcccaa
agtgctggga ttacaggtgt 24000gagccactgg gcctggcacc tggtttattt ttgtgcatgc
ttttattttt aattttccta 24060tgctactttc ttagccaaaa tttatactta atctaatcaa
gcattaatct aacaaagagt 24120ttagtgttca tataaaatac agttttacaa atctgttttt
ctttaaatta taaatttgtt 24180aagaaaatta tccaaagaat gatccagaaa caaaagaatg
gctgtgtgtc ttttcaatat 24240catcctggag cattgtctca accatctcac tttacggtga
ctaaaacatc tagaggtttt 24300ccctttgttt tctgtacttc ttagtattga ttaatactgt
tgtgctactt cagtctgaag 24360ttccatgtta atctgtagat tttttttttt ttttttgaga
cagtgtctcg ctctgtcgcc 24420caggctggag tgcagtggtg cgattggctc actgcaagct
ctgcctccca ggttcaggcc 24480attctcctgc cttagcctcc cgagtagctg ggactacagg
tgcccgccac cacgctgggc 24540taattttttc tatttttttt tttaggagag acggggtttc
accgtgttag ccaggatggt 24600cttgatctcc tgacttcgtg atctgcctac cttggcctcc
caaagtgctg ggattacagg 24660cgtgagccac tgtgcccggc tgttaatttg tagattttta
tacagaaaag cagcaaaata 24720tttctgttga gtagaaaata taactccaat gcttatgact
gtattcctta taggacacta 24780actcattatg tgtctaacct agcaatttta tgtcaacact
attttctcaa acctctataa 24840actttggctg ggcacagtgg gtcacacctg taatcttagc
actttgagag gctgaggcag 24900gtggatcacc ttaggtcagg agttcaagac aaggctggcc
aacatggcaa aaccccatct 24960ctactaaaga tacaaaaaat tagccaggca tggtgacatg
cccctgtaat cccagctact 25020caggaggctg aggcaggaga atctcttgaa ctcaggaggt
ggagccaaga tcatgccact 25080gcattccagc ctgagcaata gggtgaaact gtgcctcaaa
atgaataaat aaaataaata 25140aataagtcag agattgtgaa taggatgttg gatataccca
agttatgaat taattaggag 25200cttgaaccca ggaggcagag gttgcagtga gctgagatcg
caccactgca ctttagcctg 25260agcgatagag tgaaactgtg tctcaatcaa tcaatcaatc
agagattgtg agtaggatgt 25320tggatgtacc caagttatga attaattagg agcttgaacc
caggtttgtc tcagatcctc 25380agggactgaa gacttccaag tgaattatgg gtaatgtata
ggtctatact actccaaatt 25440tacagttttc agacttccct gggttctcat ggaccttcca
tgtcatttct atgtttaggt 25500tgaggtccct ggtcttttct cctctgtaat taatttcaca
cccaccccta tctcaactca 25560cacaacttga tcttcactcc catctgctaa gaaattgagt
ccataaaaag tgaactcctt 25620taaactctag atcttctact gctgcaagga cagacattcc
attctggctc tctctctcct 25680cctttgcttc ttccagtcct ttgctccttc tgcattctgt
tactctcctc tctcctttgt 25740cttcaatctc tccctcttgc aatagccaac tataaactgc
tcaagcttct cattcttaaa 25800agatctctct gaaatgcaaa ttccctactg ccttatggct
ctccttcaaa agtaatctac 25860attttctcta ttttctaatt cctcaacaca ctaacgtttg
aaccctgctt ctatgaccct 25920gacctaaatt tctattaaat gtacatagat aaactaatat
atatttgtga cttcctaata 25980ttgttttgtt ttttaaagag gtcaatctta ctttaactct
gtaatgatgc ggttgacctt 26040ctgatgattc tctacttctg tgaaatcctc tactgtcttg
actttttaat taatttattt 26100ttttttgaga cggagtctcg ctctgttgcc caggatggag
tgcagtggca caatctcggc 26160tcactgcaag ctccacctcc cgggttcatg ccattctcct
gcctcagcct cccgagtagc 26220tgggactaca ggtgcccgcc aacacgccca gctaattttt
ttgtattttt agtagagacg 26280gggtttcacc gtgttagcca ggatggtctt gatctcctga
cctcgtgatc tgcctgcatt 26340ggcctcccaa agagttggga ttataggcgt gagccaccgc
acctggccct actgtcttga 26400cttttatagg gtcattctat tcaagctcat tgagcgtctg
tcactatgtt tttgatctgt 26460attgctggaa tcagttcctc tatctgcctt gtgaatattc
tccattgtgc taatctaggc 26520ttctcctttc atttttcata ttccctcaca tggctttata
cactcttgtg gttttaacca 26580caatataggg tttttactgt agttatgctt tcaaattgta
tacttctttt tttttttttt 26640ttttgaaatg gagtgttact ctgttactcc agtctggagt
gcagtggtac gatcttggct 26700cactgcaact ttcgcctccc aggttcaagc gattctccta
catcagcctc ccgagtagct 26760gggattacag gcatgtgcca acacgcctgc ctaatttttt
atttttagta gagacaggat 26820ttcaccatgt tggtcaagcc cgtcacaaac tcctgacctt
aggtgatccg ccctcctcgg 26880cctccccaag tgctgaaatt acaggtatga gccatcgtgc
ccagccccaa ttgtatgttt 26940ctaatatgac ttttctcctg aactttaaac tgtgtatcca
acttctcagc acagtcatat 27000cttttgattc cacaggtaat ttaatgtcaa tatatttaaa
aatgaattta ccacctttat 27060ccccactctt tgactttcac ctgcatttct gtttcaattc
ttgtttccat ccattcattt 27120gctcacctaa ttcataaaca tggaaatcat cctcaattcc
tcttcttctt agcccaaaaa 27180ttcaattgtg caggttatgc actgagaaaa agagcctcag
gttaggggga taaatcagag 27240attggtgaac tttttctgaa gggccaaata ctaactgctt
taagcttgct taccatatgg 27300tttatgttgc aactaccaac tctcctgctg taatgtaaaa
gcaaccatag atagcatgta 27360aacaaatgag acaggctggg tgccaatgaa aattcacgaa
aattaatgta gtttactgtc 27420ccttgggtga gagttggggg tcactgaaat tcggactatg
tcttacttgg ctaaaccaca 27480ggcctagagt gggccataaa tggagctatt gggctagtga
ttttcttgcc ttaagccccc 27540agccccaaat ttaataatca catcatttta atttcatttt
ccaagtgtat ctttaatata 27600tggcttctcc tttccaaatt cactgtcatt acctaagttt
agtccttgaa caatatttta 27660aaggcttcct tatctgactt tatatcttaa agtcctacaa
atttatcttc ctaaaattca 27720aatcaaacca tgtcaccaac ttacagaaag ggaaaattca
tatattctac acacagcaca 27780tttcatgtaa ctttctaggc tcatctttca tcatcctttt
gatgcaggat tttctgctcc 27840tcagctcagc gaaatccagg atcttgtctc atgaccagga
agaattaggc aggtggacat 27900agtgaagggt gaggatgacg gaatttatta agcaaaaggg
gagttctctg caaagagagg 27960ggtttcacca gcagtctccc acctcacaat ggagcaccag
gactttcaca cacaaactga 28020aaaggctagg ctcctcccca gcataaggca tgaattcctg
gtggttccac cagttttcct 28080actatgcatg tgggtgtgcc caagcaaacc ataggtagta
tcagaaaagg caacatttga 28140ttggttaaaa ggcattattc acccaagcaa accataggta
gtatcagaaa aggcaacatt 28200tgattggtta aaaggcatta ttcagaaaga atcaatcggg
aaagggtgag ccaatagggg 28260aagttctccc tctgggtcac gggtttcatc tgggaccagg
agtctggcct ttcagccttt 28320agactgtttt aggcttgaag gtgggtttca cagggaccct
tccctatctg cctaggcatc 28380tgtctgcctc ctgcctctat cactttctct tgagttttat
attttagcaa cactgagtca 28440tctttgtccc aggaagcacc tacatctgtt tatctgctgt
cccctctacc tttactacct 28500tcccttcttc acatttatac ccagaaaagt cacttcccct
ccaaaaattg ggatcaactg 28560tcatattttt atgaatattt cactttaatt cctcacaaca
gctgacagaa ttaactactt 28620cctcttcttt gcaagttatt tggctcacac agatatcagt
aattaaacat attttactgc 28680attggcatat atctgactaa tgtgtttttc tcccgtacta
ggcaatatgc tccttagtca 28740tctgtgtatc tgaggtgagc acagggccta actagcatat
ggtgcattct caatgttcgt 28800tcaactgcat tgacttgaat tcccctgaag actgaaatgt
gaaaatagct actctcggaa 28860gcccctttcc agagaggtct aaaatattta catgtttcta
ttttaaatgc agaaagaact 28920tccagatcat tataggcctt ggatggaaat tgccaacaaa
cttcctcaat tgattgatgc 28980tcaccagctt caagctcatg tggacaaggt attcttctct
tcaccccctc atcacattct 29040gttttcatca tcataccact tttctttctt agccttgtgg
aagtgtgtca attgtcctgg 29100gaaactgttc attaccattg aacttatcag caaagctata
tcttccttcc tgaaaaacag 29160aatgacccct tcgtaatctg atacatgtgt tttcctaagg
ttttcagagc cagcacaaaa 29220caatgcctga cacatgccaa taactcacca aatgtttgtt
taaagaagaa tctgggtggg 29280aatgataaac taactaatgg acaaggtatc gcctaagaag
gtcagcttgg aaattctcag 29340gttcctcatt ccatgtacgt actcaaggct ctgttgttac
tgagggggtc taacttgatt 29400ttgtcctagg tgttatagaa tagttaaatg gagggaattt
ctgaattata aaattggcca 29460tgggttctac aaaacatcca ataagcctgt aaattccaca
aaagtgttga ttaggctgat 29520acaaaggtaa ttgcagtttt tgccattact tttaatgaca
aaaaccacaa acacttttgt 29580accaacctaa tagctatgta accctgaaaa agttactcaa
ctctgtaatc ccatttcctt 29640atttataaaa tgagagaaac tctggtctca cagtattgtt
atgggaagta aatcactttc 29700aaagtggccc ttttgtagtt cttgtcctat aatagcattc
agtatacatt cattacttct 29760ctgtagtctc ttctccatct gtcctaatct atcagtttgg
agtaccacat aattgcggaa 29820gtccatgaaa agttttccgc tctccaaaat ttccctttgc
tgatggataa tatttaatgt 29880ctagaattac aaattctttt taaaatactc attgaatgtt
tgctttgtgc aaagcactag 29940aaccttgtaa aagatgagta agggactggc ttcaatgtct
gtgaagatag caaactaaac 30000agagtaattt ctttgcctga tagataaaat gttgtgttga
catgaccaaa gaaatccaaa 30060aataagaaaa aaactatctg taaacacaga aaaatagaga
aaagttccaa tgatggaata 30120aaaatttaaa ggattttttt gaacgtatta agcaaatcat
gtataaaatc cagaaataag 30180tttacaggac ccatgtcaag gatttaacca aagcagaggg
agatccccat gagtcccctt 30240ttcccatctc agaatagcag agaagagaag caagggaagc
ctggaacagt tggcaagagg 30300gcaggttaga attcagtttg tgaattatga ggtcgtctgc
cgtaggcatt taccaggctt 30360tatttgattt aactgccata aaggaagaga aggacttgtt
aaattggggc tcctcttagc 30420acagcattga aaccagtccc tattccttct tggccttttg
gctaaaattg agtgtgaaat 30480ctatcaccta acatttgtac tgggtttagg ctgggtgtgg
tggctcacgc ctgtaatcct 30540agcactttgg gaggccaagg ctggcggatt gcctgagctc
aggagttcga gaccagcctg 30600agaaacatgg tgaaaccatg tctctactaa aaatagaaaa
aattagcagg gtatggtggc 30660acatgcctgt agtcccagct atttgggagg ctggggcaga
agaatcactt gaacccagga 30720gacagaggtt gcagttagct gagatcacac cactgaactc
tagcctgggc cacagagtga 30780gactctgtct caaaaaacaa aacaaaacaa acaaacaaat
atatatatat taaaatacaa 30840atttttactg ggtttaatag tgtcttccta gaagtcatgt
tcatgcataa tctgtgaaag 30900tggtcttatt tggaaatagg gtgtgtacag ttgtattcga
gttaagctga ggtgatactg 30960gattaaattg tatatgatga gtgtccttat aagaagagga
aaaattaaac acaggaacat 31020agactcaagg gaaaacatca cgtgaagatg gaggtagaat
tggaatgatg cattgacaag 31080ccaagatgtg ccaaggattg ctggcagtca ccaggagtta
ggagacaggc atggaacaga 31140atggaacaaa ttctccctca gaggctccag aagaaatcaa
ccctattgat accttaattt 31200gggacttcta tcttccataa ctgtggcaga gtacatttct
gctattttaa gtcatgatgt 31260ttgtggtcat tagttatggc agcgcataaa actaacacaa
cactcttggt ctctatcgct 31320tctttttttt tttttttttt ttgagacaga gtctcactct
gtctcccagg ctggaatgca 31380gtggtgcaat cttggctcac tgcaacctcc agctcccagg
ttcaagcaat tctcctgcct 31440cagcctcctg agtagctggg actacaggca cccgccacca
tgcccatgta atttttgtat 31500ttgtagtaga gacggggttt caccatattg gccaggctgg
tctcgaactc ctaaccttgt 31560gatccaccag cctcagcctc ccaaagccct gggattacag
gcctgagcca ccatgcacgg 31620cctctatccc tactcttaat tgcctggaaa atacctaaca
aatgaaggcc agtttttaga 31680ctttaccacc aaaggctgaa attgaaacag gaattgtttg
tgagaagcaa acacaatagt 31740ttcgagagac tgaatcagtt agcaatttcc tgtgagaggc
aaatgtaata gtttctagaa 31800ccacagatgg agctataaca aaaacatgtg ttctctggat
cctttacttg ctacagacaa 31860cacaataagt gaatttacag ctttgatctt acagtgcacc
taagccaacc accttgtctt 31920agaatgtctc aacataccta tctgtatctt gaaacaaaat
atattaattg ccttagaccc 31980attcactcac atttcctagg aagacatgat cagagggagc
tatgcaagaa gaaatccagc 32040agaactctgg aaatacaata agaaaatcca tattagacac
taatcttaat aaaactaacc 32100ttcgttcatg aatttgaata gacaaaatta ccaaataata
tggaaaaaat gggcaactca 32160aaaagaagag ggtagcccac ttggcattca ggaccaatgg
cctccaataa ataagatgat 32220attagtgctt taaatatttt atttagtgta tccagtatat
tgccttccta aattaagtga 32280aagctgatat ataaaaagaa ctattagaaa taaaaaacca
cacacatccc agaactcctc 32340aatataaacc taacaaattc agtaaaacat tgattgcaaa
aaatatatat agtgacttag 32400ggacttcctt gataaatttc ataaagcata aagaaaaatc
aaagagtgca aaccatcaga 32460aaaatacaaa tatataaaaa agagaaatac aggtgatcca
aattcctttt aatggaatcc 32520cataagcaga tgggtggagg aaaagtaaaa cttccaacat
ataagcacaa aatttttaga 32580ccttaagaaa tatttgagtt ttttatatca gaaagacagt
gttggggtga gggttggggg 32640gcacatgtaa atactcagat aaaattgtga attttctagg
gtaaagaaat ctgcatattc 32700atagaaaaca aaaatgaaaa atagtttatt tacagagtaa
atacatacga ctgtttacct 32760gtaatgctaa atattaaaag acagtttctt ttcttttttt
tgagacagag tttcactctt 32820gtcgcccagg ctggagtgca gtggtgctat atcgactcac
tgcaacctct gcctctgggt 32880tcaagcaatt gtcctgcctc agcttcccga gtagctggga
ttacaggcac ccgccaccac 32940acccagctca tttttgtatt tttattagag acggggtttc
accatgttgg ccaggctggt 33000ctcaaactcc tgacctcagg tgatccaccc gccttggcct
cccaaagtgc tgggattaca 33060ggcgtgagcc accgtgctgg cctaaaagac aatttcatac
ctatttgtat ggctaatttt 33120ttaaaaatct ggccatatca aaatactgaa gaggacgtat
agcaatagag actttcattc 33180attgctggtt gaaatgcaaa atggtacagc cagtttgaaa
actagcttgg cagattctta 33240taaaatgaaa catagattta ccatgcaact cagcaatggc
attcctaagc atttatccaa 33300gtaaatggaa aatgtatgtt cccagaaaaa aaatccatat
atgaatgttt ataacagctt 33360tattcataat caccaaaaaa aaaaaaaaat ctggaagaaa
acaggatatc cttcaaccgg 33420ggaatgaata aaccaaatta taataattgt aaattgtggg
atggatagtg gaatagtatt 33480cagcgataca aatgattgag caattaattt gtgcaatgac
agggatgaac cttaaataca 33540tttacctaaa tgaaagatgt caggcctata ttgtatgatt
cttttcaaat gactttttag 33600aaagggcaaa actagaagga ttaaatatag ctttatggtt
actagagaca ggtaaggagt 33660gggtagttga ctgcaaaggt aatatatagg ggaatgttta
gcatgatgaa actgttttat 33720atggcactca ggtgatggat atatggctct aggcactgaa
aaacccatgg aattgtatgt 33780cacaaagaat ggactttcat gtatgcaaat tttaaaaaat
aaaccagaaa attgggagaa 33840tactaggatg gaatgcagac tgtgataaat aaaactaact
ggactctcag caaactaaca 33900caggaacaga acaccaaaca ccgcatgttc ttacttataa
gtgggagttg aacaatgaga 33960acacaaggac acagagaggg gaacatcaca caccggggcc
tgttgtgggg tggggggcta 34020ggggagggag agcattagga caaataccta aagcatgagg
ggcttaaaac ctagatgatg 34080ggttgacagg cgcagcaaac caccatggca catgtataca
tatgtaacaa accagcacat 34140tctgcacatg tatcccagaa cttaaagcaa atttttaaaa
aagtaaaaaa aaaaaaaaca 34200aacaacaaca cctaactgga ctacaaatgc actatataac
ttcgatgaag agagtgggga 34260gtagggaaag gaacggactt aaattactcc agaaaatagt
gttgtgttgt gactagaatc 34320tataaggctt acggtaaatg aaactttaca ggatcactat
actctaattg gtaaatcagt 34380ttttcatggg gtgcgggtga acagttgtga aactgcttta
catgtagtca tacctttgca 34440ttttgcagat atttcaattt ttacaaattg aagattcgta
gcaaccttgc atcaagcaag 34500tctgtcaacc ccatttttcc aatagtgtgt acgcatttgg
tgtctgtgtg tcatattttg 34560ataattataa caatagttaa aactttttct ttactattac
atctgttaca gtgatctgtg 34620atcagtgatc tttaatgtta ctatcataat cgttttgaag
gtgccataaa ctgtgcccct 34680ataagtcctg aaacttaatt gataaatgta tgtgttctga
ctgctccact gaccagccat 34740tgccccatct ctctccccct cctcaggcct cctgatttcc
tgagacataa taatattgaa 34800attaggccaa ttaataatcc tacaatggcc tctaagtgtt
caagtgaaag gagttgcatg 34860tctctcactt taaaaatcta aaactagagg ctggtcatgg
tggctcaggc ctctaatccc 34920agcactttgg gaagccaagg cggggagatc acctgagttc
aggacttcga gaccagcctg 34980gccaacatgg cgaaactctg tcttgactaa aaatgcaaaa
attagccagg catggtggtg 35040cacacctgta atcctagcta ctcaggagac tgaggcagaa
caatcgtttg aaccctggaa 35100atggaggttg cagtgagcct agattgtgcg attgcactcc
agccagggca acaagagtaa 35160aactccttct caaaaaaaaa aaaaaaaata tctaaagcta
gaaatgatta agcttggtga 35220gaaagtcatg tcaaaaccag ataggcttaa agctgggcct
cttttgccaa acagccaagc 35280tgggagtgca aaggaaaagc ttttgaagaa aattaaaagt
gctactccag tgaacatacg 35340aatgataaga aagcaaaaga gccttattgc tggtatagag
