Methods And Kits For Diagnosing And Treating B-cell Chronic Lymphocytic Leukemia

Abstract

The present invention relates to methods and kits for detecting several polynucleotide sequence found to be indicative of a poor prognosis of B-CLL. All the polynucleotides are transcribed from a region on human chromosome 12p21-22. Most of the polynucleotides do not encode larger polypeptides, but may encode small peptides, they may function as RNAs. Four polynucleotides encode a novel protein, which in one preferred embodiment can be used as a cytokine, preferably as an interleukin. Furthermore the invention relates to methods and compositions for treating B-CLL in particular poor prognosis B-CLL.

Description

[0001] All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.

FIELD OF INVENTION

[0002] The present invention relates to methods and kits for detecting several polynucleotide sequence found to be indicative of a poor prognosis of B-CLL. All the polynucleotides are transcribed from a region on human chromosome 12p21-22. Most of the polynucleotides do not encode larger polypeptides, but may encode small peptides, they may function as RNAs. Four polynucleotides encode a novel protein, which in one preferred embodiment can be used as a cytokine, preferably as an interleukin. Furthermore the invention relates to methods and compositions for treating B-CLL in particular poor prognosis B-CLL.

BACKGROUND OF INVENTION

[0003] B-CLL is the most common form of leukaemia in Denmark, with more than 250 new cases diagnosed every year. The disease results in accumulation of CD19+CD5+CD23+ lymphocytes in the blood, bone marrow and organs of the patients. B-CLL cells are long-lived, slowly dividing and locked in the G.sub.1 phase of the cell cycle. At this time it is unknown how or why B-CLL occurs and no cure is known for B-CLL. The application of more aggressive treatment strategies has been hampered by the inability to identify reproducible and reliable prognostic predictors in patients with poor outcome in this disease. In many patients the diagnosis does not affect morbidity or mortality. Other patients suffer from an incurable cancer that inevitably results in death, regardless of treatment. Until recently this latter group of patients could not be identified at the time of diagnosis. Recently, two studies established the mutational status of immunoglobulin variable region of the heavy chain (Ig V.sub.H) genes in B-CLL as independent prognostic markers, within each clinical stage (Damle, et al. & Hamblin, et al.). Patients without somatic hypermutation show much shorter survival than patients with somatic hypermutation. FISH-studies of cytogenetic aberrations in B-CLL established specific abnormalities on chromosomes 11 (ATM), 12 (?), 13 (Leu-1 and -2) and 17 (p53) as independent prognostic markers, within each clinical stage (Dohner, et al.). Very recent studies have demonstrated that independent risk prediction, using a combined analysis of Ig V.sub.H gene mutational analysis and cytogenetics, can identify subgroups of B-CLL with median survivals ranging from less than 2.5 years to more than 15 years (Krober, et al., Lin, et al., & Oscier, et al.) (see FIG. 1). Since the process of characterising the Ig VH gene mutational status of an individual patient is cumbersome, it is desirable to provide easier tests based on diagnostic markers for use in the differential diagnosis of such cancer patients.

SUMMARY OF INVENTION

[0004] It is an object of preferred embodiments of the present invention to provide differentially expressed transcription products, which can be used as prognostic markers of disease and give information about the differences in etiology between different groups of B-CLL patients. These differentially expressed transcription products are genetic markers that can be used in an easy assay to distinguish between subgroups of B-CLL patients and especially identify B-CLL patients with a poor prognosis.

[0005] This method for diagnosing a subtype of B-cell chronic lymphocytic leukaemia (B-CLL) comprises the steps of determining the presence or absence of at least one expression product such as a transcriptional product which comprise a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 in a biological sample isolated from a individual. As evidenced by the appended examples, the present inventors have determined that the expression products of this invention are present in one subtype of B-CLL having poor prognosis and thus of great diagnostic value and independent prognostic value. Equally important, an expression product comprising a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 has not been found in any of the other tissue types tested (see e.g. FIG. 8).

[0006] The vast majority of patients which show expression of the AMB-1 gene in form of at least one of the expression products selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 show unmutated Ig V(H) genes which is consistent with poor prognosis B-CLL. The presence of an expression product of the AMB-1 gene can be determined easily using standard laboratory procedures and equipment. Therefore the diagnostic method provided by the present inventors provides an easy method of diagnosis as compared to the determination of the mutation status of Ig V(H) genes and can furthermore give additional information about the prognosis.

[0007] Accordingly, a further object of preferred embodiments of the present invention is a method for determining the progress of B-CLL comprising determining the amount of at least one expression product which comprise a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 in a biological sample isolated from an individual. The method may be used e.g. for determining the efficiency of a treatment, i.e. to see whether the amount of the expression product decreases or increases in response to a curative treatment.

[0008] The expression products of the present invention are all transcripts of SEQ ID NO:1 and/or SEQ ID No:5, the gene of the present invention called AMB-1 which also encodes a novel polypeptide (SEQ ID NO:3).

[0009] A further object of preferred embodiments of the present invention is to provide a cure and/or treatment of patients with B-CLL, in particular of patients with poor prognosis B-CLL such as the sub-type of B-CLL which is characterised by the presence of an expression product of the present invention.

[0010] The method for treating B-CLL comprises administering to an individual with a B-CLL diagnosis a compound capable of decreasing or inhibiting the formation of an expression product of SEQ ID NO:1 and/or SEQ ID NO:5. This expression product preferably comprises a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No: 17 and SEQ ID No: 18. The present inventors believe that the presence of at least one of said expression products is an etiological factor in B-CLL and that the disease can be treated or cured by inhibiting the expression of at least one of such products and/or by inhibiting the effect of such product by e.g. rendering it inactive.

[0011] A further preferred object of embodiments of the present invention is to destroy or to eliminate the transcription of at least one expression product comprising at least one nucleotide sequence selected form the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 for the treatment of cancer, such as a poor prognosis sub-type of B-CLL.

[0012] The above destruction or elimination is obtained by applying polynucleotides or oligonucleotides in the form of small interfering RNA molecules (siRNA), antisense molecules or ribozymes.

[0013] In one aspect the invention relates to a gene therapy vector capable of inhibiting or decreasing the formation of an expression product of SEQ ID NO:1 and/or SEQ ID NO:5, said gene therapy vector preferably encoding a specific siRNA molecule, a specific antisense molecule or a specific ribozyme being capable of decreasing or inhibiting the formation of an expression product of SEQ ID NO:1 and/or SEQ ID NO:5. This gene therapy vector can be used for treating B-CLL based on the finding that the AMB-1 gene encoded by SEQ ID No:1 and/or SEQ ID No:5 is an etiological factor in B-CLL.

[0014] Both SEQ ID No 1 which is a 20,000 nucleotide long sequence and SEQ ID No 5 which is a 80,000 nucleotide long sequence provides several transcriptional products in B-CLL cells in patients with poor prognosis B-CLL. Some of the transcriptional products e.g. SEQ ID No 2 and SEQ ID No 4 consists of two exons (SEQ ID No: 15 and SEQ ID No: 16) separated by the same intron. Both mRNA sequences encode an open reading frame (SEQ ID No: 17) encoding a 121 amino acid peptide (SEQ ID No 3).

[0015] Accordingly, yet another object of preferred embodiments of the present invention relates to a novel class of polypeptides. These may be described as a group of isolated polypeptides or proteins comprising or essentially consisting of the amino acid sequence of SEQ ID No. 3, or a fragment thereof, or a polypeptide functionally equivalent to SEQ ID No. 3, or a fragment thereof, wherein said fragment or functionally equivalent polypeptide has at least 60% sequence identity with the polypeptide of SEQ ID No 3. The polypeptides of the present invention may have interleukin or cytokine activity.

[0016] In a still further aspect the invention relates to an isolated polynucleotide selected from the group consisting of: [0017] i) a polynucleotide comprising nucleotides of SEQ ID No 5, [0018] ii) a polynucleotide encoding a polypeptide having the amino acid sequence of SEQ ID No 3, [0019] iii) a polynucleotide, the complementary strand of which hybridises, under stringent conditions, with a polynucleotide as defined in any of i) and ii). [0020] iv) a polynucleotide which is degenerate to the polynucleotide of iii), and [0021] v) the complementary strand of any such polynucleotide.

[0022] The polypeptides encoded by the polynucleotides may furthermore [0023] a) have at least 60% sequence identity with the amino acid sequence of SEQ ID No 3 and have interleukin or cytokine activity, [0024] b) be recognised by an antibody, or a binding fragment thereof, which is capable of recognising an epitope, wherein said epitope is comprised within a polypeptide having the amino acid sequence of SEQ ID No 3; and/or [0025] c) be competing with a polypeptide having the amino acid sequence as shown in SEQ ID No 3 for binding to at least one predetermined binding partner such as a cytokine receptor.

[0026] One further therapeutic application of the present invention is a method of vaccination against B-CLL said method comprising immunising an individual against a translational product of SEQ ID No:1 and/or SEQ ID No:5. By stimulating the immune system of an individual to produce antibodies against the translational product the individual can become immune towards B-CLL and/or the method can be used as part of therapy. The state of the art describes various ways of immunising an individual against a particular protein.

[0027] Finally, the invention provides a method for determining an increased or decreased predisposition for B-CLL comprising determining in a biological sample from an individual a germline alteration in a target nucleic acid sequence comprising 150,000 nucleotides, said target nucleic acid sequence comprising at least 10 nucleotides of SEQ ID No:1 and/or SEQ ID No:5. This aspect is based on the finding of the importance of the expression product of SEQ ID No:1 and/or SEQ ID No:5, and the absence of any detectable expression product of SEQ ID No:1 and/or SEQ ID No:5 in healthy tissue and in patients with good prognosis B-CLL. It is highly likely that the difference is caused by a germline alteration. A germline alteration can be targeted by gene therapy methods and by the methods provided in the present invention.

DESCRIPTION OF DRAWINGS

[0028] FIG. 1: Overall survival of B-CLL patients by genotype (all stages) The prognostic significance of V.sub.H homology and cytogenetic aberrations is independent of clinical stage (from Krober et al., 2002 (4)).

[0029] FIG. 2 (a-d): Survival curves for survival or time to progression based on AMB-1 expression or IgV.sub.H mutational status respectively. Patients are newly diagnosed, untreated B-CLL patients (n=34).

[0030] FIG. 3: Northern blotting demonstrating the expression level of AMB-1 in various tissue samples using as a probe an 875 base pair fragment of Exon 3/Seq ID No: 16. UPN 1, 4 and 7 are unmutated B-CLL patients, UPN 19, 9, 10, 13 and 21 are mutated B-CLL patients. Included are RNA samples from normal Colon, Spleen, Bone Marrow and PBL (peripheral blood lymphocytes) and RNA from the Ramos and Granta cell lines. Equal loading of lanes was confirmed by re-probing with an actin probe (results not shown).

[0031] FIG. 4. Alignment of AMB1 with IL4 based on structural similarity. IL4 is called d1iara in the alignment. The additional lines indicate the structural similarity.

[0032] FIG. 5. A 3D search, where the peptide sequence has been searched for similarity to known protein or peptide 3D-structures.

[0033] FIG. 6. Predicted 3-D structure of AMB-1 compared to the known 3-D structure of human IL4. Prediction is performed using SEQ ID No:3 and the method described in: Enhanced Genome Annotation using Structural Profiles in the Program 3D-PSSM. Kelley L A, MacCallum R M & Sternberg M J E (2000). J. Mol. Biol. 299(2), 499-520.

[0034] FIG. 7. Alignment of the AMB1 peptide sequence with the sequences of IL4, IL3, IL13 and GM-CSF, based on their structures.

[0035] FIG. 8. A table showing the tissue types on the MTE array used for dot blotting of AMB-1 to check for expression in other tissue types.

[0036] FIG. 9. Schematic representation of the transcriptional products of the present invention compared to the genomic AMB1 sequence (1 & 5). 2 is mRNA short form (SEQ ID No 2). 4 is mRNA long form (SEQ ID No 4). 6 (SEQ ID No:6), 7 (SEQ ID No:7), 8 (SEQ ID No:8), 9 (SEQ ID No:9), 10 (SEQ ID No:10) and 11 (SEQ ID No:11) are alternative transcription products all comprising at least one nucleotide sequence selected form the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No: 15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18.

[0037] FIG. 10. RT-PCR demonstrating the expression of AMB-1 in B-CLL patients by RT-PCR. UPN1-UPN8 are unmutated patients, UPN9-UPN16 are mutated patients.

DETAILED DESCRIPTION OF THE INVENTION

[0038] The present invention in particular relates to polynucleotide sequences found to be indicative of a poor prognosis of B-CLL and new methods and compositions for treating B-CLL in particular poor prognosis of B-CLL. An overview of the sequences disclosed by the present invention is present here:

[0039] SEQ ID No:1 includes 20.000 bp human genome sequence, derived from BAC clone acc. no. AC063949. It includes the region encoding the mRNAs corresponding to the cDNAs described in Seq ID Nos:2, 4, 6, 7, 8, 9, 10, and 11 and possible up- and down-stream regulatory sequences. Seq ID No: 1 includes a subset of the sequence described in Seq ID No:5. The sequence is derived from human 12q21-22.

[0040] SEQ ID No:2 includes a cDNA corresponding to a putative mRNA transcript that includes the region encoding the peptide sequence in Seq ID No:3 and up- and downstream regions. It is transcribed from the +strand of Seq ID No:1 and Seq ID No:5 from human 12q21-22. From position 2317, this sequence is identical to Seq ID No:4.

[0041] Seq ID No:3 contains a peptide sequence encoded by some mRNAs transcribed from the region on human chromosome 12q21-22 included in Seq ID No:1 and Seq ID No:5. It is encoded by the mRNA sequences identified as cDNAs in Seq ID Nos 02, 04, 09 and 11.

[0042] Seq ID No:4 includes a cDNA corresponding to a putative mRNA transcript that includes the region encoding the peptide sequence in Seq ID No:3 and up- and downstream regions. It is transcribed from the +strand of Seq ID No:1 and Seq ID No:5 from human 12q21-22.

[0043] Seq ID No:5 includes 80.000 bp human genome sequence, derived from BAC clone acc. no. AC063949. It is an expansion of the genomic sequence included in Seq ID No: 1. which is contained within this sequence. It includes the region encoding the mRNAs corresponding to the cDNAs described in Seq ID Nos 02, 04, 06, 07, 08, 09, 10 and 11 and possible up- and down-stream regulatory sequences. The sequence is derived from human 12q21-22.

[0044] Seq ID No:6 corresponds to a cDNA detected by cDNA cloning, corresponding to an mRNA transcript. It includes two exons. It is transcribed from the +strand of Seq ID No:1 and Seq ID No:5 from human 12q21-22.

[0045] Seq ID No:7 corresponds to a cDNA detected by cDNA cloning, corresponding to an mRNA transcript. It includes three exons, the first and third are identical to the two exons in Seq ID No:6. It is transcribed from the +strand of Seq ID No:1 and Seq ID No:5.doc from human 12q21-22.

[0046] Seq ID No:8 corresponds to a cDNA detected by cDNA cloning, corresponding to an mRNA transcript. It includes two exons, the last is also present as exon-2 in a human cDNA clone (sequence acc. no. BC036936) (Seq ID No:9.doc). It is transcribed from the +strand of Seq ID No:5.doc from human 12q21-22.

[0047] Seq ID No:9 corresponds to a human cDNA sequence (sequence acc. no. BC036936). It is transcribed from the +strand Seq ID No:5 from 12q21-22. We have not cDNA cloned this cDNA, but a splice variant (Seq ID No:8), where exon-2 of this sequence was spliced to exon-1 of Seq ID No:6 was detected by cDNA cloning. It is transcribed from the +strand of Seq ID No:5 from human 12q21-22.

[0048] Seq ID No:10 corresponds to a cDNA detected partly by cDNA cloning, partly by PCR analysis, corresponding to an mRNA transcript. It includes two exons, exon-1 includes the region encoding Seq ID No:3 and exon-1 from Seq ID No:6; exon-2 is identical to exon-2 in Seq ID No:6 and exon-3 in Seq ID No:7. It is transcribed from the +strand of Seq ID No:1.doc and Seq ID No:5 from human 12q21-22.

[0049] Seq ID No:11 corresponds to a cDNA detected by cDNA cloning, corresponding to an mRNA transcript. It includes one exon. The sequence includes the region that encodes Seq ID No:3, exons 2 and 3 from Seq ID No:7 and the region between those exons. It is transcribed from the +strand of Seq ID No:1 and Seq ID No:5 from human 12q21-22.

[0050] Seq ID No:12 Is an exon sequence. It corresponds to the first exon in Seq ID No: 9 It is transcribed from the +strand of Seq ID No:5 from human 12q2-22.

[0051] Seq ID No:13 Is an exon sequence. It corresponds to the first exon in Seq ID No: 6, 7, 8, and it is included in Seq ID No: 2. It is transcribed from the +strand of Seq ID No: 1 and 5 from human 12q21-22.

[0052] Seq ID No:14 Is an exon sequence. It is identical to Seq ID No: 13, but with an additional GT dinucleotide at the 3'end, caused by the use of an alternative splice site. It can replace Seq ID No: 13 as the first exon in Seq ID No: 6, 7, 8, and be included in Seq ID No: 2. It is transcribed from the +strand of Seq ID No:1 and 5 from human 12q21-22.

[0053] Seq ID No:15 Is an exon sequence. It corresponds to the second exon in Seq ID No:7 and it is included in Seq ID No: 2, 4, 10 and 11. It is transcribed from the +strand of Seq ID No:1 and 5 from human 12q21-22.

[0054] Seq ID No:16 Is an exon sequence. It corresponds to the third exon in Seq ID No:7, it is the second exon in Seq ID No:6 and 11 and it is included in Seq ID No:2 and 4. It is transcribed from the +strand of Seq ID No:5 from human 12q21-22.

[0055] Seq ID No:17 Is the sequence encoding the peptide in Seq ID No: 3. It is included in Seq ID No:2, 4, 10 and 11. It is transcribed from the +strand of Seq ID No:5 from human 12q21-22.

[0056] Seq ID No:18 Is an exon sequence. It corresponds to the second exon in Seq ID No:8 and 9. It is transcribed from the +strand of Seq ID No:5 from human 12q21-22.

Methods of Diagnosis

[0057] One important aspect of the present invention relates to diagnosis of a subtype of B-cell chronic lymphocytic leukaemia (B-CLL) having poor prognosis. A further important aspect of the invention relates to prognosis of B-CLL. These methods are based on the discovery by the present inventors that an expression product which comprise at least one nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 is (are) only present in particular subtypes of B-CLL associated with poor prognosis and completely absent in other subtypes of B-CLL and in healthy tissue (see in particular example 2). By completely absent is meant that the expression products are not detected in any of the other tissue types with the methods used in the appended examples. This is indicative of a complete absence of any transcript or a very low level of transcript in the other tissue types.

[0058] The expression product is encoded by SEQ ID No 1 and/or SEQ ID No 5, and the expression product is selected from the group consisting of transcriptional products and translational products.

[0059] Thus, the present invention relates to a method for detecting the presence or absence of at least one expression product, wherein the at least one expression product comprise a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No: 13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 in a biological sample isolated from an individual for establishing a differential diagnosis of B-CLL or for determining the prognosis of the B-CLL.

[0060] "Expression product" is herein meant to be a product which is the result of the expression of a polynucleotide such as DNA sequence, e.g. a genomic DNA sequence, and is in the form of either a polypeptide or in the form of a polynucleotide, i.e. an expression product can be selected from the group consisting of a transcriptional product and a translational product. In the case where the expression product is a polynucleotide, said polynucleotide is preferably mRNA selected from the group consisting of mRNA, pre-mRNA, pre-pro-mRNA.

[0061] A "transcriptional product" or a "transcription product" is herein meant to be a product resulting from a transcription of a polynucleotide such as a DNA molecule, preferably a genomic DNA molecule. A transcriptional product is inherently a nucleotide, such as an oligonucleotide or a polynucleotide.

[0062] A "translational product" or a "translation product" is herein meant to be a product resulting from a translation of a transcriptional product such as a mRNA. A translational product is inherently a oligopeptide or a polypeptide.

[0063] The expression product of the present invention has almost exclusively been found as transcription products in patients with poor B-CLL prognosis. Based on the experimental data presented in the herein, the inventors expect that it turns out that the subtype of B-CLL is characterised solely or better by the presence of a transcriptional or translational product which comprise a sequence selected from the group consisting of SEQ ID No:3, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18.

[0064] Preferably the individual is a mammal, more preferably a human. It is also expected that the gene encoded by SEQ ID No 1 and/or SEQ ID No 5 and the expression products derived from said gene can be used as a diagnostic tool in other species in particular in mammals selected from the group: domestic animals such as cow, horse, sheep, pig; and pets such as cat or dog.

[0065] In the case that the expression product is a transcriptional product, this transcriptional product just needs to comprise at least one of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18. These transcriptional products will preferably be derived from SEQ ID No 1 and/or SEQ ID No 5 and may be in the form of mRNA or any pre- or pro-forms of said mRNA. As described, the transcriptional product may comprise at least one of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18, such as one of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18, such as two of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18, such as 3 of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18, e.g. 4 of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18, such as 5 of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 and ultimately the transcriptional product may comprise all of the six nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18. The transcriptional product of the present invention can have any sequence which is a result of combining the nucleotide sequences selected from the group consisting of SEQ ID No: 12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 as long as the specific nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 can be identified as intact sequences in the transcriptional product.

[0066] Examples of transcriptional products in the form of specific mRNAs which comprise at least one of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 are the sequences corresponding to SEQ ID No 2 (short cDNA clone) SEQ ID No 4 (long cDNA clone) SEQ ID No 6, SEQ ID No 7, SEQ ID No 8, SEQ ID No 9, SEQ ID No 10 and SEQ ID No 11. These mRNA sequences have been found in patients with poor prognosis.

[0067] It is obvious for a person skilled in the art that any fragments of SEQ ID No:2, SEQ ID No:4, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10 and SEQ ID No:11 will have the same diagnostic value as long as the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 can be found in the fragments.

[0068] The mRNA sequence may be detected in a sample using hybridisation techniques. In particular when more than one analysis is to be performed at the same time it is advantageous to use a DNA array comprising e.g. an oligomer of at least 15 consecutive bases selected from the group consisting of SEQ ID No:2, SEQ ID No:4, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18.

[0069] Another way of detecting the presence or absence of the transcriptional product is by specifically amplifying the transcriptionals product having a sequence corresponding to SEQ ID No 2, 4, 6, 7, 8, 9, 10 or 11 or fragments thereof. This can be done by selecting primer pairs which cause only the amplification of these sequences.

[0070] Generally, hybridisation techniques are selected from not limited to the group consisting of in situ hybridisation, northern blots, Southern blots, dot blots and PCR based techniques.

[0071] A non-limiting list of PCR based techniques include rt-PCR, quantitative PCR and realtime PCR.

[0072] According to yet another embodiment, the translational product is a protein encoded by a polynucleotide selected from the group consisting of SEQ ID No:1, SEQ ID No:5, SEQ ID No:2, SEQ ID No:4, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10 and SEQ ID No:11. Detection of this protein can be done with state of the art methods including the detection with an antibody directed against said protein, such as Western blotting, more preferably by using a fluorescently labelled antibody, preferably wherein the method comprises the use of flowcytometry, such as FACS. Other methods include but are not limited to gel electrophoresis, gel filtration, ion exchange chromatography, FPLC, mass spectrometry and immunohistochemistry.

[0073] Preferably, said protein is selected from the group comprising SEQ ID No 3 (protein), or a protein sharing at least 60% sequence identity with SEQ ID No 3. The protein with the amino acid sequence set forth in SEQ ID No 3 is the longest open reading frame in the cDNA sequence of SEQ ID No 2 or 4.

[0074] In a specific embodiment of the present invention is a method for determining whether an individual has a B-CLL sub-type with poor prognosis, the method comprising determining the level of an expression product which comprise a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 of said individual, and indicating the individual as having a B-CLL sub-type with poor prognosis if the level of the expression product is at or beyond a discriminating value and indicating the individual as not having a B-CLL sub-type with poor prognosis if the level of the expression product is not at or beyond the discriminating value, the discriminating value being a value which has been determined by measuring the level of the expression product which comprise a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 in both a healthy control population and a population with known B-CLL sub-type with poor prognosis, thereby determining said discriminating value which identifies the B-CLL sub-type population having a poor prognosis.

[0075] In this method the individual may be a member of an unselected population or be a member of a population already identified as having a B-CLL sub-type with a poor prognosis.

[0076] The above method may be performed such that the determination is performed at several time points at intervals as part of a monitoring of a cancer patient after or during the treatment for primary cancer.

[0077] The methods described so-far relate to the determination of the presence or absence of an expression product which comprise a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18. By quantitatively measuring the amount of an expression product which comprise a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 in a biological sample isolated from an individual, it is possible to predict the progression of B-CLL in an individual.

[0078] In one embodiment the quantitative measurement is performed during treatment to estimate the efficiency of such treatment.

[0079] A preferred embodiment of the above diagnostic and prognostic methods is a method for detecting the presence or absence an expression product, wherein said at least one expression product comprise the nucleotide sequence of SEQ ID No:15 in a biological sample isolated from an individual for establishing a differential diagnosis of B-CLL or for determining the prognosis of the B-CLL.

[0080] A further preferred embodiment of the above diagnostic and prognostic methods is a method for detecting the presence or absence an expression product, wherein said at least one expression product comprise the nucleotide sequence of SEQ ID No:16 in a biological sample isolated from an individual for establishing a differential diagnosis of B-CLL or for determining the prognosis of the B-CLL.

[0081] Yet a further preferred embodiment of the above diagnostic and prognostic methods is a method for detecting the presence or absence an expression product, wherein said at least one expression product comprise the nucleotide sequence spanning the junction sequence between Exon-2 (SEQ ID No:15) and Exon-3 (SEQ ID No:16) in a biological sample isolated from an individual for establishing a differential diagnosis of B-CLL or for determining the prognosis of the B-CLL.

[0082] The nucleotide sequence spanning the junction between Exon-2 and Exon-3 is the last 20 nucleotides of the 3'-end of SEQ ID No: 15 and the first 20 nucleotides of the 5'-end of SEQ ID No:16.

[0083] The "junction sequence" between two nucleotide sequences, such as two exons, is herein defined as the at least 20 3'-nucleotides of the first exon which is located 5' relative to the second exon and the at least 20 5'-nucleotides of the second exon which is located 3' relative to the first exon.

[0084] For all diagnostic applications of the present invention, the biological sample may be selected from the group comprising blood, serum, plasma, urine, saliva, lymph node biopsy, bone marrow, spinal liquid, spleen biopsy, and liver biopsy. The cells to be assessed in a sample are preferably leukocytes, mononuclear leukocytes or lymphocytes or B-lymphocytes.

[0085] A further embodiment of the present invention also includes a diagnostic kit for ex vivo or in situ diagnosis of a subtype of B-cell chronic lymphocytic leukaemia (B-CLL) in a individual, the kit comprising a detector molecule capable of detecting the presence or absence of at least one expression product, wherein said at least one expression product comprise a nucleotide sequence selected from the group consisting of SEQ ID SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 in a biological sample isolated from the individual.

[0086] The detector molecule is preferably a nucleotide and even more preferably a nucleotide capable of hybridising to a nucleotide sequence selected from the group consisting of SEQ ID SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 under stringent condition.

B-CLL Therapy

[0087] With the identification of a new sub-type of B-CLL having a poor prognosis, the present inventors also provide methods for treatment of B-CLL in such patients. This method is based on the finding that transcription products comprising these sequence products are present in B-CLL cells of patients with the poor prognosis. By modifying the activity and/or level of these transcription products, a treatment and/or cure for B-CLL is provided.