gaagtttgag tattttggat 35400agaagatcaa accagccaca acttccctta aaccaaagcc
taattcaaag aaaggcccta 35460attctcttca attctacaaa gtctgagagg gctgaagaag
ctgtagtaaa aaagttttaa 35520accagcagaa tctggttcat gaagtatgag gctagaagcc
atctccacaa cataaaagtg 35580caaggtgaag cagcaagtgc tgatggagaa gctgcagcta
attatccaga agatccagct 35640aaaatcatca atgaaggtgg ctacatttat tttttatttt
tgttatttat taatttattt 35700attttgagac aaagtcttgc tctgtccccc aggctggagt
gtggtggcat gatgttggct 35760cactgcaacc tccacctcct aggttcaagc aattctcctg
cctcagcctt cccagtacct 35820gggattacag gcatctgcca caacgcctga ctaatttttg
tatctttggt agagacgggg 35880tttcaccaca ttggccaggc tggtcttgaa ctcctgacct
caggtgatcc acccgccttg 35940gcctcccaaa gagctggatt acaggcatga gccaccacgc
ctggccagtg gctacattta 36000aaaataggtg ttcaatgcag acaaaaccat cttttattgg
aagaagattc caaccaggac 36060tttttttttt tttttttttt tgagacagag tctcactctg
tcgccaggct ggagtgcagt 36120gatgcgatct cagctcactg caatctctgc ctcccgggtt
caagtgtttc ccctgcctca 36180gcctcctgag tagctgggac tacaggcacg tgccaccatg
cccagctaat ttttgcagtt 36240ttagtagaga cggggtttca ccatgttggc caagatggtc
tctatctctg acctcgtgat 36300ccacccccct tggcctccca aagtgctggg attacaggtg
tgagccactg cgcccggccc 36360aggactttca tagttagaaa aaagtcaatg cctagcttga
aaggacaggc tgactctctt 36420gttaggggct agtgcagctg gtgactttaa gttgaagcca
gtgctcattt accattcctg 36480aaatcttagg gcccttacca gctatgctaa atctactctg
cctgtgctct gtaaacggac 36540aataaggcct ggatgatggc atatctattt acagcatgct
ttactgaata ctttaagctc 36600actgttgcga cctactgctc agaaaaaaat attcctttca
aaatattact gcttattaac 36660aatgcctctg gtcacccaag agctctactg gagatataca
ggaaataaat gttgttttca 36720tgtctgctaa cacatttgtt ctgcaaccta tggatcaagg
ggtcattttg gctttcaagt 36780cttattattt aagaactata ctttgtaagg ctattcctga
cacagataat gatccctctg 36840aagaatctgg gcaaagtcaa atggaaacct ggaaaggatt
cactattcta gatactatta 36900aaagcattca tgattcatgg aggacgtcaa aataaaaaca
ttaataggag tttgcaagaa 36960gtcaaccctc atggatgact ttgaggggtt caagacttga
gcagaggaag tcactggaga 37020tgtcgcagaa atagtatgag aactaaaatt agaagtggaa
tctgatttta taactgagtt 37080gctgcaatct tacgattgaa cttttctttt cttttttttt
tgagatgccc ctgctgagct 37140gccagttcct gaagggtcac cgggagcagc gcctggccca
cctggtcctg agcttcctca 37200ccatgggtta tgtctggcag gaaggagagg cgcagcctgc
agaggtgagg gccagagagc 37260agcttctcct gttacccggc aggttacctg cgcctggagt
aacgtgctcc ctgcttggtg 37320ctaccctgtt ttcctggaaa atgggtactt tcttcttctc
gatgggcatc agtttaagca 37380acgatgaagg gctcatttat tatttattat tattattttt
ttattttatt ttgagccagt 37440ctcactctgt cactcaggct ggagggcagt ggggtgatct
tggctcactg caacctcccc 37500ttccaggttc aagcaattct cctgcctcag cctttcttgt
agctgagact acaggcaccc 37560accaccacac ctggctaatt tttgtatttt tagtagagat
gggtttcacc atgttgccca 37620ggctggtctc gaactcttga cctcaggtaa tctgcctgcc
tgggcttccc acagtgctgg 37680gattataggc gtgagccact gcgttcagcc tgaagggcca
tttaaatgaa ggattttttt 37740attttaattt ttctgactaa gagctaattt gttttttaaa
ctggtagcta tttcttcctt 37800ttataagctt ttgaatgttt gtttgtttgt ttttggcact
ctcttccaag aatgtttgaa 37860gacctgcatt tgaaggcaga ttgccttttt gctttaaaac
agggttgcac catgttgccc 37920aggctggagt gcagtggtgc aatcatagct cactgcagcc
tcaactcctc ccaggctcaa 37980gcaaccctcc cacctcagcc tcctgagaag ctggggctac
cagcatgtac cgccacaccc 38040agctaatgtt aaaaattttt tgtagagatg agggtcttgc
tgttttgccc aggctgatct 38100taaactcctg gcctcaagtg atcctcctgc ctttgcctcc
tgtgctggga ttacaggcgt 38160gagccaccat gccgggcctg aagacagact ctgagaattc
ataaaaacct cacagcattt 38220tgtactctta tgtatataaa ttatctaggt tgctcttcat
aatcctgtaa agtaacaaga 38280gccataccgg cccattttac aactgaaaag cacagacact
tatttcctta atcaaggtca 38340gacagcaaat tagtggaaaa gccaaggcca gaacccaggt
cttctgattt tactagtgca 38400gccttctttc cccaggggac acattgacat ttacaacact
catctttatt ttttttttaa 38460tactgctttc tatccagcca attattagtc tgtcttttaa
taattcatcc aaatctcttc 38520tgaatcattg cataactttg tacagtttcc acccacagtg
tcttttactt ttatttttgg 38580aagtaactgt ttttaaaagt tactgttatt tttaaaagtg
tgccttcccc agaaatcagg 38640gagttaccca tgtcctagaa ctccacggtg aagagaacag
cctgtgccca tcgtgtttgc 38700ctgattgatc ctacctcttg tctctcgggg aaacacagga
gactcaggga agaggaaaag 38760tgtagagtca ttgcagcctt gttatttgtc aatgcatctc
ttttcttttt ctttttcttt 38820ttttgataca gagtttcact cttgtcgccc aggctagagt
gcagtggcgt gatctcggct 38880cactgcaacc tcggcttcct gggtccaagg gattctcctg
actcagtctc ctgagtagct 38940gggattacag gcacctgccg ccacggccag ctaatttttt
ttgtattttt agtagagacg 39000ggtttcacca cgttggccag gctgatctcg aactcctgac
ctcaggtgat ccacccacct 39060gagcctccca aagtgctgtg attacaggca tgggccccag
cacccggcca gtgcattgca 39120tttttttttt ttttttcgag acggagtctc actctgtcac
ccaggctgga gtgcagtggc 39180acgatcttgg ctcactgcaa gctccgcctc ccaggttcac
gccagtctcc tatctcagcc 39240tcccaagtaa ctgggactac aggcgcccac cacaacgcct
ggctaatttt tatattttta 39300gtaaagacgg cgtttcacca tgttagccag gatggtctcg
atctcttgac ctcgtgatct 39360gcccgccttc gcctcccaaa gtgctgggat tacaggcgtg
agccaccgtg cccggcgtgc 39420atttttaaaa gtgtgtctga tgctgaaaag tttgaagtct
aggcacgtcc cagtgggtcc 39480tctttatacc atcccctctg caaaccatta tcctaaattg
gggtttgggg gagagaagag 39540tgacagtgga aagaagtctc cacctcccag ctgtgccctg
gtagttccag gggacccgga 39600ggctccccac acccaccacc ccgcctcaga tcacctttca
ctttctttgt ttctcctccc 39660ttgacttttc agctcagaaa gtacctggct ctccaatgcc
ttctgaggaa agtttacccg 39720aggttcacat tgcaagactc attaaagctc tttagtgttt
tccacccgag aaaaaattca 39780agggaaaaat gaagacaaaa gcagggcatt cttaatggat
attttatctt aaggagaaat 39840gaaaatggag atggaagagg gggcacaagg atggggtttg
aatctagact cgttcagcct 39900ttacctccga tagagaacct catacagctt ttctggactt
ctggctgata aagagccgtg 39960gagggttcct tggataaaaa aggttgaagg gggtctgtcc
tgtggtggct tacttgaagg 40020tattactggg tttgacttat ggagtaagag acggagtcag
tttccccaca ggctgaggca 40080gtctgtcctc atgcttttct agggcactgt ggtctcccag
gctcatacct aggtgcacac 40140acaggtttct gcatctagct ttgtatctct atgagtcggt
caatcaataa atctatctat 40200catctgtcta ctgatctatc atctatctat ctagctagct
atcatctctc tatcatctat 40260ctatgtatct atcatctctc tctatatatg tgtgtatata
tatatatata tgtatatata 40320tatttctatc cttccatcta cttacctatc tatcaaaatt
tttttccgtt gataatattc 40380tcgggcccca gtttatgttt aattgttttg gtaatgcctt
tctttgcaca gtcagtttac 40440agaggttatt ttatattcta tatgtatgtg tggtccagcg
ttgtaatttt cacatatatt 40500gcaccgtgta ctcataagca gtatttccac tgggtcatta
acagaaagat atgtgtgcgg 40560catatgaatg tgcatcactc aggtaattca agcttggttc
ccagatcatt tctgtaccac 40620aggattgccg aaataaaaga caaccatggt tatttcctct
gctgcaagct ttctagaata 40680tgctatttgt ctggatttat atctgaaagg tcctgccaag
gaatcttgcc cttccatttg 40740tcgaagtctc caggaacttg gggctccctc ctatcctggt
ccactcagac ttggtgctga 40800cgaactggac caaaaaagat ccagacgggt aaggaaggaa
gagaatgctt tgaatttcca 40860taactttccc ccaggaaaca cccaggcttt tttttataat
tagggaagtt catatttatg 40920gtctgccgta tggttccaaa gaaggggtga gcttgaccaa
aaattcaaat atcacaggcc 40980ccagaagttt cctcttaatc cattctgaac acattggctc
agaccatttt gtcttgtttg 41040tttccacatg acgtgtgaat ttctcaacct gaccttcaag
ctcctgcaaa atcagctttt 41100atttgttctt tctcttcaaa ctgtttattc cctaagatgc
cctccattca tatcaggtta 41160aaaccagttg gctttgataa gtaatcatta tataatgatc
agaagagaat gattatggat 41220gaattcagag cagatgctcc aggtgggttg gattgagaat
ttgattaata attccatcta 41280ttccaccaaa gtcacatcat tcctttgaca gttgggctgg
gaataggggc atttgtctac 41340agaaggaata gcatgagatt ttaacaaaca agaaattcaa
caaacagaat tagacagatg 41400atctgagatg ttaaattttc ctttcacctt aatttttgca
gccaaattta tttcagctct 41460agatgaaaga gacagcactt tcttttgtgg ctgactacaa
cagctgaaga ttcactgagg 41520tttgatatga ggaagaactt cctcagccat gggattgcca
gaggcgatga tgggaatcta 41580cttaaaaggg ttacatattt agtagacagc ctagatttta
agactaattt atgtgccccg 41640gccgggcccg gtggctcacc cctgtaatcc cggcactttg
ggaggctgag gcaggtggat 41700catctgaggt caggagttga agaccagcct ggccaacatg
gtgaaacccc gtctctacta 41760aaaatacaaa aaaattagcc gggcatggtg gcacatacct
gtaatgccag ctgctcggga 41820ggctgaggca ggagaattgc ttgaacgaag gaagtagagg
ttgcagtgag cgaaatcatg 41880ccattgcact ccagcctagg tgacaaactc tgtctcaaaa
gaaaaaaaaa ttatgtgccc 41940cattggaaga agtgagattc ggccatctca tctctctcgg
gagctctgag ccctggagtt 42000ttatgttttc tgcaattatg aattgtgatc cttgattaat
tatgctttaa taataaaatg 42060ggtgactact gaaagctgct gaatctgggt aagaatttgg
atgaaaaaaa taatatatgt 42120gcgtaattta ttctgttcaa ggtactgaat attgaataag
ctggatttat tactcaaaga 42180gaaagacaga ataagagaag gttgaaggga aaaatgactg
tactagaatg gtagtcaaaa 42240atgcaacaac aggcaggtgc agcggctcat gcctataatc
ccagcacatt gggaggccca 42300ggtgggcagg tcacctgaga tcaggagttt gagaccagcg
tggccaacat ggccaaaccc 42360cctctctact aaaaatacaa aaattagcca ggtgtggcag
tgggtgcctg caatcccagc 42420tactcaggag gctgaggcag gagaatcact tgaacctggg
aggcagaggt tgcagtaagc 42480tgagactgca ccactgcact ccagcctggg tgacagagtg
agatcctatc tcaaaaacaa 42540acaaaacaaa acaaaacaat aacaaaaaag ctattaatag
cttcctaggg agtaagagtg 42600aagggctagt ttaattccag agatgcggac acagtcctgg
gtctcaccaa ttattctgct 42660tggtaattac cttttgaagc cttttaatat gcctaacaca
gagctaagtg ctatgaagaa 42720atgaaagaaa tagaagcaaa gtactcccca tgtggttaaa
taacaagaca ctacatgaca 42780aatgtcaaag agtgactcaa acaatatgtc ctttagaatt
tcagagaaat gacatcaatg 42840caggctttac aagtcagtaa aaatcttggt gatgaggcag
aacttgatgt aaggcaaatc 42900ctaaaagttg agtaggaatc aactagctag aataaaatgt
ggggttgtgg taaatacaaa 42960aatgtaagat gagtgaaata acttatttat ttatttattt
attttcagag acggagtctc 43020cctctgtctc ccaggctgga gtgcagtggc atgatctcgg
ctcactgcaa cctctgcctc 43080ctgggtttga gcaattctcc tgcctcagcc tcctgagtag
ctgggattgc aggcacctac 43140caccacaccc gactaatttt tgtattttta gagagatggg
gttttaccac gttggccagt 43200ctggtatcga atcctcgacc tcataatcca cctgcctcag
ccttccaaag tgctaggatt 43260acaggcatga gccactgtgc ccagcctaat aatatattaa
gatggccaca ggccaaatat 43320tctggggctg gaatgtgagt ggaaatgtcg ctcacccttt
atcacatagc accccatagt 43380ccagccacaa cttgcagaat tcaaagtaag tgtggatgtg
tgtgtgcctg cagtgccttg 43440cacacaagtg tgcatgcctg tggacatgtg accctagaag
ttattaatat atctggttta 43500caaactgaat tgttctttta ttttttttct ctcttggtgg
tcatcaataa ctgaaattgg 43560gctagattcc tggaaattgg gtaagttctc agaaatcatt
tacgcacttt agaatccagg 43620ccaaatttaa aatcttacaa taaaacaaag aacaaagcat
gctaaattat atgtataata 43680taatatcaac catataaaat gcataaaaaa tatactagaa
ggaaatgtgc ctaaaattca 43740cagtctaaaa tttaacagtg attgcctctt ccttgtatag
ataagggatt tttttttact 43800gtattttcca gtctgtacat aataaaacaa gtaatgtgca
atgcaaacaa aacaaaatga 43860aactttatca aatttcagta actccttgaa gtttaatttt
ttttttgaga ctgagtctta 43920gtctgttgcc caggttggag tgcagtggtg tgatctcggc
tcactgcaac ctctgcctct 43980gggttcaagg gattctcctg cctcagcctc ccgagtacct
gagattacag gcacccacca 44040ccacacctgg ctaatttttg tatttttagt tgagacagcg
tttcactata ttggccaggc 44100aggtcttgaa ctcctgacct caggtgatcc acccgccttg
gcctcccaaa gtgctgggat 44160tgcaggcgtg agccactgca cccagttgaa gtttaatagt
gtgaaaaaaa tatttctcat 44220ctcactatat cttctatggg aggccagatt gcagattgtc
tacagaaaaa tcccttcaaa 44280agaccttgtt attacataga ctggagctca tggggcaggt
ctggtccaca catccttagg 44340ctccgcttct cctggaaaac aaaaatagcc tctgatccag
tgttgcctct cccatcacca 44400aacctcagct tctatcgcca aactcatcaa ataagagtgt
ccagtagaaa aactgggcag 44460atgggggcac agaaggtgaa gacatcattt cccaagctaa
tgttgctgct ggaacaatgt 44520aagtcttgac tttgtcttgg tttggtttgg tttgacattg
gtttgttttt catctttgtc 44580tcatgcttaa aatgtgaagg gcaaatatga tccttagagt
taaggtttta ggttttgtag 44640atgttttact ccatttaaat gacagcagat catttagaaa
tgattcctct gtaacagcct 44700tccagatccc attcgattgt acagcattga gatagataga
tagatagata gatagataga 44760tagatagata gatagacgga atttggccct gtgttcccac
ccatatctca tgtcaaattg 44820taacccccac atgtcaggag agggatccag tgggaggtga
caggatcatg gggttggatt 44880tccccaatgc tattctcatg atagtgagtt ctcacaatat
ctcattatta ttattattat 44940tattattatt gcaacagagt ctcactctat ctcccaggct
ggagtgcagt ggtgtcatct 45000cggctctctg caacctcttg cctcagtctc ttgcgtagct
gggattacag gcatgccccg 45060ccatgcccag ctaatttttg tatttttagt agagacggag
tttcaccatg ttggccaggc 45120tgatctcgaa ctcctgacct caggtaatct gcctacctcg
ctctcccaaa gtgctggaat 45180tacaggcgtg agccactgtg cctggccagt tctcacaaga
tctgatggtt taaaagtgtg 45240gcacttcccc cacctcctgc cgccatgtaa gatgcttgct
tacccttcca ccatgattga 45300aaagtttcat gaggcctcct agccatgctt cctggtaagc
ctaaggatct ctgagtcaat 45360tacacctcgt ttctttataa attacccagt ctcaggtatt
tctttatagc agtgtaagaa 45420tgaactaata cacacataaa cagattagag gcagcactgg
cctgagttgt gaaactcttc 45480ccagcctggt cctgcgatta gctggctata tgaccttgga
caagctgctt tgcttctctg 45540ggccatggtt tcatacctgc aaaaaaaaga gcatggactt
ggctgttgcc tgggtctctc 45600tagccctgtg gagaatcagc tacatctctt actaggaact
tctcattcag ccagttattc 45660cactgcggag atggtccagg accattaggg ccatgctaga
cattgggagg ctgcctgtca 45720ggtgaacatg aaattgaact tatctgttct ctttcctccc
tgaatgttgc tgaaggtaga 45780tgcccatcct cagggctgtc ttacggagag gagaaagttg
tgcagtgatt ccaccctgca 45840gttatctaac tcggcaggga actctgggca gtgagtactc
acggtacagt ctccacacct 45900ctaatcatgt gctcctctcc ttcccaagga acctggagac
catcatctca tttcctgggg 45960gagagagcct gcatggtttt atactggtga ctgctttggt
agagaaagaa gcagtgcctg 46020ggataaaggt atcttctcac ttgatagcac cttttctttt
taaatgagct tgagctttac 46080ttcccactca gtgcctttcc tgcagtggat ttctcaacac
aaatgaacat agaccttgtc 46140ctgcttagtt caagtctgag agaagagatc taagctctag
gccaccatat ttgctccctt 46200ttctcaattc ctataaaact cggaatggac cttttgtcca
ttcaacaaac aggcattggt 46260ttgggcaatg ggaaattgga tcgaacaaga cagacatttt
cccagccctg acagaagctt 46320atgatggata cagtggatga agatggatta acgtggatta
caggtgtgag ccactgcacc 46380gggcctcaaa ctggaaattc ttcaggagtc agacaggtat
caggaaggct ggatagaaga 46440caaaagacag tgatgcagct tgtgatcaac tacagcgtta
atgccttgcc taaaaatatt 46500tcagttagat ttctgccttc gctctgtcgc tcaggccaga
gtgcaatggc gtggttttag 46560ctcactgcaa tctccacctc ccaggttcaa gcaattctcc
tccctcagcc tcctaagtag 46620tgcacgccac cacgcctggc taatttttgt atttttagta
gagacagggt ttcaccatgt 46680tggtcaggct ggcctcgaac tcctgacctc gtgatctgct
tgcctcagcc tcccaaagtg 46740ctgggattac aggtgtgagc caccctgccc agccaacact
acctcccttg ataagcatat 46800gttgagcacc tactggtcct caatagggtg acccatttct
gctatattat agcgctttct 46860ttctctctca gtagttaaac tccatggtta ctttagttct
catccatgtg tttagtccat 46920tagaagatac agagtcaaat atcggccttc caagtgtagt
tcagatgaag tagagactca 46980aggaagacaa ggaagtcttc ccagcagagg ggattctaga
gctgggggct ctgtagaatc 47040tgtctgtgta ttagtccatt ttcacactgt tataaacata
ctacctgaga ctgggtaatt 47100tataaaggaa agaagtttaa ttgactcata gttctgcatg
gatggggagg cctcaggaaa 47160cttacagcca tggaggaaag tgaaggggaa gcaagaacct
cttcacgagg cagcaggaga 47220gagagcaaag gggggagctg ccaaacactt ttatacaatc
agattttgtg aaaactctcc 47280ctcgtatcat gagaacagta tgggagagcc cacccccata
attcaatcac ctcccaccag 47340gtccctccat cagcctgtgg ggattaccat ccaagatgag
atttgggtgg ggacacagat 47400ttcaacacag atttaaatct gactttatat gagagcttcg
gagcaaggat gccccagttg 47460gagatgcagt agaactgatc ataacgtgac aaatccgaga
gaagaagagt aaaataatag 47520tactcaggcc cttgggaggt gcaagaagta acagccagat
gaaattccag aaacacttac 47580ctaggggtct gtctgggagg tccccaggga gcttctggct
gtcaggccaa ccccacagtg 47640gatctagctt aggacgttcc caggaagctc tgacaaactg
tccggtcctc ccctgggttc 47700caacagtatg aggcttactc tgcctgcatg gactttaagg
gagtgctaat aagttgtgta 47760catgcatctc atccctaggc tcttgttcag gccacgaatg
ctatcttgca gcccaaccag 47820gaggccctgc tccaagccct gcagcgactg agactgtcta
ttcaggacat caccaaaacc 47880ttaggacaga tgcatggtaa gatgcttccg aagctcctga
aggatccccc aggggtcctg 47940ggctctgctt aggggaagag ggcctgggga ccaggcatgt
cctgaagggg gtgataatac 48000attcatccac cagatgacgc tggtggacta tctttgtttt
aggttaaaca catattatct 48060tggagagcta ttgtcacagc tttgtattct ccctctcctt
tatattctcc cgtgattaag 48120atggtttccc ttctgcagtg gccagatatt tcttaggcat
gttgaggtct tgcctgaagc 48180ttgagaggag gggatgggat gcacagtaat gttggtcgcg
cgtgccccat cctgcagtgt 48240taggtactgc agagcaggtt gtctacactc tgtaatgccc
cttttattct aaccccctgt 48300gttggttcct gagatgtctg accttggttt taagccttgt
ctaatggatg gcctgtattc 48360cctttctgta gctagggcag gctgatttgt caaaggtagg
aaagttgtca gaatcaaaat 48420ggagtcactt gtgttgaata aaaattttta aaccttgaca
aatagagctg gggaaggcta 48480caaagagaga gctcccgtgt ataaatgcct gataacaaaa
tcttttccaa aggactgaaa 48540aaatcaccac cttgcacaaa ggccatcaca accttacata
cacaaaaaaa tacttacaca 48600acgacatctg cccagcaact gcctttccaa cattggcctt
gtgccaccct ttttattgat 48660gctcatagcc aaggttaatg atctcaaaac agttacataa
ttgtcctcat ttttccttta 48720aaaacctttg tcttccttta tctttctgaa tacccacatg
gtttattatg gcacatgtat 48780tcccattgca atgccctatt ccagaataaa tatcagtttc
cattagggag cctctccctg 48840ttaatctgct taacacaggc atggtcagtt acggggccca
accttcctgg accggttaca 48900tcttattctg gttactgcat tcagtttcca acatctggga
ggctcttcaa attcttctct 48960cagaggaatc tgaagaatgt atgtgtttag gaggatgtga
gagaggggtg tggtttctta 49020acaagagaat atcagagtct aagtatcatt ttccctgaat
cttgcttccc tgcaggaaag 49080aaagattctg ggaaaagaga gtgtttacaa gaagcaggac
tggagggagg gagaaagacg 49140ctaggtactg ccaagcttta ttatcttgta ttaaaaaagt
aaatataatt tgtcatccca 49200gcctctcagc actagtagaa atctatctga agtcacagga
ttaggtatta tccacttcct 49260ggttttatag tttatatttg tattttctct atttccttga
attttaattt taaagccctc 49320atgatcacat cagtaggtct tctgccaaac agctccctta
agttgtatgg tggctttgcc 49380aagctgaaat gagatgagat gtgttttagc tttgccaaga
aagcctgagt ccatcactta 49440ggatagcaag gctattaggg agatagtgca ggtgtcttca
gatcacatgg atgagcaaaa 49500ggaagcaatt ttggaagatt atgagaaacc ttccaacagg
tcccagtgta catagcagta 49560agatggtgca tgcagtgtct aactgtcaca ggctttccta
gggctcactt tcagactcac 49620ttcttttttt tttttttttt ttttgtgaga tggagtctca
ctctgtcact caggctggag 49680tgcagtggca cgatcttggc tcactgcaag ctctgcctcc
cgggttcaag cgattctctt 49740gcctcagtct ccctagtagc tgggattata ggcatgcacc
accatgccca gctaattttt 49800gtatttttag tagagatggg gtttcgccat gttggccagg
ctggtctcga actcctgacc 49860tcaggtgatc tgcctacctt ggcctcccaa agtgctggga
ttacagccgt gagccactgc 49920gcccagctca gactcacttt ttaggcccag gccaacctgc
tgtgttctcc tgctcagctt 49980ctgcaggagg tctcatcgtc taaggaggtc ccagggctac
cgcccttgtt ttctcaaaag 50040gcacattttc ccacacagac ataatttcgt ttcagtgttt
tactcctagt cacattcatc 50100tatatggaca aatagctgaa tggattggac tgtgttttct
aaagatggcc ccatgccatc 50160ctgcgcgctc ctccacagcg tggcctgggc attcctttcg
accaggggtg gactctgtgc 50220ccctacttgt gatgtacgtg ttgccaatag aatgtagtat
aggggatagc acagacttct 50280gaggcaagac tagaagaggt gatgcaggtt taaccttgtg
tcctgagcca ctaggtaaaa 50340agtccaccta ccctgagatc actctgctgt gcaaacgaca
caggcaaacc acatcaaaga 50400gccatgtggg ttctccagtt ggcttctgcc caggagtgaa
ggtgccctca gatggttcta 50460ggctcccatc ccaacttatg tcctgtcttg aagtcttccc
aactgaggca ccagccactg 50520tggagcagag tcaagccatt gccatcttgt tctgcccaga
ttccccatca acagaatata 50580gtggtttttt cacacctcta tgtttggagt ggtttctatg
cagcaatagt aaccacaaga 50640aataaagtta taaaaatagt aacaaacact agaaactgca
agatttaagg aatcacctga 50700atgctccagt cattgtctct ggtttgtaat gataaacttt
cttctgcgtg ataaatagag 50760cttggctgga ctttttccct ctgcttccat tccccaaaat
ggagcgtacc aaacaattgc 50820ttctttcaga gcccagcttt agcaagagtc atgagctcta
atcccttcat ccataaatac 50880ttcctttcca ggcacgtaga gcccttcaca ctcagggctg
agtagaaaat gcctgttgca 50940gactgcagtg gcgttttgga gagccaccct cctggtacct
gagtcactag tcctttgccc 51000agcttttctc agttttgtaa agcgctcact tctgagtgga
agacagaacc agcccggtct 51060attttcataa tctgccccca taaggcagaa gtccacacgg
tactggaaac ataaccatat 51120ctatgtcagt ctgccactgc ctgccgcctg tcaaccgtgc
gtgtctgcat ccagtccttc 51180tttggagctg ctttccagcg actcagccag atctgagctt
tctgactcat tggaaggtta 51240aactattttc agactttcaa gtgttgagat tattaagaca
tgtgtttttt tttttcttct 51300ttttttggca tgcttactga tcgcccctgt tctctaggaa
gtaatgttct tcttggaaaa 51360ggtgaaggat atttttctcc ccaaaaagcc atggaaatgt
ttgcctttat ttacttccaa 51420attaacagaa tttccagctt ttgcttgacc catcggcgca
ttggcagcgt taagaatttt 51480ttcttttagc agtaatgagg agtcgaaggg tttcttccta
accatttagt gtatgcattt 51540aaatcaggtt tctttttgag taaattgggg ctaagctgta
gtgtgaactt ctgctactgt 51600tcctttctca ttagttcact tgatttcatg gaaggaattt
tccatctcag cctgtgaact 51660tattttgtct aaactcaatt ggaaagtaat taacactgag
attcttcttt aataaattct 51720atatgataat aaaatcatac aaacatctct ttatttttct
ttttgaccta gaaaagatgt 51780tcacaggcca gacctggtgg ctgaagcctg taatcccagc
acactgagag gaagaggcgg 51840gtggatcaca tgaggtcagt ccgagggcag ggtagccaac
gtggtgaaac cccatctcta 51900gtaaaaacac aaaaattagc tgggcatggt ggcacatgcc
tgcaatccca gctactcagg 51960aggctgaggc aggagaatca cttgaacctg ggagatggaa
gttgcagtga gcctagatcc 52020tgccactgca ctccagcctg ggcgacagag tgagactctg
tccccaaaaa aataaataaa 52080taaaagatgt tcacaatata ttgttaagtg aaaaaagcag
gctacataac ttgcataata 52140tgagtgcatt ttaataaaaa tatacatatt tagcaaaata
aaaggacaaa tggtatttat 52200taaaatattt acgttgatta tttcaacaca gaggatgata
gttgattttg cttaatttct 52260tccctccttc ttttcaattt gaattttcta taatgaagat
tgtttctttt tctttctttc 52320tttttttttt ttgagatgga gtttcgctct tgttgcccag
gctggggtgc gatggcgcca 52380tctcggttca ccacaacctc tgcgtcccag gtttaagtga
ttcttctgcc tcagcctccc 52440tagtagctgg gattataggc gtgtgccacc acacccggct
gattttgtat ttttagtaga 52500gacgggcttt ctccatgttg gtcaggctgg tctcgaactc
ctgaccttag gtgatctgcc 52560cacctcagcc tcccaaagtg ctgggattac aggcatgagc
caccgcgcct ggactgatta 52620ttttttaaat agggttagaa agtgaggaag ttactaaact
ccgattagcc caaatatgcc 52680ccagtgggtc cttctggcag agtaaatgtc tcggttcagc
ctgaatctgg gaaattgttc 52740ctacggttca gcctgaatct gggaaattgt tcctacctta
taaactggag tatccttcag 52800aaatgacatt tactcaaact tccttttagg cagactgcat
aatagcaatt tttaatatta 52860accatttaaa aaaaaccttc agattaatta acaccaaaag
aataattggg aaaatacaac 52920tcctcacttt aaaaaagaaa caaccaaagt aaatactaaa
aaactatatg atgttatatt 52980atctaagctt agtttactgc aaagatcaag agcacactac
tagttgacgg cctctattca 53040cactgttcat agccctcgct cgcttctcca gccattcact
cactcatgca aaaggtctgt 53100acacacaatg atgcctgatg gtataatagg aaccttaaca
tttcaattaa aaggcaaaat 53160gaggacactt accatcagcc tataaaatta ttcttattat
tcttcttctt cttctcctcc 53220tcctcctcct cttcttcctt cttcttcttc ttcttcttct
ccttctcctt ctccttctcc 53280ttctccttct ccttctcctt ctccttctcc ttcttcttct
tcctcttctt cttcttcttc 53340ttcttctttt ttttttgaga tggagtcttg ctctgttgcc
caggctggag tgcagtggtg 53400tgatctcggc tcactgcaac ctctgcctcc caggttcaag
ctattctcct gcctcagcct 53460cccaagtaac tgggattaca ggtgcatgcc accacgcccg
gataattttt tgtattttta 53520ctagggatgg ggtttcacca tgttggccag gctagtctct
aactcctgac ctcaagtgat 53580ccacctgcct cggcctccca aagtgctggg tgtgggcggc
aagccaccca ggtgccaagg 53640caagagacag agggcacgag ctgttccagt ataatgagga
aaatatatag aataagaata 53700gttatactag aaatagatta tagatatgat tacatatgaa
tatcattctt cattagtttg 53760tagcactact ctttattcca gtattataat aatctttgtt
ctacaattat aacctaggaa 53820aaaccaggcc atacagagat aggagctaaa gggacagggt
gagaagtgac cagaagagtg 53880tgagccttct gttatgcccg gacagggcca ctagagggct
ccttggtcta gcggtaacgc 53940ccgcgtctgg gaagatgcct gtcacctaac ggaccgtggt
ctagcggtag cgtcagtgcc 54000tagaaaaggc actcttttta aatatacttt ttatttttgt
ttaatcttcc ctgatttcct 54060atagatctga gatatgtcat gcttattttc attgctatct
aaaaatctca ataaacttta 54120tacctaagag taaaaaaaaa aaaaaagaaa agaaaaggcg
ctcgttactt agccgaccgg 54180gaaagggagt ctccctttcc ccgggggagt tagagaagac
tctgctccac cacctcttgt 54240ggagggcctg acatgagtca ggcctgcctg cagtcatctg
gaggcctaac cgtctccctg 54300tgatgctgtg cttcagcggt cacgctccta gtcctgaaca
cctggctccg ccttttagat 54360agcagtagca gaattagtga aagtactaaa agtctttgaa
atgcagaagt aatggcgtaa 54420gctgtcacgt ctctctctcc gcctcagctg ccaaacagag
aagggtcccc tgtccagtgg 54480acacgtgact tgggtgacct tacctgtcat tggagacgac
tcatactcct taccctgccc 54540cttgccttgt atctaataaa taacagctca atctggcatt
tggggccact actggtctcc 54600gcatcttggt ggtagtggtc ccccgggccc agccgtcttt
tattctatct ctttgtcttg 54660tgtctttatt tctaccatct cttgtctccg cacacgagga
gaaaaaccca cagaccctgt 54720agggctggcc cctacagctg ggaattacag gcatgagcca
ccgcatccag ccagcctaaa 54780attcttctga aggataataa tatagtactt gaagacacgg
tttgaaaaaa atcatactaa 54840atgaaagggc accattttac aagcactaga actacattaa
acttaaatga attccaacac 54900tcttaataat gtaactcaaa aacaagtcta gtgttaacaa
aagctccaat aactaaaact 54960acattaacag gcacaatgaa cattgtaaac gccgctaatt
ggcaccaagt ttaatagggc 55020agacaatatt ttcttctgca ttcacactta ctcagttaca
ctgttgaaaa atgctgctgc 55080tcaagctatg aatgctttac aaaagaaatc attttaataa
atacagtaaa tgctaaaact 55140ctagctaaac tattatgcaa gatatacaac caagacaaat
acaaattcat aatacaagca 55200acttgcattc aaaatgaact ctaccactat attttattaa
aagggcagac tttatgaatt 55260aacccagctg cttcctgaat tacaaaagtg gcatgactca
atatgaaaat aagaaactgt 55320ctacaaattt ctgacagtaa taaattgtaa tatacaatac
atgcaggagt cttacggaag 55380aataaactct cctaggaaac aaaaatattt tatactttta
aaatccaaag taaaaaaaaa 55440agaaatcatt gccagatgcg gtggctcatg cctgtaatcc
aagcactttg ggaggccaag 55500gcaggatcgc ttgagcccag gagtttgaga ccagcctggg
caacatagca aaaccccatc 55560tctacaaaaa aatacaaaaa ttagatggta atggtggtga
gcgcctgtgg ttccagctac 55620ccaggaggct gaggtgggag gatgcacctc aaggctgcaa
tgagccaagg tcacaccatt 55680gtactgaagc ctggggacag agtgagaccc tgtctcaata
agtaaataaa taaatatctt 55740ttatgaaaaa gattctctag tcagaattaa cacctcaact
agccaaacat caggaagtta 55800cattacagct acttaataca caaagggaca cattttcacc
agtcgttgtc ttctgatatt 55860tctattccag aaacacacac tctcacttcc ctacactccc
catcccatca tttcttcaga 55920gcatggaaac agaatttgtt gaacaccaga aatctcttgc
tatggtggta cataagtcat 55980aacatttgtt gctgcccagc agcaggtatg aagccggctg
gtgactggct agcaaatgcc 56040tattctgtaa gctcctcact tagcccatct gtagctctga
cttctccacc aattcccttc 56100tctcctttca cagcctttct gagtttctga gggataattt
cagaggttcc atataactgt 56160caaagcctat ggtagacatg gcaaagtgaa aatcctctcc
actggccatt tctgtttctc 56220ttgggggcat ctttcacttg cctcaggtgt tataaagctg
atgaacacac gtacacgttg 56280tttaacactt tcttgggcat ttcccatttg agatatggca
tgtttcatta tcctagtgac 56340atgtgcaatc agaaaatgta tattttgttc tctgcaactt
tcttttgaaa aatgtatatt 56400tgaacaaaat atacattttt tgtatcttca tgaccattca
tgctgtcctc actgtcatca 56460tgaggctcta tataacataa tgactcctcc agggcagtct
tcggaaattc ccagtgcaga 56520agcacgtgtc atacagcagt ccccattcat ctccagtgca
gctctggctg gctcccatgt 56580ctgatcagct gtttggttgg acagaaaatg actgcaaggg
aatcagttcc agtgtgagct 56640ctgtttgcag aactcagact cccctccctc ccatgttaat
gctttttttc ttcttctttt 56700tttttttttt ttttttttga cagagtctca ttctgtcacc
caggctggag tgcaatgcta 56760tgatctcggc tcactacaac ctgtgcctcc ccggttcaag
caattctcgt gcctcaactt 56820cccgagtagc tgagattaca ggtgcacacc accacacccc
actaattttt ttgtattttt 56880agtagagacg gggttttgcc atgttgccaa ggctggtgtc
aaactcctga gctcaggaaa 56940tccaccttcc tcagcctccc aaagtgctag gattacaggc
gtgagccacc atgcccagcc 57000ccatgttaat gcttctaaag tttgccctca cttctttaga
aattccttca gtacatcctt 57060taagacttcc tctagtgagt gtctgctggt ggtaaactct
cccctctaaa agttgcttta 57120tttctcctca attcctgaag gatatttttg ctagcagcta
tattctttta gatgttgaac 57180atatcggtac aaaagcttct ggtttccatg gttgctattg
agatgttagc tgtcggttta 57240tctttctccc ctgactatgt gtacctgttt ctctgtatct
gtctactttt tgggttgctc 57300aatttattgg ccttgggctt cattctgctg ctgctttttt
tttttttttt tttttgagat 57360ggagtcttcc tctgttgccc aggctggagt gcagtggtgc
aatcttggct caatgcaacc 57420tctgcctctc ggttcaagcg attctcctgc ctcagcctac
cgagtagctg ggattacagg 57480cacctgccaa cacgccaggc taatttttgt atttttagta
gaaataggat ttcactatgt 57540tggccaggct ggtctcaaac tcttgacttc aggtgatcca
cccacctcag tctcccaaag 57600tgctaagatt acaggcctga gccaccacgc ctggccacaa
tttttaaact ttttattttt 57660acaggcacct gccaacatgc acaactaatt tttgtatttt
tagtagaaac aggatttcac 57720tgtgttggcc aggctggtct caaactcttg acctcaggtc
atccaccacc ttggtctccc 57780aaagtgctag gattacaggc gggagccacc atgcctggcc
aaaattgtta aactttttat 57840tttcttcctc aagaggatga gaagaaaggt caattgtaag
ctttagaagt cttgcccaat 57900agccaatctg agaatattct ccgtaaacat tcaccagagg
cagccagtga ccatgggata 57960cttttggtga gaggaattga ttgctggggt caggaatggg
aggaaagcat acttctcatt 58020agataccttg ttgaacttcg taaattgtgt gccaaatgca
tgtcttacct agacttcata 58080aattaatttc tttaaaaata atcaaagaca attttttaaa
gacttattta atttaaggtg 58140attataaaac atccagtata ctttcactat taaaaaagta
agtattcctg tctgggcttg 58200gtggatcaca cctgtaatcc cagcactctg ggaggctgag
gtggtcggat catgaggtca 58260agagattgag accatcctgg ccaatatgat gaaaccatgt