[0088] Accordingly, in a therapeutic aspect of the present invention there is provided a method of treating a B-CLL sub-type with poor prognosis comprising administering to an individual with a poor prognosis B-CLL diagnosis a compound capable of decreasing or inhibiting the formation of an expression product which comprise a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18.

[0089] One such method is based on administering an oligonucleotide capable of inhibiting transcription from SEQ ID No 1 and/or SEQ ID No 5. Said oligonucleotide may comprises at least 8-10 consecutive nucleotides from the sequence of SEQ ID No 1. These sequences constitute the putative promoter sequences controlling the transcription products which comprise a nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18. The oligonucleotides bind specifically to the promoter sequences and inhibit transcription of the gene. Such oligonucleotides may comprises nucleotide monomers selected from the group: DNA, RNA, LNA, PNA, methylated DNA, methylated RNA, more preferably PNA or LNA.

[0090] In a more preferred embodiment the therapeutic methods comprise administering an oligonucleotide capable of binding to a transcriptional product and preventing translation by destroying the transcriptional product. One particularly preferred embodiment of this aspect is RNA interference (RNAi) oligonucleotides.

[0091] The discovery of the phenomenon RNAi has revealed an entirely new level of gene regulation in eukaryotic cells. It is based on the observation that the presence of long double stranded RNA (dsRNA) in a cell almost completely eliminates the expression of the gene having the same sequence, whereas expression of other unrelated genes are left undisturbed. Although this observation had been know for time in plants as posttranscriptional gene silencing (PTGS) it was not before it was characterised as a general mechanism throughout the animal kingdom that its potentials were fully appreciated. Over the last few years it has been developed as a robust technique to knock down any desirable gene in worms and flies, and quickly a large body of information was gathered about the function of genes in these organisms. Due to the activation of the interferon system by long dsRNA the RNAi method was at that time not applicable in a mammalian system.

[0092] A key observation that allowed the harnessing of RNAi as a tool for regulating gene expression in mammals was the observation that chemically synthesised oligo-mer small interfering RNAs (siRNA) effectively suppress gene expression in several human cell lines without inflecting interferon response. This has triggered new promises for siRNA as a therapeutic drug in humans.

[0093] RNAi works by hybridising specifically to the mRNA transcribed by the cell to form a (partly) double stranded RNA molecule. This is recognised as a double stranded molecule by the cell's own nucleases, which degrade them.

[0094] In order for the technique to work efficiently, the siRNA oligonucleotide comprises a sequence of 5-30 consecutive nucleotides which is the complementary sequence of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18. By targeting at least one of the nucleotide sequences selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No: 15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18, the transcriptional products characterised by the nucleotide sequences from the group of SEQ ID No:2, SEQ ID No:4, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10 and SEQ ID No:11 will be eliminated. Example 5 shows that cells characteristic for the poor prognosis B-CLL sub-type can be eliminated by destroying the herein mentioned transcription products.

[0095] By "complementarity" is meant a nucleic acid that can form hydrogen bond(s) with other DNA or RNA sequence by either traditional Watson-Crick or other non-traditional types of base-paired interactions, e.g. Hoogsteen type.

[0096] Preferred siRNA molecules of the present invention are between 5 to 30 nucleotides long, such as 8-30 nucleotides long, such as 8-25 nucleotides, e.g. 8-24 nucleotides, e.g. 8-23 nucleotides, e.g. 8-22 nucleotides, e.g. 8-21 nucleotides, such as 8-20 nucleotides, e.g. 9-23 nucleotides, e.g. 10-23 nucleotides, such as 11-23 nucleotides, e.g. 12-23 nucleotides such as 13-23 nucleotides, e.g. 14-23 nucleotides, e.g. 15-23 nucleotides, such as 16-23 nucleotides, such as 8 nucleotides, 9 nucleotides, 10 nucleotides, 11 nucleotides, 12 nucleotides, 13 nucleotides, 14 nucleotides, 15 nucleotides, 16 nucleotides, 17 nucleotides, 18 nucleotides, 19 nucleotides, 20 nucleotides, 21 nucleotides, 22 nucleotides, 23 nucleotides, 24 nucleotides, 25 nucleotides, 26 nucleotides, 27 nucleotides, 28 nucleotides, 29 nucleotides, such as 30 nucleotides long.

[0097] RNAi oligonucleotides may be administered to the cell, or a vector may be transfected into the cells, said vector comprising a promoter region capable of directing the expression of at least one RNAi oligonucleotide. Due to the very restricted expression of the AMB-1 gene, it is not important only to target the RNAi oligos or the vectors to B-CLL cells.

[0098] One way of targeting to blood cells comprises using a heparin receptor for targeting to blood cells.

[0099] Another way of targeting the transcriptional products which comprise at least one nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18 is to use an antisense construct comprising a promoter sequence capable of directing the transcription of at least part of the antisense equivalent of SEQ ID No 1 or 2 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 specifically to the poor prognosis B-CLL sub-type.

[0100] When desired targeting to B-CLL cells can be performed using the CD19 or CD20 receptor. The CD19 receptor is particularly preferred since it internalises its ligand.

[0101] In a further therapeutic embodiment the compound is a gene therapy vector comprising a promoter sequence operably linked to a sequence coding for a protein capable of inhibiting cell division in the cell and/or capable of killing the cell, said promoter sequence being a tissue specific promoter capable of directing expression only in B cells, more preferably only in B-CLL cells. One particularly preferred promoter sequence is the extremely cell specific promoter of SEQ ID No:1 or SEQ ID No:5. When this promoter is used targeting of the suicide vector is not very important, since it will only be active in the cells in which AMB-1 is expressed and these are the cells to be targeted by the suicide gene.

[0102] Deletion studies will determine the exact length of the promoter sequence counted from the transcription start site. Accordingly, the promoter may comprise at least 100 nucleotides of Seq_ID:1 or Seq_ID:5, such as at least 200 nucleotides, for example at least 300 nucleotides, such as at least 400 nucleotides, for example at least 500 nucleotides, such as at least 600 nucleotides, for example at least 700 nucleotides, such as at least 800 nucleotides, for example at least 900 nucleotides, such as at least 1000 nucleotides, for example at least 1100 nucleotides, such as at least 1200 nucleotides, for example at least 1300 nucleotides, such as at least 1400 nucleotides, for example at least 1500 nucleotides, such as at least 1600 nucleotides, for example at least 1700 nucleotides, such as at least 1800 nucleotides, for example at least 1900 nucleotides, such as at least 2000 nucleotides, for example at least 2500 nucleotides, such as at least 3000 nucleotides, for example at least 3500 nucleotides, such as at least 5000 nucleotides, for example at least 10,000 nucleotides.

[0103] The specificity of expression of mRNAs described by the present invention are striking. The RT-PCR data and the Northern blot data using the dot-blot disclose that the mRNAs of the present invention are expressed either at very low levels in other tissues or only in the B-CLL patients where one can detect it.

[0104] Thus one embodiment of the present invention is the use of the promotor region for use in gene therapy. The promotor is defined as any sequence within SEQ ID No:1 and SEQ ID No:5 that directs the formation of an expression product which comprise a nucleotide sequence selected from the group consisting of SEQ ID No: 12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18, said expression product being any of the sequences selected from the group consisting of SEQ ID No:2, SEQ ID No:4, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10 and SEQ ID No:11 in B-CLL cells or any other cell or tissue types in which any of the sequences are transcribed.

[0105] One way that one can use the promotor region in gene therapy is to make a gene therapy construct where the promotor drives the expression of a cell suicide gene such as but not limited to the gene for HSV-1 thymidine kinase, the varicella-zoster, virus thymidine kinase gene, E. Coli cytosine deaminase, the nitroreductase gene or the E. Coli Deo gene (Yazawa et al. & Kirn D. et al.). This would allow for selective expression of the suicide genes in B-CLL cells.

[0106] Alternatively, the promotor could be used for a selective expression of genes that could have curative effects when expressed in B-CLL cells, but unwanted effects if expressed ubiquitously.

[0107] Also, one embodiment of the present invention relates to the use of the promotor region for use in screening assays where the promotor is linked to a reporter gene and transfected into B-CLL cells in which the reporter gene will be expressed. This approach would allow for easy screening for compounds that would turn off the expression of the reporter gene for example by killing the cell.

[0108] A presently preferred embodiment relates a gene therapy vector of the present invention comprising an oligonucleotide capable of inhibiting transcription from SEQ ID No 1 and/or SEQ ID No 5, wherein the promoter is a B-CLL specific promoter, which may or may not be operably linked to a protein selected from the group comprising HSV-1 thymidine kinase, the varicella-zoster, virus thymidine kinase gene, E. Coli cytosine deaminase, the nitroreductase gene or the E. Coli Deo gene.

[0109] In one embodiment the compound is a therapeutic antibody directed against a polypeptide having the amino acid sequence of SEQ ID No 3, preferably wherein said antibody is a human or humanised antibody. Another possibility is to identify a modulator of binding of SEQ ID No 3 to its receptor within or outside the cell and to administer this modulator to the cells.

4-Helical Cytokines

[0110] A further object of preferred embodiments of the present invention is an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: [0111] i) an amino acid sequence of SEQ ID NO: 3, [0112] ii) an amino acid sequence having at least 60% sequence identity compared to the full length sequence of SEQ ID NO:3 [0113] ii) a fragment of SEQ ID NO:3 having at least 60% sequence identity compared to the full length sequence of SEQ ID NO:3.

[0114] The protein encoded by SEQ ID No 1 and/or SEQ ID No 5 shares a very small sequence identity with any known protein. However, it has been possible to use 2D and 3D analytical tools to Identify the protein as a 4-helical cytokine. The 3D structure of the protein is very similar to 4-helical cytokines and in particular to IL4.

[0115] IL4 is a very important cytokine in B-CLL biology. IL4 is not expressed by B-CLL cells, but the IL4 receptor is found on the cells. The IL4 that stimulates B-CLL cells is believed to be produced by T-lymphocytes. The role of IL4 in B-CLL biology is complicated. It has been suggested that IL4 can inhibit B-CLL DNA synthesis and proliferation. Other reports demonstrated that IL4 protects B-CLL cells from apoptosis by upregulating Bcl-2, and IL4 was shown to inhibit apoptosis without stimulating proliferation. Recently, a clinical study in Sweden has confirmed these in vitro studies since IL4 administration to B-CLL patients resulted in increased numbers of B-CLL cells in the blood, suggesting that IL4 had a stimulatory or anti-apoptotic effect on the B-CLL cells in vivo (Lundin, et al.).

[0116] In many systems the effects of IL13 are largely similar to those of IL4, but IL13 is slightly less potent that IL4. It is unclear whether B-CLL cells express IL13, but the cells do express the IL13 receptor. The effects of IL13 in B-CLL are controversial. While Chaouchi et al. suggested that IL13, like IL4 protects B-CLL cells from apoptosis (Chaouchi et al), studies by Fluckiger et al. suggest that this is not the case (Fluckiger et al.).

[0117] The combined finding of 2D and 3D structure similarity to 4-helical cytokines and the importance of IL4 in B-CLL strongly suggests that the novel class of proteins of which the AMB-1 protein is one representative are cytokines.

[0118] These polypeptides constitute a novel class of proteins sharing 2D and 3D structure similarities with 4-helical cytokines. In a preferred embodiment, the isolated polypeptide comprises or essentially consists of the amino acid sequence of SEQ ID No. 3 or a fragment thereof. This particular protein at least can be used for diagnosis, for raising antibodies for use in therapy against B-CLL, and for protective or therapeutic immunisation of an individual against B-CLL.

[0119] Consequently, the isolated polypeptide preferably has interleukin activity or interleukin like activity, such as having IL3, IL13, GM-CSF, TGF-.beta., IGF activity, more preferably having IL4 activity or IL4 like activity.

[0120] Probably the isolated polypeptides are capable of forming homo- or hetero-oligomer with each other and among themselves. Such oligomers are also within the scope of the present invention. Such oligomers may comprise at least one isolated polypeptides as defined in any the present invention, such as a dimer, a trimer, a quatramer, a quintamer, a hexamer, an octamer, a decamer, a dodecamer. In biological systems the activity may be attributed only to dimer or higher-mer.

[0121] The protein defined by SEQ ID No 3 shares very little sequence identity with known cytokines and interleukines and as a matter of fact very little sequence identity with any known protein. Consequently the present inventors contemplates that the group comprises functionally equivalent polypeptide sharing at least 60% sequence identity with SEQ ID No 3, more preferably at least 70% sequence identity, more preferably at least 80% sequence identity, such as at least 90% sequence identity, for example at least 95% sequence identity, such as at least 97% sequence identity, for example at least 98% sequence identity.

[0122] Activity as a cytokine or interleukin can be assessed in a biological assay where the polypeptide is contacted with a cytokine dependent cell line. Accordingly, polypeptides with cytokine or interleukin like activity can also be identified by similar methods.

[0123] One approach to assess cytokine/interleukin activity in a biological assay is to express the CDS (SEQ ID No:17) reading frame in a baculovirus system (Invitrogen, Carlsbad, USA) and purify the protein. The recombinant protein can be assayed in cytokine induced proliferation assays as described in general in the eBioscience catalog & Reference Manual 2002 p. 260-262 (eBioscience, San Diego, USA). In particular IL4 activity can be determined using the CTh4S cell line as described by Petersen et al (see Example 8).

[0124] The promoter sequence (which forms part of SEQ ID No 1 and/or SEQ ID No 5) and the coding sequences (SEQ ID No:3) can be used in various aspects of gene therapy and immunotherapy.

[0125] Further polynucleotide sequences from other individuals or other species with the same function can be isolated by one of the following methods, which each form independent aspects of the present invention.

[0126] A first method for identifying a nucleotide sequence encoding a 4-helical cytokine comprises the steps of:

i) isolating mRNA from a biological sample, ii) hybridising the mRNA to a probe comprising at least 10 nucleotides of the coding sequence of SEQ ID No 1 and/or SEQ ID No 5 under stringent conditions, iii) determining the nucleotide sequence of a sequence capable of hybridising under step ii), and iv) determining the presence of an open reading frame in the nucleotide sequence determined under step iii).

[0127] A second method for identifying a nucleotide sequence encoding a 4-helical cytokine is a computer assisted method comprising the steps of

i) performing a sequence similarity search of at least 10 nucleotides of the coding sequence SEQ ID No 1 and/or SEQ ID No 5, ii) aligning "hits" to said coding sequence, iii) determining the presence of an open reading frame in the "hits".

[0128] It is highly likely that other similar polypeptides encoding further 4-helical cytokines can be found in other individuals and/or other species of mammals. In particular, individuals of other geographical origin may carry genes which differ from the polynucleotides of the present invention. It is also conceivable that similar sequences can be found in closely and even in distantly related species.

Functional Equivalents

[0129] Modification and changes may be made in the structure of the peptides of the present invention and DNA segments which encode them and still obtain a functional molecule that encodes a protein or peptide with desirable characteristics. The following is a discussion based upon changing the amino acids of a protein to create an equivalent, or even an improved, second-generation molecule. The amino acid changes may be achieved by changing the codons of the DNA sequence, according to the genetic code.

[0130] For example, certain amino acids may be substituted for other amino acids in a protein structure without appreciable loss of interactive binding capacity with structures such as, for example, antigen-binding regions of antibodies, binding sites of receptors, or binding sites on substrate molecules. Since it is the interactive capacity and nature of a protein that defines that protein's biological functional activity, certain amino acid sequence substitutions can be made in a protein sequence, and, of course, its underlying DNA coding sequence, and nevertheless obtain a protein with like properties. It is thus contemplated by the inventors that various changes may be made in the peptide sequences of the disclosed compositions, or corresponding DNA sequences which encode said peptides without appreciable loss of their biological utility or activity.

[0131] In making such changes, the hydropathic index of amino acids may be considered. The importance of the hydropathic amino acid index in conferring interactive biologic function on a protein is generally understood in the art (Kyte and Doolittle, 1982, incorporate herein by reference). It is accepted that the relative hydropathic character of the amino acid contributes to the secondary structure of the resultant protein, which in turn defines the interaction of the protein with other molecules, for example, enzymes, substrates, receptors, DNA, antibodies, antigens, and the like. Each amino acid has been assigned a hydropathic index on the basis of their hydrophobicity and charge characteristics (Kyte and Doolittle, 1982), these are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

[0132] It is known in the art that certain amino acids may be substituted by other amino acids having a similar hydropathic index or score and still result in a protein with similar biological activity, ie. still obtain a biological functionally equivalent protein. In making such changes, the substitution of amino acids whose hydropathic indices are within .+-.2 is preferred, those which are within .+-.1 are particularly preferred, and those within .+-.0.5 are even more particularly preferred. It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity. U.S. Pat. No. 4,554,101, incorporated herein by reference, states that the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with a biological property of the protein.

[0133] As detailed in U.S. Pat. No. 4,554,101, the following hydrophilicity values have been assigned to amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0.+-.1); glutamate (+3.0.+-.1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5.+-.1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5); tryptophan (-3.4). It is understood that an amino acid can be substituted for another having a similar hydrophilicity value and still obtain a biologically equivalent, and in particular, an immunologically equivalent protein. In such changes, the substitution of amino acids whose hydrophilicity values are within .+-.2 is preferred, those which are within .+-.1 are particularly preferred, and those within .+-.0.5 are even more particularly preferred.

[0134] As outlined above, amino acid substitutions are generally therefore based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions which take various of the foregoing characteristics into consideration are well known to those of skill in the art and include: arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine and isoleucine.

[0135] Functional equivalents and variants are used interchangably herein. In one preferred embodiment of the invention there is also provided variants of a 4-helical cytokine, and variants of fragments thereof. When being polypeptides, variants are determined on the basis of their degree of identity or their homology with a predetermined amino acid sequence, said predetermined amino acid sequence being SEQ ID No. 3 or a fragment thereof.

[0136] Accordingly, variants preferably have at least 60% sequence identity, for example at least 65% sequence identity, such as at least 70% sequence identity, for example at least 75% sequence identity, for example at least 80% sequence identity, such as at least 85% sequence identity, for example at least 90% sequence identity, such as at least 91% sequence identity, for example at least 91% sequence identity, such as at least 92% sequence identity, for example at least 93% sequence identity, such as at least 94% sequence identity, for example at least 95% sequence identity, such as at least 96% sequence identity, for example at least 97% sequence identity, such as at least 98% sequence identity, for example 99% sequence identity with the predetermined sequence.

[0137] To determine the percent identity of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity # of identical positions/total # of positions (e.g., overlapping positions).times.100). In one embodiment the two sequences are the same length. The sequence identity is preferably calculated relative to the full length sequence of the molecule of the present invention.

[0138] A degree of "sequence identity" of amino acid sequences is a function of the number of identical amino acids at positions shared by the amino acid sequences. A degree of "sequence homology" or "sequence similarity" of amino acid sequences is a function of the number of amino acids, i.e. structurally related, at positions shared by the amino acid sequences. Sequence identity is determined by the alignment algorithm that performs global alignments which has been described by Smith T F and Waterman M S (Smith T F et al.)

[0139] A list of the standard qualifiers and the default values for the alignment algorithm is given below:

TABLE-US-00001 Allowed values Default Standard (Mandatory) qualifiers [-asequence] Sequence USA Readable sequence Required (Parameter 1) [-bsequence] Sequence database USA Readable Required (Parameter 2) sequence(s) -gapopen The gap open penalty is the score taken Number from 1.000 10.0 for any away when a gap is created. The best value to 100.000 sequence depends on the choice of comparison matrix. The default value assumes you are using the EBLOSUM62 matrix for protein sequences, and the EDNAFULL matrix for nucleotide sequences. -gapextend The gap extension penalty is added to the Number from 0.100 0.5 for any standard gap penalty for each base or to 10.000 sequence residue in the gap. This is how long gaps are penalized. Usually you will expect a few long gaps rather than many short gaps, so the gap extension penalty should be lower than the gap penalty. An exception is where one or both sequences are single reads with possible sequencing errors in which case you would expect many single base gaps. You can get this result by setting the gap open penalty to zero (or very low) and using the gap extension penalty to control gap scoring. [-outfile] Output alignment file name Alignment output (Parameter 3) file Additional (Optional) qualifiers -data file This is the scoring matrix file used when Comparison matrix EBLOSUM62 for comparing sequences. By default it is the file in EMBOSS data protein EDNAFULL file `EBLOSUM62` (for proteins) or the file path for DNA `EDNAFULL` (for nucleic sequences). These files are found in the `data` directory of the EMBOSS installation. Advanced (Unprompted) qualifiers -[no]brief Brief identity and similarity Boolean value Yes Yes/No

[0140] An "unrelated" or "non-homologous" sequence shares less than 40% identity, though preferably less than 25% identity, with one of the 4-helical cytokine sequences of the present invention. The term "substantial identity" means that two peptide sequences, when optimally aligned, such as by the Smith and Waterman algorithm using default gap weights, share at least 80 percent sequence identity, preferably at least 90 percent sequence identity, more preferably at least 95 percent sequence identity or more (e.g., 99 percent sequence identity). Preferably, residue positions which are not identical differ by conservative amino acid substitutions.

[0141] Additionally, variants are also determined based on a predetermined number of conservative amino acid substitutions as defined herein below. Conservative amino acid substitution as used herein relates to the substitution of one amino acid (within a predetermined group of amino acids) for another amino acid (within the same group), wherein the amino acids exhibit similar or substantially similar characteristics.

[0142] Within the meaning of the term "conservative amino acid substitution" as applied herein, one amino acid may be substituted for another within the groups of amino acids indicated herein below: [0143] Amino acids having polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gin, Ser, Thr, Tyr, and Cys,) [0144] Amino acids having non-polar side chains (Gly, Ala, Val, Leu, Ile, Phe, Trp, Pro, and Met) [0145] Amino acids having aliphatic side chains (Gly, Ala Val, Leu, Ile) [0146] Amino acids having cyclic side chains (Phe, Tyr, Trp, His, Pro) [0147] Amino acids having aromatic side chains (Phe, Tyr, Trp) [0148] Amino acids having acidic side chains (Asp, Glu) [0149] Amino acids having basic side chains (Lys, Arg, His) [0150] Amino acids having amide side chains (Asn, Gin) [0151] Amino acids having hydroxy side chains (Ser, Thr) [0152] Amino acids having sulphor-containing side chains (Cys, Met), [0153] Neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr) [0154] Hydrophilic, acidic amino acids (Gin, Asn, Glu, Asp), and [0155] Hydrophobic amino acids (Leu, Ile, Val)

[0156] Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, and asparagine-glutamine.

[0157] Accordingly, a variant or a fragment thereof according to the invention may comprise, within the same variant of the sequence or fragments thereof, or among different variants of the sequence or fragments thereof, at least one substitution, such as a plurality of substitutions introduced independently of one another.

[0158] It is clear from the above outline that the same variant or fragment thereof may comprise more than one conservative amino acid substitution from more than one group of conservative amino acids as defined herein above.

[0159] The addition or deletion of at least one amino acid may be an addition or deletion of from preferably 2 to 250 amino acids, such as from 10 to 20 amino acids, for example from 20 to 30 amino acids, such as from 40 to 50 amino acids. However, additions or deletions of more than 50 amino acids, such as additions from 50 to 100 amino acids, addition of 100 to 150 amino acids, addition of 150-250 amino acids, are also comprised within the present invention. The deletion and/or the addition may--independently of one another--be a deletion and/or an addition within a sequence and/or at the end of a sequence.

[0160] The polypeptide fragments according to the present invention, including any functional equivalents thereof, may in one embodiment comprise less than 250 amino acid residues, such as less than 240 amino acid residues, for example less than 225 amino acid residues, such as less than 200 amino acid residues, for example less than 180 amino acid residues, such as less than 160 amino acid residues, for example less than 150 amino acid residues, such as less than 140 amino acid residues, for example less than 130 amino acid residues, such as less than 120 amino acid residues, for example less than 110 amino acid residues, such as less than 100 amino acid residues, for example less than 90 amino acid residues, such as less than 85 amino acid residues, for example less than 80 amino acid residues, such as less than 75 amino acid residues, for example less than 70 amino acid residues, such as less than 65 amino acid residues, for example less than 60 amino acid residues, such as less than 55 amino acid residues, for example less than 50 amino acid residues.

[0161] "Functional equivalency" as used in the present invention is according to one preferred embodiment established by means of reference to the corresponding functionality of a predetermined fragment of the sequence.

[0162] Functional equivalents or variants of a 4-helical cytokine will be understood to exhibit amino acid sequences gradually differing from the preferred predetermined 4-helical cytokine, as the number and scope of insertions, deletions and substitutions including conservative substitutions increases. This difference is measured as a reduction in homology between the preferred predetermined sequence and the fragment or functional equivalent.

[0163] All fragments or functional equivalents of SEQ ID No. 3 are included within the scope of this invention, regardless of the degree of homology that they show to the respective, predetermined 4-helical cytokines disclosed herein. The reason for this is that some regions of the 4-helical cytokines are most likely readily mutatable, or capable of being completely deleted, without any significant effect on the binding activity of the resulting fragment.

[0164] A functional variant obtained by substitution may well exhibit some form or degree of native cytokine activity, and yet be less homologous, if residues containing functionally similar amino acid side chains are substituted. Functionally similar in this respect refers to dominant characteristics of the side chains such as hydrophobic, basic, neutral or acidic, or the presence or absence of steric bulk. Accordingly, in one embodiment of the invention, the degree of identity is not a principal measure of a fragment being a variant or functional equivalent of a preferred predetermined fragment according to the present invention.

[0165] One particularly preferred method of determining the degree of functional equivalence is by performing a biological or chemical assay such as the assays described in the appended examples. Preferred functional equivalents of SEQ ID No 3 are those that have a K.sub.D with respect to a predefined receptor which is less than 10 times higher than the K.sub.D of the polypeptide of SEQ ID No 1 with respect to the same receptor, more preferably less than 5 times higher, more preferably less than 2 times higher.

[0166] With respect to functional equivalence this may be defined in a biological assay based on a cytokine dependent or stimulated cell line. Such cell lines are e.g. available from American Type Culture Collection, P.O. Box 1549, Manassas, Va. 20108 USA. The following cell lines at least are available for testing cytokines and in particular interleukins:

TABLE-US-00002 Accession number Description Activity CRL-1841 TH-2 clone A5E IL2 dependent, IL4 stimulated CRL-2003 TF-1 IL3 dependent CRL-2407 NK-92 IL2 dependent CRL-2408 NK-92MI IL2 dependent CRL-2409 NK92CI IL2 dependent CRL-9589 AML-193 IL3 stimulated, GM-CSF dep. CRL-9591 MV-4-11 GM-CSF dependent TIB-214 CTLL-2 IL2 dependent

[0167] The following cell lines are available from DSMZ--Deutsche Sammiung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1b, D-38124 Braunschweig, GERMANY. As can be seen from the table, some of the cell lines can be used to broadly assess cytokine activity whereas others are only reported to respond to one or a few specific cytokines.

TABLE-US-00003 Accession number Description Acvitity ACC 211 Mouse hybridoma, B9 IL6 dependent ACC 137 Human acute myeloid leukemia, UT-7 Constitutively cytokine responsive to various cytokines. ACC 104 Human acute megakaryoblastic leukemia Respond with proliferation to: GM-CSF, IFN-alpha, IFN-a, IFN-gamma, IL2, IL3, IL4, IL6, IL15, NG F, SCF, TNF-alpha, TPO ACC 247 Human acute myeloid leukemia, OCI- G-GSF, GM-CSF, IL3, FTL3- AML5 ligand ACC 271 Human acute myeloid leukemia, MUTZ-2 IL3, SCF, G-CSF, M-CSF, IFN-gamma ACC 334 Human erythroleukemia, TF-1 GM-CSF, IFN-gamma, IL3, IL4, IL5, IL6, IL13, LIF, NGF, OSM, SCF, TNF- alpha, and TPO

[0168] The TF-1 cell line mentioned above can be used for assaying IL13 function. This cell line is sensitive to various different cytokines but gives a very strong proliferative response when exposed to IL13. This cell line can in particular be used if there is no response in the IL4 sensitive cell line (CT.h4S). Further cell lines which can be used for distinguishing between IL4 and IL13 activity include cell lines/hybridomas such as B-9-1-3 (Bouteiller et al.) and A201.1 (Andrews et al.).

Pharmaceutical Uses of Isolated Polypeptides

[0169] Apart from being used for diagnosis, it is also within the scope of the present invention to use an isolated polypeptide as defined in the invention for a pharmaceutical composition together with a pharmaceutically acceptable carrier. Such pharmaceutical compositions may be used for any of the purposes for which cytokines and in particular interleukin is used at present.

[0170] Examples of such uses include the treatment of bone disorders, inflammation, for lowering blood serum cholesterol, allergy, infection, viral infections, hematopoietic disorders, preneoplastic lesions, immune related diseases, autoimmune related diseases, infectious diseases, tuberculosis, cancer, viral diseases, septic shock, reconstitution of the haematopoietic system, induction of the granulocyte system, pain, cardial dysfunction, CNS disorders, depression, artheritis, psoriasis, dermatitis, collitis, Crohn's disease, diabetes, in an individual in need thereof.

[0171] It is also within the scope of the present invention to use an isolated polypeptide according to the invention as an adjuvant or as an immune anhancer, for regulating TH2 immune responses, and for suppressing Th1 immune responses.

[0172] A further use of an isolated polypeptide of the invention is as a growth factor for administration to cell cultures or as a growth factor for veterinary use, e.g. for stimulating the growth of livestock.

Immunotherapy

[0173] Having identified a transcriptional and/or translational product of SEQ ID No 1 and/or SEQ ID No 5 as an etiological factor in B-CLL it is also within the scope of the present invention to perform an immunisation of a patient in need thereof against B-CLL, wherein the immunisation generates an immune response in the patient which recognises a translational product of SEQ ID No 2, SEQ ID No 4, SEQ ID No 6, SEQ ID No 7, SEQ ID No 8, SEQ ID No 9, SEQ ID No 10 and SEQ ID No 11. A preferred immunotherapy is a vaccination against B-CLL by immunising an individual against a translational product of SEQ ID No 1 and/or SEQ ID No 5. In this way the individual builds up antibodies directed against said translational product and any developing B-CLL will be stopped by these antibodies.

[0174] Immunisation may be performed in various ways, such as by immunising said individual with at least one isolated polypeptide as defined the present invention and optionally adjuvants and carriers or immunising with an expression construct capable of expressing an isolated polypeptide according to the invention in the cells (DNA vaccination).

[0175] Another method comprises peptide loading of dendritic cells, or ex vivo expansion and activation of T-cells, or inducing a CTL response that targets cells expressing the polypeptide encoded by SEQ ID No 1 and/or SEQ ID No 5.

Antibodies

[0176] Antibodies against any of the polypeptides belonging to the novel class of proteins identified by the present inventors can be produced by any known method of immunisation.

[0177] In one embodiment, the antibodies are produced in a non-human mammal, or in an insect. If antibodies are to be used for therapy in human beings they are preferably subsequently humanised. In one embodiment, the antibody is formulated into a single-chain antibody.

[0178] In another embodiment, in particular for therapeutic purposes, the host organism is a human being and the antibody is subsequently produced recombinantly in a non-human mammal, such as a mouse. The antibody may also be produced as a monoclonal antibody in a hybridoma. One way of producing a monoclonal antibody is described in U.S. Pat. No. 5,681,729 in which a human lymphocyte producing an antibody is generated by the steps, in the order mentioned, comprising [0179] 1. transplanting human lymphocytes to a mouse lacking both functional T and B cells so that said human lymphocytes take in said mouse's body; [0180] 2. immunizing said mouse with a desired antigen so as to generate human lymphocytes producing an antibody specific to said antigen; [0181] 3. administering to said mouse an antiserum to mouse cells; [0182] 4. recovering lymphocyte containing cells from said mouse; [0183] 5. separating human lymphocytes from the recovered cells by centrifugation; and [0184] 6. separating said human lymphocytes producing said antibody. [0185] 7. immortalizing said human lymphocytes [0186] 8. cloning the obtained immortalized human-derived lymphocytes producing said antibody; and recovering a monoclonal antibody specific to said desired antigen from the cloned immortalized human-derived lymphocytes.

[0187] The antibodies of the present invention may be provided as part of a pharmaceutical composition. Such a pharmaceutical composition may be used for treating cancer, preferably for treating leukaemia, more preferably for treating B-CLL leukaemia, more preferably for treating poor prognosis B-CLL leukaemia.

Use of Antibodies in Therapy

[0188] Antibodies directed against epitopes can be used for prevention and/or therapy of for example B-CLL. Antigenic epitopes can be used in vaccines to stimulate an immunological response in a mammal that is directed against cells having the B-CLL-associated epitope found in the AMB-1 protein(s) or functional equivalents. Antibodies directed against the antigenic epitopes of the invention can combat or prevent B-CLL.

[0189] An antigenic epitope may be administered to the mammal in an amount sufficient to stimulate an immunological response against the antigenic epitope. The antigenic epitope may be combined in a therapeutic composition and administered in several doses over a period of time that optimizes the immunological response of the mammal. Such an Immunological response can be detected and monitored by observing whether antibodies directed against the epitopes of the invention are present in the bloodstream of the mammal.

[0190] Such antibodies can be used alone or coupled to, or combined with, therapeutically useful agents. Antibodies can be administered to mammals suffering from any B-CLL that displays the B-CLL-associated epitope. Such administration can provide both therapeutic treatment, and prophylactic or preventative measures. For example, therapeutic methods can be used to determine the spread of a B-CLL and lead to its remission.

[0191] Therapeutically useful agents include, for example, leukeran, adrimycin, aminoglutethimide, aminopterin, azathioprine, bleomycin sulfate, bulsulfan, carboplatin, carminomycin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyclosporine, cytarabidine, cytosine arabinoside, cytoxin dacarbazine, dactinomycin, daunomycin, daunorubicin, doxorubicin, esperamicins, etoposide, fluorouracil, ifosfamide, Interferon-.alpha., lomustine, melphalan, mercaptopurine, methotrexate, mitomycin C, mitotane, mitoxantrone, procarbazine HCl, taxol, taxotere (docetaxel), teniposide, thioguanine, thiotepa, vinblastine sulfate, vincristine sulfate and vinorelbine. Additional agents include those disclosed in Chapter 52, Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner), and the introduction thereto, pp. 1202-1263, of Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Eighth Edition, 1990, McGraw-Hill, Inc. (Health Professions Division). Toxins can be proteins such as, for example, pokeweed anti-viral protein, cholera toxin, pertussis toxin, ricin, gelonin, abrin, diphtheria exotoxin, or Pseudomonas exotoxin. Toxin moieties can also be high energy-emitting radionuclides such as cobalt-60, I-131, I-125, Y-90 and Re-186, and enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof.

[0192] Chemotherapeutic agents can be used to reduce the growth or spread of B-CLL cells and tumors that express the AMB-1 associated epitope of the invention. Animals that can be treated by the chemotherapeutic agents of the invention include humans, non-human primates, cows, horses, pigs, sheep, goats, dogs, cats, rodents and the like. In all embodiments human B-CLL antigens and human individuals are preferred.

[0193] Species-dependent antibodies can be used in therapeutic methods. Such a species-dependent antibody has constant regions that are substantially non-immunologically reactive with the chosen species. Such species-dependent antibody is particularly useful for therapy because it gives rise to substantially no immunological reactions. The species-dependent antibody can be of any of the various types of antibodies as defined above, but preferably is mammalian, and more preferably is a humanized or human antibody.

Compositions

[0194] Therapeutically useful agents can be formulated into a composition with the antibodies of the invention and need not be directly attached to the antibodies of the invention. However, in some embodiments, therapeutically useful agents are attached to the antibodies of the invention using methods available to one of skill in the art, for example, standard coupling procedures.

[0195] Compositions may contain antibodies, antigenic epitopes or trypsin-like protease inhibitors. Such compositions are useful for detecting the AMB-1 protein (for example antigenic epitopes) and for therapeutic methods involving prevention and treatment of B-CLLs associated with the presence of the AMB-1 (for example antigenic epitopes).

[0196] The antibodies, (and for example antigenic epitopes and protease inhibitors) can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration. Routes for administration include, for example, intravenous, intra-arterial, subcutaneous, intramuscular, intraperitoneal and other routes selected by one of skill in the art.

[0197] Solutions of the antibodies, (and for example antigenic epitopes and protease inhibitors) can be prepared in water or saline, and optionally mixed with a nontoxic surfactant. Formulations for intravenous or intra-arterial administration may include sterile aqueous solutions that may also contain buffers, liposomes, diluents and other suitable additives.

[0198] The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions comprising the active ingredient that are adapted for administration by encapsulation in liposomes. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage.

[0199] Sterile injectable solutions are prepared by incorporating the antibodies, antigenic epitopes and protease inhibitors in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.

Polynucleotides

[0200] In a still further aspect the invention relates to an isolated polynucleotide selected from the group consisting of: [0201] i) a polynucleotide comprising nucleotides of SEQ ID No 5, [0202] ii) a polynucleotide encoding a polypeptide having the amino acid sequence of SEQ ID No 3, [0203] iii) a polynucleotide, the complementary strand of which hybridises, under stringent conditions, with a polynucleotide as defined in any of i) and ii). [0204] iv) a polynucleotide which is degenerate to the polynucleotide of iii), and [0205] v) the complementary strand of any such polynucleotide.

[0206] The polypeptides encoded by the polynucleotides may furthermore [0207] a) have at least 60% sequence identity with the amino acid sequence of SEQ ID No 3 and have interleukin or cytokine activity, [0208] b) be recognised by an antibody, or a binding fragment thereof, which is capable of recognising an epitope, wherein said epitope is comprised within a polypeptide having the amino acid sequence of SEQ ID No 3; and/or [0209] c) be competing with a polypeptide having the amino acid sequence as shown in SEQ ID No 3 for binding to at least one predetermined binding partner such as a cytokine receptor.

[0210] Specific examples of fragments of SEQ ID No 1 include the nucleotide sequence selected from the group consisting of SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ ID No:15, SEQ ID No:16, SEQ ID No:17 and SEQ ID No:18.

Hybridisation

[0211] The entire nucleotide sequence of the coding sequence of SEQ ID No 1 and/or SEQ ID No 5 or portions thereof can be used as a probe capable of specifically hybridising to corresponding sequences. To achieve specific hybridisation under a variety of conditions, such probes include sequences that are unique and are preferably at least about 10 nucleotides in length, and most preferably at least about 20 nucleotides in length. Such probes can be used to amplify corresponding sequences from a chosen organism or individual by the well-known process of polymerase chain reaction (PCR) or other amplification techniques. This technique can be used to isolate additional nucleotide sequences from a desired organism or as a diagnostic assay to determine the presence of the coding sequence in an organism or individual. Examples include hybridisation screening of plated DNA libraries (either plaques or colonies; see e.g. Innis et al. (1990) PCR Protocols, A Guide to Methods and Applications, eds., Academic Press).

[0212] The terms "stringent conditions" or "stringent hybridisation conditions" include reference to conditions under which a probe will hybridise to its target sequence, to a detectably greater degree than other sequences (e.g., at least twofold over background). Stringent conditions are target sequence dependent and will differ depending on the structure of the polynucleotide. By controlling the stringency of the hybridisation and/or washing conditions, target sequences can be identified which are 100% complementary to a probe (homologous probing).

[0213] Alternatively, stringency conditions can be adjusted to allow some mismatching in sequences so that lower degrees of similarity are detected (heterologous probing).

[0214] Generally, probes for hybridisation of this type are in a range of about 1000 nucleotides in length to about 250 nucleotides in length.

[0215] An extensive guide to the hybridisation of nucleic acids is found in Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology-Hybridization with Nucleic Acid Probes, Part I, Chapter 2, "Overview of principles of hybridization and the strategy of nucleic acid probe assays", Elsevier, New York (1993); and Current Protocols in Molecular Biology, Chapter 2, Ausubel, et al., Eds., Greene Publishing and Wiley-Interscience, New York (1995). See also Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual (2nd ed. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).

[0216] Specificity is typically the function of post-hybridisation washes, the critical factors being the ionic strength and temperature of the final wash solution.

[0217] Generally, stringent wash temperature conditions are selected to be about 5.degree. C. to about 2.degree. C. lower than the melting point (Tm) for the specific sequence at a defined ionic strength and pH. The melting point, or denaturation, of DNA occurs over a narrow temperature range and represents the disruption of the double helix into its complementary single strands. The process is described by the temperature of the midpoint of transition, Tm, which is also called the melting temperature.

[0218] Formulas are available in the art for the determination of melting temperatures.

[0219] Preferred hybridisation conditions for the nucleotide sequence of the invention include hybridisation at 42.degree. C. in 50% (w/v) formamide, 6.times.SSC, 0.5% (w/v) SDS, 100 mg/ml salmon sperm DNA. Exemplary low stringency washing conditions include hybridization at 42.degree. C. in a solution of 2.times.SSC, 0.5% (w/v) SDS for 30 minutes and repeating. Exemplary moderate stringency conditions include a wash in 2.times.SSC, 0.5% (w/v) SDS at 50.degree. C. for 30 minutes and repeating.

[0220] Exemplary high stringency conditions include a wash in 2.times.SSC, 0.5% (w/v) SDS, at 65.degree. C. for 30 minutes and repeating. Sequences that correspond to the AMB-1 gene or fractions thereof according to the present invention may be obtained using all the above conditions. For purposes of defining the invention, the high stringency conditions are used.

Mutations

[0221] Finally, the invention provides a method for determining an increased or decreased predisposition for B-CLL comprising determining in a biological sample from an individual a germline alteration in a target nucleic acid sequence comprising 150,000 nucleotides, said target nucleic acid sequence comprising at least 10 nucleotides of SEQ ID No 1 and/or SEQ ID No:5. This aspect is based on the finding of the importance of the expression product of SEQ ID No 1 and/SEQ ID No:5, and the complete absence of any detectable expression product of SEQ ID No 1 and/or SEQ ID No:5 in healthy tissue and in patients with good prognosis B-CLL. It is highly likely that the difference is caused by a germine alteration. A germline alteration can be targeted by gene therapy methods and by the methods provided in the present invention.

[0222] Preferably, said predisposition is a predisposition for poor prognosis of B-CLL.

EXAMPLES

Example 1

cDNA Cloning

[0223] By Differential Display (Pardee et al., 1992, Jorgensen et al., 1999) part of a gene (hereafter referred to as AMB-1) was found that is expressed in unmutated B-CLL patients with poor prognosis. This gene is not found in the mutated B-CLL patients. When AMB-1 was sequenced and aligned to known sequences in GenBank, perfect homology was found to 225 base pairs (bp) of human genomic DNA from chromosome 12.

[0224] RNA was prepared using the RNeasy kit from Qiagen, as described by the manufactor (Qiagen, Hilden, Germany). RNA was prepared from patients with B-CLL without hyper mutation who, by PCR analysis, using primers FDP5 (CCTTTATGTGTGTGACAAGTG) and F10 (ATCCAGCCAGGATGAAATAGAA), showed a high level of the resulting PCR fragment. Poly-A.sup.+ RNA was isolated from total RNA by the "MicroPoly(A)Purist" kit from Ambion, as described by the manufactor (Ambion, Inc., Texas, USA). Cloning-ready cDNA was prepared from 8 .mu.g poly-A.sup.+ RNA using the "ZAP Express.RTM. XR Library Construction Kit" from Stratagene as described by the manufactor (Stratagene, San Diego, USA). The cDNA was size fractionated and two size fractions (fraction-1: >2500 bp and fraction-2 300-2500 bp) were independently ligated to pre-digested lambda Zap vectors and packed into phage particles as described by the manufacture (Stratagene, San Diego, USA). The titer was determined for each library and 200,000 pfu of from the fraction-1 library were plated onto two 22.times.22 cm screening plates (100,000 pfu on each plate) and 750,000 pfu of the fraction-2 library were plated on five 22.times.22 cm screening plates (150,000 pfu on each) as described by Stratagene, San Diego, USA. The plates were incubated at 37.degree. C. for 18 hours and the plaques transferred to replica nylon filters (Amersham) and denatured and renatured to allow hybridisation. All procedures were made as described by the manufactures (Stratagene, San Diego, USA & Amersham Biosciences, Buckinghamshire, UK).

[0225] The filters were screened by independent hybridisations with alpha[.sup.32P]-dATP-labelled DNA fragments; alpha[.sup.32P]-dATP was purchased from Amersham Biosciences, Buckinghamshire, UK. Between succesive hybridisations, the old probe was removed by incubation for 20 min in 2 l 90-100.degree. C. water containing 0.1% SDS. The DNA fragments used as probes were (all positions relate to sequence ID # X): 1) pos. 48978-49250; 2) pos. 50011-51591; 3) pos. 51461-52182; 4) pos. 51901-52589; 5) pos. 53121-56521; 6) pos. 58163-59408. All hybridisations and washes were made according to the instructions from Stratagene, San Diego, USA and Amersham Biosciences, Buckinghamshire, UK; Washing was done at a high stringency (0.1.times.SSC at 65.degree. C. for 20 min).

[0226] A total of 38 plaques that showed a positive response from one or more of the screenings, were excised from the screening plates and grown as plasmids as described (Stratagene, San Diego, USA).

[0227] A total of 8 cDNAs were identified by cDNA cloning or by a combination of cDNA cloning, PCR analysis and RACE (rapid amplification of cDNA ends-polymerase chain reaction) using the SMART RACE cDNA amplification kit (Clontech, Palo Alto, Calif.) according to the manufacturer's instructions.

Example 2

Bioinformatic Analysis of AMB-1

[0228] The DNA and protein sequence data bases (GenBank and EBI) have been searched for sequences with similarity to AMB1. There is no significant DNA sequence similarity to any known gene. In particular, the coding region of the AMB1 mRNA (SEQ ID no 3) is not present in any known EST. The only significant match to the complete mRNA sequences and the DNA sequence of the putative coding region were BAC clones derived from the region on human chromosome 12 where the gene is located. The "AMB-1 gene" had not been annotated as a gene on the chromosome. Searches with the peptide sequence in the sptrnr data base of peptide sequences (includes Sprot and nrtrembl) showed a low similarity to putative intron maturases from cloroplasts and to bovine IL4. The percentage similarity to both maturases and bovine IL4 was low (25.6% and 30.3%, respectively) and the similarity to maturases only included a match to 75 amino acids of the much larger maturases. In contrast, the match to bovine IL4 extended over the full peptide sequence. IL4, and other 4-helical cytokines, include a leader peptide sequence (signal peptide) allowing the proteins to be secreted. The AMB1 peptide sequence includes a N-terminal peptide sequence with similarity to signal peptide sequences, however, it is not a typical sequence.

[0229] A 3D search has been performed, where a peptide sequence is searched for similarity to known protein or peptide 3D-structures. The two best matches were the thioredoxin fold and the human 4-helical cytokine IL4 (FIG. 5). The two matches had almost similar probability scores (2.88 and 3.05, respectively). Searches with 4-helical cytokine peptide sequences (IL4, IL3, IL13 and GM-CSF) revealed that all could be folded into both a 4-helical cytokine structure and the thioredoxin fold. Alignment based on the structural similarity between IL4 (d1iara) and AMB-1 is shown in FIG. 5. Thus, the AMB1 peptide sequence share this property with 4-helical cytokines. The structural similarity is not perfect (FIG. 6) and there are no obvious glycosylation sites in the AMB1 sequence, however, the similarity is significant. Alignment of the AMB1 peptide sequence with the sequences of IL4, IL3, IL13 and GM-CSF, based on their structures, showed very little sequence conservation but a high degree of structural conservation (FIG. 7). Based on this alignment, AMB1 has similarities to all the 4-helical cytokines, and the length of AMB1 and the position of gaps in the alignment could suggest a higher similarity to e.g. IL13, but searches at 3D-PSSM only identified a significant similarity to the structure of IL4, not IL13, IL3 or GM-CSF. However, the search algorithms are not perfect and may therefore not detect a possible low structural similarity.

Example 3

Differential Expression of AMB-1

Patient Material

[0230] Blood samples were collected from newly diagnosed untreated patients with B-CLL. Mononuclear cells were isolated by Lymphoprep separation (Nycomed Pharma, Oslo, Norway), and the percentage of CD5+CD20+ B-CLL cells in the mononuclear fraction was >90% in all samples as determined by flow cytometric analysis.

Isolation of RNA and Conversion to cDNA.

[0231] Material for RNA production was isolated mononuclear cells from B-CLL patients or mononuclear cells from lymphoprep separated buffy coats from normal donors. Total RNA was isolated from 5.times.10.sup.7 or more cells using the QIAamp RNA Blood Mini kit (Qiagen, Valencia, Calif.) with DNAse treatment. RNA (1 ug) was converted to cDNA by incubation with a mixture of random-primers (1 .mu.g) and T24-primer (1 .mu.g) for 5 minutes at 70.degree. C. After cooling on ice, the reaction mixture was added to a final volume of 25 .mu.l containing 30 U of AMV Reverse Transcriptase HC (Promega, Madison, Wis., USA), 1.times. First Strand Buffer (5 mM Tris-HCl, pH 8.3, 50 mM KCl, 10 mM MgCl.sub.2, 10 mM DTT, 0.5 mM spermidine), 2.5 mM of each dNTP and 60 U rRNasin ribonuclease inhibitor (Promega, Madison, Wis., USA). The reaction was performed for 60 minutes at 37.degree. C.

Determination of Somatic Hypermutation Status

[0232] Two .mu.l of cDNA was amplified using a GeneAmp PCR System 2700 (Applied Biosystems, Warrington, UK) with a 40 pmol specific upstream primer corresponding to 1 of the 6 human VH family leader sequences (VH1: 5'-CCATGGACTGGACCTGGAGG-3', VH2: 5'-ATGGACATACTTTGTTCCAGC-3', VH3: 5'-CCATGGAGTTTGGGCTGAGC-3', VH4: 5'-ATGAAACACCTGTGGTTCTT-3', VH5: 5'-ATGGGGTCAACCGCGATCCT-3', VH6: 5'-ATGTCTGTCTCCTTCCTCAT-3') and a 40 pmol downstream primer (C.mu.:5'-GAGGCTCAGCGGGAAGACCTT-3' or C.gamma.:5'-GGGGAAGACCGATGGGCCCCT-3') corresponding to a consensus sequence of the constant region of IgM or IgG respectively. The Reverse Transcription (RT)-PCR reaction contained 1.times.PCR buffer (10 mM Tris-HCl, pH 9.0, 50 mM KCl, 0.1% Triton X-100), 2.5 mM MgCl.sub.2, 0.2 mM of each dNTP and 1.5 U Taq DNA Polymerase (Promega, Madison, Wis., USA) in a final volume of 100 .mu.l. The RT-PCR was performed under the following conditions: 1 cycle of 94.degree. C. for 5 minutes, 30 cycles of denaturation at 94.degree. C. for 30 secs, annealing at 62.degree. C. for 30 sec. and extension at 72.degree. C. for 30 sec, and a final extension at 72.degree. C. for 7 minutes. The RT-PCR products were analysed on 2% agarose gels and sequenced in an HBI Prism 310 Genetic Analyzer (Perkin Elmer, Foster City, Calif., USA) using the BigDye Terminator Cycle Sequencing Ready Reaction kit (Applied Biosystems, Warrington, UK) following the manufacturer's Instructions.

[0233] Sequences obtained from each sample were compared to germ line sequences in the V base sequence directory (I. M. Tomlinson, MRC Center for Protein Engineering, Cambridge, UK) using BLAST, and the closest germ line sequence was assigned. A gene sequence was considered to be mutated if it had equal or more than 2% sequence alterations when compared to the closest published germ line sequence.

RT-PCR that Amplifies the Exon 2-Exon 3 Junction

[0234] To evaluate the mRNA expression pattern of AMB1 in unmutated and mutated B-CLL patients RT-PCR was performed. Exon-overlapping oligonucleotide primers were: 5'-ATCCAGCCAGGATGAAATAGAA-3' and 5'-CACTTGTCACACACATAAAGG-3'. The RT-PCR was performed in a GeneAmp PCR System 2700 thermal cycler with an initial denaturation at 94.degree. C. for 2 minutes, 40 cycles of 96.degree. C. for 25 sec., 62.degree. C. for 25 sec. and 72.degree. C. for 90 secs, and a final extension at 72.degree. C. for 5 minutes. The reactions contained 2 .mu.l cDNA, 1.times.DDRT-PCR buffer (10 mM Tris-HCl, pH 8.3, 50 mM KCl, 1.8 mM MgCl.sub.2, 0.1% Triton X-100, 0.005% gelatine), 0.25 mM of each dNTP, 30 pmol of each primer and 0.5 U Taq DNA Polymerase (Promega, Madison, Wis., USA) in a 30 .mu.l final volume. RT-PCR products were analyzed by gel electrophoresis on 2% agarose gels and visualized with a Gene Genius Bio Imaging System (Syngene, Frederick, Md.) after staining with ethidium bromide. An actin control RT-PCR was performed using the primers: 5'-TGACGGGGTCACCCACACTGTGCCCATCTA-3' and 5'-CTAGAAGCATTTGCGGTGGACGATGGAGGG-3'.

RT-PCR that Amplifies the Exon 1-Exon 3 Junction:

[0235] To evaluate the mRNA expression pattern of AMB1 in unmutated and mutated B-CLL patients RT-PCR was performed. Exon-overlapping oligonucleotide primers were: 5'-AGACGGCTCTCACC AATAAG-3' and 5'-CACTTGTCACACACATAAAGG-3'. The RT-PCR was performed in a GeneAmp PCR System 2700 thermal cycler with an initial denaturation at 94.degree. C. for 2 minutes, 40 cycles of 96.degree. C. for 25 sec., 62.degree. C. for 25 sec. and 72.degree. C. for 90 secs, and a final extension at 72.degree. C. for 5 minutes. The reactions contained 2 .mu.l cDNA, 1.times.DDRT-PCR buffer (10 mM Tris-HCl, pH 8.3, 50 mM KCl, 1.8 mM MgCl.sub.2, 0.1% Triton X-100, 0.005% gelatine), 0.25 mM of each dNTP, 30 pmol of each primer and 0.5 U Taq DNA Polymerase (Promega, Madison, Wis., USA) in a 30 .mu.l final volume. RT-PCR products were analyzed by gel electrophoresis on 2% agarose gels and visualized with a Gene Genius Bio Imaging System (Syngene, Frederick, Md.) after staining with ethidium bromide (Continental Lab Products, San Diego, USA).

Statistical Analysis

[0236] Statistical significance of the correlation between somatic hypermutation status and AMB1 expression was analyzed using Fisher's exact test.