ctctcctaaa aatacaaaaa 58320ctagctgggc gtagtggcgt gcctgtagtc ctagttactc
aggaagctga ggcaggagaa 58380tcgcttgaac ccaggaggcg gaggttgcag tgaactgaga
tcgtgccact gcactccagt 58440gtggcaacag agtgagactc catcttcaaa aaaaaaaaaa
agtattccta aacagcatat 58500tatcatgata tattattttg ttttgtaggg ttttgaacct
tgtctaaaaa gaattaaaat 58560gtataaattt cttcctgcaa tttccctatt tcactaaggg
tcattcacat tggtcatata 58620gacatagcac attttcacca ctatatagca gcattttgta
caaatagact acaatttact 58680tattctgcac ttatttctgt ttgtttgttt tgctatgaaa
agcaatgtca ttacatatat 58740tcatgcccat agctacaagt ttacatattt caggttttct
gtagggtgga caccagggag 58800ttgaattgtt caacaggact ttacattcat ctttagtttt
attggccaac accaaattgt 58860tcttcacaat gtttgaacta agttgaaatt ccacctcccc
atcacattta gttttgtcaa 58920cttcatttct tcattcatta attcattcat tcagtctttt
gtttatttgt ttattgccag 58980tctgataggc gtatagtggt gcttcatcat ggttttactt
tgcatttctc tgattttctt 59040tttaaatttt taaaaaatta tttttatgta gaaacaaggt
ctcgctacat ggcccaggct 59100ggtcttgaac tcctggcttc aaatgatcct cccacattgg
cctttcaaag taccgagatt 59160gattataggc gtgtgccact gtggccagct gatttccctg
atttctgatg agttaacaat 59220ctcttctttc tctctctctc tctctgtgta tacaggtact
caccattcgt gcctattttc 59280tgtaaaatat gtggctttcc tcattttttt tttttttttt
tttttttgag gcagagtctc 59340gctctgttgc aggctagagt gcagtggtgc gatcttggct
caccacaacc tccacttcct 59400gggttcgagc aattctcctg cctcagcctt cagagtagct
gggactacag gcgtgcacca 59460ccatgcccag ctaatttttg tatttttagt agagattggg
tttcactatg ttggccagac 59520tggtctcaaa ctcctgactt tgtgatctgc ccacctcagc
ctcccaaagt gctgggatta 59580caggagtgag ccactgcgcc cagccatctt tcctcatttt
tatactaatt aggcttttat 59640cttacttgtt ttttttaatg ttttttgtac actctgaagg
ctgatttttg ttaattgtat 59700gtgttgcatt ttttatggtt tgtcttatgc cttttgaaag
taaaagttct taatttaaat 59760atagccaacc tgtaaatcat ttgtgaaagt ctgtggttta
agaggtcttg aataagaaat 59820tatcccatca tcataagtca taaatacttt tttgttgttg
ttgagacaga atctcatttt 59880gttgtccagg ctggagtgca gtgggttgat ctcagctcac
tgcaacctct gcctcctggg 59940ttcagcaatt ctcctgcctc agcctcccaa gtagctgtga
taataagcat gtgccaccac 60000accagtctaa tttttgtatt tttagtggag acaggatttc
atcatgttgg ccaggctggt 60060ctcaaactcc tgacttcaag tgatccacct gtctcagcct
cccaaagtgc tgggattata 60120ggtgtgaacc accatgcctg gcccataaat acatttttat
gtattttctt ctaaagttgt 60180tttgtctttc actttttagt ttttaattca catataatta
ctacttgcta cttataatta 60240tctgtaagta gtatgagatg agaaataaat tctatttccc
tcctatggat aagcacaaac 60300ctgcagtatt agcacagtct tatgtcagat tttctaaaat
gaatgggtgt gttttctagg 60360ctctctgttc tgtttcatta tctgtctttt cctgcaacga
tatcatctgc cttaaaaact 60420ctagccttgt ggtattcctc attttcaagc agagcaaacc
ccgtcacctt gcttttctcc 60480tccagcatcg cttgtgctat cctggactaa gaccttcata
tagactgtta gaatcatcta 60540gccaagttcc attttaaaaa tctatgttgg agctgggcgc
ggtggctcac gcctgtaatc 60600ccagcacttt gggaggctga ggagggcaga tcacttgagg
tcaggagttg gagaccagcc 60660tgatgaaacc ccgtctctac taaaaataca aaaattagct
ggacgttggg cacttgaatt 60720ctagctactc aggaggctga ggcaggagaa tcgcttgaac
ctggcaggcg gggggtgcag 60780tgagccgcga tcatgccact gtactccagc ctgggtgaca
gagtgaggct ccatctccaa 60840aaataaataa ataaataaaa taaaatatct atgttggaaa
ttttgtacaa attttattaa 60900atgtctacat taatttggag aaaaatgact tgattttgat
tatctattca atatttctgt 60960attatgaata aggcaaaaag agaggcagag aatagcataa
aataataact aaaattcctg 61020ggtaaaccac ctcaaatcat ttcttcatat ggctcaatat
tcttttgtga catggcctga 61080aatatatcca gacagagaac tcttctcttc aatacatttc
ttcttttagg tattcatatt 61140gagttttcct gtccatgaac atggtataag agagtatatc
ccttcgggag gccaaggtgg 61200gtggatcacc tgaggtcagg agtttgagac gagcctggcc
aacatggtaa agtcccatct 61260ctactaaaaa cccaagaatt atccaggtgt ggtgacacat
gcctgtagtc ccagctactc 61320aggatgctga agcaggagaa ttgcttgaac caaggaggcg
gaggttgcaa tgagccaagg 61380tcatgccatt gcactccagc ctgggtgaag agcgagactc
catctcaaaa aaaaaaaaaa 61440aaaaaaaaag aaaacgagaa tatatccttt catttactag
tttttcttca atttctttca 61500agataaaggg cttacctatc ttctgcttta ttcatagtta
cttgatattt ttgtttctaa 61560taaatatggt gtctgtctat ttacctgcct cttacctgtt
catttccagt ttcaaaaatg 61620atgttgatat ttgaatatta accttaaatc tagcaccttg
gtaaacacta ttattcattc 61680taataattat cagtagatta tatgtgtttt ttatttataa
atcatattgt ttgagtagca 61740tgctttgctt cttcatttat aaaatttaca acttttattt
ctttttaata atttttttct 61800tattctcctg gctaggactt ctaacacagt attgagtgga
agtgctgatc cttgtttagt 61860ttcacatttg aaaaaagatt gcttttacta tttcactgtt
aagtataata tgcaccatag 61920gctttctgtg gattcctttt atccatttaa gaacatctct
tattcctaat tagctgaagt 61980tttctgcatg tttgttttca tcatgagtgg atttttttac
atctattgaa atcattttac 62040atagaagata tttcacacct attgaaatgg tcatttcact
tttccttctt taatatgtta 62100agttgggcaa aatattaaag tatcacctgt cattctgctt
cagcaaaaag tagtagtgtc 62160ttagcagtat tggtgaaaag acagcatcaa ataaaaaaga
tgtagaagta ggacccagta 62220aaaatctagc gcatggggca ttgtcacatg taagcagaca
gaatgtgaca ccaccaagga 62280gcatctgaag ggctggaggc tgaaggaaga catgagtcac
ccaggctcat ggacacttca 62340gagaaattag ggagcaggaa gaagaaatag gatcaaagac
tacgtatgtt ggttggaaaa 62400ggaagctgat ggtatggaga tgttattatt taggtctcac
ataaaagatg tagataaata 62460ggtagatagg tagatagatg atagatagag agatagatag
ataaatacat agatagatag 62520atgataaata gatgttgtta tttaggcctc acataaagat
gtagacagat tagacagaca 62580gatgatagat agatagatag atagatagat agatagatag
atagacgata gatagataga 62640tagataatct cagaaacaga gacacagtga tctcagtaag
ataggcatat gccaggtgac 62700agaattcaga ggggtcccac tacgtgaaaa caatagaaca
accttcgaaa agaaatttag 62760tacaaataag agggcaggct tccttacata caagttagta
aactggaaga atcagttatc 62820ctcaaacatt ggaatagatc aaaaatagtt gtttatatta
atgaaggtag ctaaacatga 62880agctaagtga acctgtctct gacctagtgt ggcaatccct
gggcaaggga cacttgctcc 62940gctcttgtat ccttcactga atattcagac tttcagttaa
gcatcggtga atttagtttt 63000catctcttgt gaaaaccttg agagaggtaa ttctctctgc
ttttcttctt ttcccttcct 63060tcattttctc aaacattgcc tgtttaaaat acgaaatttt
aaaagatggc cttgttctct 63120tttttgttgt tattattaag tacagagaaa ggaagaacca
caaatagcaa agggcaacat 63180atggaatagt ttagaagttc cgggagcacc catgagggca
actgcagaag agaacattct 63240atcccccgtt gctgcagctt tcattccagg tctccatgca
tatcagatag ggaaggaact 63300ccgggacagc agcagggccc atgcacatgt aaccaattgc
tttctttgcc tgtagtaaag 63360ttcacatttt gattgcttct ccagattatg tagatccaga
catattttat gcaggcatcc 63420ggatctttct ctctgggtaa gtatagttca gttgttttcc
tgtgtgaagt ctctgtagca 63480ttgactgaat gtataagggg acgaagagac agaagcttcc
tagcgtaaga aacataccaa 63540gtgactcttg ctagggatcc actctcaggt aaaagaagtg
ggataccatc tgcacaacaa 63600ataacactga gggctaagta tttcagttaa gagtgtttgt
tcctaggcag ttcagatcca 63660tttatattca cttttcttag aatcctagct caatgacaga
agaagaaaaa cacagtatgt 63720cactcacaca gttctatcac ttacatctac tttttcttct
tgttattaag gcatgtagaa 63780ggctggggag tgtagtatag agttggatag catcgaagct
ttcttctaaa gttcctggaa 63840gagctacact gtggtttgaa cgaatgtgtc cctccaaaat
tcatatgtta aaacctaatt 63900gtgatggtga ggtattcgaa ggtgggttct ctgggaggtg
attatgtctc ctctgagagg 63960agaagacaat cccctgagtg gaactaatgc ccttataaag
gggctggagg gagttcactt 64020ggcccttttt gctccttttt tcttccattc cttgtccctt
ccactatgtg aggacacggg 64080agttgaggca ttaccttgga cgtggagacc aggccctcac
cagacactga acttgccagc 64140accttgatct tggacttccc agcctccaga actgtgagaa
atacatttct gttatgggta 64200gtccccaact caatacagtt tgacttacca ttttttgact
ttatgttggt gcaaaagcat 64260acatattcag tagaaactac tttgagtacc catacaacca
ttctgttttt cacatttggt 64320acagtattta ataaattcca taacatattc aacatgttga
cataaataag ctttgcgtta 64380ggtgattttg cccaactgtg ggctaatgta agtgttctga
gcacatttaa gggcagctag 64440gctaagctaa ggtgtttggt aggtcagatg tattaaatgc
attttttgtc ttatgatatt 64500ttcaacttac attgggttta tcaggatgta acccactgtg
aattaaggaa tatctgtatt 64560tacaaattac ccagtctaat gtattttgtt gtagcaacag
gaacaaacta aaacactacc 64620ccaaaccatt tttttcatat tttctgagta ctcttctttt
gtcacatggc ttgaaatttc 64680ttcacataga gaactctact attattttat tttattttat
tttattttat tttttgagac 64740agagtcttgc tcttttcacc caggctggag tgcagtggtg
ccatcttggc tcacggcaac 64800ctctgcctcc tggattcaaa ctactctcct gcctcagcct
cccgagtagc tgcgattaca 64860ggtggctgcc accaagcctg gctaattctt gtatttttag
tagagacgga gtattgccat 64920gttagtcagg ctggtctcga actcctgacc tcaggtgatc
tgcccacctt ggcctcccaa 64980aatgttggga ttacaggctt gagccaccac gtctggctga
taactctact tttagatact 65040ctctttgctt aaacaaatta gccattcctt ccttgacatg
ttttaatcag attgccttcc 65100tattaacttc ggaaattaag agtttctgct atgtttttgt
ttaattttta aacagtgaaa 65160aatgaaaggt ggaggcaatg gctggatgag gtgaatatgt
caaatagata tcatctagtg 65220ggccatctta ttaactagga gacacctgaa gtgctatcaa
tagaaataat ctgaagctgt 65280gtctggatac agcaagagac atgcaaatgc taaaaatcta
ctatattaca ttggtgcaag 65340gacagagtag caacacatac taagtatttt ctccagattg
ggtgtgtttg acgtgtgaag 65400cacttcaaac agagtccagc ctgggaggga gtggggatgg
aatcctcctt gtagagggta 65460cagagtggaa gcaagaaggt ttccaagatt gagagtaatg
ggtgtatggt ttatggggga 65520aagggaaaac aaaaagaagg gtgcagaaat ggagctggga
gtgtgtttta gtatttaggc 65580tttctctgta tacctttgat aggattagaa aaagaaaaat
ggaccatttt taaaaatttc 65640atgctaccac atagcaggct tatactatag atgcagaaac
agactgggat ttaggaagca 65700ccccaattct ggaaaatccc tttttgcttc acattgctct
ctaaatctgt atgttttccc 65760ttgttacgta acaatttacc acaaatttag cagcttaaaa
caatatgcat tcattgtttc 65820acaattctgt aagtcggaat cataggcaag ctcaactgac
ttttccattt agggtcgcaa 65880aaggccgaag tcaatttatc tattgggctg ggctcttaac
tgaagatctg gggaagaatt 65940cccttcaaaa ctcatttagg ttgttgtcag aattcagtgt
tttgtggttc tagaactgag 66000atctgtttcc ttgttggctg tcagacagga gctgctctca
gcttcttgag gcatccagta 66060ttccttatca tgtgtttttt tttttccatc tcagcactgg
cacttttttt tttttttttt 66120ttgagacaga gtcttgcttt gtcacccagg ctggggtgca
gtggcacgat ctcggctcac 66180cacaacctcc atctcccggg ttcaagtgat tctcctgcct
cagcctcccg agtagctggg 66240attacaggca cccgccacca gcccggctga tttttgtatt
tttcatagag atgtggtctc 66300accatgttgg ccaggctggt cttgaactcc tgacctcaag
tgatcctccc acttcagcct 66360cccaaagtgc tgagattaca ggcatgagcc atcatgccca
gccagcactg acaattctaa 66420tccttctagc actttgattc cttctcacct ctccttctgc
ctctagccag agaaaactct 66480ctgattttaa aggtcttatg tgattagatt cagcttacct
aggtaattca ggataactcc 66540ctatgtcaag gtcaactgat taataacctt aattacacct
gcaaagtccc ctttgccata 66600atatatcata ctgacagaca tgctatagca taatactaat
agttctaaga attatgataa 66660gaatcttgga aaaccatttt tagaattata cctaccacag
tatccttcaa gggataaatt 66720gattctactt cttctctatg tcagaagcat ctgatgagga
tgaactatat attctgaaat 66780ccccatgatt agatgtgtac tagaaggtga ttttactttc
attaaaataa attcggagtc 66840attgacacat tttatctttg atttacataa atgcctccgc
tctgtttctt accctcaaaa 66900tatttcccat gtagctaagt ggccagtacc gaatcctaca
tgcattaata agtgtagatg 66960gacaaaaata tctggattac tgagaattcc cattagcatt
gtctagaaaa atgtaaattt 67020gcttttttgt tcttgattta tcctattttt gatttattat
ttatatttat ttatttattt 67080atttattttt agatggaggt ctcgctttgt cgcccaggct
ggagcgcaat ggcgcaatct 67140tggctcactg caacctctgc ctcccaggtt caagctttcc
tcctgcctca gcctcccaag 67200tagctgggac tacaggcacc tgccacagtg cccggctaat
ttttgtattt tcagtagaga 67260cagggttttg ccctgtgggc caggctgttc ttgaactcct
gacctcaggt gatctgccca 67320ccttggtccc ccaaagtgct gggattacag gcatgagcca
ccacacctgg cctttttgct 67380tactttttaa aaacattttt atttaggaga atggagatat
ttcatatgta gatgacacat 67440attcattccc tttagttccc acacacattc aatttcttga
ggaagttagc ctttgcaaaa 67500aaaaaaaaat gatctcattt ttttttcccc actaaaactt
ctcattttct tggggttgct 67560agaaagttgc tacaagaaag gctaaaaata attgtgccta
cagatatttg aaaggaaaat 67620agttcctctt ttttcacagt agcagcttgg acctgagaat
gtatgggagc aataattggg 67680ctgctcaaag aaacacaatt tcccttcctc agactagaat
taccaaccta gagaacatga 67740gtttttaaag tagatgtgct tcttttatct ttttggactt
gtatgctggt gttttctctg 67800tcaccttcac tgtggaaatc ctcttgaggg tgaggcactg
aaagcagatt gattaatgtc 67860tcttggccat ttgagacatt ggatggctct tttaagttgg
ccacgttctt tcaagaacta 67920tgcttgggct acatattctg gatatataat acatacttgt
aggatgttat ttttaaatca 67980ttcatttatc acatatttag tgagtgccta ccccatgtca
gttctaggtg ctggaaatag 68040agcagtaaaa ccaaccctca acttggcccc tctggagctt
acatttcaat gcggtgggtg 68100gggggatgga caattaatac acaagtaaat ctaataaaag
cgtcatacaa tatacattac 68160aatggtaagc acaatgaaga aatggaaagc tggatagaga
gtattagaga ctgtcgaatg 68220tagtggccaa attttcctgt ttattgtggt ccaagagtgc
cacagccctc tatgacattt 68280gagcagacac ctggaggaag tgagggagtg agccgccaag
aaggaatggc aagtgcaata 68340accctgaggt gggagcgtgt tggtcgtggt ggaagagctg
caggaagcca gcagggccgc 68400aacactcagg ggagaataag aaagagtgag gtgacagtag
agaccggatc atgtagagct 68460ttgtcagctt cttttctgag tgagatggac aacacggaca
cgttttgaaa agaataacaa 68520tgtgatctgc cttcagttgc aaatcatctc tgtattgact
gagtaggaaa taaactccaa 68580gaataaagac ggaaacaggg aaaatattta agaagcgatc
attacaatcc agggtggtgg 68640cttgtactag ggtacaaggg ctaaaggtgt tgagaaatgg
tcagattctg gatatatact 68700gaaatcaaag ttgatggaaa gatatgagtc aaagataatt
tgcaggtttt ggggtcctgg 68760ttcactgaaa gaacagagac atcatttact ccaatgagga
agactatagg aggaacaggt 68820ttagcaaaga agaaaggaaa tcaggagatc agtttgggga
cacggtcata tcaagtaggc 68880agttggatgt atgggtctgg aatatagggg agtggtctag
ctatcagtgt aaatagcttt 68940ttacatttgt aaatagtcag gatataggct tttctttttc
tttttgtgag acacagtctt 69000gctctttcgc ccaaactgga gtgcaatggc acaatctcag
ctcactgcaa cctctgcctc 69060tgggttcaag cgatactcct gcctcagcct cccgagtagc
tgggactaca ggtgtgcacc 69120accataccag gctaattttt gtgtttttaa tggaaatggg
gtttcaccat gttgaccagg 69180ctggtgtcaa actcctgacc tcaatcgatc tccccgcctg
ggcctcccaa agtgctggga 69240ttacaggcat gagccacccc atccagctgg gatatagttg
ttttctaaat ctatgaggct 69300agagaagacc atttgggaat tgagagcagt gagcagtcca
cggactgacc ctttgagagt 69360gcaacattta gcagtactca agatgggaag gagctagtga
aaaagcccca aatgactaca 69420taagaccatc aaccagatta caaagaaaga cccgaacatg
tgtgcccata tatcacccaa 69480cagcagttat gtctttcatg tttcttcccc ataaaatgtt
gttcatcaac tttattagac 69540tagggtctta acattggaca aatcacaaaa cctctctgga
gcctatttta tttttcaaca 69600gctgtaggaa gcaaatacaa attggaaatc taaggctcag
aaagatttgt acaaagttac 69660acagtaatga aaggggagcc gggattccca ctcactctaa