[0237] Northern blotting. RNA from spleen, bone marrow and colon was purchased from Clontech. The AMB1 probe was an 896 base pair fragment (57661-56766) obtained by RT-PCR as described above with the primers 5'-TCACCTGGGAGCTCAGAGGA-3' and 5'-GTGATCCTGGGAGMTCTCT-3'. For Northern blotting, 5 .mu.g of RNA was run on a 1% agarose-gel with 6% formaldehyde dissolved in 1.times.MOPS (20 mM 3-(N-morpholino)-propane-sulfonic acid, 5 mM sodium acetate, 1 mM EDTA, pH 7.0) for size separation. The presence of equal amounts of RNA in each lane was ensured by ethidium bromide staining. The RNA was transferred to a Hybond-N membrane (Amersham, Little Chalfont, UK) by capillary blotting and fixed by UV-irradiation. The filters were pre-hybridized for 1-2 hours at 42.degree. C. in 6 ml ULTRAhyb (Ambion, Austin, Tex., USA) preheated to 68.degree. C. and hybridized overnight at 42.degree. C. after addition of further 4 ml containing the .sup.32P-labeled probe and sheared salmon sperm DNA (10 .mu.g/ml). The membranes were washed for 2.times.15 min. at 42.degree. C. in 2.times.SSC, 0.1% SDS followed by 1.times.15 min. in 0.2.times.SSC, 0.1% SDS and 2.times.15 min. in 0.1.times.SSC, 0.1% SDS at 42.degree. C. The blot was developed and quantified by a phosphoimager. The sizes of the mRNAs were determined by reference to 18S and 28S ribosomal RNA, which were visualized by ethidium bromide staining. The AMB1 probe used for hybridization was radiolabeled with [.alpha.-.sup.32P] dCTP using the Random Primers DNA Labeling System (Gibco BRL).

[0238] Dot blot of multiple tissue expression (MTE) array. An MTE array (Clontech, Palo Alto, Calif., USA) was hybridised to AMB1 at 65.degree. C. in ExpressHyb (Clontech) supplemented with sheared salmon sperm DNA (7.5 .mu.g/ml) and human C.sub.ot-1 DNA (1.5 .mu.g/ml) according to the manufacturers recommendations. The tissue types represented on the MTE array are shown in FIG. 11. Following hybridisation the filter was washed 5.times.20 min. at 65.degree. C. in 2.times.SSC (1.times.SSC=150 mM NaCl, 15 mM sodium citrate, pH 7.0), 1% SDS and 2.times.20 min at 65.degree. C. in 0.1.times.SSC, 0.5% SDS. The blot was developed and quantified by a phosphoimager (Fuji Imager Analyzer BAS-2500, Image Reader ver. 1.4E, Image Gauge ver. 3.01 software, Fuji, Stockholm, Sweden). The membranes were stripped by boiling in 0.5% SDS for 10 min. before rehybridization. The probe used for hybridization were radiolabeled with [.alpha.-.sup.32P] dCTP using the Random Primers DNA Labeling System (Gibco BRL, Rockville, ML, USA).

Results

[0239] Based on the known sequence of the AMB-1 cDNA RT-PCRs with primers that extend across the Exon 2-Exon 3 junction and the Exon 1-Exon 3 junction were set up. As shown in FIG. 10, where the Exon 2-Exon 3 junction has been amplified, AMB-1 is expressed in the unmutated patients (UPN1-8) while no expression of AMB-1 is seen in mutated patients (UPN9-16).

[0240] Northern blot analysis was performed to determine the size of AMB-1's mRNA transcript. As shown in FIG. 3 the probe identifies transcripts in the samples from the three patients without somatic hypermutation (UPN1, UPN4 and UPN7). However, the probe does not recognise any transcripts from the patients with somatic hypermutation (UPN9, UPN10, UPN13, UPN21) or the various cell lines and tissue samples. Similar results were obtained when cell lines and tissue samples were investigated by RT-PCR (results not shown). Dot blot analysis on a purchased filter with 96 different RNA samples (FIG. 8) only revealed specific binding to the total DNA control dot, but not to any specific tissue (results not shown). Thus AMB-1 is only expressed in B-CLL cells without hypermutation or AMB-1 is expressed at extremely low levels in other tissues.

[0241] We next tested the predictive value, in terms of IgV.sub.H mutational status, of expression of AMB-1 in 29 consecutive newly diagnosed patients. At present 13 somatically unmutated and 16 somatically mutated patients have been included in our prospective patient database. The sensitivity and specificity for expression of AMB-1 in predicting mutational status is well above 90% (p<0.0001), which is at the level obtained by sequencing.

Example 4

Investigation of the Prognostic Significance of AMB-1 in Terms of Patient Survival

[0242] To obtain information about the ability of AMB-1 to predict survival or time to progression for B-CLL patients survival curves were made. For each patient the following data were collected: clinical stage at time of diagnosis (Rai and Binet staging), date of diagnosis, date of first time of treatment and last follow up date. Time to treatment (progression free survival) and survival time were calculated based on these dates using the Microsoft Excel software. Survival times and progression free survival times were plotted be the Kaplan-Meier Method and compared using the log-rank test (Prism 3.0 Graph Pad software).

[0243] 34 newly diagnosed, untreated B-CLL patients were investigated as described above. As shown in FIG. 2a-d AMB-1 expression is a good predictor of B-CLL patient survival and B-CLL patient time to progression.

Example 5

siRNA Assays

Materials and Methods:

[0244] Frozen cells from unmutated or mutated B-CLL patients purified and characterized for mutational status as previously described were thawed and Ficoll separated to obtain the live cells. Cells were counted and resuspended at 2.times.10.sup.6 cells/ml in RPMI 1640 medium with glutamax-1 (RPMI, GIBCO, Paisley, UK). 1.times.10.sup.6 cells (500 .mu.l of cell suspension) were incubated on ice for 10 minutes with the appropriate siRNA or combination of siRNAs at a final concentration of 100 nM each. The suspension was electroporated using a 4 mm cuvette (Molecular BioProducts, San Diego, Calif., USA) in a BioRad Gene Pulser. Following electroporation the cells were incubated on ice for 10 minutes, washed once in RPMI with 20% FCS and 100 units/ml Penicillin and 100 .mu.g/ml Streptomycin (GIBCO, Paisley, UK), resuspended at a concentration of 4.times.10.sup.6 cells/ml in the same medium and Incubated for 48 hours. For each patient the optimal voltage allowing for maximum siRNA uptake was determined by making a voltage curve (300-450V, 960 .mu.F) using a FITC-labeled unspecific probe (Xeragon, Qiagen, Hilden, Germany) at a final concentration of 200 nM and the uptake was followed by flow cytometry.

[0245] The siRNAs were produced using the Silencer.TM. siRNA Construction Kit, (Ambion, Texas, USA) according to the manufacturers instructions. SiRNAs had the following target sequences:

TABLE-US-00004 TABLE 1 Overview of the siRNAs used in electroporation experiments siRNA name: mRNA target sequence: Exon 1 A 5'-AAUAAGGGCAGGCAUCAUCCA-3' SEQ ID No:19 Exon 1 B 5'-AAUUACACUGCCAGGUUUCCU-3' SEQ ID No:20 Exon 2 A 5'-AAUUCAUUCACAAUGAUUGCU-3' SEQ ID No:21 Exon 2 B 5'-AAUUUCUCUUGGGUAAUUCAG-3' SEQ ID No:22 Exon 3 5'-AAAAUCAGAAUCUGCGCAGCA-3' SEQ ID No:23 (DDend) A Exon 3 5'-AAUGAUGAUGGGAAGAAGGAA-3' SEQ ID No:24 (DDend) B CDS A 5'-AAACUUAGUAAUUGAGUGUGA-3' SEQ ID No:25 CDS B 5'-AAUAUGUCACUUUCAUAAAGC-3' SEQ ID No:26 Transcript 5'-AAUGAUGAUGGGAAGAAGGAA-3' on-strand A Transcript 5'-AAACUAUGAGAUUUCAGAAGG-3' on-strand B

[0246] After 48 hours of incubation the various B-CLL samples were counted and live and dead cells were distinguished by nigrosin exclusion (0.1% in Nigrosin in PBS from Fluka, Buchs, Switzerland).

Results:

[0247] Following 48 hours of incubation with control GFP siRNA or siRNAs against various regions of the cDNAs (see table 1), the viable cells and dead cells were counted based on the ability of the cells to exclude nigrosin. As shown in table 2, in 3 out of 4 patients introduction of siRNAs against Exon 1, Exon 2 and Exon 3 resulted in an increase of dead cells as compared to the controls (no siRNA or GFP siRNA).

TABLE-US-00005 TABLE 2 Percent dead cells of total cells following electroporation and incubation with siRNAs. Treatment: UPN 67 UPN 66 UPN 62 UPN 73 No siRNA 33.0% 19.7% 30.9% 20.2% Control siRNA 28.4% 26.7% 24.0% 16.0% CDS siRNA 23.7% 25.5% 21.0% 13.3% Ex1-3 siRNA 47.3% 54.1% 17.2% 29.1%

Example 6

Identification of Possible Cytogenetic Aberrations Near or Within the Region Encoding AMB-1 on Chromosome 12

[0248] Rationale: The limited expression profile of AMB-1 suggests that it may be a result of a genetic aberration (e.g. deletion, translocation or alternative splicing) or that the promotor region controlling the expression of AMB-1 is uniquely activated in unmutated B-CLL. Another gene is situated about 200.000 bases upstream of the AMB-1 gene (SEQ ID No 1) on chromosome 12 and the inventors we have determined that this gene is expressed at equal levels in unmutated and mutated patients.

[0249] Methods: Using primers, initially spaced about 20.000 bp apart; this region on chromosome 12 is characterised in unmutated B-CLL patients. If genetic aberrations within the region are detected by PCR analysis of chromosomal DNA, detailed molecular genetic studies using FISH, microsatellite analysis and Southern blotting will be employed. The whole region from unmutated patients is sequenced.

Example 7

Polyclonal Antibodies

Production of Polyclonal Antibodies:

[0250] Synthetic peptides CDLETNSEINKLIIYLFSQNNRIRF and CQVSKKHIIYSTFLSKNF were synthesized and conjugated to KLH (K.J.Ross-Petersen Aps, Holte, Denmark). Polyclonal antibodies were produced by immunization of rabbits with these conjugated peptides by DAKO (DAKO Cytomation A/S, Glostrup, Denmark).

Testing of Polyclonal Antibodies:

[0251] At the present time we have produced polyclonal antibodies from three rabbits that have been immunized with peptides representing predicted immunogenic regions of the protein that can be predicted from the CDS sequence (SEQ ID No:17) (cDNA 4). The antibodies are tested in various ways. The proposed reading frame of CDS (SEQ ID No:17) is expressed in 293 cells and the binding of antibodies to lanes on a western blot with non-transfected 293 cells versus transfected 293 cells are compared. The size of the band in the lanes with transfected 293 cells is compared to the size of western blot bands in lanes with proteins from B-CLL patients. Specificity of the bands is secured by peptide blocking experiments.

[0252] Additionally the polyclonal antibodies are tested in B-CLL immunoprecipitation experiments where the antibodies are used to immunoprecipitate the protein produced from the CDS sequence and the immunoprecipitates are analyzed by western blotting.

Example 8

Assay for the Biological Activity of 4-Helix Cytokines

[0253] The assay is based on the use of a cytokine dependent or stimulated cell line, for example an IL4 dependent cell line ("Optimisation of the CT.h4S bioassay for detection of human interleukin-4 secreted by mononuclear cells stimulated by phytohaemaglutinin or by human leukocyte antigen mismatched mixed lymphocyte culture", Petersen, S. L., Russell, C. A., Bendtzen, K. & Vindelov, L. L., Immunology Letters 84 (2002) 29-39). Other examples of cytokine dependent cell lines include IL13 dependent cell lines. A list of commercially available cytokine dependent cell lines is disclosed in the general part of the description. These can all be used for assessing cytokine activity. The most preferred cell lines are those that are IL4 dependent.

[0254] The assay can be performed in two ways. The first assay comprises providing recombinantly produced AMB1 protein or a functional equivalent thereof and determine the proliferation rate of the cell line. The proliferation rate (either rate of proliferation or .+-.proliferation) can be compared to the proliferation rate of the cell line exposed to IL4 or another known 4-helical cytokine or interleukin.

[0255] If a positive result is obtained with a polypeptide an assay will be performed on the same cell line with the IL4 receptor blocked. This will check whether the stimulus goes through IL4R.

[0256] The second assay is based on transfection of a gene encoding a 4-helix cytokine according to the invention into cytokine dependent cells and observe proliferation or non-proliferation during transient expression.

Example 9

Cytokine Receptor Binding Assays

[0257] The following is a description of the layout of a cytokine receptor binding assay used to determine the cytokine activity of the 4-helix cytokines according to the present invention.

[0258] The assays can be performed with any cytokine receptor. Preferred receptors include but is not limited to the receptors for IL4 IL13, IL3, and GM-CSF.

[0259] The ability of recombinant cytokine receptor to bind to 4-helical cytokine is assessed in a competitive binding ELISA assay as follows. Purified recombinant cytokine receptor (IL4, IL13, IL3 or GM-CSF receptors) (20 .mu.g/ml in PBS) is bound to a Costar EIA/RIA 96 well microtiter dish (Costar Corp, Cambridge Mass., USA) in 50 .mu.L overnight at room temperature. The wells are washed three times with 200 .mu.L of PBS and the unbound sites blocked by the addition of 1% BSA in PBS (200 .mu.l/well) for 1 hour at room temperature. The wells are washed as above. Biotinylated AMB-1 (1 .mu.g/ml serially diluted in twofold steps to 15.6 ng/mL; 50 .mu.L) is added to each well and incubated for 2.5 hours at room temperature. The wells are washed as above. The bound biotinylated AMB-1 is detected by the addition of 50 .mu.l/well of a 1:2000 dilution of streptavidin-HRP (Pierce Chemical Co., Rockford, Ill.) for 30 minutes at room temperature. The wells are washed as above and 50 .mu.L of ABTS (Zymed, Calif.) added and the developing blue color monitored at 405 nm after 30 min. The ability of unlabelled 4-helical cytokine to compete with biotinylated AMB-1, respectively, is assessed by mixing varying amounts of the competing protein with a quantity of biotinylated AMB-1 shown to be non-saturating (i.e., 70 ng/mL; 1.5 nM) and performing the binding assays as described above. A reduction in the signal (Abs 405 nm) expected for biotinylated 4-helical cytokine indicates a competition for binding to immobilised cytokine receptor.

[0260] The above identified assays can be used to identify 4-helical cytokines with similar binding affinities as AMB-1 (SEQ ID No. 3). In the competitive binding assays biotinylated IL4, IL13, IL3, or GM-CSF can be used to identify 4-helical cytokines which can compete with these cytokines.

REFERENCES

[0261] 1. U.S. Pat. No. 4,554,101 [0262] 2. U.S. Pat. No. 5,681,729 [0263] 3. Antineoplastic Agents (Paul Calabresi and Bruce A. Chabner [0264] 4. Andrews, R., L. Rosa, M. Daines, and G. Khurana Hershey. 2001. Reconstitution of a functional human type II IL4/IL13 receptor in mouse B cells: demonstration of species specificity. J Immunol 166, no. 3:1716 [0265] 5. Ausubel, et al., Current Protocols in Molecular Biology, Chapter 2, Eds., Greene Publishing and Wiley-Interscience, New York (1995). [0266] 6. Bouteiller, C. L., R. Astruc, A. Minty, P. Ferrara, and J. H. Lupker. 1995. Isolation of an IL13-dependent subclone of the B9 cell line useful for the estimation of human IL13 bioactivity. J Immunol Methods 181, no. 1:29 [0267] 7. Chaouchi, N., C. Wallon, C. Goujard, G. Tertian, A. Rudent, D. Caput, P. Ferrera, A. Minty, A. Vazquez, and J. F. Delfraissy. 1996. Interleukin-13 inhibits interleukin-2-induced proliferation and protects chronic lymphocytic leukemia B cells from in vitro apoptosis. Blood 87, no. 3:1022 [0268] 8. Damle, R. N., T. Wasil, F. Fais, F. Ghiotto, A. Valetto, S. L. Allen, A. Buchbinder, D. Budman, K. Dittmar, 3. Kolitz, S. M. Lichtman, P. Schulman, V. P. Vinciguerra, K. R. Rai, M. Ferrarini, and N. Chiorazzi. 1999. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94, no. 6:1840 [0269] 9. Dancescu, M., M. Rublo-Trujillo, G. Biron, D. Bron, G. Delespesse, and M. Sarfati. 1992. Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression. J Exp Med 176, no. 5:1319 [0270] 10. Dohner, H., S. Stilgenbauer, A. Benner, E. Leupolt, A. Krober, L. Bullinger, K. Dohner, M. Bentz, and P. Lichter. 2000. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343, no. 26:1910 [0271] 11. Fluckiger, A. C., F. Briere, G. Zurawski, J. M. Bridon, and J. Banchereau. 1994. IL13 has only a subset of IL4-like activities on B chronic lymphocytic leukaemia cells. Immunology 83, no. 3:397 [0272] 12. Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Eighth Edition, 1990, McGraw-Hill, Inc. (Health Professions Division) [0273] 13. Hamblin, T. J., Z. Davis, A. Gardiner, D. G. Oscier, and F. K. Stevenson. 1999. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94, no. 6:1848 [0274] 14. Innis et al. (1990) PCR Protocols, A Guide to Methods and Applications, eds., Academic Press [0275] 15. Jorgensen M, Bevort M, Kledal T S, Hansen B V, Dalgaard M, and Leffers H (1999) Differential Display Competitive PCR: An Optimal Tool for Assaying Gene Expression. Electrophoresis 20:230-240 [0276] 16. Kim D. et al., "The emerging fields of suicide gene therapy and virotherapy", Trends Mol. Med. 2002, 8:568-573 [0277] 17. 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Luo, H. Y., M. Rubio, G. Biron, G. Delespesse, and M. Sarfati. 1991. Antiproliferative effect of interleukin-4 in B chronic lymphocytic leukemia. J Immunother 10, no. 6:418 [0283] 23. Merrifield, 3. Am. Chem. Soc. 85:2149-2146, 1963) [0284] 24. Oscier, D. G., A. C. Gardiner, S. J. Mould, S. Glide, Z. A. Davis, R. E. Ibbotson, M. M. Corcoran, R. M. Chapman, P. W. Thomas, J. A. Copplestone, J. A. Orchard, and T. J. Hamblin. 2002, Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood 100, no. 4:1177 [0285] 25. Panayiotidis, P., K. Ganeshaguru, S. A. Jabbar, and A. V. Hoffbrand. 1993. Interleukin-4 inhibits apoptotic cell death and loss of the bcl-2 protein in B-chronic lymphocytic leukaemia cells in vitro. Br J Haematol 85, no. 3:439 [0286] 26. Petersen, S. L., Russell, C. A., Bendtzen, K. & Vindelov, L. L., Optimisation of the CT.h45 bioassay for detection of human Interleukin-4 secreted by mononuclear cells stimulated by phytohaemaglutinin or by human leukocyte antigen mismatched mixed lymphocyte culture", Immunology Letters 84 (2002) 29-39) [0287] 27. Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual (2nd ed. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.). [0288] 28. Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology-Hybridization with Nucleic Acid Probes, Part I, Chapter 2, "Overview of principles of hybridization and the strategy of nucleic acid probe assays", Elsevier, New York (1993) [0289] 29. Yazawa et al., Current Progress in suicide gene therapy for cancer, World J. Surg. 2002, 26(7):783-789.