agaatatgat aaaatggcta 69720gtattcactg aatgcttaac atgttccagg ccctgggcag
gtattatttt aattagttct 69780cacaataatc caataaggga gatactaatt tactcagatg
agaaagctga ggctcagaga 69840ggttaatgaa ctaagccaag gctcactgtt aataaatagc
aaaggtaaaa ttaaattcca 69900tatctgcttg agatagaggc cttgctccta atagctgcag
cctgtcaggg cctggcagca 69960gtaacctctc ctttcctctt cccaccattc ccctgcactg
ctttctgtac cgcatctctt 70020ttcagagtga tgttgcccca attgcggagg ccactgtgct
gtttatccag tgaaagctgt 70080agcacagcca acccaaagcg tccccagtga aaacaacctg
gctccttaca gcacttccag 70140cctcagagca gtatttgaaa aatatcatga acagcaaaca
cagcagtctg tctgtggctt 70200ttatatgtgt atatggtgtg tgtgtatgtc ccttctcttg
agcaaaataa cttttagaat 70260tatagaaaaa aaatgtgcaa catcaatgtg gatctgctgt
ttaaactcat aacagagaaa 70320gtagcttgtt tctggctata ggaggaaaag acgatattcc
ttagtaaaaa tggaaatcca 70380catatggggt tcttgtaaaa atgaagatag aaaattgcaa
gtttggggat caagttctgg 70440ttctatcatc ctttaacagt atgaccctgg aaccttaatt
gctttgagtc tttgttactt 70500tatctatgaa atgaagtatt taaaaaaact ccaaaaatct
gtcctgatgt acacacaaga 70560ggtcaaatga gaaaatgaat gtgaagatgc tttataaact
atacagcatg gtaggtgcaa 70620atgtgacatg aacttgtttt ggacacatta taaagtcacc
cccacaaact gtgattgttc 70680aagactatgc aaagtcagac acaggaaaat aagtaaaaca
gatggaggca taaagagggg 70740gaactcagag aaaacagtga agaacaggaa tcaggaagac
aaaggagagg aaaggtgggg 70800aggagaggag aaggaaaggg ggaagggaat ggaggagagg
agaacagctg cttcacagag 70860catggccggc agcccagtcc cagcctttct gcatgtccct
gacttcagcc tctggcgagg 70920cacaggctta ctctgtgctt cctgctgtta ctcttcttat
ccatccttat tatcaatacc 70980tgtggtcaac aaagtatttg ataaaggcat cctcaaagtc
aggtaacatc tgtacgttat 71040agattacaaa gttgagtaat atccagaatt ggtagtttaa
cgtgatgact tcttaacaat 71100tatcactgtt tcagggaagg gcaaaggtgt gtgtgtgtgt
gtgttcatct gtgtgtatct 71160gtgtatgtaa ttgtgggtgt ttgtgtatat ttgtgaggct
ctttacttgg cggagttaaa 71220aagtatctgc tcatcaaggt tgagattagc aaaggaagtg
aagatttttc cagagcccct 71280aaaatgtgcc ttttgaccaa cactgaggac atctttataa
ctgagtatgt gcaataaata 71340tgtcttggga cctgtgccac aaattcctct ctaaatagcc
tttacctctc tggaataacc 71400ctttagatga ggaagaaaag ggctgtgatt ttatagcttg
ttatgaagct ggagtgaaga 71460tgatgcttca gtacttaccc tacaaagata cccccaatcc
ctcaccctaa aattaccatt 71520gaaatcatgt tccctttctc attcactctc agtttccatg
tcagaaaata taccattacc 71580tccctgcacc cctttcatct ctctcacttt tctcttgctt
agatggaaag acaacccagc 71640aatgcctgca gggctgatgt atgaaggagt ttcccaagag
cccctgaaat actccggcgg 71700gagtgcagct cagagcacag tgcttcatgc ctttgatgag
ttcttaggca ttcgtcatag 71760caaggaaagt ggtaagtcag acattttgtt ttcccttgag
agtagaggga ggaagaggag 71820aggtgttttt tttttttcca attgataaaa ccaaatataa
attaaaatgt catgaagttt 71880atacttctct aagtcagcca agaaactgca tgactgccaa
tgtttttgtg tcaagccaat 71940taatattgga atatcagatg tcagcttgat cttgggtttt
acttccaaat cttaaaatgt 72000tgctctgttt ccaactgttc actatcactt tggtttggat
ctttagacac tagcttcctt 72060tttctgaaat gggggagaga tgtggagttt gaaggctatg
agtctgggcc agctggaaac 72120aggtctggga tcttccaaga aagtccttcc ccacaaaatg
gtgcaacttc tagccaaatc 72180tatttatacc agcagaggga tctatcaccc tggaagcttg
aaattgttca ttttcttacc 72240tgccaggatc aagttaagtt tttaacagtt gcaaaaagac
acttcatact atggagtttt 72300caagttggat tagaagaaaa agaatcacca gaacttagtg
tcgtagattc aagtcacttc 72360tctaaaactg tcataatttt tcacggattt tggcatttgg
tgacattaat ggttgattta 72420cttaccatgc ataatattaa acccataacg aatttcctat
aaatatctat tgatttgatt 72480tttaaatcac ttggcttcaa gaggctatta ctaaaacagt
gactcattct ttatcttttt 72540tgccttcacg ggctttatat aactttctcc ttttcttgtg
ctccctccaa aacaaagcac 72600tgagaaaaca aaattcacca gagtattcag ctagtcagtt
caagggtttg tgttctacat 72660ttgaagatat tccttatagc agctaccaac gggatacttt
gtttacattt gttgtgtagt 72720aaatatttat atattggcaa acaaatctag ttccaactct
gtcatctgag atgttcttac 72780tttgtttcct cttctccatc tcctgtcaac tgttagaaat
atacatttga gtacgtgaag 72840tctgcaaaca aaagggccaa ggtagatttg agttagaaca
ccagcaacag tttctggtgc 72900attcttgtct gaaaaagcag agaagattgg gcaccgtggg
tcatgcctgt aatcccaaaa 72960ttttggaagt ctgaggcagg tggatcgctt gagcccagga
gttcaagaca agcctgggca 73020acatagcaag aacccgtctc tactaaaagg aatacaaaaa
aatattagct gggtgtggtg 73080gcgcacacct gtagtttcag ctactcagaa gactgaggtg
ggaggatcac ttgaactcag 73140gggcagaggt ggcagtaagc tgagatcaca ccactgcact
ccagcctggg caacagagca 73200agatctcatc tagagaaaaa aaaaataaaa aagaagaaga
agcagacgag ctctgctata 73260tttccatgtg gagctatgac gttatgctgt attgtttctt
tcaggtgact ttctgtacag 73320aatgagggat tacatgcctc cttcccataa ggccttcata
gaagacatcc actcagcacc 73380ttccctgagg gactacatcc tgtcatctgg acaggaccac
ttgctgacag cttataacca 73440gtgtgtgcag gccctggcag agctgcggag ctatcacatc
accatggtca ccaaatacct 73500catcacagct gcagccaagg caaagcatgg gaagccaaac
catctcccag ggcctcctca 73560ggctttaaaa gacaggggca caggtggaac cgcagttatg
agctttctta agagtgtcag 73620ggataagacc ttggagtcaa tccttcaccc acgtggttag
7366022890DNAHomo sapiens 22ggcttatgga gccccacaga
ccgaatgtga agacagcagt gccattgtct ttggaaagct 60atcacatatc tgaagagtat
ggctttcttc ttccagattc tctgaaagaa cttccagatc 120attataggcc ttggatggaa
attgccaaca aacttcctca attgattgat gctcaccagc 180ttcaagctca tgtggacaag
attcctggaa attgggctct tgttcaggcc acgaatgcta 240tcttgcagcc caaccaggag
gccctgctcc aagccctgca gcgactgaga ctgtctattc 300aggacatcac caaaacctta
ggacagatgc atgattatgt agatccagac atattttatg 360caggcatccg gatctttctc
tctggatgga aagacaaccc agcaatgcct gcagggctga 420tgtatgaagg agtttcccaa
gagcccctga aatactccgg cgggagtgca gctcagagca 480cagtgcttca tgcctttgat
gagttcttag gcattcgtca tagcaaggaa agtggtgact 540ttctgtacag aatgagggat
tacatgcctc cttcccataa ggccttcata gaagacatcc 600actcagcacc ttccctgagg
gactacatcc tgtcctctgg acaggaccac ttgctgacag 660cttataacca gtgtgtgcag
gccctggcag agctgcggag ctatcacatc accatggtca 720ccaaatacct catcacagct
gcagccaagg caaagcatgg gaagccaaac catctcccag 780ggcctcctca ggctttaaaa
gacaggggca caggtggaac cgcagttatg agctttctta 840agagtgtcag ggataagacc
ttggagtcaa tccttcaccc acgtggttag 890231177DNAHomo sapiens
23ggcttatgga gccccacaga ccgaatgtga agacagcagt gccattgtct ttggaaagct
60atcacatatc tgaagagtat ggctttcttc ttccagattc tctgaaagaa cttccagatc
120attataggcc ttggatggaa attgccaaca aacttcctca attgattgat gctcaccagc
180ttcaagctca tgtggacaag atgcccctgc tgagctgcca gttcctgaag ggtcaccggg
240agcagcgcct ggcccacctg gtcctgagct tcctcaccat gggttatgtc tggcaggaag
300gagaggcgca gcctgcagag gtcctgccaa ggaatcttgc ccttccattt gtcgaagtct
360ccaggaactt ggggctccct cctatcctgg tccactcaga cttggtgctg acgaactgga
420ccaaaaaaga tccagacgga ttcctggaaa ttgggaacct ggagaccatc atctcatttc
480ctgggggaga gagcctgcat ggttttatac tggtgactgc tttggtagag aaagaagcag
540tgcctgggat aaaggctctt gttcaggcca cgaatgctat cttgcagccc aaccaggagg
600ccctgctcca agccctgcag cgactgagac tgtctattca ggacatcacc aaaaccttag
660gacagatgca tgatggaaag acaacccagc aatgcctgca gggctgatgt atgaaggagt
720ttcccaagag cccctgaaat actccggcgg gagtgcagct cagagcacag tgcttcatgc
780ctttgatgag ttcttaggca ttcgtcatag caaggaaagt ggtgactttc tgtacagaat
840gagggattac atgcctcctt cccataaggc cttcatagaa gacatccact cagcaccttc
900cctgagggac tacatcctgt cctctggaca ggaccacttg ctgacagctt ataaccagtg
960tgtgcaggcc ctggcagagc tgcggagcta tcacatcacc atggtcacca aatacctcat
1020cacagctgca gccaaggcaa agcatgggaa gccaaaccat ctcccagggc ctcctcaggc
1080tttaaaagac aggggcacag gtggaaccgc agttatgagc tttcttaaga gtgtcaggga
1140taagaccttg gagtcaatcc ttcacccacg tggttag
1177241077DNAHomo sapiens 24ggcttatgga gccccacaga ccgaatgtga agacagcagt
gccattgtct ttggaaagct 60atcacatatc tgaagagtat ggctttcttc ttccagattc
tctgaaagaa cttccagatc 120attataggcc ttggatggaa attgccaaca aacttcctca
attgattgat gctcaccagc 180ttcaagctca tgtggacaag atgcccctgc tgagctgcca
gttcctgaag ggtcaccggg 240agcagcgcct ggcccacctg gtcctgagct tcctcaccat
gggttatgtc tggcaggaag 300gagaggcgca gcctgcagag gtcctgccaa ggaatcttgc
ccttccattt gtcgaagtct 360ccaggaactt ggggctccct cctatcctgg tccactcaga
cttggtgctg acgaactgga 420ccaaaaaaga tccagacgga ttcctggaaa ttgggctctt
gttcaggcca cgaatgctat 480cttgcagccc aaccaggagg ccctgctcca agccctgcag
cgactgagac tgtctattca 540ggacatcacc aaaaccttag gacagatgca tgatggaaag
acaacccagc aatgcctgca 600gggctgatgt atgaaggagt ttcccaagag cccctgaaat
actccggcgg gagtgcagct 660cagagcacag tgcttcatgc ctttgatgag ttcttaggca
ttcgtcatag caaggaaagt 720ggtgactttc tgtacagaat gagggattac atgcctcctt
cccataaggc cttcatagaa 780gacatccact cagcaccttc cctgagggac tacatcctgt
cctctggaca ggaccacttg 840ctgacagctt ataaccagtg tgtgcaggcc ctggcagagc
tgcggagcta tcacatcacc 900atggtcacca aatacctcat cacagctgca gccaaggcaa
agcatgggaa gccaaaccat 960ctcccagggc ctcctcaggc tttaaaagac aggggcacag
gtggaaccgc agttatgagc 1020tttcttaaga gtgtcaggga taagaccttg gagtcaatcc
ttcacccacg tggttag 1077251096DNAHomo sapiens 25ggcttatgga gccccacaga
ccgaatgtga agacagcagt gccattgtct ttggaaagct 60atcacatatc tgaagagtat
ggctttcttc ttccagattc tctgaaagaa cttccagatc 120attataggcc ttggatggaa
attgccaaca aacttcctca attgattgat gctcaccagc 180ttcaagctca tgtggacaag
atgcccctgc tgagctgcca gttcctgaag ggtcaccggg 240agcagcgcct ggcccacctg
gtcctgagct tcctcaccat gggttatgtc tggcaggaag 300gagaggcgca gcctgcagag
ggaacctgga gaccatcatc tcatttcctg ggggagagag 360cctgcatggt tttatactgg
tgactgcttt ggtagagaaa gaagcagtgc ctgggataaa 420ggctcttgtt caggccacga
atgctatctt gcagcccaac caggaggccc tgctccaagc 480cctgcagcga ctgagactgt
ctattcagga catcaccaaa accttaggac agatgcatga 540ttatgtagat ccagacatat
tttatgcagg catccggatc tttctctctg gatggaaaga 600caacccagca atgcctgcag
ggctgatgta tgaaggagtt tcccaagagc ccctgaaata 660ctccggcggg agtgcagctc
agagcacagt gcttcatgcc tttgatgagt tcttaggcat 720tcgtcatagc aaggaaagtg
gtgactttct gtacagaatg agggattaca tgcctccttc 780ccataaggcc ttcatagaag
acatccactc agcaccttcc ctgagggact acatcctgtc 840ctctggacag gaccacttgc
tgacagctta taaccagtgt gtgcaggccc tggcagagct 900gcggagctat cacatcacca
tggtcaccaa atacctcatc acagctgcag ccaaggcaaa 960gcatgggaag ccaaaccatc
tcccagggcc tcctcaggct ttaaaagaca ggggcacagg 1020tggaaccgca gttatgagct
ttcttaagag tgtcagggat aagaccttgg agtcaatcct 1080tcacccacgt ggttag
1096261229DNAHomo sapiens
26ggcttatgga gccccacaga ccgaatgtga agacagcagt gccattgtct ttggaaagct
60atcacatatc tgaagagtat ggctttcttc ttccagattc tctgaaagaa cttccagatc
120attataggcc ttggatggaa attgccaaca aacttcctca attgattgat gctcaccagc
180ttcaagctca tgtggacaag atgcccctgc tgagctgcca gttcctgaag ggtcaccggg
240agcagcgcct ggcccacctg gtcctgagct tcctcaccat gggttatgtc tggcaggaag
300gagaggcgca gcctgcagag gtcctgccaa ggaatcttgc ccttccattt gtcgaagtct
360ccaggaactt ggggctccct cctatcctgg tccactcaga cttggtgctg acgaactgga
420ccaaaaaaga tccagacgga ttcctggaaa ttgggaacct ggagaccatc atctcatttc
480ctgggggaga gagcctgcat ggttttatac tggtgactgc tttggtagag aaagaagcag
540tgcctgggat aaaggctctt gttcaggcca cgaatgctat cttgcagccc aaccaggagg
600ccctgctcca agccctgcag cgactgagac tgtctattca ggacatcacc aaaaccttag
660gacagatgca tgattatgta gatccagaca tattttatgc aggcatctgg atctttctct
720ctggatggaa agacaaccca gcaatgcctg cagggctgat gtatgaagga gtttcccaag
780agcccctgaa atactccggc gggagtgcag ctcagagcac agtgcttcat gcctttgatg
840agttcttagg cattcgtcat agcaaggaaa gtggtgactt tctgtacaga atgagggatt
900acatgcctcc ttcccataag gccttcatag aagacatcca ctcagcacct tccctgaggg
960actacatcct gtcctctgga caggaccact tgctgacagc ttataaccag tgtgtgcagg
1020ccctggcaga gctgcggagc tatcacatca ccatggtcac caaatacctc atcacagctg
1080cagccaaggc aaagcatggg aagccaaacc atctcccagg gcctcctcag gctttaaaag
1140acaggggcac aggtggaacc gcagttatga gctttcttaa gagtgtcagg gataagacct
1200tggagtcaat ccttcaccca cgtggttag
1229271225DNAHomo sapiens 27tatggagccc cacagaccga atgtgaagac agcagtgcca
ttgtctttgg aaagctatca 60catatctgaa gagtatggct ttcttcttcc agattctctg
aaagaacttc cagatcatta 120taggccttgg atggaaattg ccaacaaact tcctcaattg
attgatgctc accagcttca 180agctcatgtg gacaagatgc ccctgctgag ctgccagttc
ctgaagggtc accgggagca 240gcgcctggcc cacctggtcc tgagcttcct caccatgggt
tatgtctggc aggaaggaga 300ggcgcagcct gcagaggtcc tgccaaggaa tcttgccctt
ccatttgtcg aagtctccag 360gaacttgggg ctccctcctg tcctggtcca ctcagacttg
gtgctgacga actggaccaa 420aaaagatcca gacggattcc tggaaattgg gaacctggag
accatcatct catttcctgg 480gggagagagc ctgcatggtt ttatactggt gactgctttg
gtagagaaag aagcagtgcc 540tgggataaag gctcttgttc aggccacgaa tgctatcttg
cagcccaacc aggaggccct 600gctccaagcc ctgcagcgac tgagactgtc tattcaggac
atcaccaaaa ccttaggaca 660gatgcatgat tatgtagatc cagacatatt ttatgcaggc
atccggatct ttctctctgg 720atggaaagac aacccagcaa tgcctgcagg gctgatgtat
gaaggagttt cccaagagcc 780cctgaaatac tccggcggga gtgcagctca gagcacagtg
cttcatgcct ttgatgagtt 840cttaggcatt cgtcatagca aggaaagtgg tgactttctg
tacagaatga gggattacat 900gcctccttcc cataaggcct tcatagaaga catccactca
gcaccttccc tgagggacta 960catcctgtcc tctggacagg accacttgct gacagcttat
aaccagtgtg tgcaggccct 1020ggcagagctg cggagctaac acatcaccat ggtcaccaaa
tacctcatca cagctgcagc 1080caaggcaaag catgggaagc caaaccatct cccagggcct
cctcaggctt taaaagacag 1140gggcacaggt ggaaccgcag ttatgagctt tcttaagagt
gtcagggata agaccttgga 1200gtcaatcctt cacccacgtg gttag
122528407PRTHomo sapiens 28Met Glu Pro His Arg Pro
Asn Val Lys Thr Ala Val Pro Leu Ser Leu1 5
10 15 Glu Ser Tyr His Ile Ser Glu Glu Tyr Gly Phe
Leu Leu Pro Asp Ser 20 25 30
Leu Lys Glu Leu Pro Asp His Tyr Arg Pro Trp Met Glu Ile Ala Asn
35 40 45 Lys Leu Pro
Gln Leu Ile Asp Ala His Gln Leu Gln Ala His Val Asp 50
55 60 Lys Met Pro Leu Leu Ser Cys Gln
Phe Leu Lys Gly His Arg Glu Gln65 70 75
80 Arg Leu Ala His Leu Val Leu Ser Phe Leu Thr Met Gly
Tyr Val Trp 85 90 95
Gln Glu Gly Glu Ala Gln Pro Ala Glu Val Leu Pro Arg Asn Leu Ala
100 105 110 Leu Pro Phe Val Glu
Val Ser Arg Asn Leu Gly Leu Pro Pro Ile Leu 115
120 125 Val His Ser Asp Leu Val Leu Thr Asn
Trp Thr Lys Lys Asp Pro Asp 130 135
140 Gly Phe Leu Glu Ile Gly Asn Leu Glu Thr Ile Ile Ser
Phe Pro Gly145 150 155
160 Gly Glu Ser Leu His Gly Phe Ile Leu Val Thr Ala Leu Val Glu Lys
165 170 175 Glu Ala Val Pro
Gly Ile Lys Ala Leu Val Gln Ala Thr Asn Ala Ile 180
185 190 Leu Gln Pro Asn Gln Glu Ala Leu Leu
Gln Ala Leu Gln Arg Leu Arg 195 200