Sequence CWU 1

1

43119999DNAHomo Sapiensgene40000-60000Sequence of ac063949.emhum 1cacacgtagg ctacgagtgg ccctcagcct gcctcatcat ggacctgtgt tataataaat 60atgtttaatt gtgctgtttt cttatagagg aaagtcctga tgttagttgc cttgaagtca 120gacacccaga gagaatcaca ggttttcaga ttaattcatc gcttgattct tatccctgaa 180gtcatatctc tggatctctg gttctcacat tataaatttc aatgattctt tttctatatg 240gccatgtcat tcatatcctg tgtaatatgg ggaaactgag gtatgaatga catcattcaa 300aaagcacctg caatttttct ttgccaagca cttacagctt tttctcatgt tgctttcaaa 360aagtcattga aatattgttc acatattttg cagatgagga aatgaatatt caaatgcatt 420aggtatcttg tccaagttct tacagccaga aagtagagaa atgaatttga attacaaatc 480ttctacctct tggcttatgc tcttttcatg acactgggaa taaatgtctg aacaagcatg 540acttcatgtt tcaactattt atcaaatact tgttttctac taagatcttg cactcactca 600gtgggatccc ctgaagcctg ctgattattt gtcctttggc atttatcact ctctgtggga 660ccttactctc ctatggtaaa gttttattgt tattaaaagt attatttgac aataaatgta 720gaaatcctac agatcatact caacaacatg tctaatgtca gcacacaatg tctaacaatc 780atttatgaat actttatgtc aaacataagc aataacctaa ttaaggaagg tatttttaat 840aaattgacac tttttgacat aaccatattt caagtggctc cattgttttg tttatttatt 900tatttattta tttatttatt tatttttgag aaagggtctc actctgttgc ccagactgga 960gtgcagtggc aacatcatag ctcactacag cctcgacctc tctgggctca agcaatcctc 1020ccatctcagc ttcccaagta gctgggacta caggtgtgta ccatcatgcc aggctaattt 1080ttcgtatttt gtagagacgg ggttttgcct ggtcgtccgg gttggtctca aactcctggg 1140tgttccgccc accttggcct cccaaagtgc tgggattata ggcatgagcc tcaagtggct 1200actttttagg gttgaaattt atattgactg tcaactagct tccctagtta gtatttggga 1260tctgctaact aatttatatt accatccaac ttgtcaacat ttgttgaaat ataactgtcc 1320tcactttttt tgtgtgaaca ttgaatacac tttcagacta aatttggttt attacttaat 1380gtcttattct ttattagagt taataatatt tcttaatact ttgccttcca caaatgaata 1440acttgtttgt gatggctacc tctttttttc tcttagcctg tcacaggtat tatggataaa 1500aattagcacg gctgggcaaa aacaatgaaa gaaatacact tgcctgggaa agctggggag 1560gggtaaatga atataattca aaataccata tatttattca acactgttgg aatatatgtc 1620ctgttggaaa tgtaaaagtg acatatgttc tcttcctggg tctcagactt ttaggatcta 1680gttgagggaa ctggacttat acacaaaata caattcaaca acattatgag ctagaaaatc 1740catgagctaa agtctttggc aaagacatta ggtaacatga ggagtcagga aaaggagaaa 1800ttactgtggg ctggaatggt ctgggaacat gagatggagg aagtggcttg ttactggaga 1860aaggatgagg ttcaaagaga tgggaaaaaa agaaagagag aagaaagaaa agaaatgagg 1920aaaaacaagt tgccagaaag aacaaggaag aatagaggca ggtaagcagt ggattttgcc 1980ctagggaagg taatataact agagacggca gtttctaaca ggccatgatg aataagatac 2040actttagccc tcattggtac gtgcagaaat tcaaatttgg aaattcaagc ttacatgaca 2100gtaaatatat gttgggaaaa aaataaccgg taaacattta catcagctct ttttcctaaa 2160gagaaaccta ttccatgcta tgaaatattt gtcacaattc tgttttcaaa atacttgctc 2220tacttttcca agccacaaga ggaaacattt tctctgccaa cactctctga ccttaaccag 2280tttctccact acgtctactc ttaagctctc tttagagctg tgtgtatctc gtctttatgt 2340aaacctccta gatgatatac ttatggaaat attcaggcaa ctttttcatg aactttacca 2400ggaaagacat ttctagcagg agagcatgaa tagaaatgga ctcttcccca gtctctgctg 2460ggttctgact gtggtcactc taactataaa aagtgtgtaa aaatcatgag cagattattt 2520catttccttg gggtccctaa aaatttcaag gtatctgtat tagcacagga agatttaaat 2580tgatttctca acacattcag atatcttatg aactttatta agataaattt cctccagcat 2640tcagaaactc atatattaca gaataaaaaa taaagcagaa aattagtgta cctggctaaa 2700aatgagagca gggttctatt tcattttgga aagtcactaa gacagtaata ataccattaa 2760tgataaaatg ttaacattag ttaattatta gatgtgtttt tgtatgccag ccacataata 2820tatactttta tatgtatcac ctacatttct agatgtaaat gtgagggaat tatagtagta 2880tctacctcgt atgattgctg gatgatttaa atgagctgtt gtctcaaaaa cttggtatag 2940aaagcagaaa cttttagtta ttaagattct tactattcca atatttgaat aaaacagtga 3000cctgctaaga aaccccaata atattctgat acatcaaaac cttctggcat tagatgtttc 3060taatctaaca tcttcatatt aattttttta tgttttgatt atctacattc agtagtgaat 3120gtgtttctaa acgctggatg catttttaac taaatgtgtt ttgtaccaca ttttgacaac 3180ttttgtttta actatgattc agcttataac aaaacaaaac aatgcatctt ctctccactg 3240ttaataaggt taatgaaaag ttgacttatg aaaaaaatcc taatttatgc acattctcat 3300tgttttcctt gctaaggata ttagtacttg acgattctgt aacaaagaat tatcatggga 3360tgaaactttg atgcaaatat cttatcaata caatgtgctt gattttacct agatgagatt 3420tttcttttct tctttctttt ttgagacagg gttttgctgt gttacccagg ctagcctcaa 3480acccctggcc cctggcctca agtgatcctc tcacctctgc ctcccaaagt gctgggtatt 3540acagatgtga gtcactgaat ccagcctcac ttagttggct ttcttagtga attattttat 3600ctggttctaa aactttttga taatactctc aaatatttat ggattttata acataattta 3660tggattacgt agttatgaat ttcataaatg attttgtgat attgccacag atcatcacca 3720ttatacagga tgtataacat aaccatggtt taatatattt tcataaacta tagaccaaac 3780aaagactggt caggaccagg gcacgcatgc attttatatg tgtggtgcct attggaatat 3840gccaggcctc ctgtgaaaaa aatcagtaag tgcttatctc ataggaccaa cggcccaaca 3900ttcctgaagt cactaccaca ctttgcactt atctccatgt ggaaatagat agccactgtt 3960gaattctggt gagaacgaca cgtctgaaat ctctcagctt cacaacccct attacagccc 4020tcagagaatc ttctcacata gcgccaaaca acaactttag gaagtgatgt tcctagaatg 4080aatcaatttc taaaattaaa agtgaaaaca atgacaagga gaagggaggg tcagagagga 4140aaggctgatg ttactaaaag acaaaagaca gtataacctc ttatgaggat ggtccagaca 4200ctcagggaaa tgcaggaaga aataaaagat aggagtttga accacactgt gatggctaac 4260tttatgtgtg gacccgaccg atctatggga cacccagata gcttgtaaag cactatttct 4320gggtgcgtca gtgagggtgt ttttggaaga gatcaacact tgagtcagta gactgagtaa 4380agcagatggt cctcaccaat gtgggtgcac attgtttaat ctgttgagtg cctggataga 4440caaaaaaggc aaaagaaggg tgaattccct ttctcgtctt aagctgggac agccatcctt 4500tcctaccctc agacatgaga ggtttggatt cttggatctt tggtcccaag ggctgacact 4560ggtggccacc tctggtttca ggtctttggc cccagattgt aagttacacc atcagcttcc 4620ttggttcttg ggccttgaga ctcaagctaa aatacactac cagcttccct tgttctctag 4680tgtagggaca gcaaatcatg aaaccttctg cctccataat catataagtc aattcccgta 4740ataaatctgt gcttatatat ctatagcttt ccttttggtc tgtttctcca aagaacctta 4800atgtacacac tatatgacct aacctgtagt aatgataacc ttatgcaggt ttgaataaga 4860tgatggtatt ctcagtatct gggaggtatg ggctagagtg atgaaccacc gccatgagcc 4920taggactgag gagatttctg aaatgtggaa tatttggtgt caaaaccaag agataatata 4980gccatgtgga aaacatgtag aactatcgta tgattcagca acccaaccac tgggaattta 5040cccaaaggaa aggaaaccag tatattaaag agaatctgca ctcccatggt tattgcagca 5100ttattctcaa tagcctagat atggactcaa cctaggagat tagatgaatg gacaaagaaa 5160atgtggcata tgtacaccat gaaatactta ccagctataa aaaagaatta gccaaagcag 5220tggtgtgtgc ctgtcatccc agctccttgg gaggctgagg tgggaagatc tcgaggccag 5280aagtttgaga ccagcctggg caaaataata agactcggtc tctaaaacaa tttaaaaata 5340ggccttcctt aaaaaaagaa taaaatcatg tcattcacgg caacatagat gggactggag 5400gatattactg ttaagtgaaa ttagccagga acagcaagtt aaaccccaca tattctgatt 5460catatgcgga agctaaaaaa acgttgatct catagaagta aaaagtagaa cagaggatgc 5520tggagactag aaaaggtagg gagaaggaag ggagagggaa aaatttgtta acaggtacaa 5580aaacaaaatt acagttagtt agggagaatt aattccagca tcctgtagca ctataggatg 5640actatagtta ataataatac tttaattagt ctcaaatagc tagaaggagg atattgaatg 5700ttcccaacac acacaaaaaa atgataatgt atgagatgat ggatatggta gttatcctga 5760tctgatcact ctacattata tgtatcaaca catcactatg taccccacaa atatgtagaa 5820tttttatttg tccatttaaa aaagataaca aatttaaaaa taaaataaaa actaaattag 5880tgttccatgt aaacctggat gaactggtca ccctacgtct gcccatctag atggctggtc 5940aaagtttccc aggctccaca tcaagttgtt ccactgctca ctggaacttc cctagtcagg 6000ttgggcaaat agtaatttac agcaatagtg aatttatcac tgacatttct tcagttcccc 6060tctttggcat ctgcttcttc ttttctgtaa tgctgtttgt tgaaatgccc aacattcttt 6120ttcttcccta gagctattca gggtgacctt tcttttcgca ttttcccatg ccacttccat 6180tatatcaaaa taaaacagtc ctgtgtggcc actgctcatg accttgtttc ctgccatgtg 6240aagataggat cggctgctct ttcttctcct cctttttttt cagagacagg atctctccct 6300gtcacccaga ctggagtgca atggcacagt cgtagcttgc tgcagcctcg aactcctgga 6360cctcctcagc ctcctgagta gctgggacta caggtgcaca ccaccatgcc ttcctaatct 6420gatatatata tatatatata ttatatatat aaaatatata tataaatata tatattttat 6480atattatata tataatatat atattttata tataaaatat atatattata tatatatatt 6540atatataaaa tatatatatt atatatatat atatatatta tagagatggg gtcttgctct 6600gtcacccagg ctgaagatca gctgctcttt ctaatctgtg gttagataag atctgtctcc 6660caggggataa aatactacct ggaataaagg tatctttaaa ataatcccag agaagaaaac 6720atttttatag tatgacagag gcagagaaaa cagagaatat ttgttaaggc aggactttca 6780ccactcccag tacaatcatc tgtctgttac ctgcatacct tacacgggct ggcactgctg 6840ggggtacaaa gtagatgcca aacttcacaa tggttagatt catgtttaaa aagccattgg 6900atcaaacctt tgtgaaagtt tccagctttt ttctgttcca aatatgtgtc cattataaaa 6960gaatctcaag agcataattg ccaagatagt ctatgtccat gagtatttca acatctctca 7020tgaaatctgt tcccatcatt actcaagata ttgtatgaac agtattccac ataaactagg 7080tgctcaataa tgattgattg gccaatggag ggtcattatt taatgcacta caatctttta 7140tgcaaggggc ccacaggaat cagtatgatc ccataggaat ccttttcttt tccattgaaa 7200aagaaacaga tagtggcttg tattaggttt cttgtgtgtg ttgtgaggtg gaaagatatg 7260aaaagaaatt tgatcagagc ataaatctga gcccatggga taggaaagaa tgagggaata 7320aggaagaaaa cacagattat agacaggaaa atcaaaccta ttaaaactga taattttcga 7380atactaaaaa tgtacattca tttgaacaaa aagattctat aaagcaagat ttctctgttc 7440ttaccagcac taccatgccc aaactacctt aggaaatgaa tagcagagtc aaacttaaaa 7500gcacctgaaa tttaaaacaa aaaccaattt acattttatt taagaaaagc aaacagatgg 7560gcctgctaac aatgtcaaag tctcgtttac aaagaaaaaa acaaatctgg aacctgaagt 7620caaacgagtt caaaataaaa agcaaaccaa taaacagaaa ccaacataaa cagaagttac 7680taccatctcc ctcagcctgt gaaattctgg aacttctctt tctttctcgc cttcttcttc 7740tctcacctgg aagacgagca gagtgaacac atcaggggtt gtcagttccc cagatggcac 7800cacattcata aaccaccgac tccaggagaa tgtaggaagc ttagttaagg ccaaagttct 7860ctttggatct tcctcatggg cttcaaggca aaagaaaaaa aagtttgctt gagaatatct 7920tcatatctat tagtttgaac catgcaaaat tacagttttt ataggtaaaa tgagtgcata 7980ttggcaattt caaatgatta accctaatac attatgcttt tgggtataga aatattcaga 8040tcttaaacat atgctgttac atacaaaatc aggtatattc ctgcttctat aattaaagca 8100aagagaattt cttttggtca ctactccttc tgacatgagg tatgaaccaa gttcaggacc 8160cctaaaggtc tgggtctggg tcatttctcc acctctaact tgtgccgctt tcttggtcag 8220tcattgtgtt ctgagctgtc tcataaaaca tctgctatga ctttactttc tcctgatagg 8280gtggctttcc atcgttggca cttcgttggc cttattggta tgctttatac actggttctc 8340gtttccaaat tggcattatt attgttatga ttcctgctgc tctcccacat ttcccatctt 8400tctcctgatc tctctcacct gtacatttct tacattttct cctgtgcttc cttcttccca 8460tcatcattgc ccaagtgtgt cttctttctt ctccttgtca catttccttt gcccgctctc 8520acatatgcag agatggctct tggttttcct tctgaaatct catagtttgg aggtaaactt 8580gttagcaagg ccactgagaa gagaacaaaa gggaaacata agagaaacca agtcactatc 8640tctctcattt cctggtttct agaagtaaga cccaaagaac tcactgtttc agtgctttca 8700gctcaggcca aactagggtg atcaaactga gcttctgagt gctgatcaaa acctataaaa 8760ccaagtagac agaccatcta caaatcttca ctgttaaata ccataaagaa tgaaaaggtc 8820actaattggt aagactatat gtgtgataat taaatttatg catcaacctg gctaggctaa 8880aggatgacca ggtagctggt aaaacattat tctgggtgtg tccataagag tgttttcgga 8940agagatcagc atttgaattg gtgaacttag taaagcagac ggctctcacc aataagggca 9000ggcatcatcc aatctgtcga aagcttgaat aaaacaaaaa gaggaaggga aaatttgctt 9060cttttcttct tgatctagta tatcatcttc tcctgccctt ggatgtgagt gggccttcag 9120acttaaacca ggagttacac ctttggcttc cctggttctc agttctttgg acttggactg 9180aattacactg ccaggtttcc tggttctcca gcttgcagat ggcagatcat gggacttctt 9240ggcctccata attgtgtgag tcaatttcca ttttatttac atatccagtt atgcattgct 9300taacaatgga gacaggttct gagaaatgca ttgttaagtg atttcatcat tgtgcaaaca 9360tcatagagtg taactacaca aacctggaca gcatagacta ctacacatct aggctacatg 9420gtgtagcttg taacctcatg ataagtatgt ataacatcat gataagtatg tatgtatcta 9480ccatatctaa atgtagaaaa ggtacagtaa aaatatggta taatcttatg ggatcaccat 9540catatatgca atcctttgta gactgaaatg tcattgtgta gtgcatgact gtatacgcac 9600acatacacaa acacacacaa atatactatt ggttcttttt ctctgaagag ccctaataca 9660atatgttata catttatatt gactctattt caaaatttat ggttttggtg aaacatatgt 9720ggagatgggg cataggtgtg tgaactggga tagtgtcctg ctgatgaatg ggtgggaggc 9780atcatttggg acaagcccag ggcatcagct tatagatatc aagagctcaa caagagcact 9840ttatggcaaa acctcccaca agacctctca gaagttgaga aactgctaaa agtttcttta 9900tgacagatga catttatgga taaaataggg attagcagga ttctttaaat actttcgaac 9960actaaccttc atttctacca ggcagtgggg ccccaagtgc agggccatag gaagtacaag 10020tctgggagat actaggctgc actgtctgta gagaatctga aaaaataata gagtcactga 10080aatgcagttt ggtataatta ttgccatgca tcataattct aaatcatact agtggtcaaa 10140tactcttccc tgaaaaaaca ttttcttggt ttgaattcta aataattgtt gtggtcacca 10200ctgagctttt aaatatataa atactttcaa gtttgcatat ttttattacc tgttccttaa 10260caaacattga attcaacatg aaaatgatta tgggaaacat tcgggtatac agtccctgac 10320tcttaaggac tcaggtaaat acttagggta tttcatggcc ctagtctttg gggtaccaca 10380tgtttcttct tcaaatcaca gattcaaaat caagaatgat aacacagtga ttgtgtagac 10440aaaataagtg aaccaaaatt gcttgcttct gtcattctat ggaaccactg agagttttta 10500cttgtgctta aaattttgaa tagtaaaaca gagtgtcaac ttcatgctgg aatatttttg 10560gctttttaga cacaatttta agtacatgaa gtatttttac aagactaagt aacatcactg 10620aaattacagc tttcttcttt ttaaaactgg tatttgttat aaaactaaag agcgaatcaa 10680gaaaagcata attattactg attattacag gattattact gaaaaagaaa tgtacggaat 10740agaggaggaa ggagttaaca aatgatccac tctgggtgtt gaaaacacca ataagcctgc 10800ttccaggaag tgcctaagac agagctggct cagcttgctg ggtcacagca tgtaaggaaa 10860ctgctgggct acatgccacc atcctcagtt gtccagatag ataatcccat agccccatgg 10920ggaaataatc tttaattatg atatagctga caccattcaa agcactatgc taagtccttt 10980atgtgaatta acttttgtca aatttatttt tcataaataa cccaaatatg tataccacta 11040ttatcctacc ttaaagagga gaaactgagc tcctaaagtt taaatatcta acccaagtta 11100agactgctag tcaccctagg ctattaactc aggcagtcta actcaggtat aataacatta 11160tgctactgtt tgcagctttg actatgcctg aattataacg tcatgctatc taactaaaaa 11220gctaagggaa ataaaatgag ccatagggct caatttcata aaaggagaga aaatactggg 11280gaaaagtgat aatgcagagt ttaaaatatt tttgtaaaag tgccagagat tgagtataac 11340aagtgtgacc aaaaaaaaaa aaaaaaaaaa aaaaggaaga aggtaaaaaa aagagggagg 11400tctgagaaat agaaatatca gaggaaggaa ataaaggagg gtgagagtaa attctctttt 11460agcattcaga ttccacagat tccacaaatc acatttcttt ttttaccaac taaggaaaaa 11520taacacttga cctaacattt cattgcagtt agctaaagga tgctagaaaa actatgttgc 11580agtggtttgc tctaatttct tcaggaatag agaaaagtga caaaaagatc agagaagaga 11640agaaaggaaa ctatcagaaa aatacagaat tggagtagga tataacatat ttgggttgaa 11700ggtaaaattt tatattgtaa tcttaagtat cttgctactt cagtttggtc cctggaacag 11760cagcatcaga atctgccgag ggcttgttaa aaaggcagaa tctcaggtcc catcccagac 11820tcactgaatc agaatataaa tactgacaag atgccccggg attcatatgc acagtagagc 11880tggcgaagtt ccattgtagc ctgtgattgt tttctgcaac ttagtatttc tgagttttcc 11940caaggaagaa aacccaggcc ttagcttctg gcagacttgt gtttctcctt tacttactag 12000ctgcatgact catgagcaag gaaatcaaac tttatgtgcc tgagtttcct catctataaa 12060atggagacta taataatcat ctcctaggct tgttttgagg atgttcaaca aatgctcctt 12120tcattcctct atttacagac ctgccgcaga caattctgct agcagccttt gtgctattat 12180ctgttttcta aacttagtaa ttgagtgtga tctggagact aactctgaaa taaataagct 12240gattatttat ttattttctc aaaacaacag aatacgattt agcaaattac ttcttaagat 12300attattttac atttctatat tctcctaccc tgagttgatg tgtgagcaat atgtcacttt 12360cataaagcca ggtatacatt atggacaggt aagtaaaaaa catattattt attctacgtt 12420tttgtccaaa aattttaaat ttcaactgtt gcgcgtgtgt tggtaatgta aaacaaactc 12480agtacagtag tattcagtac agtatttaag cccctgtact taaacatatt cctcgtacca 12540atgaagttac atgaaaagca aatttgtgtg agatatcgta gatggaagta aattagtctt 12600tatgttcccc acaaattgaa atgcatttca aaaactctgt gtgtgtatgt gtgtgtgtga 12660cagagtgtgt gtgagagaga gacagagaga tacgctttgg ttgcctccat aagctggctg 12720ctatgattaa taagaccaag ttttctaaag aaaatgagat cataacaaaa gccctcttta 12780tgactatctt ttatcagggg caaaaaggaa agagacaaaa cagcatgaaa tgatgagacc 12840aagtgatgaa aattcattca caatgattgc tttcaagagt aatttctctt gggtaattca 12900gcagcctgtt actatggctc tctggagtga tagctaatgt aaatgaagcc tctaaaagtg 12960gattatcctg acaagaatat actcagccaa taatgcaaca gaaatccatt caaagcattc 13020gggaaaaatt caaaagaata aatattcttt tttttttttt aaagttaatg acctacgatc 13080catttcttcc ctgactaaca agcagcaagc acttaaaaat atccagccag gatgaaatag 13140aaacccacct gacttgttaa tatttttgtt tggtcccagg gactcagatt ctaagccaaa 13200ttctttgaat gatcttggca aatgtctcga attatttttg ccaacttttc tttatcttgg 13260aaaaaaagtt tcatgaatgg gtgtcaaaat tgattagttt taaaaacctt tcttgcagat 13320acgtatggca ccctaaaact gtattagaaa aaaagtaagt actctgtagt gtgaaaaatt 13380cttaaaggac accctctttt acaaactcac aaaaacagcc tttggaatac ccacatgaag 13440tagctgttgt tattgctttc tatataccta catcttgtct attataaaaa gactggtttt 13500tggcaggtgt ggtggctcac acctgtaatt ccagcacttt gggaggccaa ggcgggcgga 13560tcacctgaga tcaggagttc aggaccagcc tgatcaatat ggtgaaaccc agtctttact 13620gaaaatacaa aaatcacccg ggtgtggtga cgggcgcctg tagtcccagc tactcgggta 13680gctgaggcag gagaatcact tgaactcagg agtcagaggt tgcagtgagc tgagatcatg 13740ccactgcact ccagcctggg tgacagagca agactccatc tcaaaaaaaa aaaaaaaaaa 13800gactggtttt tcaacagcta ttcccacccc tctgcatgga aatattcacc cagtcaattg 13860ttttcctagt ttgggtaatg gccctctggg caggactgga gtggggcaca caggagaagc 13920tgcaaactat gtttagaagc atgtctggga aatgtcatgc aagaaaagac atatttaaag 13980gtaggctttg catgaatgga aaaggagagt aattctatgt agagcagagc ctcttacttg 14040cagtgagaga agcaaaagtg gggaagcaag aggaattatg cttttcatca gccaaatttg 14100caggtaggag gattggctca gtcatcttgg ctgaggctca tgaaaccagg tgtaaagaaa 14160gtggactaga ttaatttcat ccattacagg aagaggagcc gtgaaagata atccagaaat 14220cattgggatt tgatggtaga aggtattttg ggactattcc atttgaaatg agaaggtacc 14280tgacattctt tgaattcctt tcaagcaaag gattaaattt acccatgagt tgactcagaa 14340aaaacataaa aagtattgtt gctctgctca gagttttatc taactcattc tcacttctta 14400ttccatgatg aaatgacata aatgaggttt tttattgttg ttgttgttgt tttctggaca 14460caaggcaagg tagctacctg ggcagagctg ttttatttct ctatgccgtg gagagaaatt 14520ggttaattgg ccatggaagg cagtcattaa gatgttccca tgcgagtgaa ctttccaggg 14580ttcccagctt ctgcatcctt ccctgtccct caattccatt gttggtgatg acaatgtctc 14640tcccatcagc ctcatgaagt tctctctcat ttattaaaat ttgctttcag gaaaaatttt 14700gaaaatgtgt ccagtaatgc ctgattggcc ccttatccta aaggcttaaa ctggaggaag 14760gaagctaaac tgagaaatct tgcaaatcat tgagccaaaa acgtattaat agcaagatct 14820atcatttatt gactagtatg tggcaggcag tgccctttta tttaggcagg gagagttgat 14880ggggggggcg gggttcacac atcttaaaga ggtgctatct cctcctatat aaatcatgta 14940agtcaagaga gtaaggaatt gtctttgttt ggttatattc aggggattag agtatacagt

15000agaagatccc aagaaacctt gggatcattt tagactaaga aatgccaata ccgccgggcg 15060cggtggctca cgcctgtaat cccagcactt tgagaggccg aggtgggcgg atcacaaggt 15120caggagattg agaccgtcct ggctaacgtg gtgaaaccct gtctctacta aaaatacaaa 15180aaattagccg ggcgtggtgg cgggcgcctg tagtcccagc tactcgggag gcggaggcag 15240gagaatggtg tgaactcagg aggcggagct tgcagtcagc cgagattgcc ccaatgcact 15300ccagcctggg cgacagaacg agactccgtc tcagaacaaa acaaaaggaa atgccaatac 15360cagcagaaat agagccaaat catgaacata agctaaacaa atgttggcag tgtagcctag 15420tggttaagag agcagactct taactagaac actgcactcc atgtcctcac tgtagaccct 15480cactgtgggg ttctaattaa cccctgttac ttaccagtgg cagtcttaag gcattcctta 15540agttcgttgt gccccaattt gttcatctgt agaaggggta ggatgacagt agtgtttact 15600ttataggctt actgtgagca ttaaatgagt tactactgta tttgtaaagt gcttaaaatg 15660ctgctccaaa agagtttgtt aaacacttaa gaactgattt acttgcatct aaactgacag 15720ctctcaataa ctggaaatga tcaagcatag gccctggaat ataagcaggt ctacatgaag 15780gcaaaaatgt tcgtttcttt tgttcagccc tgtgcctaga tcaatatcta gtgatcatgc 15840tcaagaaata ttgttgaatg aatcaatgaa cctaccgagg tagttacata aaagagttct 15900gcatgagtac aaatctgggc aaagtgacct ccaaggaaat ttccactttt agattctgtg 15960atttccttaa ggaactgata aattggtgtg atacaatgta aaaaaatgtg cctatatgat 16020ttgagaaaaa cttattttct ctccctcttt tttccttcct tccttcctcc ctcccttcct 16080tccttcctcc ctcccttcct tcctccctcc ctcccttcct tccttctctt tcttcttttc 16140tttctttctt tctttctttc tttctttctt tctttctttc tttctttctt ctcttctctt 16200tcctttcttt cttcctttct ttgtgccttt ctttctttct ttctttcttc tctgtccttt 16260ctttcttcct ttctttcttt ctgcctttct ttctctttgt ttttctttct ttccttcttt 16320tttcctttaa gcagaccatg tctgttagat gaatgccttt ttctagttaa aaggttaaac 16380aggaaagtga agcacaatta tcaagggtct ccagtcatct ccacatgttc ttaatcatta 16440tcttctttta cagtttcata tctccaggcc tttcattggg tcaggttggc atttcgctgc 16500cctttatgtg tgtgacaagt gaaaataagg aaagaaaaaa actcaagtga agaaaatcag 16560aatctgcgca gcagttcctg ggcgtttcag ctgcttccca catcacctgc ctcatcaagc 16620cccagcatcc atctccttgc tcatcttaca ccctgtgtgc atgacaggcc caccattcat 16680ttatcagagc aaaggctctc ccactattct ggttcacccc cctacttagc cagatataca 16740agaatatctg cacggatgac ctgcctcacc tgggagctca gaggagctca gattccatta 16800ctatcgcacc aaggacagat ctcccagcaa gaatgacaga aaagactaac tgcccccaaa 16860atctcccttc caaaacacag ttctcttaat tctcccaaga aaccagaatg tgactgctca 16920cctctctaag gacctgaaaa caactggcca tttcagctat ttaaatcaac tttaaaaaat 16980ccaaccgcca aaatattaaa ccattttggt tggaatgata acataactaa cctgctgaca 17040gctgcttctg ctaggtgcaa aaatggaaaa aaaaatactt ctaatcaggt caaatcactc 17100tacctttggg attctaaatt tactcatatt ctcaaagaaa tatattcagt catagtgggg 17160aaaataggat tattccttta gctcgataag caaccagaag ttcttccttc aaatcttgac 17220atttaatcaa tcagaaattg atttttggaa aactgtttcc tatgaagcta tctctgcctg 17280aaggattttt cttttacaat ccagactata gaaggaaatt cacaacctgg actttcacct 17340ccattggtca gagttttact gaccaattcc cacctctgcc ttacacctaa cggaagttta 17400tgcctgtttt ctcttcacat accccaacag ttacaaatgg ttgttattat taagcatctt 17460ttattttgtg gcctctgatt acatggtccc ctaaattttg acctaatcac aaaagattgg 17520taaaatttct taacatatta ataatatttt gtttatgtgt caatatctta gcatgtatca 17580attaagacag aggtcttaac gttctctttt tgaaagagaa tattaggatt cagagatatt 17640aagagattct cccaggatca cagttaggta acagagctgg attttagtcc aggtctgtct 17700acagctctaa cgtatataca ccctttgtat aacatgtcac gaattcagca taaagggatc 17760ttcagtgatc taagtcaggg gtcagcaacc ttttctaaaa aggaccaaat agtaatattt 17820caggctttgt ggaccctatg gtctctatca taactgttca aatcaccatg tagtgtaaaa 17880ggagccataa gcaaaatata aactaacgaa tgtggctgtt ttatgggatt tttttttaac 17940tctttattta caaaagcagg tggcagatca gaactcactt atgggccata gttctctgac 18000ccctgacctg agaaaatctt atatttatgg acaacattta gactgtgact tgccaagtaa 18060gaacaagaag ctctgtcaac tgaaggtcaa ggctggagtt ctgaaagcaa agagctgtct 18120ggtgttaatg ataagtgaaa tagttaaagt tagaagatcc cagttataag aagcacaaag 18180aataatgacc atagactcct gaacaagaat gtctggactt ctggcttagg cactcttgtt 18240gtatggtcca ggccaagtta cctaatctct ccaggcctcc attttcttat cattaaatga 18300agataataaa agtattttcc tcagagagct gtaagaataa actgagctaa cccatgtcaa 18360gcacatagaa tagggcccag cctatattaa tttatcaata aatgccagct acatattagt 18420tctctatatt tttattcatt atcataaaat gtttatctac agattggcat tgtaaggatg 18480gagttaaaat tgtatgtatg tgaagggaaa ttattcctgt tactattgat ctgcatcaca 18540ttaccccaaa tttgatggct taaagtaaca acattcattt tgcaaacaaa tttgaaattt 18600gaggagggct tgtctgggaa gacttgtctc tgccctatgt ggtatcagca gggggaggct 18660tgacggactg gcacatgccc ttccagaatg gcccactcgc atgcctgcca agttggtgct 18720ggctcttggc tgggagctca gctggggctg agtgctaggg tccctgggag gttccttgtg 18780gcctgaactt cctcaccaca aggcggctgc ggtgcgagag tgagcatttc aagatagagc 18840caagatgaca ctgtattact gtgtaagacc cagcctggga attaatgtag cctcacttcc 18900atcccactct atttttaaaa agtgaattat taaggtcacc ccatattcaa ggggatagga 18960attagacttc atctgtatta agaaaaatgt ttttaaaaat tgtagacatg ttttaaaatt 19020ctaaagtcca cttactggct gcagattatt tatatataca tgcaagatac actcctacat 19080tctcttctta gaaggctcag ttgcaggtac agatgaagct cttcaagtga gatttcttat 19140gtatttatcc tctcaatctg aagacttgta aactaagaga caagttattt gcaacctaca 19200tacgcaatat tcaatggtaa agtatacata ggacagccac tacagacact cttgttttaa 19260atagaggaaa atgagagcac ataacagtca ttggctcata gcaactctga tatccagaca 19320gcaaacacaa gcaggtcttt ttttaggtct cagtcctact gcctggattc cctactgctc 19380ttgggtcttc cctccaggtt cttggttctt ggacctcttt tcatttaata ctatttctgt 19440tcctttaagt tcaagctggc aaaatatgat tgtacaattc tgtttaaaat tccaggactt 19500cctgtgattc ttattgggga atactccatt agacaagaat ctctttgaca taagccattc 19560tctacctgag atccctgtaa ggctgtgatg ggaccacata accttaaaat tattagaaga 19620ctcattgttt actgagagaa tatgcctagc atatgcttag atccttagag gaactctgtt 19680tcaaagggct tatgagacat taccttatat ctttctaagg tacaaacaaa aggtctttgg 19740cttttgagtt tgatctttga gctgacacct tttcttaatt tgagaatccc ctgctctatg 19800gagagactga caaagagaaa tagttttata tttgaatgta acatcttgga tctttaatag 19860attatcttaa aattttcctg aaaatgtaac agttcctttt tttaaaattc attctcccta 19920cacacttatt atatatgact aaaagaaact ccctggcatt ttcaacattc tggttagaat 19980ttttcttagc ccaatctac 1999923893DNAHomo sapiens 2atcagaggaa ggaaataaag gagggtgaga gtaaattctc ttttagcatt cagattccac 60agattccaca aatcacattt ctttttttac caactaagga aaaataacac ttgacctaac 120atttcattgc agttagctaa aggatgctag aaaaactatg ttgcagtggt ttgctctaat 180ttcttcagga atagagaaaa gtgacaaaaa gatcagagaa gagaagaaag gaaactatca 240gaaaaataca gaattggagt aggatataac atatttgggt tgaaggtaaa attttatatt 300gtaatcttaa gtatcttgct acttcagttt ggtccctgga acagcagcat cagaatctgc 360cgagggcttg ttaaaaaggc agaatctcag gtcccatccc agactcactg aatcagaata 420taaatactga caagatgccc cgggattcat atgcacagta gagctggcga agttccattg 480tagcctgtga ttgttttctg caacttagta tttctgagtt ttcccaagga agaaaaccca 540ggccttagct tctggcagac ttgtgtttct cctttactta ctagctgcat gactcatgag 600caaggaaatc aaactttatg tgcctgagtt tcctcatcta taaaatggag actataataa 660tcatctccta ggcttgtttt gaggatgttc aacaaatgct cctttcattc ctctatttac 720agacctgccg cagacaattc tgctagcagc ctttgtgcta ttatctgttt tctaaactta 780gtaattgagt gtgatctgga gactaactct gaaataaata agctgattat ttatttattt 840tctcaaaaca acagaatacg atttagcaaa ttacttctta agatattatt ttacatttct 900atattctcct accctgagtt gatgtgtgag caatatgtca ctttcataaa gccaggtata 960cattatggac aggtaagtaa aaaacatatt atttattcta cgtttttgtc caaaaatttt 1020aaatttcaac tgttgcgcgt gtgttggtaa tgtaaaacaa actcagtaca gtagtattca 1080gtacagtatt taagcccctg tacttaaaca tattcctcgt accaatgaag ttacatgaaa 1140agcaaatttg tgtgagatat cgtagatgga agtaaattag tctttatgtt ccccacaaat 1200tgaaatgcat ttcaaaaact ctgtgtgtgt atgtgtgtgt gtgacagagt gtgtgtgaga 1260gagagacaga gagatacgct ttggttgcct ccataagctg gctgctatga ttaataagac 1320caagttttct aaagaaaatg agatcataac aaaagccctc tttatgacta tcttttatca 1380ggggcaaaaa ggaaagagac aaaacagcat gaaatgatga gaccaagtga tgaaaattca 1440ttcacaatga ttgctttcaa gagtaatttc tcttgggtaa ttcagcagcc tgttactatg 1500gctctctgga gtgatagcta atgtaaatga agcctctaaa agtggattat cctgacaaga 1560atatactcag ccaataatgc aacagaaatc cattcaaagc attcgggaaa aattcaaaag 1620aataaatatt cttttttttt ttttaaagtt aatgacctac gatccatttc ttccctgact 1680aacaagcagc aagcacttaa aaatatccag ccaggatgaa atagaaaccc acctgacttg 1740ttaatatttt tgtttggtcc cagggactca gattctaagc caaattcttt gaatgatctt 1800ggcaaatgtc tcgaattatt tttgccaact tttctttatc ttggaaaaaa agtttcatga 1860atgggtgtca aaattgatta gttttaaaaa cctttcttgc agatacgtat ggcaccctaa 1920aactgtatta gaaaaaaatt tcatatctcc aggcctttca ttgggtcagg ttggcatttc 1980gctgcccttt atgtgtgtga caagtgaaaa taaggaaaga aaaaaactca agtgaagaaa 2040atcagaatct gcgcagcagt tcctgggcgt ttcagctgct tcccacatca cctgcctcat 2100caagccccag catccatctc cttgctcatc ttacaccctg tgtgcatgac aggcccacca 2160ttcatttatc agagcaaagg ctctcccact attctggttc acccccctac ttagccagat 2220atacaagaat atctgcacgg atgacctgcc tcacctggga gctcagagga gctcagattc 2280cattactatc gcaccaagga cagatctccc agcaagaatg acagaaaaga ctaactgccc 2340ccaaaatctc ccttccaaaa cacagttctc ttaattctcc caagaaacca gaatgtgact 2400gctcacctct ctaaggacct gaaaacaact ggccatttca gctatttaaa tcaactttaa 2460aaaatccaac cgccaaaata ttaaaccatt ttggttggaa tgataacata actaacctgc 2520tgacagctgc ttctgctagg tgcaaaaatg gaaaaaaaaa tacttctaat caggtcaaat 2580cactctacct ttgggattct aaatttactc atattctcaa agaaatatat tcagtcatag 2640tggggaaaat aggattattc ctttagctcg ataagcaacc agaagttctt ccttcaaatc 2700ttgacattta atcaatcaga aattgatttt tggaaaactg tttcctatga agctatctct 2760gcctgaagga tttttctttt acaatccaga ctatagaagg aaattcacaa cctggacttt 2820cacctccatt ggtcagagtt ttactgacca attcccacct ctgccttaca cctaacggaa 2880gtttatgcct gttttctctt cacatacccc aacagttaca aatggttgtt attattaagc 2940atcttttatt ttgtggcctc tgattacatg gtcccctaaa ttttgaccta atcacaaaag 3000attggtaaaa tttcttaaca tattaataat attttgttta tgtgtcaata tcttagcatg 3060tatcaattaa gacagaggtc ttaacgttct ctttttgaaa gagaatatta ggattcagag 3120atattaagag attctcccag gatcacagtt aggtaacaga gctggatttt agtccaggtc 3180tgtctacagc tctaacgtat atacaccctt tgtataacat gtcacgaatt cagcataaag 3240ggatcttcag tgatctaagt caggggtcag caaccttttc taaaaaggac caaatagtaa 3300tatttcaggc tttgtggacc ctatggtctc tatcataact gttcaaatca ccatgtagtg 3360taaaaggagc cataagcaaa atataaacta acgaatgtgg ctgttttatg ggattttttt 3420ttaactcttt atttacaaaa gcaggtggca gatcagaact cacttatggg ccatagttct 3480ctgacccctg acctgagaaa atcttatatt tatggacaac atttagactg tgacttgcca 3540agtaagaaca agaagctctg tcaactgaag gtcaaggctg gagttctgaa agcaaagagc 3600tgtctggtgt taatgataag tgaaatagtt aaagttagaa gatcccagtt ataagaagca 3660caaagaataa tgaccataga ctcctgaaca agaatgtctg gacttctggc ttaggcactc 3720ttgttgtatg gtccaggcca agttacctaa tctctccagg cctccatttt cttatcatta 3780aatgaagata ataaaagtat tttcctcaga gagctgtaag aataaactga gctaacccat 3840gtcaagcaca tagaataggg cccagcctat attaatttat caataaatgc cag 38933121PRTpeptidePEPTIDE(0)...(0) 3Met Phe Asn Lys Cys Ser Phe His Ser Ser Ile Tyr Arg Pro Ala Ala 1 5 10 15Asp Asn Ser Ala Ser Ser Leu Cys Ala Ile Ile Cys Phe Leu Asn Leu 20 25 30Val Ile Glu Cys Asp Leu Glu Thr Asn Ser Glu Ile Asn Lys Leu Ile 35 40 45Ile Tyr Leu Phe Ser Gln Asn Asn Arg Ile Arg Phe Ser Lys Leu Leu 50 55 60Leu Lys Ile Leu Phe Tyr Ile Ser Ile Phe Ser Tyr Pro Glu Leu Met65 70 75 80Cys Glu Gln Tyr Val Thr Phe Ile Lys Pro Gly Ile His Tyr Gly Gln 85 90 95Val Ser Lys Lys His Ile Ile Tyr Ser Thr Phe Leu Ser Lys Asn Phe 100 105 110Lys Phe Gln Leu Leu Arg Val Cys Trp 115 12046209DNAHomo sapiens 4ggatgtgagt gggccttcag acttaaacca ggagttacac ctttggcttc cctggttctc 60agttctttgg acttggactg aattacactg ccaggtttcc tggttctcca gcttgcagat 120ggcagatcat gggacttctt ggcctccata attgtgtgag tcaatttcca ttttatttac 180atatccagtt atgcattgct taacaatgga gacaggttct gagaaatgca ttgttaagtg 240atttcatcat tgtgcaaaca tcatagagtg taactacaca aacctggaca gcatagacta 300ctacacatct aggctacatg gtgtagcttg taacctcatg ataagtatgt ataacatcat 360gataagtatg tatgtatcta ccatatctaa atgtagaaaa ggtacagtaa aaatatggta 420taatcttatg ggatcaccat catatatgca atcctttgta gactgaaatg tcattgtgta 480gtgcatgact gtatacgcac acatacacaa acacacacaa atatactatt ggttcttttt 540ctctgaagag ccctaataca atatgttata catttatatt gactctattt caaaatttat 600ggttttggtg aaacatatgt ggagatgggg cataggtgtg tgaactggga tagtgtcctg 660ctgatgaatg ggtgggaggc atcatttggg acaagcccag ggcatcagct tatagatatc 720aagagctcaa caagagcact ttatggcaaa acctcccaca agacctctca gaagttgaga 780aactgctaaa agtttcttta tgacagatga catttatgga taaaataggg attagcagga 840ttctttaaat actttcgaac actaaccttc atttctacca ggcagtgggg ccccaagtgc 900agggccatag gaagtacaag tctgggagat actaggctgc actgtctgta gagaatctga 960aaaaataata gagtcactga aatgcagttt ggtataatta ttgccatgca tcataattct 1020aaatcatact agtggtcaaa tactcttccc tgaaaaaaca ttttcttggt ttgaattcta 1080aataattgtt gtggtcacca ctgagctttt aaatatataa atactttcaa gtttgcatat 1140ttttattacc tgttccttaa caaacattga attcaacatg aaaatgatta tgggaaacat 1200tcgggtatac agtccctgac tcttaaggac tcaggtaaat acttagggta tttcatggcc 1260ctagtctttg gggtaccaca tgtttcttct tcaaatcaca gattcaaaat caagaatgat 1320aacacagtga ttgtgtagac aaaataagtg aaccaaaatt gcttgcttct gtcattctat 1380ggaaccactg agagttttta cttgtgctta aaattttgaa tagtaaaaca gagtgtcaac 1440ttcatgctgg aatatttttg gctttttaga cacaatttta agtacatgaa gtatttttac 1500aagactaagt aacatcactg aaattacagc tttcttcttt ttaaaactgg tatttgttat 1560aaaactaaag agcgaatcaa gaaaagcata attattactg attattacag gattattact 1620gaaaaagaaa tgtacggaat agaggaggaa ggagttaaca aatgatccac tctgggtgtt 1680gaaaacacca ataagcctgc ttccaggaag tgcctaagac agagctggct cagcttgctg 1740ggtcacagca tgtaaggaaa ctgctgggct acatgccacc atcctcagtt gtccagatag 1800ataatcccat agccccatgg ggaaataatc tttaattatg atatagctga caccattcaa 1860agcactatgc taagtccttt atgtgaatta acttttgtca aatttatttt tcataaataa 1920cccaaatatg tataccacta ttatcctacc ttaaagagga gaaactgagc tcctaaagtt 1980taaatatcta acccaagtta agactgctag tcaccctagg ctattaactc aggcagtcta 2040actcaggtat aataacatta tgctactgtt tgcagctttg actatgcctg aattataacg 2100tcatgctatc taactaaaaa gctaagggaa ataaaatgag ccatagggct caatttcata 2160aaaggagaga aaatactggg gaaaagtgat aatgcagagt ttaaaatatt tttgtaaaag 2220tgccagagat tgagtataac aagtgtgacc aaaaaaaaaa aaaaaaaaaa aaaaggaaga 2280aggtaaaaaa aagagggagg tctgagaaat agaaatatca gaggaaggaa ataaaggagg 2340gtgagagtaa attctctttt agcattcaga ttccacagat tccacaaatc acatttcttt 2400ttttaccaac taaggaaaaa taacacttga cctaacattt cattgcagtt agctaaagga 2460tgctagaaaa actatgttgc agtggtttgc tctaatttct tcaggaatag agaaaagtga 2520caaaaagatc agagaagaga agaaaggaaa ctatcagaaa aatacagaat tggagtagga 2580tataacatat ttgggttgaa ggtaaaattt tatattgtaa tcttaagtat cttgctactt 2640cagtttggtc cctggaacag cagcatcaga atctgccgag ggcttgttaa aaaggcagaa 2700tctcaggtcc catcccagac tcactgaatc agaatataaa tactgacaag atgccccggg 2760attcatatgc acagtagagc tggcgaagtt ccattgtagc ctgtgattgt tttctgcaac 2820ttagtatttc tgagttttcc caaggaagaa aacccaggcc ttagcttctg gcagacttgt 2880gtttctcctt tacttactag ctgcatgact catgagcaag gaaatcaaac tttatgtgcc 2940tgagtttcct catctataaa atggagacta taataatcat ctcctaggct tgttttgagg 3000atgttcaaca aatgctcctt tcattcctct atttacagac ctgccgcaga caattctgct 3060agcagccttt gtgctattat ctgttttcta aacttagtaa ttgagtgtga tctggagact 3120aactctgaaa taaataagct gattatttat ttattttctc aaaacaacag aatacgattt 3180agcaaattac ttcttaagat attattttac atttctatat tctcctaccc tgagttgatg 3240tgtgagcaat atgtcacttt cataaagcca ggtatacatt atggacaggt aagtaaaaaa 3300catattattt attctacgtt tttgtccaaa aattttaaat ttcaactgtt gcgcgtgtgt 3360tggtaatgta aaacaaactc agtacagtag tattcagtac agtatttaag cccctgtact 3420taaacatatt cctcgtacca atgaagttac atgaaaagca aatttgtgtg agatatcgta 3480gatggaagta aattagtctt tatgttcccc acaaattgaa atgcatttca aaaactctgt 3540gtgtgtatgt gtgtgtgtga cagagtgtgt gtgagagaga gacagagaga tacgctttgg 3600ttgcctccat aagctggctg ctatgattaa taagaccaag ttttctaaag aaaatgagat 3660cataacaaaa gccctcttta tgactatctt ttatcagggg caaaaaggaa agagacaaaa 3720cagcatgaaa tgatgagacc aagtgatgaa aattcattca caatgattgc tttcaagagt 3780aatttctctt gggtaattca gcagcctgtt actatggctc tctggagtga tagctaatgt 3840aaatgaagcc tctaaaagtg gattatcctg acaagaatat actcagccaa taatgcaaca 3900gaaatccatt caaagcattc gggaaaaatt caaaagaata aatattcttt tttttttttt 3960aaagttaatg acctacgatc catttcttcc ctgactaaca agcagcaagc acttaaaaat 4020atccagccag gatgaaatag aaacccacct gacttgttaa tatttttgtt tggtcccagg 4080gactcagatt ctaagccaaa ttctttgaat gatcttggca aatgtctcga attatttttg 4140ccaacttttc tttatcttgg aaaaaaagtt tcatgaatgg gtgtcaaaat tgattagttt 4200taaaaacctt tcttgcagat acgtatggca ccctaaaact gtattagaaa aaaatttcat 4260atctccaggc ctttcattgg gtcaggttgg catttcgctg ccctttatgt gtgtgacaag 4320tgaaaataag gaaagaaaaa aactcaagtg aagaaaatca gaatctgcgc agcagttcct 4380gggcgtttca gctgcttccc acatcacctg cctcatcaag ccccagcatc catctccttg 4440ctcatcttac accctgtgtg catgacaggc ccaccattca tttatcagag caaaggctct 4500cccactattc tggttcaccc ccctacttag ccagatatac aagaatatct gcacggatga 4560cctgcctcac ctgggagctc agaggagctc agattccatt actatcgcac caaggacaga 4620tctcccagca agaatgacag aaaagactaa ctgcccccaa aatctccctt ccaaaacaca 4680gttctcttaa ttctcccaag aaaccagaat gtgactgctc acctctctaa ggacctgaaa 4740acaactggcc atttcagcta tttaaatcaa ctttaaaaaa tccaaccgcc aaaatattaa 4800accattttgg ttggaatgat aacataacta acctgctgac agctgcttct gctaggtgca 4860aaaatggaaa aaaaaatact tctaatcagg tcaaatcact ctacctttgg gattctaaat 4920ttactcatat tctcaaagaa atatattcag tcatagtggg gaaaatagga ttattccttt 4980agctcgataa gcaaccagaa gttcttcctt caaatcttga catttaatca atcagaaatt 5040gatttttgga aaactgtttc ctatgaagct atctctgcct gaaggatttt tcttttacaa 5100tccagactat agaaggaaat tcacaacctg gactttcacc tccattggtc agagttttac 5160tgaccaattc ccacctctgc cttacaccta acggaagttt atgcctgttt tctcttcaca 5220taccccaaca gttacaaatg gttgttatta ttaagcatct tttattttgt ggcctctgat 5280tacatggtcc cctaaatttt gacctaatca caaaagattg