205 Leu Ser Ile Gln Asp Ile Thr Lys Thr Leu Gly Gln Met His
Asp Tyr 210 215 220
Val Asp Pro Asp Ile Phe Tyr Ala Gly Ile Arg Ile Phe Leu Ser Gly225
230 235 240 Trp Lys Asp Asn Pro
Ala Met Pro Ala Gly Leu Met Tyr Glu Gly Val 245
250 255 Ser Gln Glu Pro Leu Lys Tyr Ser Gly Gly
Ser Ala Ala Gln Ser Thr 260 265
270 Val Leu His Ala Phe Asp Glu Phe Leu Gly Ile Arg His Ser Lys
Glu 275 280 285 Ser
Gly Asp Phe Leu Tyr Arg Met Arg Asp Tyr Met Pro Pro Ser His 290
295 300 Lys Ala Phe Ile Glu Asp
Ile His Ser Ala Pro Ser Leu Arg Asp Tyr305 310
315 320 Ile Leu Ser Ser Gly Gln Asp His Leu Leu Thr
Ala Tyr Asn Gln Cys 325 330
335 Val Gln Ala Leu Ala Glu Leu Arg Ser Tyr His Ile Thr Met Val Thr
340 345 350 Lys Tyr Leu
Ile Thr Ala Ala Ala Lys Ala Lys His Gly Lys Pro Asn 355
360 365 His Leu Pro Gly Pro Pro Gln Ala
Leu Lys Asp Arg Gly Thr Gly Gly 370 375
380 Thr Ala Val Met Ser Phe Leu Lys Ser Val Arg Asp Lys
Thr Leu Glu385 390 395
400 Ser Ile Leu His Pro Arg Gly 405 29101DNAHomo
sapiens 29gacacgggag ttgaggcatt accttggacg tggagaccag gccctcacca
gacactgaac 60ttgccagcac cttgatcttg gacttcccag cctccagaac t
1013024DNAArtificial SequencePrimer 30actctgacct ggtgctgaca
aact 243124DNAArtificial
SequencePrimer 31tgcaggatgt gaacctctaa cgct
243224DNAArtificial SequencePrimer 32tggagcctca aagtcagagc
atga 243324DNAArtificial
SequencePrimer 33agtttgtcag caccaggtca gagt
243424DNAArtificial SequencePrimer 34tgcctgatgg cctataacca
gtgt 243524DNAArtificial
SequencePrimer 35tgcaggatgt gaacctctaa cgct
243624DNAArtificial SequencePrimer 36aaccacacag aagacacagc
tgga 243724DNAArtificial
SequencePrimer 37tgagggcaat ttccatccaa ggct
243824DNAArtificial SequencePrimer 38accgcacaag tacaaccaca
caga 243922DNAArtificial
SequencePrimer 39agccttatgg gaaggcggca tg
224021DNAArtificial SequencePrimer 40actgatttcc aacggtcctt c
214121DNAArtificial
SequencePrimer 41tcggagctgg cggttctcga t
214219DNAArtificial SequencePrimer 42aaggtgctgc caagatctc
194318DNAArtificial
SequencePrimer 43cttcatgcct tcgatgag
184424DNAArtificial SequencePrimer 44agagaaagaa gcagtgcctg
ggat 244524DNAArtificial
SequencePrimer 45taagctgtca gcaagtggtc ctgt
244624DNAArtificial SequencePrimer 46tgagacactg cgcaactaac
tgga 244724DNAArtificial
SequencePrimer 47atcccaggca ctgcttcttt ctct
244824DNAArtificial SequencePrimer 48acaggaccac ttgctgacag
ctta 244924DNAArtificial
SequencePrimer 49acgtgggtga aggattgact ccaa
245023DNAArtificial SequencePrimer 50tgttggcaat ttccatccaa
ggc 235124DNAArtificial
SequencePrimer 51aaccacgtgg gtgaaggatt gact
245222DNAArtificial SequencePrimer 52ttcagtgaca ctttccatgc
ag 225322DNAArtificial
SequencePrimer 53atggagcccc acagaccgaa tg
225422DNAArtificial SequencePrimer 54gaagggcaag attccttggc
ag 225522DNAArtificial
SequencePrimer 55attgatgctc accagcttca ag
225622DNAArtificial SequencePrimer 56cttcatacat cagccctgca
gg 225722DNAArtificial
SequencePrimer 57gtagagaaag aagcagtgcc tg
225822DNAArtificial SequencePrimer 58ggcatccgga tctttctctc
tg 225923DNAArtificial
SequencePrimer 59ctaaccacgt gggtgaagga ttg
236018DNAArtificial SequencePrimer 60ggtactgcca tgctgagc
186121DNAArtificial
SequencePrimer 61aagctgcccg ttctcaatca g
216222DNAArtificial SequencePrimer 62ctcgtatgtc atgggcccat
tg 226322DNAArtificial
SequencePrimer 63gaagttccgg tgggctggag gc
226421DNAArtificial SequencePrimer 64ggtgctgccc cgcaataatg c
216520DNAArtificial
SequencePrimer 65ccagagtctt gatgtccttc
206621DNAArtificial SequencePrimer 66cctcaaatgt ggaaagcaga g
216728DNAArtificial
SequencePrimer 67atccggtacc atggagcctc aaagtcag
286824DNAArtificial SequencePrimer 68gttgagctct ccaggaactt
ggga 246927DNAArtificial
SequencePrimer 69agtgttgaat tcctacagga aatgagg
277027DNAArtificial SequencePrimer 70ctgaaagctt ataaccagtg
tgtggag 277121DNAArtificial
SequencePrimer 71catcctgtac acgtgagctc g
217224DNAArtificial SequencePrimer 72tggagagctc aacaaaagga
atgg 247330DNAArtificial
SequencePrimer 73ctgtaggaat tcaacacttt ccttgcaatg
307424DNAArtificial SequencePrimer 74tataagcttt caggcagtcc
ccag 247521DNAArtificial
SequencePrimer 75gaagacacag ctggaaagct c
217620DNAArtificial SequencePrimer 76ccatgctgac ctccaggctc
207728DNAArtificial
SequencePrimer 77atccggtacc atggcactca gtaaaata
287824DNAArtificial SequencePrimer 78gaagtgtaca agctgcccac
actg 247922DNAArtificial
SequencePrimer 79gaggatgcat gactttgtgg ac
228023DNAArtificial SequencePrimer 80agcttgtaca cttcttctcg
aag 238124DNAArtificial
SequencePrimer 81gtcatgcatc ctcttaaaaa taac
248233DNAArtificial SequencePrimer 82gtcgcgctag caaactcaat
ggtgatggtg atg 338323DNAArtificial
SequenceTarget sequence 83aatgtgaaga cagcagtgcc att
238423DNAArtificial SequenceTarget sequence
84aagacagcag tgccattgtc ttt
238523DNAArtificial SequenceTarget sequence 85aattgattga tgctcaccag ctt
238623DNAArtificial
SequenceTarget sequence 86aacctggaga ccatcatctc att
238723DNAArtificial SequenceTarget sequence
87aaccttagga cagatgcatg att
238823DNAArtificial SequenceTarget sequence 88aaggagtttc ccaagagccc ctt
238923DNAArtificial
SequenceTarget sequence 89aatgagggat tacatgcctc ctt
239023DNAArtificial SequenceTarget sequence
90aagagtgtca gggataagac ctt
239121RNAArtificial SequencesiRNA 91ugugaagaca gcagugccau u
219221RNAArtificial SequencesiRNA
92gacagcagug ccauugucuu u
219321RNAArtificial SequencesiRNA 93uugauugaug cucaccagcu u
219421RNAArtificial SequencesiRNA
94ccuggagacc aucaucucau u
219521RNAArtificial SequencesiRNA 95ccuuaggaca gaugcaugau u
219621RNAArtificial SequencesiRNA
96ggaguuuccc aagagccccu u
219721RNAArtificial SequencesiRNA 97ugagggauua caugccuccu u
219821RNAArtificial SequencesiRNA
98gagugucagg gauaagaccu u
219925DNAArtificial SequencesiRNA 99caaacuuccu caauugauug augct
2510025DNAArtificial SequencesiRNA
100gugccauugu cuuuggaaag cuatc
2510125DNAArtificial SequencesiRNA 101gugccauugu cuuuggaaag cuatc
2510225RNAArtificial SequencesiRNA
102caaggaaagu ggugacuuuc uguac
2510325DNAArtificial SequencesiRNA 103gcagcucaga gcacagugcu ucatg
2510425RNAArtificial SequencesiRNA
104gcaugggaag ccaaaccauc uccca
2510525DNAArtificial SequencesiRNA 105agagaaagaa gcagugccug ggata
2510625DNAArtificial SequencesiRNA
106ccuuaggaca gaugcaugau uaugt
2510721RNAArtificial SequencesiRNA 107aggcacugcu gucuucacau u
2110821RNAArtificial SequencesiRNA
108agacaauggc acugcugucu u
2110921RNAArtificial SequencesiRNA 109gcuggugagc aucaaucaau u
2111021RNAArtificial SequencesiRNA
110ugacaugaug gucuccaggu u
2111121RNAArtificial SequencesiRNA 111ucaugcaucu guccgaaggu u
2111221RNAArtificial SequencesiRNA
112ggggcucuug ggaaacuccu u
2111321RNAArtificial SequencesiRNA 113ggaggcaugu aaucccucau u
2111421RNAArtificial SequencesiRNA
114ggucuuaucc cugacacucu u
2111527RNAArtificial SequencesiRNA 115agcaucaauc aauugaggaa guuuguu
2711627RNAArtificial SequencesiRNA
116gauagcuuuc caaagacaau ggcacug
2711727RNAArtificial SequencesiRNA 117cuccaagguc uuaucccuga cacucuu
2711827RNAArtificial SequencesiRNA
118guacagaaag ucaccacuuu ccuugcu
2711927RNAArtificial SequencesiRNA 119caugaagcac ugugcucuga gcugcac
2712027RNAArtificial SequencesiRNA
120ugggagaugg uuuggcuucc caugcuu
2712127RNAArtificial SequencesiRNA 121uaucccaggc acugcuucuu ucucuac
2712227RNAArtificial SequencesiRNA
122uaucccaggc acugcuucuu ucucuac
2712327RNAArtificial SequencesiRNA 123acauaaucau gcaucugucc uaagguu
2712421RNAArtificial SequencesiRNA
124aaggaaccca gaaggaccgu u
2112521RNAArtificial SequencesiRNA 125ccuggaaacc aucaucucau u
2112621RNAArtificial SequencesiRNA
126ugagggacua caugccgccu u
2112721RNAArtificial SequencesiRNA 127aaggugcugc caagaucucu u
2112825DNAArtificial SequencesiRNA
128ccagaaggac cguuggaaau cagta
2512925RNAArtificial SequencesiRNA 129gaaguacucu ggaggaagug cagcc
2513025RNAArtificial SequencesiRNA
130caaggaaagu guuggcuuuc uacac
2513125RNAArtificial SequencesiRNA 131ccaugggauu cgucuggcag gaggg
2513225RNAArtificial SequencesiRNA
132guacugccau gcugagcuuc uugaa
2513325DNAArtificial SequencesiRNA 133cuaugaaggu gcugccacag agcct
2513425RNAArtificial SequencesiRNA
134gugucaggga gaagaccaug gaggc
2513525RNAArtificial SequencesiRNA 135gucagagcau gacgcuggag gugcc
2513621RNAArtificial SequencesiRNA
136cgguccuucu ggguuccuuu u
2113721RNAArtificial SequencesiRNA 137ugugaugaug guuuccaggu u
2113821RNAArtificial SequencesiRNA
138ggcggcaugu agucccucau u
2113921RNAArtificial SequencesiRNA 139gagaucuugg cagcaccuuu u
2114027RNAArtificial SequencesiRNA
140uacugauuuc caacgguccu ucugggu
2714127RNAArtificial SequencesiRNA 141ggcugcacuu ccuccagagu acuucag
2714227RNAArtificial SequencesiRNA
142guguagaaag ccaacacuuu ccuugca
2714327RNAArtificial SequencesiRNA 143cccuccugcc agacgaaucc cauggug
2714427RNAArtificial SequencesiRNA
144uucaagaagc ucagcauggc aguaccc
2714527RNAArtificial SequencesiRNA 145aggcucugug gcagcaccuu cauagac
2714627RNAArtificial SequencesiRNA
146gccuccaugg ucuucucccu gacacuc
2714727RNAArtificial SequencesiRNA 147ggcaccucca gcgucaugcu cugacuu
2714838DNAArtificial SequencePrimer
148actggcggcc gcatgccgaa tctattacca ttactgcc
3814934DNAArtificial SequencePrimer 149actgggtacc acaccttcat agaccagccc
caca 3415040DNAArtificial SequencePrimer
150actgcgtacg catatgtgtg gggctggtct atgaaggtgt
4015135DNAArtificial SequencePrimer 151actggtcgac gggatatagc acaagaacag
ctaag 3515237DNAArtificial SequencePrimer
152actgggcgcg cccttagctg ttcttgtgct atatccc
3715338DNAArtificial SequencePrimer 153actgcccggg ggtgtctgtg agattttgag
aatagtcc 38154865DNAArtificial
SequenceSynthetic Sequence 154atgccgaatc tattaccatt actgccaagt cccattggga
gaaaaactaa agtgtgcatt 60cgtgcatgtg tgcgtgtacg tgtgtgtcta gaactgaaaa
ttttatttcc ttgcaagtat 120cagactagag ttttcctggc ctgctaggtc ctctgttgcc
tctccccacc atgtccccaa 180tttgactcct gacacagcac tggcacttgg catttttcta
gaattacaca ttttcctgac 240ttttctcttg actaccgcca gaggaaattt ctcttaaagg
ggctcctgtg gctgtgctca 300atctagtcgg atgagtcagg gaaattccca cattaaagct
aaactgatca gtggccttaa 360tcccatctga aaagtcctcc tgccctgtcc tgtaataaat
atatcatggt gaccggaaca 420gctcatagta ttaagagtcc taggaattcg gttgggaacc
ttggggagct atttttagaa 480tcctaccctc cagtgtcttt caaaggaatc atttctactt
cctcttggca gagacttgat 540aagaaccaga aggggacttt gtttgcatcg acataagttc
cgggcaatga cactttttat 600ctggtatttg gcataaaggc catccctcca cttcaaatgc
tgagactgtt tactgtgccg 660ctaagtggct gtacaagatc ctaaatgtag ctgtagtttc
aacaaacatc tggattgttg 720ggagtttcca gtagacttct ctttaaaatg tcagcctcgc
tattctgcat ctatcccgag 780tttctcattt gcttctttaa aacacagttt tatttaagag
tggatgtcct gtggaaatga 840gatgtattcc ctccagttcc cagcc
865155948DNAArtificial SequenceSynthetic Sequence
155tgagtgtatg ctcgtgtatg tatgtgagca ctgcaggtgt ctgcatggtg tgccatggtg
60ctccactggg cttcatgctg tgctccccta ggcttcagtc aagtcaagac taggtcaagt
120catggagggt aaacagaaga gagagagagc agaaaatgag ggacacagga agggtagagg
180gggaaagaga gggttgtgaa gctcacgcgt gatcaggagc cccaggcttt cttcttccag
240ccgcccatag gctctggtgc ccacaacatt ggttacaacc ccgctctcca tcatcatgct
300tgtcatcact gctgtgacaa accgcttaat aatggttctc acggaacatt aaaagccaag
360ccaagtttaa cacctcgaac atttccaagt gttatgggga ataacagtta agtgtctggg
420tgtgcttgtg tgtaattggg aatctgtagt ggtggggtta ccagtgtcag gccacagtgt
480ttgtgatgag cagaggggtc ggggtctttc tcagatccct tatcttgtcc tgtcaatggt
540ggtgatgtaa taggtgcacg cctgtgacag agctgtttaa agcattgtaa gaccaatgag
600taaagttcct acccttgctt ctcctttaag tgaggcagaa aaaggctcca ccatgacgtg
660gtgtaaagat gaagtcaatc taatacttcc ttggatactc tagcaagctt cattcacact
720ttttatttct tcctcttcct cttcctcttc ctcttcctct tcctcttcct cttcccctcc
780tcctcttcct cctcctcttc ctcctcctct tcctcctcct cctcttcctc cttctcctct
840tcctcctccc cctccccttc ccctgtgctc ctcattatta ttattattgc tcctgtctag
900gtggaaggac aatccagcca tgcctgtggg gctggtctat gaaggtgt
948156700DNAArtificial SequenceSynthetic Sequence 156ggtaccaaag
gccgcaatgg ccaaacctgc aggaagtacc agagctccct aggttctaga 60accggtgacg
tcaagctcga ataacttcgt ataatgtatg ctatacgaag ttatcctgca 120ggtcgatcga
gaccgtacgc tatgtgtggg gctggtctat gaaggtgttg ccacagagcc 180tctgaagtac
tctggaggaa gtgcagccca gagctccgtg cttcatgcct tcgatgagtt 240cctgggcatt
gagcattgca aggaaagtgg tgagcagcag tctgatctca cctatgcttt 300gatgggacag
cgaggtagac tagggagaca tctctagcaa ctgataaaga cgggtgtaaa 360tgaaaatgtc
ctgaagttta tccttgccta agccagcagg cagctgtgtg catgtgccct 420ctcttacact
gagttagtca gtattggggc atcggatctt attagggtct tccaacagtc 480ctgtgacctg
ggttgttcac tgtcctgttg gctggggtct tttatccgca gattcccctt 540tctacaatga
ggtgataatg tcacattgaa aggccagtct ggagcagcaa gtgatagtgc 600tgaacttctc
tgctaaagcc tttcccatga aatggcccag cctcccactg aatctatgtg 660gaccaggcga
gggagcccat cgctttgaag cctttaaaat
700157803DNAArtificial SequenceSynthetic Sequence 157cagaaatgaa
catttgagca tttggcagct ataacaaaag cccgacaagg ctgagggaga 60gccctatcaa
gcatttctgg tacctgagtg tttggaacag tgggcaaacc ctcccaaatg 120tctgcctcga
gctaacgtat ttctcccggc tgtttctttc agttggcttt ctacacagaa 180tgagggacta
catgccgcct tcccataagg ctttcctgga agatctccac gtagctcctt 240ctctgagaga
ctacatactg gcctctggtc ctggggactg cctgatggcc tataaccagt 300gtgtggaggc
cctgggagag ctgcgcagtt accacatcaa tgtcgtggcc agatacatta 360tctccgctgc
caccagggcc aggagcaggg ggctaactaa tccctcaccc catgccttgg 420aagacagggg
cactgggggt actgccatgc tgagcttctt gaagagtgtc agggagaaga 480ccatggaggc
cctcctgtgt cctggtgctt agcagtcatg tcctgcaccc taacacttag 540atgttctcat
cctgcatccc agcgttagag gttcacatcc tgcatcctag tgcttagctg 600ttcttgtgct
atatcccgtc gacgaagttc ctatactttc tagagaatag gaacttcgga 660tccacgattc
gagggcccct gcaggtcaat tctaccgggt aggggaggcg cttttcccaa 720ggcagtctgg
agcatgcgct ttancagccc cgctgggcac ttggcgctac acaagtggcc 780tctggcctcg
cacacattcc aca
803158575DNAArtificial SequenceSynthetic Sequence 158atcccagcgc
ttagcagtca tgtcctgcat cctagtgctt agcattttat atccagcatc 60ttagtgctta
gagattcaca tcctgcatcc tagagcttag cattttatat ccagcatcct 120tgtgcgtatc
agctatgttt tgtatcctgc ttagcagtta acatcctgca tcctagtact 180tatctgttct
catcctgcat cctagagctt agcagtcagg tcccgtggga gcaagaacca 240gggtctgagc