gtaaaatttc ttaacatatt 5340aataatattt tgtttatgtg tcaatatctt agcatgtatc aattaagaca gaggtcttaa 5400cgttctcttt ttgaaagaga atattaggat tcagagatat taagagattc tcccaggatc 5460acagttaggt aacagagctg gattttagtc caggtctgtc tacagctcta acgtatatac 5520accctttgta taacatgtca cgaattcagc ataaagggat cttcagtgat ctaagtcagg 5580ggtcagcaac cttttctaaa aaggaccaaa tagtaatatt tcaggctttg tggaccctat 5640ggtctctatc ataactgttc aaatcaccat gtagtgtaaa aggagccata agcaaaatat 5700aaactaacga atgtggctgt tttatgggat ttttttttaa ctctttattt acaaaagcag 5760gtggcagatc agaactcact tatgggccat agttctctga cccctgacct gagaaaatct 5820tatatttatg gacaacattt agactgtgac ttgccaagta agaacaagaa gctctgtcaa 5880ctgaaggtca aggctggagt tctgaaagca aagagctgtc tggtgttaat gataagtgaa 5940atagttaaag ttagaagatc ccagttataa gaagcacaaa gaataatgac catagactcc 6000tgaacaagaa tgtctggact tctggcttag gcactcttgt tgtatggtcc aggccaagtt 6060acctaatctc tccaggcctc cattttctta tcattaaatg aagataataa aagtattttc 6120ctcagagagc tgtaagaata aactgagcta acccatgtca agcacataga atagggccca 6180gcctatatta atttatcaat aaatgccag 6209589650DNAHomo sapiensgene(0)...(0)human genome sequence 5cacacgtagg ctacgagtgg ccctcagcct gcctcatcat ggacctgtgt tataataaat 60atgtttaatt gtgctgtttt cttatagagg aaagtcctga tgttagttgc cttgaagtca 120gacacccaga gagaatcaca ggttttcaga ttaattcatc gcttgattct tatccctgaa 180gtcatatctc tggatctctg gttctcacat tataaatttc aatgattctt tttctatatg 240gccatgtcat tcatatcctg tgtaatatgg ggaaactgag gtatgaatga catcattcaa 300aaagcacctg caatttttct ttgccaagca cttacagctt tttctcatgt tgctttcaaa 360aagtcattga aatattgttc acatattttg cagatgagga aatgaatatt caaatgcatt 420aggtatcttg tccaagttct tacagccaga aagtagagaa atgaatttga attacaaatc 480ttctacctct tggcttatgc tcttttcatg acactgggaa taaatgtctg aacaagcatg 540acttcatgtt tcaactattt atcaaatact tgttttctac taagatcttg cactcactca 600gtgggatccc ctgaagcctg ctgattattt gtcctttggc atttatcact ctctgtggga 660ccttactctc ctatggtaaa gttttattgt tattaaaagt attatttgac aataaatgta 720gaaatcctac agatcatact caacaacatg tctaatgtca gcacacaatg tctaacaatc 780atttatgaat actttatgtc aaacataagc aataacctaa ttaaggaagg tatttttaat 840aaattgacac tttttgacat aaccatattt caagtggctc cattgttttg tttatttatt 900tatttattta tttatttatt tatttttgag aaagggtctc actctgttgc ccagactgga 960gtgcagtggc aacatcatag ctcactacag cctcgacctc tctgggctca agcaatcctc 1020ccatctcagc ttcccaagta gctgggacta caggtgtgta ccatcatgcc aggctaattt 1080ttcgtatttt gtagagacgg ggttttgcct ggtcgtccgg gttggtctca aactcctggg 1140tgttccgccc accttggcct cccaaagtgc tgggattata ggcatgagcc tcaagtggct 1200actttttagg gttgaaattt atattgactg tcaactagct tccctagtta gtatttggga 1260tctgctaact aatttatatt accatccaac ttgtcaacat ttgttgaaat ataactgtcc 1320tcactttttt tgtgtgaaca ttgaatacac tttcagacta aatttggttt attacttaat 1380gtcttattct ttattagagt taataatatt tcttaatact ttgccttcca caaatgaata 1440acttgtttgt gatggctacc tctttttttc tcttagcctg tcacaggtat tatggataaa 1500aattagcacg gctgggcaaa aacaatgaaa gaaatacact tgcctgggaa agctggggag 1560gggtaaatga atataattca aaataccata tatttattca acactgttgg aatatatgtc 1620ctgttggaaa tgtaaaagtg acatatgttc tcttcctggg tctcagactt ttaggatcta 1680gttgagggaa ctggacttat acacaaaata caattcaaca acattatgag ctagaaaatc 1740catgagctaa agtctttggc aaagacatta ggtaacatga ggagtcagga aaaggagaaa 1800ttactgtggg ctggaatggt ctgggaacat gagatggagg aagtggcttg ttactggaga 1860aaggatgagg ttcaaagaga tgggaaaaaa agaaagagag aagaaagaaa agaaatgagg 1920aaaaacaagt tgccagaaag aacaaggaag aatagaggca ggtaagcagt ggattttgcc 1980ctagggaagg taatataact agagacggca gtttctaaca ggccatgatg aataagatac 2040actttagccc tcattggtac gtgcagaaat tcaaatttgg aaattcaagc ttacatgaca 2100gtaaatatat gttgggaaaa aaataaccgg taaacattta catcagctct ttttcctaaa 2160gagaaaccta ttccatgcta tgaaatattt gtcacaattc tgttttcaaa atacttgctc 2220tacttttcca agccacaaga ggaaacattt tctctgccaa cactctctga ccttaaccag 2280tttctccact acgtctactc ttaagctctc tttagagctg tgtgtatctc gtctttatgt 2340aaacctccta gatgatatac ttatggaaat attcaggcaa ctttttcatg aactttacca 2400ggaaagacat ttctagcagg agagcatgaa tagaaatgga ctcttcccca gtctctgctg 2460ggttctgact gtggtcactc taactataaa aagtgtgtaa aaatcatgag cagattattt 2520catttccttg gggtccctaa aaatttcaag gtatctgtat tagcacagga agatttaaat 2580tgatttctca acacattcag atatcttatg aactttatta agataaattt cctccagcat 2640tcagaaactc atatattaca gaataaaaaa taaagcagaa aattagtgta cctggctaaa 2700aatgagagca gggttctatt tcattttgga aagtcactaa gacagtaata ataccattaa 2760tgataaaatg ttaacattag ttaattatta gatgtgtttt tgtatgccag ccacataata 2820tatactttta tatgtatcac ctacatttct agatgtaaat gtgagggaat tatagtagta 2880tctacctcgt atgattgctg gatgatttaa atgagctgtt gtctcaaaaa cttggtatag 2940aaagcagaaa cttttagtta ttaagattct tactattcca atatttgaat aaaacagtga 3000cctgctaaga aaccccaata atattctgat acatcaaaac cttctggcat tagatgtttc 3060taatctaaca tcttcatatt aattttttta tgttttgatt atctacattc agtagtgaat 3120gtgtttctaa acgctggatg catttttaac taaatgtgtt ttgtaccaca ttttgacaac 3180ttttgtttta actatgattc agcttataac aaaacaaaac aatgcatctt ctctccactg 3240ttaataaggt taatgaaaag ttgacttatg aaaaaaatcc taatttatgc acattctcat 3300tgttttcctt gctaaggata ttagtacttg acgattctgt aacaaagaat tatcatggga 3360tgaaactttg atgcaaatat cttatcaata caatgtgctt gattttacct agatgagatt 3420tttcttttct tctttctttt ttgagacagg gttttgctgt gttacccagg ctagcctcaa 3480acccctggcc cctggcctca agtgatcctc tcacctctgc ctcccaaagt gctgggtatt 3540acagatgtga gtcactgaat ccagcctcac ttagttggct ttcttagtga attattttat 3600ctggttctaa aactttttga taatactctc aaatatttat ggattttata acataattta 3660tggattacgt agttatgaat ttcataaatg attttgtgat attgccacag atcatcacca 3720ttatacagga tgtataacat aaccatggtt taatatattt tcataaacta tagaccaaac 3780aaagactggt caggaccagg gcacgcatgc attttatatg tgtggtgcct attggaatat 3840gccaggcctc ctgtgaaaaa aatcagtaag tgcttatctc ataggaccaa cggcccaaca 3900ttcctgaagt cactaccaca ctttgcactt atctccatgt ggaaatagat agccactgtt 3960gaattctggt gagaacgaca cgtctgaaat ctctcagctt cacaacccct attacagccc 4020tcagagaatc ttctcacata gcgccaaaca acaactttag gaagtgatgt tcctagaatg 4080aatcaatttc taaaattaaa agtgaaaaca atgacaagga gaagggaggg tcagagagga 4140aaggctgatg ttactaaaag acaaaagaca gtataacctc ttatgaggat ggtccagaca 4200ctcagggaaa tgcaggaaga aataaaagat aggagtttga accacactgt gatggctaac 4260tttatgtgtg gacccgaccg atctatggga cacccagata gcttgtaaag cactatttct 4320gggtgcgtca gtgagggtgt ttttggaaga gatcaacact tgagtcagta gactgagtaa 4380agcagatggt cctcaccaat gtgggtgcac attgtttaat ctgttgagtg cctggataga 4440caaaaaaggc aaaagaaggg tgaattccct ttctcgtctt aagctgggac agccatcctt 4500tcctaccctc agacatgaga ggtttggatt cttggatctt tggtcccaag ggctgacact 4560ggtggccacc tctggtttca ggtctttggc cccagattgt aagttacacc atcagcttcc 4620ttggttcttg ggccttgaga ctcaagctaa aatacactac cagcttccct tgttctctag 4680tgtagggaca gcaaatcatg aaaccttctg cctccataat catataagtc aattcccgta 4740ataaatctgt gcttatatat ctatagcttt ccttttggtc tgtttctcca aagaacctta 4800atgtacacac tatatgacct aacctgtagt aatgataacc ttatgcaggt ttgaataaga 4860tgatggtatt ctcagtatct gggaggtatg ggctagagtg atgaaccacc gccatgagcc 4920taggactgag gagatttctg aaatgtggaa tatttggtgt caaaaccaag agataatata 4980gccatgtgga aaacatgtag aactatcgta tgattcagca acccaaccac tgggaattta 5040cccaaaggaa aggaaaccag tatattaaag agaatctgca ctcccatggt tattgcagca 5100ttattctcaa tagcctagat atggactcaa cctaggagat tagatgaatg gacaaagaaa 5160atgtggcata tgtacaccat gaaatactta ccagctataa aaaagaatta gccaaagcag 5220tggtgtgtgc ctgtcatccc agctccttgg gaggctgagg tgggaagatc tcgaggccag 5280aagtttgaga ccagcctggg caaaataata agactcggtc tctaaaacaa tttaaaaata 5340ggccttcctt aaaaaaagaa taaaatcatg tcattcacgg caacatagat gggactggag 5400gatattactg ttaagtgaaa ttagccagga acagcaagtt aaaccccaca tattctgatt 5460catatgcgga agctaaaaaa acgttgatct catagaagta aaaagtagaa cagaggatgc 5520tggagactag aaaaggtagg gagaaggaag ggagagggaa aaatttgtta acaggtacaa 5580aaacaaaatt acagttagtt agggagaatt aattccagca tcctgtagca ctataggatg 5640actatagtta ataataatac tttaattagt ctcaaatagc tagaaggagg atattgaatg 5700ttcccaacac acacaaaaaa atgataatgt atgagatgat ggatatggta gttatcctga 5760tctgatcact ctacattata tgtatcaaca catcactatg taccccacaa atatgtagaa 5820tttttatttg tccatttaaa aaagataaca aatttaaaaa taaaataaaa actaaattag 5880tgttccatgt aaacctggat gaactggtca ccctacgtct gcccatctag atggctggtc 5940aaagtttccc aggctccaca tcaagttgtt ccactgctca ctggaacttc cctagtcagg 6000ttgggcaaat agtaatttac agcaatagtg aatttatcac tgacatttct tcagttcccc 6060tctttggcat ctgcttcttc ttttctgtaa tgctgtttgt tgaaatgccc aacattcttt 6120ttcttcccta gagctattca gggtgacctt tcttttcgca ttttcccatg ccacttccat 6180tatatcaaaa taaaacagtc ctgtgtggcc actgctcatg accttgtttc ctgccatgtg 6240aagataggat cggctgctct ttcttctcct cctttttttt cagagacagg atctctccct 6300gtcacccaga ctggagtgca atggcacagt cgtagcttgc tgcagcctcg aactcctgga 6360cctcctcagc ctcctgagta gctgggacta caggtgcaca ccaccatgcc ttcctaatct 6420gatatatata tatatatata ttatatatat aaaatatata tataaatata tatattttat 6480atattatata tataatatat atattttata tataaaatat atatattata tatatatatt 6540atatataaaa tatatatatt atatatatat atatatatta tagagatggg gtcttgctct 6600gtcacccagg ctgaagatca gctgctcttt ctaatctgtg gttagataag atctgtctcc 6660caggggataa aatactacct ggaataaagg tatctttaaa ataatcccag agaagaaaac 6720atttttatag tatgacagag gcagagaaaa cagagaatat ttgttaaggc aggactttca 6780ccactcccag tacaatcatc tgtctgttac ctgcatacct tacacgggct ggcactgctg 6840ggggtacaaa gtagatgcca aacttcacaa tggttagatt catgtttaaa aagccattgg 6900atcaaacctt tgtgaaagtt tccagctttt ttctgttcca aatatgtgtc cattataaaa 6960gaatctcaag agcataattg ccaagatagt ctatgtccat gagtatttca acatctctca 7020tgaaatctgt tcccatcatt actcaagata ttgtatgaac agtattccac ataaactagg 7080tgctcaataa tgattgattg gccaatggag ggtcattatt taatgcacta caatctttta 7140tgcaaggggc ccacaggaat cagtatgatc ccataggaat ccttttcttt tccattgaaa 7200aagaaacaga tagtggcttg tattaggttt cttgtgtgtg ttgtgaggtg gaaagatatg 7260aaaagaaatt tgatcagagc ataaatctga gcccatggga taggaaagaa tgagggaata 7320aggaagaaaa cacagattat agacaggaaa atcaaaccta ttaaaactga taattttcga 7380atactaaaaa tgtacattca tttgaacaaa aagattctat aaagcaagat ttctctgttc 7440ttaccagcac taccatgccc aaactacctt aggaaatgaa tagcagagtc aaacttaaaa 7500gcacctgaaa tttaaaacaa aaaccaattt acattttatt taagaaaagc aaacagatgg 7560gcctgctaac aatgtcaaag tctcgtttac aaagaaaaaa acaaatctgg aacctgaagt 7620caaacgagtt caaaataaaa agcaaaccaa taaacagaaa ccaacataaa cagaagttac 7680taccatctcc ctcagcctgt gaaattctgg aacttctctt tctttctcgc cttcttcttc 7740tctcacctgg aagacgagca gagtgaacac atcaggggtt gtcagttccc cagatggcac 7800cacattcata aaccaccgac tccaggagaa tgtaggaagc ttagttaagg ccaaagttct 7860ctttggatct tcctcatggg cttcaaggca aaagaaaaaa aagtttgctt gagaatatct 7920tcatatctat tagtttgaac catgcaaaat tacagttttt ataggtaaaa tgagtgcata 7980ttggcaattt caaatgatta accctaatac attatgcttt tgggtataga aatattcaga 8040tcttaaacat atgctgttac atacaaaatc aggtatattc ctgcttctat aattaaagca 8100aagagaattt cttttggtca ctactccttc tgacatgagg tatgaaccaa gttcaggacc 8160cctaaaggtc tgggtctggg tcatttctcc acctctaact tgtgccgctt tcttggtcag 8220tcattgtgtt ctgagctgtc tcataaaaca tctgctatga ctttactttc tcctgatagg 8280gtggctttcc atcgttggca cttcgttggc cttattggta tgctttatac actggttctc 8340gtttccaaat tggcattatt attgttatga ttcctgctgc tctcccacat ttcccatctt 8400tctcctgatc tctctcacct gtacatttct tacattttct cctgtgcttc cttcttccca 8460tcatcattgc ccaagtgtgt cttctttctt ctccttgtca catttccttt gcccgctctc 8520acatatgcag agatggctct tggttttcct tctgaaatct catagtttgg aggtaaactt 8580gttagcaagg ccactgagaa gagaacaaaa gggaaacata agagaaacca agtcactatc 8640tctctcattt cctggtttct agaagtaaga cccaaagaac tcactgtttc agtgctttca 8700gctcaggcca aactagggtg atcaaactga gcttctgagt gctgatcaaa acctataaaa 8760ccaagtagac agaccatcta caaatcttca ctgttaaata ccataaagaa tgaaaaggtc 8820actaattggt aagactatat gtgtgataat taaatttatg catcaacctg gctaggctaa 8880aggatgacca ggtagctggt aaaacattat tctgggtgtg tccataagag tgttttcgga 8940agagatcagc atttgaattg gtgaacttag taaagcagac ggctctcacc aataagggca 9000ggcatcatcc aatctgtcga aagcttgaat aaaacaaaaa gaggaaggga aaatttgctt 9060cttttcttct tgatctagta tatcatcttc tcctgccctt ggatgtgagt gggccttcag 9120acttaaacca ggagttacac ctttggcttc cctggttctc agttctttgg acttggactg 9180aattacactg ccaggtttcc tggttctcca gcttgcagat ggcagatcat gggacttctt 9240ggcctccata attgtgtgag tcaatttcca ttttatttac atatccagtt atgcattgct 9300taacaatgga gacaggttct gagaaatgca ttgttaagtg atttcatcat tgtgcaaaca 9360tcatagagtg taactacaca aacctggaca gcatagacta ctacacatct aggctacatg 9420gtgtagcttg taacctcatg ataagtatgt ataacatcat gataagtatg tatgtatcta 9480ccatatctaa atgtagaaaa ggtacagtaa aaatatggta taatcttatg ggatcaccat 9540catatatgca atcctttgta gactgaaatg tcattgtgta gtgcatgact gtatacgcac 9600acatacacaa acacacacaa atatactatt ggttcttttt ctctgaagag ccctaataca 9660atatgttata catttatatt gactctattt caaaatttat ggttttggtg aaacatatgt 9720ggagatgggg cataggtgtg tgaactggga tagtgtcctg ctgatgaatg ggtgggaggc 9780atcatttggg acaagcccag ggcatcagct tatagatatc aagagctcaa caagagcact 9840ttatggcaaa acctcccaca agacctctca gaagttgaga aactgctaaa agtttcttta 9900tgacagatga catttatgga taaaataggg attagcagga ttctttaaat actttcgaac 9960actaaccttc atttctacca ggcagtgggg ccccaagtgc agggccatag gaagtacaag 10020tctgggagat actaggctgc actgtctgta gagaatctga aaaaataata gagtcactga 10080aatgcagttt ggtataatta ttgccatgca tcataattct aaatcatact agtggtcaaa 10140tactcttccc tgaaaaaaca ttttcttggt ttgaattcta aataattgtt gtggtcacca 10200ctgagctttt aaatatataa atactttcaa gtttgcatat ttttattacc tgttccttaa 10260caaacattga attcaacatg aaaatgatta tgggaaacat tcgggtatac agtccctgac 10320tcttaaggac tcaggtaaat acttagggta tttcatggcc ctagtctttg gggtaccaca 10380tgtttcttct tcaaatcaca gattcaaaat caagaatgat aacacagtga ttgtgtagac 10440aaaataagtg aaccaaaatt gcttgcttct gtcattctat ggaaccactg agagttttta 10500cttgtgctta aaattttgaa tagtaaaaca gagtgtcaac ttcatgctgg aatatttttg 10560gctttttaga cacaatttta agtacatgaa gtatttttac aagactaagt aacatcactg 10620aaattacagc tttcttcttt ttaaaactgg tatttgttat aaaactaaag agcgaatcaa 10680gaaaagcata attattactg attattacag gattattact gaaaaagaaa tgtacggaat 10740agaggaggaa ggagttaaca aatgatccac tctgggtgtt gaaaacacca ataagcctgc 10800ttccaggaag tgcctaagac agagctggct cagcttgctg ggtcacagca tgtaaggaaa 10860ctgctgggct acatgccacc atcctcagtt gtccagatag ataatcccat agccccatgg 10920ggaaataatc tttaattatg atatagctga caccattcaa agcactatgc taagtccttt 10980atgtgaatta acttttgtca aatttatttt tcataaataa cccaaatatg tataccacta 11040ttatcctacc ttaaagagga gaaactgagc tcctaaagtt taaatatcta acccaagtta 11100agactgctag tcaccctagg ctattaactc aggcagtcta actcaggtat aataacatta 11160tgctactgtt tgcagctttg actatgcctg aattataacg tcatgctatc taactaaaaa 11220gctaagggaa ataaaatgag ccatagggct caatttcata aaaggagaga aaatactggg 11280gaaaagtgat aatgcagagt ttaaaatatt tttgtaaaag tgccagagat tgagtataac 11340aagtgtgacc aaaaaaaaaa aaaaaaaaaa aaaaggaaga aggtaaaaaa aagagggagg 11400tctgagaaat agaaatatca gaggaaggaa ataaaggagg gtgagagtaa attctctttt 11460agcattcaga ttccacagat tccacaaatc acatttcttt ttttaccaac taaggaaaaa 11520taacacttga cctaacattt cattgcagtt agctaaagga tgctagaaaa actatgttgc 11580agtggtttgc tctaatttct tcaggaatag agaaaagtga caaaaagatc agagaagaga 11640agaaaggaaa ctatcagaaa aatacagaat tggagtagga tataacatat ttgggttgaa 11700ggtaaaattt tatattgtaa tcttaagtat cttgctactt cagtttggtc cctggaacag 11760cagcatcaga atctgccgag ggcttgttaa aaaggcagaa tctcaggtcc catcccagac 11820tcactgaatc agaatataaa tactgacaag atgccccggg attcatatgc acagtagagc 11880tggcgaagtt ccattgtagc ctgtgattgt tttctgcaac ttagtatttc tgagttttcc 11940caaggaagaa aacccaggcc ttagcttctg gcagacttgt gtttctcctt tacttactag 12000ctgcatgact catgagcaag gaaatcaaac tttatgtgcc tgagtttcct catctataaa 12060atggagacta taataatcat ctcctaggct tgttttgagg atgttcaaca aatgctcctt 12120tcattcctct atttacagac ctgccgcaga caattctgct agcagccttt gtgctattat 12180ctgttttcta aacttagtaa ttgagtgtga tctggagact aactctgaaa taaataagct 12240gattatttat ttattttctc aaaacaacag aatacgattt agcaaattac ttcttaagat 12300attattttac atttctatat tctcctaccc tgagttgatg tgtgagcaat atgtcacttt 12360cataaagcca ggtatacatt atggacaggt aagtaaaaaa catattattt attctacgtt 12420tttgtccaaa aattttaaat ttcaactgtt gcgcgtgtgt tggtaatgta aaacaaactc 12480agtacagtag tattcagtac agtatttaag cccctgtact taaacatatt cctcgtacca 12540atgaagttac atgaaaagca aatttgtgtg agatatcgta gatggaagta aattagtctt 12600tatgttcccc acaaattgaa atgcatttca aaaactctgt gtgtgtatgt gtgtgtgtga 12660cagagtgtgt gtgagagaga gacagagaga tacgctttgg ttgcctccat aagctggctg 12720ctatgattaa taagaccaag ttttctaaag aaaatgagat cataacaaaa gccctcttta 12780tgactatctt ttatcagggg caaaaaggaa agagacaaaa cagcatgaaa tgatgagacc 12840aagtgatgaa aattcattca caatgattgc tttcaagagt aatttctctt gggtaattca 12900gcagcctgtt actatggctc tctggagtga tagctaatgt aaatgaagcc tctaaaagtg 12960gattatcctg acaagaatat actcagccaa taatgcaaca gaaatccatt caaagcattc 13020gggaaaaatt caaaagaata aatattcttt tttttttttt aaagttaatg acctacgatc 13080catttcttcc ctgactaaca agcagcaagc acttaaaaat atccagccag gatgaaatag 13140aaacccacct gacttgttaa tatttttgtt tggtcccagg gactcagatt ctaagccaaa 13200ttctttgaat gatcttggca aatgtctcga attatttttg ccaacttttc tttatcttgg 13260aaaaaaagtt tcatgaatgg gtgtcaaaat tgattagttt taaaaacctt tcttgcagat 13320acgtatggca ccctaaaact gtattagaaa aaaagtaagt actctgtagt gtgaaaaatt 13380cttaaaggac accctctttt acaaactcac aaaaacagcc tttggaatac ccacatgaag 13440tagctgttgt tattgctttc tatataccta catcttgtct attataaaaa gactggtttt 13500tggcaggtgt ggtggctcac acctgtaatt ccagcacttt gggaggccaa ggcgggcgga 13560tcacctgaga tcaggagttc aggaccagcc tgatcaatat ggtgaaaccc agtctttact 13620gaaaatacaa aaatcacccg ggtgtggtga cgggcgcctg tagtcccagc tactcgggta 13680gctgaggcag gagaatcact tgaactcagg agtcagaggt tgcagtgagc tgagatcatg 13740ccactgcact ccagcctggg tgacagagca agactccatc tcaaaaaaaa aaaaaaaaaa 13800gactggtttt tcaacagcta ttcccacccc tctgcatgga aatattcacc cagtcaattg 13860ttttcctagt ttgggtaatg gccctctggg caggactgga gtggggcaca caggagaagc 13920tgcaaactat gtttagaagc atgtctggga aatgtcatgc aagaaaagac atatttaaag 13980gtaggctttg catgaatgga aaaggagagt aattctatgt agagcagagc ctcttacttg 14040cagtgagaga agcaaaagtg gggaagcaag aggaattatg cttttcatca

gccaaatttg 14100caggtaggag gattggctca gtcatcttgg ctgaggctca tgaaaccagg tgtaaagaaa 14160gtggactaga ttaatttcat ccattacagg aagaggagcc gtgaaagata atccagaaat 14220cattgggatt tgatggtaga aggtattttg ggactattcc atttgaaatg agaaggtacc 14280tgacattctt tgaattcctt tcaagcaaag gattaaattt acccatgagt tgactcagaa 14340aaaacataaa aagtattgtt gctctgctca gagttttatc taactcattc tcacttctta 14400ttccatgatg aaatgacata aatgaggttt tttattgttg ttgttgttgt tttctggaca 14460caaggcaagg tagctacctg ggcagagctg ttttatttct ctatgccgtg gagagaaatt 14520ggttaattgg ccatggaagg cagtcattaa gatgttccca tgcgagtgaa ctttccaggg 14580ttcccagctt ctgcatcctt ccctgtccct caattccatt gttggtgatg acaatgtctc 14640tcccatcagc ctcatgaagt tctctctcat ttattaaaat ttgctttcag gaaaaatttt 14700gaaaatgtgt ccagtaatgc ctgattggcc ccttatccta aaggcttaaa ctggaggaag 14760gaagctaaac tgagaaatct tgcaaatcat tgagccaaaa acgtattaat agcaagatct 14820atcatttatt gactagtatg tggcaggcag tgccctttta tttaggcagg gagagttgat 14880ggggggggcg gggttcacac atcttaaaga ggtgctatct cctcctatat aaatcatgta 14940agtcaagaga gtaaggaatt gtctttgttt ggttatattc aggggattag agtatacagt 15000agaagatccc aagaaacctt gggatcattt tagactaaga aatgccaata ccgccgggcg 15060cggtggctca cgcctgtaat cccagcactt tgagaggccg aggtgggcgg atcacaaggt 15120caggagattg agaccgtcct ggctaacgtg gtgaaaccct gtctctacta aaaatacaaa 15180aaattagccg ggcgtggtgg cgggcgcctg tagtcccagc tactcgggag gcggaggcag 15240gagaatggtg tgaactcagg aggcggagct tgcagtcagc cgagattgcc ccaatgcact 15300ccagcctggg cgacagaacg agactccgtc tcagaacaaa acaaaaggaa atgccaatac 15360cagcagaaat agagccaaat catgaacata agctaaacaa atgttggcag tgtagcctag 15420tggttaagag agcagactct taactagaac actgcactcc atgtcctcac tgtagaccct 15480cactgtgggg ttctaattaa cccctgttac ttaccagtgg cagtcttaag gcattcctta 15540agttcgttgt gccccaattt gttcatctgt agaaggggta ggatgacagt agtgtttact 15600ttataggctt actgtgagca ttaaatgagt tactactgta tttgtaaagt gcttaaaatg 15660ctgctccaaa agagtttgtt aaacacttaa gaactgattt acttgcatct aaactgacag 15720ctctcaataa ctggaaatga tcaagcatag gccctggaat ataagcaggt ctacatgaag 15780gcaaaaatgt tcgtttcttt tgttcagccc tgtgcctaga tcaatatcta gtgatcatgc 15840tcaagaaata ttgttgaatg aatcaatgaa cctaccgagg tagttacata aaagagttct 15900gcatgagtac aaatctgggc aaagtgacct ccaaggaaat ttccactttt agattctgtg 15960atttccttaa ggaactgata aattggtgtg atacaatgta aaaaaatgtg cctatatgat 16020ttgagaaaaa cttattttct ctccctcttt tttccttcct tccttcctcc ctcccttcct 16080tccttcctcc ctcccttcct tcctccctcc ctcccttcct tccttctctt tcttcttttc 16140tttctttctt tctttctttc tttctttctt tctttctttc tttctttctt ctcttctctt 16200tcctttcttt cttcctttct ttgtgccttt ctttctttct ttctttcttc tctgtccttt 16260ctttcttcct ttctttcttt ctgcctttct ttctctttgt ttttctttct ttccttcttt 16320tttcctttaa gcagaccatg tctgttagat gaatgccttt ttctagttaa aaggttaaac 16380aggaaagtga agcacaatta tcaagggtct ccagtcatct ccacatgttc ttaatcatta 16440tcttctttta cagtttcata tctccaggcc tttcattggg tcaggttggc atttcgctgc 16500cctttatgtg tgtgacaagt gaaaataagg aaagaaaaaa actcaagtga agaaaatcag 16560aatctgcgca gcagttcctg ggcgtttcag ctgcttccca catcacctgc ctcatcaagc 16620cccagcatcc atctccttgc tcatcttaca ccctgtgtgc atgacaggcc caccattcat 16680ttatcagagc aaaggctctc ccactattct ggttcacccc cctacttagc cagatataca 16740agaatatctg cacggatgac ctgcctcacc tgggagctca gaggagctca gattccatta 16800ctatcgcacc aaggacagat ctcccagcaa gaatgacaga aaagactaac tgcccccaaa 16860atctcccttc caaaacacag ttctcttaat tctcccaaga aaccagaatg tgactgctca 16920cctctctaag gacctgaaaa caactggcca tttcagctat ttaaatcaac tttaaaaaat 16980ccaaccgcca aaatattaaa ccattttggt tggaatgata acataactaa cctgctgaca 17040gctgcttctg ctaggtgcaa aaatggaaaa aaaaatactt ctaatcaggt caaatcactc 17100tacctttggg attctaaatt tactcatatt ctcaaagaaa tatattcagt catagtgggg 17160aaaataggat tattccttta gctcgataag caaccagaag ttcttccttc aaatcttgac 17220atttaatcaa tcagaaattg atttttggaa aactgtttcc tatgaagcta tctctgcctg 17280aaggattttt cttttacaat ccagactata gaaggaaatt cacaacctgg actttcacct 17340ccattggtca gagttttact gaccaattcc cacctctgcc ttacacctaa cggaagttta 17400tgcctgtttt ctcttcacat accccaacag ttacaaatgg ttgttattat taagcatctt 17460ttattttgtg gcctctgatt acatggtccc ctaaattttg acctaatcac aaaagattgg 17520taaaatttct taacatatta ataatatttt gtttatgtgt caatatctta gcatgtatca 17580attaagacag aggtcttaac gttctctttt tgaaagagaa tattaggatt cagagatatt 17640aagagattct cccaggatca cagttaggta acagagctgg attttagtcc aggtctgtct 17700acagctctaa cgtatataca ccctttgtat aacatgtcac gaattcagca taaagggatc 17760ttcagtgatc taagtcaggg gtcagcaacc ttttctaaaa aggaccaaat agtaatattt 17820caggctttgt ggaccctatg gtctctatca taactgttca aatcaccatg tagtgtaaaa 17880ggagccataa gcaaaatata aactaacgaa tgtggctgtt ttatgggatt tttttttaac 17940tctttattta caaaagcagg tggcagatca gaactcactt atgggccata gttctctgac 18000ccctgacctg agaaaatctt atatttatgg acaacattta gactgtgact tgccaagtaa 18060gaacaagaag ctctgtcaac tgaaggtcaa ggctggagtt ctgaaagcaa agagctgtct 18120ggtgttaatg ataagtgaaa tagttaaagt tagaagatcc cagttataag aagcacaaag 18180aataatgacc atagactcct gaacaagaat gtctggactt ctggcttagg cactcttgtt 18240gtatggtcca ggccaagtta cctaatctct ccaggcctcc attttcttat cattaaatga 18300agataataaa agtattttcc tcagagagct gtaagaataa actgagctaa cccatgtcaa 18360gcacatagaa tagggcccag cctatattaa tttatcaata aatgccagct acatattagt 18420tctctatatt tttattcatt atcataaaat gtttatctac agattggcat tgtaaggatg 18480gagttaaaat tgtatgtatg tgaagggaaa ttattcctgt tactattgat ctgcatcaca 18540ttaccccaaa tttgatggct taaagtaaca acattcattt tgcaaacaaa tttgaaattt 18600gaggagggct tgtctgggaa gacttgtctc tgccctatgt ggtatcagca gggggaggct 18660tgacggactg gcacatgccc ttccagaatg gcccactcgc atgcctgcca agttggtgct 18720ggctcttggc tgggagctca gctggggctg agtgctaggg tccctgggag gttccttgtg 18780gcctgaactt cctcaccaca aggcggctgc ggtgcgagag tgagcatttc aagatagagc 18840caagatgaca ctgtattact gtgtaagacc cagcctggga attaatgtag cctcacttcc 18900atcccactct atttttaaaa agtgaattat taaggtcacc ccatattcaa ggggatagga 18960attagacttc atctgtatta agaaaaatgt ttttaaaaat tgtagacatg ttttaaaatt 19020ctaaagtcca cttactggct gcagattatt tatatataca tgcaagatac actcctacat 19080tctcttctta gaaggctcag ttgcaggtac agatgaagct cttcaagtga gatttcttat 19140gtatttatcc tctcaatctg aagacttgta aactaagaga caagttattt gcaacctaca 19200tacgcaatat tcaatggtaa agtatacata ggacagccac tacagacact cttgttttaa 19260atagaggaaa atgagagcac ataacagtca ttggctcata gcaactctga tatccagaca 19320gcaaacacaa gcaggtcttt ttttaggtct cagtcctact gcctggattc cctactgctc 19380ttgggtcttc cctccaggtt cttggttctt ggacctcttt tcatttaata ctatttctgt 19440tcctttaagt tcaagctggc aaaatatgat tgtacaattc tgtttaaaat tccaggactt 19500cctgtgattc ttattgggga atactccatt agacaagaat ctctttgaca taagccattc 19560tctacctgag atccctgtaa ggctgtgatg ggaccacata accttaaaat tattagaaga 19620ctcattgttt actgagagaa tatgcctagc atatgcttag atccttagag gaactctgtt 19680tcaaagggct tatgagacat taccttatat ctttctaagg tacaaacaaa aggtctttgg 19740cttttgagtt tgatctttga gctgacacct tttcttaatt tgagaatccc ctgctctatg 19800gagagactga caaagagaaa tagttttata tttgaatgta acatcttgga tctttaatag 19860attatcttaa aattttcctg aaaatgtaac agttcctttt tttaaaattc attctcccta 19920cacacttatt atatatgact aaaagaaact ccctggcatt ttcaacattc tggttagaat 19980ttttcttagc ccaatctacc agtttattag gtatatttgt attttccacg tcactgtagg 20040tgacaatctt gctaaacttt ctgccactac ataacaagga tccctttctc cagttttcag 20100taacaatcta ccaatagcct cctcaaggtc taccaagctt ctactaaaaa tctctttcag 20160ccccttccaa cttctgccca ccaactagtc ccagaagcaa tacccatgtt ttaggtttca 20220ttatagcagc atctagtttc gagttctcag aacctgtttc gatcatgttt cactgtttcc 20280aaaacatccc aaaacagtag cttaagacag taacacttat tttgctcaca ggctgtacgg 20340gaagcatggc tggagaggtc tcaggaaata tacaatcatg gtggaaggca aagaggaagg 20400aggtatgtct tacatggcca gagcaggaga aagagaaggg gaaggtgcca cacacttttt 20460agaaacccag atctcatgag aacttactca ctatcatgag aacagcaaag aagaaatctg 20520tctccatgat ccaatcacct cccaccaggc ccctcctccc acactgggga ttacaattcg 20580acatgagatt tgggcaggga cacaaatcca aaccataaca gttggcaacc cttttttaaa 20640gaaagtaatg acatcaactc cttggggatg tggattgggg gagaatattg gagaggatcc 20700aggggaagtg aagatatcaa gttctttata cataaataga tctatctttt tagggaagta 20760gaatatgtca tttaggatag ggaaagttga agatgttact ctattcagct ttagggaaac 20820tccaagatgt aacactatgt cctgtgaata ttagtcttgt ggaaagtgct ccattggaag 20880aagacagaaa atgtcctgct gcacagagat ccatatcttc atgccacgtc ttgcaaatgc 20940agtcagggag cttgctctaa attcgtgttg ccttttagga agttacagag catatttctt 21000tatatcttct ttatttttgc ccttgatagg agactgccag ggattcagtt attataattt 21060tacatttatt tatccttttc tgggagcatc tcataccttt tttactagag aggccaaggt 21120cacaattaag attagggaga caatacagag tcaagacacc tgaattttgc cacactactc 21180ttgggccact ttaattggtg tttctgggcc tcatttttat tactattatt attaattatt 21240ttatggtgtg tataggagct ggaagatagt gacttctatt agaatttatt cttataaaca 21300atgctgtatg gctcttggat taagaagtaa atagaaaaca aaaagggtct ttgaactgct 21360gtctcttcta ggtcttctca gagtgctact gggaattaga tgggattaga tgggtgaatt 21420tcctttttct tttgtttgag aggtctagat ttttgaagta tctaaaccat ctttagatct 21480aagttaatct ccaaaaagct ttattgcctg aaacattcca gttctaggaa gtttgcattt 21540ctctgagtgt aagggtctgg tctgtaactc cttgagatca ggaatgtgtc tttttatccc 21600catagttcag cgcctaccct agtgtcttcc ctacaagtga tcattgaatg aagaaaggaa 21660taaattcctt cttctctaac atacatcaga gacctctgac ccttattggg tcccccttcc 21720ctattgatat acctctccat ctccagacat ccacatggcc tcctaggggt atgggattct 21780tcactcttct cctggtacaa gctccttgcc tgaaattttt ctgacccacc cccatttcta 21840accgtcacag gtttagattt tctgaagcaa acatacagac agagttcgag ttacaagaca 21900tttaatagga atcgactctt gtgaaaggaa gaggggaaga tgtgggactg ggctcagtga 21960gaagccaagc tgtgacacaa tgaaaacctc agcccaccct gcacagagct caggaatgag 22020tgtcacgtgt tagagctgac ctgggtcagg tcaacattgc tgggtgtttc tgcttctgcc 22080tcgttcagtt gtcagatgca agctgacctg ggaagggttt gactgggcaa gatggctgtc 22140tgcagatgag gtcaatcaga aggggctgac agccaaaagt ggtttgctca tctcactacc 22200cacagctggg tggcaagtcc ttcaagaggg agctggatga tgcttctcca cctctaccac 22260accaaacaaa gcatttcttt cttattcttt ttcttcctgt ctcccttccc cctcccccct 22320ctcccctttt ctcctcctcc tcctcctcct ccttcttctt cttcttcctc ttttttctcc 22380ttcctctttc tttagagaca gggtcttgct tggttgccca ggctggagtg cagtggcaag 22440gtcatagctc actgcagcct caacctcctg tgtttaagca atcctctcac cttggcctcc 22500caagtagctg ggactacagg catgtgctat catgcccgac taatttttta atttttacta 22560gagacagtct cactatgttg cctgggctgg agcatttcta ttcatgggtt ttgttcctct 22620ggagctgtgc tgttctcttt gataacatga atatggattt gtatttaccc ccttctggcc 22680atcttaacta atggcccaaa ggaaggccag tggtgaagat gtttctctac agggaagttt 22740ctaagtgttt ctcagcctac atgtgtgagt gtattaatgg gaatactggg gataattgga 22800tagaatgtat gaaattagga ttggcctaaa ctatctggtc caaagtttat cctagtggcc 22860ctaataacat ctccagtgat ggtctttcct gaggttatag aatgagctat aggaaagagt 22920gatagtacag gaatgagagg attggatcgt cttttctctt tgttctattc ctctatgatt 22980atttgatttc ttttttttgt gatggagtct cactctgtcg attatttgat ttttgtttca 23040gattaaggcc agctttcttt gactgagcag acccacgtat atgggaaacg gccacacacc 23100aaattaaacc attcactgac acccgggcac acccattttc accactctgc tcttgcccgt 23160gccattgcct ttgcatccaa gggattcttc cttctgtggc aatctgtatg acatccttac 23220taagaaggcc tccctcagtg cccttggccc tctcacagcc ctttccatgg ccttctccac 23280tagactgtga ggaacccagt gtctggaaca gttcatggca ttgttgttag tgttgtcatt 23340ttgttgttaa gccttctgct gtcagtggtc atttcatatg tttgcatatt tacgccctgc 23400ctctttttgg tatgcagtgt ggaccctatt gcacggctac ttgtgtttca gtggctttgt 23460cctattccac cttctatgcc acttactctg aatgcctggc acattggtag gtgcccaata 23520ccaacttgga aagtgaatga atttgttttc tcattacctt ttgaaatgcc tatacagatg 23580ttcctccact tatgatggag ttcattctga aaagctcatg ataagtagaa gatattatgt 23640cagaaatgta ttttattgta ttttttattt tttaatcttt ctttctcttt ctttctttct 23700ttcattcatt cattctttct ttctttcttt ttctttcttt cctttcatct ttcttttagt 23760agagacaatg tctcactata ttgcctaggc tggtcttgaa ctcttgggct aaaagcaatt 23820ctcctgcctt gctctgccaa agggctgaga ttacaggcat caactactgc acctagttga 23880aaaatgcatt taatgctcca ataaacccat cataaagtca aaccatcagc agtcagtgac 23940tatctgtata ccttaggact aagttagaag ttggagatgg taaagtttct aaattagtac 24000aagcacagga gctcttattc ctgccatttt atgaaagtca tgtgagtatt ggtgaccatc 24060actaatgggg ctggtagaaa ctttaggacc agtctgtctt agtcagctgg gctgctacaa 24120taaaaaacca tggactgagt gggttaaaca atggacattt acttctcaca gttctggaag 24180atgggaagtc caagatcaag aagccaacat ggctggattc tgatgagggc tttttctgga 24240atgcagatga tcaccttctt gccttgtcct catgtggaag agagagcaaa ctctctagtc 24300tctctttctt ttcttaaagg acaataatcc cattatggag gcctcatgct catgacctca 24360tctaaaccta gttacttctt aaaggctcca actccaaata ccatcacact gaaggttagg 24420gtttccacat ataaacttcg gagggacaca aacattcggt tcataacaag tgcattctac 24480aggactccag ggagtgtgtt ggctaccctt catcccacac agctgcaaca atcctaatcc 24540actgatatca agtcaccata tatttgaaat tcactcagtt cccaagaaaa tatctgcttt 24600cataatcatt tctcagctaa ggaatgaaag ctatgataag aaagtctagc acttagtggg 24660aaacaaactt gaattaggcc aggacccctt aaatattgtc actatgaaat ccaagggcag 24720tatttacatg cttttccttc atgatgacct tagatttcgc ttctttatgc tgcaatcaac 24780tgaaaacatt ccactgttgg taatccttta tcttctaaca aatctaattt agtagatctt 24840gttactcctt atttttgaaa atattaaact aaacaataag tgatctttca gggaaattct 24900gcaagggaag tggcttctag agaatgcctc ttctccaaaa ggcctagttc tatttctgat 24960atctaatcag ttctgctccc tttaaataat tactgaaact agtttattgt ttaaatgacc 25020tcatttgaaa gtgggacttt cccctttgcc ttcttccctt ttaatttctg tttttaatta 25080atgtaagtgc agtcagaact gacggtgtca acctttcctg taactgtgat tgccacttgt 25140ggacattctg tactcataag agtgattctc acaagttctt taagtttttt ggaagtgcaa 25200acccaacagg aagaaagaat aggactccct gcattctatt ttgctctgca gtgaagatgc 25260attgttgagt aatttgcttt acattcagat atacccagat tcccatcttc ccaatccatg 25320tgacttggct aagttacaac tctttataag cctcaatgcc tgcaactgaa taagaaagtg 25380gtaaccatct catggggcat tgggtaaatg agataatact tatgaagtat gcagcacaca 25440gccaagagcg taacgtgttc aatcaatgat atccattatt attacatgtc aaatcacatc 25500tgacttctgt gattctactg gggaaaagga tgcaaaatcc tcttgccgtt ggggtgtcaa 25560atattttagt acttatttcc aaattcattg gaggggtctt tccctgaagt ttacagatgt 25620ggaatacacc attcaggcag gctttcttca gtagtgcagg tcatttcagg ggttctccac 25680attctagaat aatttttttt tttacccact acagacacat ttactggcaa ggcccatgat 25740aacaaaatga aattaataca ggctttacag tcagagacct aggcgacctt gggtaattca 25800ttaatatctc tgagcctcta tttcctcagc tttgaaagag gcataagaat tgctctgaag 25860aataatcatg agtataaaat aagataaatg agataactat gtaatatgca ttagtttagc 25920accaagccat atacaaaggc acaataaaga gaatctaata tgtttccttt attcccactg 25980ctatgaactg aatgtgtgtg tcccccgccc accgcaaatt catatgatga agccctaatc 26040cacattgtaa aggtatttgg aggtggggca tttgtgaggg aactaggttt aaatgaactc 26100atgaaggtgg agcccccatg ctgagatcaa tgcccttatt taacaaaaat cagaaacaac 26160aacaacacaa aggaagacag catgaaatct ctctctcttt ctcttttccc ctctccctct 26220gccttcatcc ccatcgccat gcacccgcaa aagaaaggcc atgtgaggac ataaccagag 26280ccctcccaag accctgaccc tgctggcgct ctgatctcag acttccagcc tccaggacca 26340tgaaaaataa atgttggttg ttcaagccac ccagtctatg gtatttcagt gtagcagttt 26400gaactgagat acctattaac agatgttcct ttccttcttc tccctcattt ttatggcaca 26460ttaccagtgt ttggtactaa atactagctg ttaattctcc cttagtagaa gacaatagag 26520taatgctgag ttggtctcag ctgtgggaaa ccttttgccc agagagaaaa attaagtctc 26580ctaacagaaa gctggcactt tcccttactg ggcatcagcg aaaacctgat tcccatgggt 26640aaagtgagta attgctaaag ggaaacagat catgtgcatt tacatagtca gagatgtttt 26700atgggattag gtgggtgatg aagagtaatc attataataa ttttacaacc cagacataaa 26760agagaaagag cagagaaaga ccagttctct tgtgaaatat ttgccattta atatcttttt 26820atctttgggc aagccaactt attttcttac aaataagcag taactagaca cagatattta 26880agaggagaaa tggaccttag atgttctgtg gcataatttt cctttcacat aggggaaaac 26940caggaccaga gcagcggatg aagatgccaa gatcaggcac tgccaattgt tttgactacc 27000tctagggaga tcctctcatg actcacacat tgcctctctc ttgaaaatga gtaaagagtt 27060gcccaaccaa attcttgaaa taaggtcagt tataaatgcc tatagcagct accttctttt 27120ttattattta gaaaatgatc attggaactt gttatcagaa gacacaggct gagagggaag 27180ggatgtattt tttcacatgt caaggaacca ggggtaatat aacattcaca ttctagagaa 27240aggtcaaata ataaattgcc ataaaataca gactgctcat gagctgtttt gaaatcttgg 27300cttcttgtca aaaaactaaa ggtggaggag agtaaaatcc ataactgtgt gctttttgtg 27360taggtgtgtt ggactgaatg tacatatgat tggatcatag agatgatcaa agaagtgtat 27420actattcctc aacagaagag gacaaaaaac gaaattgaca tttgttgaca tttccttggc 27480cttagaagtg tttgtaaatg acagagttag gatttgaacc cagttccagc gagtttaaag 27540cccaggttat ttcccaataa gccaaagaaa tttccaatgc caacctattc ctggcatctt 27600tagcagcaag agtgattata gtttccacag acagaaattg tgtacagagt tgggtgaaag 27660aacagtagct ccaacatgct tggcatcaag gctgtgactg cacgaactat tccaggaaaa 27720ctagtcatca caggtgattg aaaagagaag atatctttta gcagactaaa atctgcaggc 27780atcttcatca ctccttaatg cagacagaca aaactgattg gctagactaa taagatcaga 27840ctttgttttg gaaactaaat gtctattaag acacgcgaga agacaagatt tcctaaacat 27900agactatgaa tagactatga atagtcaaga gggaggtcga ggaaaaggga attcccctta 27960acatggcaga tcaaatattt aaattttaat gacatattag atggaatata agaagttttt 28020gtgttatgaa ataaaaagaa ctcattcttt taaaaaatgg caatccaata tttatacacg 28080ttcttctatc ttatagcatg actgaattcg aagtgttctt gttcatgtct ccttctctga 28140gaaagagtaa gtgcctccac aaacacattc actgggagtc cagaagtgga gagtatcgtg 28200ttttcactgt tcaaggtcac gtagtggttc ctggcccaaa caagtaggag ctttctaaaa 28260ttaaaggcaa ctatccataa aggttccttc atctgctgtc tcctagtcca ttggcaggac 28320ttggcaggga aagccctctt cttgatagag atattggacc tccaacctat ctcttcatct 28380tctcccatac atctcctcca tacagggttg tcaggtcagt aatccctact ggccatttag 28440aaggtgacat ttatcaatta taattaggtg acttaggagg cttactcaac tccccagaat 28500ctcagtgtcc tcatctgtga aactggaaat aataaagcct atttcataaa cctaattctt 28560catattaaat gggataacat atataaagca cttagcacat gctatgaccc cagaagatac 28620agattcacag agcagatgga gcactgctgt gtctcatgat actcaagctt gaatatcaag 28680cttgactccc attctgctaa ttctccctct ggctactagg acatcttgac tttcagggtc 28740tggactctgg gccttaaggg aaagctaaga ctcgtccttg tatttctact ttatgtaggt 28800agaagctgat ctgcattagg gctggttgct cccttctccc catctcaagc cccagaatct 28860cttcttgtat taatctctct cccaaagttc ttgctgaggt cagatttcat agtcctgctt 28920tttcagcacc tgttcttaat tagttcaaac ttttgcaggt tttctttcag gccatatttt 28980atttgtttcc tcagaaactc ctcttagact acatccttta tctccagaca cctgggatcc 29040acattgattc ttttattttc cacaatttct aaccctgaac agctgcatga atgtaagcaa 29100gcttctaagc atagatgggt gggtggttgg gatgtgtaca cgttattcat