tctgtctgag cccaagcatg gctttactgc tttgttaatt gtggctccca 300cctccacccc
accccagcca gtttgcttgc tagaagcctt tctgcactgc ctaatccccc 360tgcctcacag
cagagagctg cagccatgac ctcctcattc agtattaggt ggacaagtcg 420gagataccca
aactcaattt taaaagaatc aagttgcttt tggggcatgt tacttcatct 480tttcttaccc
tgggcctcta tgacctcctc attcagtatt aggtggacaa gtcggagata 540cccaaactca
attttaaaag aatcaagttg ctttt
575159753DNAArtificial SequenceSynthetic Sequence 159agctctaaga
gaaggaatac agcttgggac agagtttgtt ttgaagtggg gttcaggtgc 60atttcctggg
tgtgtccctc atttgggggt gttaggaggc agacaatgct aagggcatgg 120tttgatatgg
tagactgacc atcctggggt cccttcagct tgtgacactc gctgtactgc 180tggactctgc
tgagcccttt gaagccagga ctcctcctct gctgcaggag tgcagtgtcc 240ttcttgctgt
atgaagctgg gacaatgctc tttggccttc atactggaca tcccattgag 300aagcttgtca
ctctgtagag aatagacatc gcccccttgt ggttgtgagg ctgcccagga 360cttactgcgg
gggggggggg ggcatgttgt ccagcataag gagagaagac cccactgcat 420gctgctggga
aaaggaaagt aacgttcaga gtagtttcta ctggctgcct gcgctctcac 480gcctgtaaga
acaaacgtcc taatgtctgc atgtggagga aggagccagg ggtgcttagg 540gtgctgttgg
tcccaccaat gtactactca tctggaagac cttgtcttgg ttttcttgcc 600actgggacaa
agtgggattg ggtatcagtc tccccatgtc gggcaaatgt acttgaacaa 660gcagcatggt
ggaccagaca tgggactatt ctcaaaatct cacagacacc cccggggggc 720atgttacttc
atcttttctt accctgggcc tct
753160453DNAArtificial SequenceSynthetic Sequence 160ctagggagtc
aggaagtcac actggtgaag agtgggggtg tgggatgacc acactgagga 60gtcacacttg
aggaaggggg gtggccacac tgaggagtgt ctgaaagcat tgagactgta 120catctcaggt
tatcagggct tcagagaaaa cagacaggga gaagagacaa gaactggatt 180ctgtgcgcaa
agggggaaaa gcaagcagat gtgaagggtg tgctgttaga gtttatctaa 240agatgtttct
ttcagaaata aagagatata agctttaatt tggatgaaat aaatgtggtc 300taatttccca
gaatgtagag gaactcacta atgtagcaag attggccttt caaagcagac 360caaagacatt
gagaattaag atagctatga tggcgtgctt ccttaggtgg aagtcctata 420tggaatccca
tactccccaa atgtgactgg tcg
453161361DNAArtificial SequenceSynthetic Sequence 161aggcaggagg
gtcaggagtt caaggccagc ctagtataca tgcaacagtg tctcaaaaat 60caaaacagag
aggagggcag gaaaggagaa gggagccagg gagagaaggg aagaggaagg 120gagggagggg
gaaatggagg gagggggaga tggagggagg gggagatgga gggaggggga 180gatggaggga
gggggagatg gagggagggg gagatggagg gagggggatg ggaaagaggg 240tttacagccc
tggtttatct tgaacagaat ccttactttg tccctcagag tgacaggact 300gaaaagattg
tcccaggatt ttggctgcaa agcaaggtcc actcagagac cacagagctc 360g
36116210543DNAArtificial SequenceSynthetic Sequence 162aagctttact
cgtaaagcga gttgaaggat catatttagt tgcgtttatg agataagatt 60gaaagcacgt
gtaaaatgtt tcccgcgcgt tggcacaact atttacaatg cggccaagtt 120ataaaagatt
ctaatctgat atgttttaaa acacctttgc ggcccgagtt gtttgcgtac 180gtgactagcg
aagaagatgt gtggaccgca gaacagatag taaaacaaaa ccctagtatt 240ggagcaataa
tcgatttaac caacacgtct aaatattatg atggtgtgca ttttttgcgg 300gcgggcctgt
tatacaaaaa aattcaagta cctggccaga ctttgccgcc tgaaagcata 360gttcaagaat
ttattgacac ggtaaaagaa tttacagaaa agtgtcccgg catgttggtg 420ggcgtgcact
gcacacacgg tattaatcgc accggttaca tggtgtgcag atatttaatg 480cacaccctgg
gtattgcgcc gcaggaagcc atagatagat tcgaaaaagc cagaggtcac 540aaaattgaaa
gacaaaatta cgttcaagat ttattaattt aattaatatt atttgcattc 600tttaacaaat
actttatcct attttcaaat tgttgcgctt cttccagcga accaaaacta 660tgcttcgctt
gctccgttta gcttgtagcc gatcagtggc gttgttccaa tcgacggtag 720gattaggccg
gatattctcc accacaatgt tggcaacgtt gatgttacgt ttatgctttt 780ggttttccac
gtacgtcttt tggccggtaa tagccgtaaa cgtagtgccg tcgcgcgtca 840cgcacaacac
cggatgtttg cgcttgtccg cggggtattg aaccgcgcga tccgacaaat 900ccaccacttt
ggcaactaaa tcggtgacct gcgcgtcttt tttctgcatt atttcgtctt 960tcttttgcat
ggtttcctgg aagccggtgt acatgcggtt tagatcagtc atgacgcgcg 1020tgacctgcaa
atctttggcc tcgatctgct tgtccttgat ggcaacgatg cgttcaataa 1080actcttgttt
tttaacaagt tcctcggttt tttgcgccac caccgcttgc agcgcgtttg 1140tgtgctcggt
gaatgtcgca atcagcttag tcaccaactg tttgctctcc tcctcccgtt 1200gtttgatcgc
gggatcgtac ttgccggtgc agagcacttg aggaattact tcttctaaaa 1260gccattcttg
taattctatg gcgtaaggca atttggactt cataatcagc tgaatcacgc 1320cggatttagt
aatgagcact gtatgcggct gcaaatacag cgggtcgccc cttttcacga 1380cgctgttaga
ggtagggccc ccattttgga tggtctgctc aaataacgat ttgtatttat 1440tgtctacatg
aacacgtata gctttatcac aaactgtata ttttaaactg ttagcgacgt 1500ccttggccac
gaaccggacc tgttggtcgc gctctagcac gtaccgcagg ttgaacgtat 1560cttctccaaa
tttaaattct ccaattttaa cgcgagccat tttgatacac gtgtgtcgat 1620tttgcaacaa
ctattgtttt ttaacgcaaa ctaaacttat tgtggtaagc aataattaaa 1680tatgggggaa
catgcgccgc tacaacactc gtcgttatga acgcagacgg cgccggtctc 1740ggcgcaagcg
gctaaaacgt gttgcgcgtt caacgcggca aacatcgcaa aagccaatag 1800tacagttttg
atttgcatat taacggcgat tttttaaatt atcttattta ataaatagtt 1860atgacgccta
caactccccg cccgcgttga ctcgctgcac ctcgagcagt tcgttgacgc 1920cttcctccgt
gtggccgaac acgtcgagcg ggtggtcgat gaccagcggc gtgccgcacg 1980cgacgcacaa
gtatctgtac accgaatgat cgtcgggcga aggcacgtcg gcctccaagt 2040ggcaatattg
gcaaattcga aaatatatac agttgggttg tttgcgcata tctatcgtgg 2100cgttgggcat
gtacgtccga acgttgattt gcatgcaagc cgaaattaaa tcattgcgat 2160tagtgcgatt
aaaacgttgt acatcctcgc ttttaatcat gccgtcgatt aaatcgcgca 2220atcgagtcaa
gtgatcaaag tgtggaataa tgttttcttt gtattcccga gtcaagcgca 2280gcgcgtattt
taacaaacta gccatcttgt aagttagttt catttaatgc aactttatcc 2340aataatatat
tatgtatcgc acgtcaagaa ttaacaatgc gcccgttgtc gcatctcaac 2400acgactatga
tagagatcaa ataaagcgcg aattaaatag cttgcgacgc aacgtgcacg 2460atctgtgcac
gcgttccggc acgagctttg attgtaataa gtttttacga agcgatgaca 2520tgacccccgt
agtgacaacg atcacgccca aaagaactgc cgactacaaa attaccgagt 2580atgtcggtga
cgttaaaact attaagccat ccaatcgacc gttagtcgaa tcaggaccgc 2640tggtgcgaga
agccgcgaag tatggcgaat gcatcgtata acgtgtggag tccgctcatt 2700agagcgtcat
gtttagacaa gaaagctaca tatttaattg atcccgatga ttttattgat 2760aaattgaccc
taactccata cacggtattc tacaatggcg gggttttggt caaaatttcc 2820ggactgcgat
tgtacatgct gttaacggct ccgcccacta ttaatgaaat taaaaattcc 2880aattttaaaa
aacgcagcaa gagaaacatt tgtatgaaag aatgcgtaga aggaaagaaa 2940aatgtcgtcg
acatgctgaa caacaagatt aatatgcctc cgtgtataaa aaaaatattg 3000aacgatttga
aagaaaacaa tgtaccgcgc ggcggtatgt acaggaagag gtttatacta 3060aactgttaca
ttgcaaacgt ggtttcgtgt gccaagtgtg aaaaccgatg tttaatcaag 3120gctctgacgc
atttctacaa ccacgactcc aagtgtgtgg gtgaagtcat gcatctttta 3180atcaaatccc
aagatgtgta taaaccacca aactgccaaa aaatgaaaac tgtcgacaag 3240ctctgtccgt
ttgctggcaa ctgcaagggt ctcaatccta tttgtaatta ttgaataata 3300aaacaattat
aaatgctaaa tttgtttttt attaacgata caaaccaaac gcaacaagaa 3360catttgtagt
attatctata attgaaaacg cgtagttata atcgctgagg taatatttaa 3420aatcattttc
aaatgattca cagttaattt gcgacaatat aattttattt tcacataaac 3480tagacgcctt
gtcgtcttct tcttcgtatt ccttctcttt ttcatttttc tcctcataaa 3540aattaacata
gttattatcg tatccatata tgtatctatc gtatagagta aattttttgt 3600tgtcataaat
atatatgtct tttttaatgg ggtgtatagt accgctgcgc atagtttttc 3660tgtaatttac
aacagtgcta ttttctggta gttcttcgga gtgtgttgct ttaattatta 3720aatttatata
atcaatgaat ttgggatcgt cggttttgta caatatgttg ccggcatagt 3780acgcagcttc
ttctagttca attacaccat tttttagcag caccggatta acataacttt 3840ccaaaatgtt
gtacgaaccg ttaaacaaaa acagttcacc tcccttttct atactattgt 3900ctgcgagcag
ttgtttgttg ttaaaaataa cagccattgt aatgagacgc acaaactaat 3960atcacaaact
ggaaatgtct atcaatatat agttgctgat atcatggaga taattaaaat 4020gataaccatc
tcgcaaataa ataagtattt tactgttttc gtaacagttt tgtaataaaa 4080aaacctataa
atattccgga ttattcatac cgtcccacca tcgggcgcgg atcagatctg 4140cagcggccgc
tccagaattc tagaaggtac catggagcct caaagtcaga gcatgacgct 4200ggaggtgccg
ttgtccttgg ggagatacca catttctgag gaatatggct ttctccttcc 4260aaatcctctg
gaagcacttc cagatcatta caagccttgg atggaaattg ccctcagact 4320tcctcactta
atcgagaacc gccagctccg agctcacgtg tacaggatgc ctctcctgga 4380ctgcagattc
ctaaagagtt accgtgagca gcgcctggca cacatggcgc tggccgctat 4440caccatggga
ttcgtctggc aggaggggga aggccaaccc caaaaggtgc tgccaagatc 4500tcttgccatt
ccttttgttg aggtatccag gaacttggga ctcccgccta tcctggtcca 4560ctctgacctg
gtgctgacaa actggaccaa aaggaaccca gaaggaccgt tggaaatcag 4620taacctggaa
accatcatct catttccggg gggagagagc ctgcggggct tcatcctagt 4680gacagtcttg
gtggagaagg cagcagtgcc cggccttaag gccctggttc agggaatgga 4740ggccattcgg
caacacagtc aggacaccct gctagaagcc ctgcagcagc tgagactctc 4800catccaggat
atcaccagag ccttggccca aatgcatgat tatgtggacc cagacatatt 4860ttactcggtc
atccggatct tcctctctgg gtggaaggac aatccagcca tgcctgtggg 4920gctggtctat
gaaggtgctg ccacagagcc tctgaagtac tctggaggaa gtgcagccca 4980gagctccgtg
cttcatgcct tcgatgagtt cctgggcatt gagcattgca aggaaagtgt 5040tggctttcta
cacagaatga gggactacat gccgccttcc cataaggctt tcctggaaga 5100tctccacgta
gctccttctc tgagagacta catactggcc tctggtcctg gggactgcct 5160gatggcctat
aaccagtgtg tggaggccct gggagagctg cgcagttacc acatcaatgt 5220cgtggccaga
tacattatct ccgctgccac cagggccagg agcagggggc taactaatcc 5280ctcaccccat
gccttggaag acaggggcac tgggggtact gccatgctga gcttcttgaa 5340gagtgtcagg
gagaagacca tggaggccct cctgtgtcct ggtgcttagg gtcaagacaa 5400ttctgcagat
atccagcaca gtggcggccg ctcgagtcta gagggcccgc ggttcgaagg 5460taagcctatc
cctaaccctc tcctcggtct cgattctacg cgtaccggtc atcatcacca 5520tcaccattga
gtttgctagc cactagtacc gactctgctg aagaggagga aattctcctt 5580gaagtttccc
tggtgttcaa agtaaaggag tttgcaccag acgcacctct gttcactggt 5640ccggcgtatt
aaaacacgat acattgttat tagtacattt attaagcgct agattctgtg 5700cgttgttgat
ttacagacaa ttgttgtacg tattttaata attcattaaa tttataatct 5760ttagggtggt
atgttagagc gaaaatcaaa tgattttcag cgtctttata tctgaattta 5820aatattaaat
cctcaataga tttgtaaaat aggtttcgat tagtttcaaa caagggttgt 5880ttttccgaac
cgatggctgg actatctaat ggattttcgc tcaacgccac aaaacttgcc 5940aaatcttgta
gcagcaatct agctttgtcg atattcgttt gtgttttgtt ttgtaataaa 6000ggttcgacgt
cgttcaaaat attatgcgct tttgtatttc tttcatcact gtcgttagtg 6060tacaattgac
tcgacgtaaa cacgttaaat aaagcttgga catatttaac atcgggcgtg 6120ttagctttat
taggccgatt atcgtcgtcg tcccaaccct cgtcgttaga agttgcttcc 6180gaagacgatt
ttgccatagc cacacgacgc ctattaattg tgtcggctaa cacgtccgcg 6240atcaaatttg
tagttgagct ttttggaatt atttctgatt gcgggcgttt ttgggcgggt 6300ttcaatctaa
ctgtgcccga ttttaattca gacaacacgt tagaaagcga tggtgcaggc 6360ggtggtaaca
tttcagacgg caaatctact aatggcggcg gtggtggagc tgatgataaa 6420tctaccatcg
gtggaggcgc aggcggggct ggcggcggag gcggaggcgg aggtggtggc 6480ggtgatgcag
acggcggttt aggctcaaat gtctctttag gcaacacagt cggcacctca 6540actattgtac
tggtttcggg cgccgttttt ggtttgaccg gtctgagacg agtgcgattt 6600ttttcgtttc
taatagcttc caacaattgt tgtctgtcgt ctaaaggtgc agcgggttga 6660ggttccgtcg
gcattggtgg agcgggcggc aattcagaca tcgatggtgg tggtggtggt 6720ggaggcgctg
gaatgttagg cacgggagaa ggtggtggcg gcggtgccgc cggtataatt 6780tgttctggtt
tagtttgttc gcgcacgatt gtgggcaccg gcgcaggcgc cgctggctgc 6840acaacggaag
gtcgtctgct tcgaggcagc gcttggggtg gtggcaattc aatattataa 6900ttggaataca
aatcgtaaaa atctgctata agcattgtaa tttcgctatc gtttaccgtg 6960ccgatattta
acaaccgctc aatgtaagca attgtattgt aaagagattg tctcaagctc 7020gccgcacgcc
gataacaagc cttttcattt ttactacagc attgtagtgg cgagacactt 7080cgctgtcgtc
gacgtacatg tatgctttgt tgtcaaaaac gtcgttggca agctttaaaa 7140tatttaaaag
aacatctctg ttcagcacca ctgtgttgtc gtaaatgttg tttttgataa 7200tttgcgcttc
cgcagtatcg acacgttcaa aaaattgatg cgcatcaatt ttgttgttcc 7260tattattgaa
taaataagat tgtacagatt catatctacg attcgtcatg gccaccacaa 7320atgctacgct
gcaaacgctg gtacaatttt acgaaaactg caaaaacgtc aaaactcggt 7380ataaaataat
caacgggcgc tttggcaaaa tatctatttt atcgcacaag cccactagca 7440aattgtattt
gcagaaaaca atttcggcgc acaattttaa cgctgacgaa ataaaagttc 7500accagttaat
gagcgaccac ccaaatttta taaaaatcta ttttaatcac ggttccatca 7560acaaccaagt
gatcgtgatg gactacattg actgtcccga tttatttgaa acactacaaa 7620ttaaaggcga
gctttcgtac caacttgtta gcaatattat tagacagctg tgtgaagcgc 7680tcaacgattt
gcacaagcac aatttcatac acaacgacat aaaactcgaa aatgtcttat 7740atttcgaagc
acttgatcgc gtgtatgttt gcgattacgg attgtgcaaa cacgaaaact 7800cacttagcgt
gcacgacggc acgttggagt attttagtcc ggaaaaaatt cgacacacaa 7860ctatgcacgt
ttcgtttgac tggtacgcgg cgtgttaaca tacaagttgc taacgtaatc 7920atggtcatag
ctgtttcctg tgtgaaattg ttatccgctc acaattccac acaacatacg 7980agccggaagc
ataaagtgta aagcctgggg tgcctaatga gtgagctaac tcacattaat 8040tgcgttgcgc
tcactgcccg ctttccagtc gggaaacctg tcgtgccagc tgcattaatg 8100aatcggccaa
cgcgcgggga gaggcggttt gcgtattggg cgctcttccg cttcctcgct 8160cactgactcg
ctgcgctcgg tcgttcggct gcggcgagcg gtatcagctc actcaaaggc 8220ggtaatacgg
ttatccacag aatcagggga taacgcagga aagaacatgt gagcaaaagg 8280ccagcaaaag
gccaggaacc gtaaaaaggc cgcgttgctg gcgtttttcc ataggctccg 8340cccccctgac
gagcatcaca aaaatcgacg ctcaagtcag aggtggcgaa acccgacagg 8400actataaaga
taccaggcgt ttccccctgg aagctccctc gtgcgctctc ctgttccgac 8460cctgccgctt
accggatacc tgtccgcctt tctcccttcg ggaagcgtgg cgctttctca 8520tagctcacgc
tgtaggtatc tcagttcggt gtaggtcgtt cgctccaagc tgggctgtgt 8580gcacgaaccc
cccgttcagc ccgaccgctg cgccttatcc ggtaactatc gtcttgagtc 8640caacccggta
agacacgact tatcgccact ggcagcagcc actggtaaca ggattagcag 8700agcgaggtat
gtaggcggtg ctacagagtt cttgaagtgg tggcctaact acggctacac 8760tagaaggaca
gtatttggta tctgcgctct gctgaagcca gttaccttcg gaaaaagagt 8820tggtagctct
tgatccggca aacaaaccac cgctggtagc ggtggttttt ttgtttgcaa 8880gcagcagatt
acgcgcagaa aaaaaggatc tcaagaagat cctttgatct tttctacggg 8940gtctgacgct
cagtggaacg aaaactcacg ttaagggatt ttggtcatga gattatcaaa 9000aaggatcttc
acctagatcc ttttaaatta aaaatgaagt tttaaatcaa tctaaagtat 9060atatgagtaa
acttggtctg acagttacca atgcttaatc agtgaggcac ctatctcagc 9120gatctgtcta
tttcgttcat ccatagttgc ctgactcccc gtcgtgtaga taactacgat 9180acgggagggc
ttaccatctg gccccagtgc tgcaatgata ccgcgagacc cacgctcacc 9240ggctccagat
ttatcagcaa taaaccagcc agccggaagg gccgagcgca gaagtggtcc 9300tgcaacttta
tccgcctcca tccagtctat taattgttgc cgggaagcta gagtaagtag 9360ttcgccagtt
aatagtttgc gcaacgttgt tgccattgct acaggcatcg tggtgtcacg 9420ctcgtcgttt
ggtatggctt cattcagctc cggttcccaa cgatcaaggc gagttacatg 9480atcccccatg
ttgtgcaaaa aagcggttag ctccttcggt cctccgatcg ttgtcagaag 9540taagttggcc
gcagtgttat cactcatggt tatggcagca ctgcataatt ctcttactgt 9600catgccatcc
gtaagatgct tttctgtgac tggtgagtac tcaaccaagt cattctgaga 9660atagtgtatg
cggcgaccga gttgctcttg cccggcgtca atacgggata ataccgcgcc 9720acatagcaga
actttaaaag tgctcatcat tggaaaacgt tcttcggggc gaaaactctc 9780aaggatctta
ccgctgttga gatccagttc gatgtaaccc actcgtgcac ccaactgatc 9840ttcagcatct
tttactttca ccagcgtttc tgggtgagca aaaacaggaa ggcaaaatgc 9900cgcaaaaaag
ggaataaggg cgacacggaa atgttgaata ctcatactct tcctttttca 9960atattattga
agcatttatc agggttattg tctcatgagc ggatacatat ttgaatgtat 10020ttagaaaaat
aaacaaatag gggttccgcg cacatttccc cgaaaagtgc cacctgacgt 10080ctaagaaacc
attattatca tgacattaac ctataaaaat aggcgtatca cgaggccctt 10140tcgtctcgcg
cgtttcggtg atgacggtga aaacctctga cacatgcagc tcccggagac 10200ggtcacagct
tgtctgtaag cggatgccgg gagcagacaa gcccgtcagg gcgcgtcagc 10260gggtgttggc
gggtgtcggg gctggcttaa ctatgcggca tcagagcaga ttgtactgag 10320agtgcaccat
atgcggtgtg aaataccgca cagatgcgta aggagaaaat accgcatcag 10380gcgccattcg
ccattcaggc tgcgcaactg ttgggaaggg cgatcggtgc gggcctcttc 10440gctattacgc
cagctggcga aagggggatg tgctgcaagg cgattaagtt gggtaacgcc 10500agggttttcc
cagtcacgac gttgtaaaac gacggccagt gcc
1054316310511DNAArtificial SequenceSynthetic Sequence 163aagctttact
cgtaaagcga gttgaaggat catatttagt tgcgtttatg agataagatt 60gaaagcacgt
gtaaaatgtt tcccgcgcgt tggcacaact atttacaatg cggccaagtt 120ataaaagatt
ctaatctgat atgttttaaa acacctttgc ggcccgagtt gtttgcgtac 180gtgactagcg
aagaagatgt gtggaccgca gaacagatag taaaacaaaa ccctagtatt 240ggagcaataa
tcgatttaac caacacgtct aaatattatg atggtgtgca ttttttgcgg 300gcgggcctgt
tatacaaaaa aattcaagta cctggccaga ctttgccgcc tgaaagcata 360gttcaagaat
ttattgacac ggtaaaagaa tttacagaaa agtgtcccgg catgttggtg 420ggcgtgcact
gcacacacgg tattaatcgc accggttaca tggtgtgcag atatttaatg 480cacaccctgg
gtattgcgcc gcaggaagcc atagatagat tcgaaaaagc cagaggtcac 540aaaattgaaa
gacaaaatta cgttcaagat ttattaattt aattaatatt atttgcattc 600tttaacaaat
actttatcct attttcaaat tgttgcgctt cttccagcga accaaaacta 660tgcttcgctt
gctccgttta gcttgtagcc gatcagtggc gttgttccaa tcgacggtag 720gattaggccg
gatattctcc accacaatgt tggcaacgtt gatgttacgt ttatgctttt 780ggttttccac
gtacgtcttt tggccggtaa tagccgtaaa cgtagtgccg tcgcgcgtca 840cgcacaacac
cggatgtttg cgcttgtccg cggggtattg aaccgcgcga tccgacaaat 900ccaccacttt
ggcaactaaa tcggtgacct gcgcgtcttt tttctgcatt atttcgtctt 960tcttttgcat
ggtttcctgg aagccggtgt acatgcggtt tagatcagtc atgacgcgcg 1020tgacctgcaa
atctttggcc tcgatctgct tgtccttgat ggcaacgatg cgttcaataa 1080actcttgttt
tttaacaagt tcctcggttt tttgcgccac caccgcttgc agcgcgtttg 1140tgtgctcggt
gaatgtcgca atcagcttag tcaccaactg tttgctctcc tcctcccgtt 1200gtttgatcgc
gggatcgtac ttgccggtgc agagcacttg aggaattact tcttctaaaa 1260gccattcttg
taattctatg gcgtaaggca atttggactt cataatcagc tgaatcacgc 1320cggatttagt
aatgagcact gtatgcggct gcaaatacag cgggtcgccc cttttcacga 1380cgctgttaga
ggtagggccc ccattttgga tggtctgctc aaataacgat ttgtatttat 1440tgtctacatg
aacacgtata gctttatcac aaactgtata ttttaaactg ttagcgacgt 1500ccttggccac
gaaccggacc tgttggtcgc gctctagcac gtaccgcagg ttgaacgtat 1560cttctccaaa
tttaaattct ccaattttaa cgcgagccat tttgatacac gtgtgtcgat 1620tttgcaacaa
ctattgtttt ttaacgcaaa ctaaacttat tgtggtaagc aataattaaa 1680tatgggggaa
catgcgccgc tacaacactc gtcgttatga acgcagacgg cgccggtctc 1740ggcgcaagcg
gctaaaacgt gttgcgcgtt caacgcggca aacatcgcaa aagccaatag 1800tacagttttg
atttgcatat taacggcgat tttttaaatt atcttattta ataaatagtt 1860atgacgccta
caactccccg cccgcgttga ctcgctgcac ctcgagcagt tcgttgacgc 1920cttcctccgt
gtggccgaac acgtcgagcg ggtggtcgat gaccagcggc gtgccgcacg 1980cgacgcacaa
gtatctgtac accgaatgat cgtcgggcga aggcacgtcg gcctccaagt 2040ggcaatattg
gcaaattcga aaatatatac agttgggttg tttgcgcata tctatcgtgg 2100cgttgggcat
gtacgtccga acgttgattt gcatgcaagc cgaaattaaa tcattgcgat 2160tagtgcgatt
aaaacgttgt acatcctcgc ttttaatcat gccgtcgatt aaatcgcgca 2220atcgagtcaa
gtgatcaaag tgtggaataa tgttttcttt gtattcccga gtcaagcgca 2280gcgcgtattt
taacaaacta gccatcttgt aagttagttt catttaatgc aactttatcc 2340aataatatat
tatgtatcgc acgtcaagaa ttaacaatgc gcccgttgtc gcatctcaac 2400acgactatga
tagagatcaa ataaagcgcg aattaaatag cttgcgacgc aacgtgcacg 2460atctgtgcac
gcgttccggc acgagctttg attgtaataa gtttttacga agcgatgaca 2520tgacccccgt
agtgacaacg atcacgccca aaagaactgc cgactacaaa attaccgagt 2580atgtcggtga
cgttaaaact attaagccat ccaatcgacc gttagtcgaa tcaggaccgc 2640tggtgcgaga
agccgcgaag tatggcgaat gcatcgtata acgtgtggag tccgctcatt 2700agagcgtcat
gtttagacaa gaaagctaca tatttaattg atcccgatga ttttattgat 2760aaattgaccc
taactccata cacggtattc tacaatggcg gggttttggt caaaatttcc 2820ggactgcgat
tgtacatgct gttaacggct ccgcccacta ttaatgaaat taaaaattcc 2880aattttaaaa
aacgcagcaa gagaaacatt tgtatgaaag aatgcgtaga aggaaagaaa 2940aatgtcgtcg
acatgctgaa caacaagatt aatatgcctc cgtgtataaa aaaaatattg 3000aacgatttga
aagaaaacaa tgtaccgcgc ggcggtatgt acaggaagag gtttatacta 3060aactgttaca
ttgcaaacgt ggtttcgtgt gccaagtgtg aaaaccgatg tttaatcaag 3120gctctgacgc
atttctacaa ccacgactcc aagtgtgtgg gtgaagtcat gcatctttta 3180atcaaatccc
aagatgtgta taaaccacca aactgccaaa aaatgaaaac tgtcgacaag 3240ctctgtccgt
ttgctggcaa ctgcaagggt ctcaatccta tttgtaatta ttgaataata 3300aaacaattat
aaatgctaaa tttgtttttt attaacgata caaaccaaac gcaacaagaa 3360catttgtagt
attatctata attgaaaacg cgtagttata atcgctgagg taatatttaa 3420aatcattttc
aaatgattca cagttaattt gcgacaatat aattttattt tcacataaac 3480tagacgcctt
gtcgtcttct tcttcgtatt ccttctcttt ttcatttttc tcctcataaa 3540aattaacata
gttattatcg tatccatata tgtatctatc gtatagagta aattttttgt 3600tgtcataaat
atatatgtct tttttaatgg ggtgtatagt accgctgcgc atagtttttc 3660tgtaatttac
aacagtgcta ttttctggta gttcttcgga gtgtgttgct ttaattatta 3720aatttatata
atcaatgaat ttgggatcgt cggttttgta caatatgttg ccggcatagt 3780acgcagcttc
ttctagttca attacaccat tttttagcag caccggatta acataacttt 3840ccaaaatgtt
gtacgaaccg ttaaacaaaa acagttcacc tcccttttct atactattgt 3900ctgcgagcag
ttgtttgttg ttaaaaataa cagccattgt aatgagacgc acaaactaat 3960atcacaaact
ggaaatgtct atcaatatat agttgctgat atcatggaga taattaaaat 4020gataaccatc
tcgcaaataa ataagtattt tactgttttc gtaacagttt tgtaataaaa 4080aaacctataa
atattccgga ttattcatac cgtcccacca tcgggcgcgg atcagatctg 4140cagcggccgc
tccagaattc tagaaggtac ccatggagcc ccacagaccg aatgtgaaga 4200cagcagtgcc
attgtctttg gaaagctatc acatatctga agagtatggc tttcttcttc 4260cagattctct
gaaagaactt ccagatcatt ataggccttg gatggaaatt gccaacaaac 4320ttcctcaatt
gattgatgct caccagcttc aagctcatgt ggacaagatg cccctgctga 4380gctgccagtt
cctgaagggt caccgggagc agcgcctggc ccacctggtc ctgagcttcc 4440tcaccatggg
ttatgtctgg caggaaggag aggcgcagcc tgcagaggtc ctgccaagga 4500atcttgccct
tccatttgtc gaagtctcca ggaacttggg gctccctcct atcctggtcc 4560actcagactt
ggtgctgacg aactggacca aaaaagatcc agacgggttc ctggaaattg 4620ggaacctgga
gaccatcatc tcatttcctg ggggagagag cctgcatggt tttatactgg 4680tgactgcttt
ggtagagaaa gaagcagtgc ctgggataaa ggctcttgtt caggccacga 4740atgctatctt
gcagcccaac caggaggccc tgctccaagc cctgcagcga ctgagactgt 4800ctattcagga
catcaccaaa accttaggac agatgcatga ttatgtagat ccagacatat 4860tttatgcagg
catccggatc tttctctctg ggtggaaaga caacccagca atgcctgcag 4920ggctgatgta
tgaaggagtt tcccaagagc ccctgaaata ctccggcggg agtgcagctc 4980agagcacagt
gcttcatgcc tttgatgagt tcttaggcat tcgtcatagc aaggaaagtg 5040gtgactttct
gtacagaatg agggattaca tgcctccttc ccataaggcc ttcatagaag 5100acatccactc
agcaccttcc ctgagggact acatcctgtc atctggacag gaccacttgc 5160tgacagctta
taaccagtgt gtgcaggccc tggcagagct gcggagctat cacatcacca 5220tggtcaccaa
atacctcatc acagctgcag ccaaggcaaa gcatgggaag ccaaaccatc 5280tcccagggcc
tcctcaggct ttaaaagaca ggggcacagg tggaaccgca gttatgagct 5340ttcttaagag
tgtcagggat aagaccttgg agtcaatcct tcacccacgt ggttaacgct 5400cgagtctaga
gggcccgcgg ttcgaaggta agcctatccc taaccctctc ctcggtctcg 5460attctacgcg
taccggtcat catcaccatc accattgagt ttgctagcca ctagtaccga 5520ctctgctgaa
gaggaggaaa ttctccttga agtttccctg gtgttcaaag taaaggagtt 5580tgcaccagac
gcacctctgt tcactggtcc ggcgtattaa aacacgatac attgttatta 5640gtacatttat
taagcgctag attctgtgcg ttgttgattt acagacaatt gttgtacgta 5700ttttaataat
tcattaaatt tataatcttt agggtggtat gttagagcga aaatcaaatg 5760attttcagcg
tctttatatc tgaatttaaa tattaaatcc tcaatagatt tgtaaaatag 5820gtttcgatta
gtttcaaaca agggttgttt ttccgaaccg atggctggac tatctaatgg 5880attttcgctc
aacgccacaa aacttgccaa atcttgtagc agcaatctag ctttgtcgat 5940attcgtttgt
gttttgtttt gtaataaagg ttcgacgtcg ttcaaaatat tatgcgcttt 6000tgtatttctt
tcatcactgt cgttagtgta caattgactc gacgtaaaca cgttaaataa 6060agcttggaca
tatttaacat cgggcgtgtt agctttatta ggccgattat cgtcgtcgtc 6120ccaaccctcg
tcgttagaag ttgcttccga agacgatttt gccatagcca cacgacgcct 6180attaattgtg
tcggctaaca cgtccgcgat caaatttgta gttgagcttt ttggaattat 6240ttctgattgc
gggcgttttt gggcgggttt caatctaact gtgcccgatt ttaattcaga 6300caacacgtta
gaaagcgatg gtgcaggcgg tggtaacatt tcagacggca aatctactaa 6360tggcggcggt
ggtggagctg atgataaatc taccatcggt ggaggcgcag gcggggctgg 6420cggcggaggc
ggaggcggag gtggtggcgg tgatgcagac ggcggtttag gctcaaatgt 6480ctctttaggc
aacacagtcg gcacctcaac tattgtactg gtttcgggcg ccgtttttgg 6540tttgaccggt
ctgagacgag tgcgattttt ttcgtttcta atagcttcca acaattgttg 6600tctgtcgtct
aaaggtgcag cgggttgagg ttccgtcggc attggtggag cgggcggcaa 6660ttcagacatc
gatggtggtg gtggtggtgg aggcgctgga atgttaggca cgggagaagg 6720tggtggcggc
ggtgccgccg gtataatttg ttctggttta gtttgttcgc gcacgattgt 6780gggcaccggc
gcaggcgccg ctggctgcac aacggaaggt cgtctgcttc gaggcagcgc 6840ttggggtggt
ggcaattcaa tattataatt ggaatacaaa tcgtaaaaat ctgctataag 6900cattgtaatt
tcgctatcgt ttaccgtgcc gatatttaac aaccgctcaa tgtaagcaat 6960tgtattgtaa
agagattgtc tcaagctcgc cgcacgccga taacaagcct tttcattttt 7020actacagcat
tgtagtggcg agacacttcg ctgtcgtcga cgtacatgta tgctttgttg 7080tcaaaaacgt
cgttggcaag ctttaaaata tttaaaagaa catctctgtt cagcaccact 7140gtgttgtcgt
aaatgttgtt tttgataatt tgcgcttccg cagtatcgac acgttcaaaa 7200aattgatgcg
catcaatttt gttgttccta ttattgaata aataagattg tacagattca 7260tatctacgat
tcgtcatggc caccacaaat gctacgctgc aaacgctggt acaattttac 7320gaaaactgca
aaaacgtcaa aactcggtat aaaataatca acgggcgctt tggcaaaata 7380tctattttat
cgcacaagcc cactagcaaa ttgtatttgc agaaaacaat ttcggcgcac 7440aattttaacg
ctgacgaaat aaaagttcac cagttaatga gcgaccaccc aaattttata 7500aaaatctatt
ttaatcacgg ttccatcaac aaccaagtga tcgtgatgga ctacattgac 7560tgtcccgatt
tatttgaaac actacaaatt aaaggcgagc tttcgtacca acttgttagc 7620aatattatta
gacagctgtg tgaagcgctc aacgatttgc acaagcacaa tttcatacac 7680aacgacataa
aactcgaaaa tgtcttatat ttcgaagcac ttgatcgcgt gtatgtttgc 7740gattacggat
tgtgcaaaca cgaaaactca cttagcgtgc acgacggcac gttggagtat 7800tttagtccgg
aaaaaattcg acacacaact atgcacgttt cgtttgactg gtacgcggcg 7860tgttaacata
caagttgcta acgtaatcat ggtcatagct gtttcctgtg tgaaattgtt 7920atccgctcac
aattccacac aacatacgag ccggaagcat aaagtgtaaa gcctggggtg 7980cctaatgagt
gagctaactc acattaattg cgttgcgctc actgcccgct ttccagtcgg 8040gaaacctgtc
gtgccagctg cattaatgaa tcggccaacg cgcggggaga ggcggtttgc 8100gtattgggcg
ctcttccgct tcctcgctca ctgactcgct gcgctcggtc gttcggctgc 8160ggcgagcggt
atcagctcac tcaaaggcgg taatacggtt atccacagaa tcaggggata 8220acgcaggaaa
gaacatgtga gcaaaaggcc agcaaaaggc caggaaccgt aaaaaggccg 8280cgttgctggc
gtttttccat aggctccgcc cccctgacga gcatcacaaa aatcgacgct 8340caagtcagag
gtggcgaaac ccgacaggac tataaagata ccaggcgttt ccccctggaa 8400gctccctcgt
gcgctctcct gttccgaccc tgccgcttac cggatacctg tccgcctttc 8460tcccttcggg
aagcgtggcg ctttctcata gctcacgctg taggtatctc agttcggtgt 8520aggtcgttcg
ctccaagctg ggctgtgtgc acgaaccccc cgttcagccc gaccgctgcg 8580ccttatccgg
taactatcgt cttgagtcca acccggtaag acacgactta tcgccactgg 8640cagcagccac
tggtaacagg attagcagag cgaggtatgt aggcggtgct acagagttct 8700tgaagtggtg
gcctaactac ggctacacta gaaggacagt atttggtatc tgcgctctgc 8760tgaagccagt
taccttcgga aaaagagttg gtagctcttg atccggcaaa caaaccaccg 8820ctggtagcgg
tggttttttt gtttgcaagc agcagattac gcgcagaaaa aaaggatctc 8880aagaagatcc
tttgatcttt tctacggggt ctgacgctca gtggaacgaa aactcacgtt 8940aagggatttt
ggtcatgaga ttatcaaaaa ggatcttcac ctagatcctt ttaaattaaa 9000aatgaagttt
taaatcaatc taaagtatat atgagtaaac ttggtctgac agttaccaat 9060gcttaatcag
tgaggcacct atctcagcga tctgtctatt tcgttcatcc atagttgcct 9120gactccccgt
cgtgtagata actacgatac gggagggctt accatctggc cccagtgctg 9180caatgatacc
gcgagaccca cgctcaccgg ctccagattt atcagcaata aaccagccag 9240ccggaagggc
cgagcgcaga agtggtcctg caactttatc cgcctccatc cagtctatta 9300attgttgccg
ggaagctaga gtaagtagtt cgccagttaa tagtttgcgc aacgttgttg 9360ccattgctac
aggcatcgtg gtgtcacgct cgtcgtttgg tatggcttca ttcagctccg 9420gttcccaacg
atcaaggcga gttacatgat cccccatgtt gtgcaaaaaa gcggttagct 9480ccttcggtcc
tccgatcgtt gtcagaagta agttggccgc agtgttatca ctcatggtta 9540tggcagcact
gcataattct cttactgtca tgccatccgt aagatgcttt tctgtgactg 9600gtgagtactc
aaccaagtca ttctgagaat agtgtatgcg gcgaccgagt tgctcttgcc 9660cggcgtcaat
acgggataat accgcgccac atagcagaac tttaaaagtg ctcatcattg 9720gaaaacgttc
ttcggggcga aaactctcaa ggatcttacc gctgttgaga tccagttcga 9780tgtaacccac
tcgtgcaccc aactgatctt cagcatcttt tactttcacc agcgtttctg 9840ggtgagcaaa
aacaggaagg caaaatgccg caaaaaaggg aataagggcg acacggaaat 9900gttgaatact
catactcttc ctttttcaat attattgaag catttatcag ggttattgtc 9960tcatgagcgg
atacatattt gaatgtattt agaaaaataa acaaataggg gttccgcgca 10020catttccccg
aaaagtgcca cctgacgtct aagaaaccat tattatcatg acattaacct 10080ataaaaatag
gcgtatcacg aggccctttc gtctcgcgcg tttcggtgat gacggtgaaa 10140acctctgaca
catgcagctc ccggagacgg tcacagcttg tctgtaagcg gatgccggga 10200gcagacaagc
ccgtcagggc gcgtcagcgg gtgttggcgg gtgtcggggc tggcttaact 10260atgcggcatc
agagcagatt gtactgagag tgcaccatat gcggtgtgaa ataccgcaca 10320gatgcgtaag
gagaaaatac cgcatcaggc gccattcgcc attcaggctg cgcaactgtt 10380gggaagggcg
atcggtgcgg gcctcttcgc tattacgcca gctggcgaaa gggggatgtg 10440ctgcaaggcg
attaagttgg gtaacgccag ggttttccca gtcacgacgt tgtaaaacga 10500cggccagtgc c
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