tcattcagtc 29160atacatttat tatttataaa ctacttattg aacacttcct agtgcttgga atttttttaa 29220aaatctcaag cgatatgcat atcaatacaa aataatttca gttctcaaga aacttaatct 29280tgggaaggat aaacaaagac ttataataca atatggtgca agatttacaa taaagcagtg 29340gttctcagca ttggctgaat aatagaacca cctggctata ttatatagtg atgcttgact 29400ccaactcaga ccaatgaaat caaaatccct gtgagtaaga cctgggcatt gctatgtttt 29460gatagctttc caggtgattc cattctgcag ggaggtttga gaatcccttg gatagaggga 29520agtatgggct gccttgggac cacaattaag aggtccctac tctaattggt aaggtgctaa 29580aggctgcaaa gggaagatga catctgagct aagtcttttt tttttttttt tttttttttt 29640tttgagacag agtctcgctc tgtcacccag gctgaagtgt agtggcataa tctcggctca 29700ctgcaacctc cgcctcctgg gttcaagcaa ttctcctgcc tcagctgccc cagtagctgg 29760gataacatgc acccgccact atgcttggct aatgttttgt atttttagta gagatggggt 29820ttcaccatgt tgaccaggct ggctcaaact cctgacctca agtaatctac ccaccttggc 29880ctcccaaagt gctgggatta caggcatgag ccaccacacc cggccctgag ctaagtcttg 29940acaaatgagt tgcccaagtg aagatgtggg aaagccattt caagggcaga ggaacaagat 30000gagttcatag aactgcctgt aattttgggt acagtttaga gagtgctaaa tgctaaagca 30060tttagcctgt ctctggcagg caaaaggaga gtcattgaag gattgttaaa aaggaaataa 30120tatggtcagt attatataca tctgaagtac caagacatca gttggggagc aaattttact 30180ttcattgcat cttgccccag cagaactatc tccctttaat aagaccttta aaactgttgg 30240cacctccctg gcttcaaaca ttagaaacag gaaactctac ccatgagcta accttcaccc 30300catcctttcc tgaaacaaag aacatctgtt ctcccacttg gatgtgcctg gagtaaagag 30360gggcgcctaa gtattctcag ttgactacag agaaatgatt ggcgtcacgt agattagtca 30420tacatacatg cagatgatga catagtcaaa tgtattgaga cattttagtt ccaaaaagta 30480agtgttttgt ttctgataca gtgctgtcac ccttggccag ggaaacccag ggatcatagc 30540tgctacagat aaattatgat ttattccttg gaagagggcc tgaactcaaa agaaattaag 30600tagtaataac acttgaaaat tctctttctc caatttcagt atgcaaatct atttacatat 30660caaccaagcc tttgggacag gttagttatt gtttgtggtg gtagtggttg tgttgtttat 30720gtttgagttt tgtgtttttc tttaattctg agatacatta tcaatttaat gacaactttg 30780caggataaaa aaggaggagg agaaagaagg ggaggaagag aaaggggaag aggaggagaa 30840gaagggaaaa aagagaaaaa atgattaaat ttaatttgtg ttctaattgt gaaacaatct 30900aatttcaaaa atgttaaaat ctgtgtgttg ggttagagat gggaaaagta tgctgtataa 30960taaaaaaaaa atccccagga ggaaaatgaa atatttttag aggtactagg aattttatag 31020tcaatgggat ccaaagctgt atttttagac agagaaatct gaggcacagg tagacgagaa 31080attttcttca aattctcgag ggaattactt agtagtgaag ctggaatcag aaacctcatt 31140tctcagcctc aagtttggtt tgctttccat gacaccctag aatattccaa ctaatatctg 31200agaagcaaaa aagcatctca tcctttctac tcatatttct ggctgaggga actattcaaa 31260gagataaagt acatgaataa ataaaaaatg tgtatcacag ctaagtacat cttagcaaag 31320aaataagcaa aagactatgg tgcctcagtt ctcaacactc tcttttgttc atttatttag 31380tggctgttat cttgagtagg tgattcttgc atatcaaatt gcattttggt gtgtcaaagt 31440gactggtttt acttgtttgt tggttcctaa agctaattat tatttttaac accttttgat 31500atgctaaatc aggctaatga gactaaaatg ggatttctca tgggtttatt agtcatcaac 31560accatcttac atatgtgtat atatgtttta atgctttcaa agtgtaaata aatgattata 31620cttgagactc atacaaatat cataaagcag ctttttcctt agtattcctc ctagaaaata 31680gatatttcat tggcagagtc gtggtgaaag atgtggtgtc atacaataaa tttacttcag 31740ccagctgtgc gagcttaagt tacccagttc ttttctgcct cagtggcctc ttctgtaata 31800tggactgata ggggatctca catgcctgtg tttagaatta agtcggataa ttcatgtaaa 31860gtgcttagca agtcacctgg cctattataa ctagccatta ttgtttgcta gaacatttat 31920ctgttcacaa attatgcatt gattgcctat aataactaaa cttgaggaat gcttattacg 31980taccacgtac tattcgaagc acatcacaag tagtaactca tttcattttt ataatgactc 32040tttgaggtaa gaactattat taccatctct gctttacaaa tgaggaaatt gaggcataga 32100gacgtaaagt cacttgttca aagcctagca tctgggaaac agtagaggtg ggactcaaac 32160tcagaaagcc tggctatagg ctctgctctg ctgtctcccg ggattggcca catgctaagc 32220attggggcaa cagcaatgag gcccataggg tttctgctct caaggagatc actataaatc 32280agccccggga gatgatccct aaaagagaag tacgtcgttt gcaaaatgac agcacagacg 32340cacgagttct gaactcttcc tcagagtttg gggaagttgt ttagccctgc tttctgccct 32400ctctatgggt cacacacata ctccgagtga agaatgacgg agttacccat cttctggctc 32460cttcccgtga cactggctac cctatgctaa aaaccagccc ccagattcca catccctgaa 32520tgtcttattt acaggttctg tcattttcat gataaccttt ctaatgttct aaatttcctt 32580tctgtgggtt gtcaagcaaa ttcattctcg gcagtcagta agaactcctt gttcaaaatg 32640ccacacatta cagagtcaat gattctaaac acattttttt ttagtgcatc caacttataa 32700gctgcagtgc tagaaacaaa ttcacactcc ctttacacta cagtgccatc ttttccgagg 32760gtggggctcg cgtttcttca ccatccagtt tctcatacgt agattatgat ttctgctttt 32820gccaaacagg acattgtttg accaagtcct tatgggagga agcacagccc agtgagcaga 32880acaatgattt gaaagtcctg ggttctattt tcagctcctc tgttgactag ctgcgcattc 32940agccctagga aggtcaaaag cagaatggcc ttgctttgac gactttctct gcatgtacag 33000ctctagatgg aaaatatatc aggcatctgg ctctcagcct tgaggagctg gtctttggag 33060aatacatgtg tagtcacact ttgttttcat ttttaaagca aaagaacaaa acaaactctc 33120tagggggaaa atgggctggt agagaatgga agagagaaac ctaataacat tttaaacaat 33180ccaggagtta agggattgct tgagtcattc agatcaaaga aggctctttg gcacaagttg 33240gagtctccgg catttgaaaa tggaagaggc aaagaggagg aagctttgag agactttttc 33300aaaccgggac ggtagcagat actcagaact ctgcctgtag ggaccaggcg gggaactcag 33360gcaggttaag gcctgtgggc aaactggaaa gcccaggcca cctgtgaagt ggtctgctgc 33420tagtgatacc agatgcttgt tgtggaagaa ggaagttact cttgccagaa cagctgaatt 33480ttcaagagaa actgaacatt gagatttttg tcattagaac ccctgatttt tttacatgat 33540gaaatctaat catcattttt aaacttttaa aggggcactg agcaggcaag atcaaacata 33600tagcctaagc aatgtactcc ccatgtctct tctatatgta gatggggtgt ggttccttaa 33660gggctttagt tgtatgttct gtgaatgaat agaggctaga ttccagacaa aaatgattag 33720cagtgactca actttagctg cactttggaa tacctgggtg ttacctggga ctgcagcctg 33780agcactggga ttttataaat gcttctcaag tgattccagc atgcaaccat gaataagaac 33840cactatgtta ggatattgcg agaaggttta agcattacag aaagttgggt tttaacttga 33900taagatacat aatcttatca agacacatgt gatctctgaa catggatcag ggaattgaca 33960ttcaatataa atggcatttt cttttctttt tttagactct tttgagagtt ccagttaaaa 34020actctctagc atcattgctg atggccgtaa ttaatatctt tgggttcatt agcaatcagc 34080taacaacaga catccattgg caaaacaagg gtatagtggt agaggtcaaa cacaacgaaa 34140gccaaaggac aagtgcaagc cctgagcaca gataagtatt tacagggaaa attaactttt 34200tttctgatgg ccatgaagca aaatagacag tagagcaaag ggagcctttt acaagagcag 34260ttcaatcttt gtccacattc taatggctat aaaactcacc atgaagctag caaatggtgc 34320atacaactaa tactttcagt cttttcttcc ttatttcaca ggtcttatgc attataaata 34380acacgactaa gtctcagcgg ttgtatccat ggctagttct tatttcagct ttggttcctc 34440ttgctattta ctatgtttct cataaaagat gttagtgtgg attgagtata tgaaatcatg 34500tacaatggaa tgttaaatgg ggcattccct cttgtctagg tatatcagaa gaggcccaat 34560acacttggtg ccaaggaagc tcaccttcta aaaccagatg gtagcttgcc tataaaagga 34620tacactaaga ggttctaccc aagttatcac attggcagcc tccagcttat caagagagac 34680tttaaagaac ttggcagtgg ggatctttct agagggcgtt gtcaatttag gaagcatctt 34740cgtcttcatg cctcaccttt ccgataagtt tgtttcttcc ttaatgcaaa caaaatgaga 34800gacactttga tgggaccact tgcagagctt gacatgtgtc atctggattt taacagacag 34860atatcattga gatatctgac tcacacctga aaacactgta actagaacta ctctctctct 34920ctctctctct ttctctctct ctctctctct ctctctctct ctctctttat gcctaaaaca 34980gagctatgtg gaggctaagc aggacttcca aaatttgaaa caaataagga acctgttcaa 35040agaaggcaga ttgaggcatc ttgaaagaaa ttgcctggca gggtgtcatg actccattag 35100ggggaacgta ccatttgaag ccaagagaat aaagaagtca tggatgacta gcttgagaag 35160gcgtaactgg agtcagggaa acagttactg agagagatgt cctgcaatgt agggaaaaag 35220agggagcttc cccaaactca acacaatgct ctatgaaaca cacatcagtt gggatgttca 35280ctaaactcag aggatcacaa tgacagatta taagagcgcc agtcaagtta gaacttctta 35340ttccatctta cgaccttcct cttcctcccc tacactcctc tgtattcttc ctcttgctcc 35400cccacagcct ctatactctg agaagcagtc tcttgctctg ctccttctgt gaattgttaa 35460ttcaattatt tcaaatttct cacttcattc tctgtctagt gggtgtgagt cctgggtgtc 35520tggggatctc atatgtgatt tattgtggtc agaatgcaaa aatataggca aaatcataac 35580atagtagtta aatttataat tatttggatt attgaaatac atctataaaa agtattttat 35640aatttgtttt gaatactttg tctttggaga ggccagaaat cacagacagg aaaggaggag 35700gagatagaga gaggagaaga tggggaaacc aacctggcct ctcctcctac tcctggattt 35760ccaatctgat aacagagttg tgagaaaaga cagagcttaa gtttacatgg ataagacttt 35820tgactagact ttttactacc ttggaaaaaa gcttttttaa aaaatttatt acctgttggt 35880aatcagaaaa gccaagagag aactactcag agttttatta gttagaggaa cctggggatt 35940gagggtgagt actcaaaatg tcaggtttgg aggggcagaa gcaaaattta aaaaattgtt 36000tatacctgca acctgtcaag tccagtttac acaataatac aaaataaacc aatttaactt 36060gaacacataa aatgttttca tgatgtggat tcaatttaac aagggcacaa catgatacca 36120cagtcatctt tcaaaattct catctttagg attcagcttt ggtaccttaa agatatattg 36180ggttacagca acatttctgc aggaagctaa tatgtattcc ttaaaaagag ttccatgatc 36240aaagatattg gtgacaaact tgttcactca aaaaataaat agaggccagc catggtggct 36300catgcctgta atcccagaac tttggcagga caaggcagga ggatcacttg agccccagag 36360ttggaaacca gcctagacaa tatagcaaga ccctgtctct aaaaaagaaa tagctgaaag 36420tggtggcatg tgcctgtagt cccagctact tgggaggctg aggtgtgatg atcatctgag 36480tccaggaatt taaagctgct gtgaactatg aaggctccat tgcaccccag cctgggtgac 36540agagcaagac cctacctcaa aaagtaaaat aaataaataa gtaagtaggg tttttttttg 36600ttgttttttg ttttgttttg tttttaactg taggtctcct agaatgtttt aatgtgtgtt 36660gtaagggaac aattctataa gaaagaatac ctggtggtgg cattttcaag ctcatttgtt 36720caaaggctgt tattattccc aaatatttag gcttccattt attaaatatt tgctgaacat 36780ctaccatgtg caggcatggg ggatgggtgt tggggtttaa ttaaatatat caaatgggct 36840cctctcactc aaagatctta tgatctaatg gattgcttat tttagtcctc atcttagttt 36900gaaaatctct ttggagagat ctgttctatg ccatttttca gatttctgcc actgcaaaac 36960tatttgttaa cacaaaaata caaattacct gaggaagaag ttgtgttgta aaatagatgt 37020gtttttataa aacaaaattt aaaagtgcat tcacaaccaa gcataacaaa tatgctttgg 37080tcacctttcc tttctgtcct tgatcaactt cagctgatta tggaaaattc ttgataaagt 37140tataaagtca tccacctctt ttttctctag gtctaactcc tttccttgta ttggacgtca 37200aatccccaca ttctactctt tctgctccct cagaaaagat ctgacatcag tcattcggat 37260tggtgtgggc ttcctgtgag atattttgac aaaggttttc tttatgtgtt agcactgaac 37320agttttggca attttcttcc ccttcaccag cctactacac atgaccacac aggtgtttac 37380atatgtacat acacacacgt gcacacttac cttccttcaa aacaggccaa atgcaacatc 37440ttgtctcctt cttgcaggca aagtaggaga cctgtgttga gtgacagaat tcctttacct 37500tctgggctat agcatcccag agaatgtcct cacctgggag ttttctatgc atggctttcc 37560ttgattccca ggaagatcta catccagtta acttaactat ggcagctgaa tcctgacaat 37620ggtgtgaagg aaaacatggt ggatacaaat gagcaccatg ggtacagctt gatgatgtcc 37680agctttatgc ataatgtgga ctggcagggc ctttgatcat gcctcaatag ctgtgaagat 37740agcagatggc aaaagaagtg gtaggttcta agtaggttcc ccttctctac tggttgccac 37800agactcaaaa ggaattttta ctacaggaag ggacccaaat attctagcct agcctctata 37860ctctgaaaag cagtctcttg ctctactccc tctgtgaatt gttaattcaa ttctttcaaa 37920tttctcaatg gattctctgt ctagtgggtg tgggtcctgg gtgtctgggg atctcataca 37980tgatttcttg cggtcaaaat acaaaaatgt aggcaaaatt ataacatagt agttgaattt 38040ataattattt ggattattga agtacatcca taaaaagtat tttataagtt gttttaaggc 38100cttgacctgt tcaacatatt tcttaaatgt atctcaattc cttctacatt ttgctatcat 38160acgtatcgcc atttatgtct aggctaccat catctaagac cacaataata ggtaccaact 38220tatcttccca cttttgtcct ctgcaattga aaaataaatc agggttttta cttctgacca 38280aaatggaggt ctcaggtgtt tgactaaagg tagtatagca ctgtgatgct aaaataaggg 38340aaagcaatga cgtgacattg agtgattgtg agtggccaac catccccatt ctcctagttt 38400gcttgggact gagggagttc ccagaacatg agactttcag tgctaccact gaaaatgtcc 38460tggccaaacc aggataagtt gttcatctga aagccctgtg tttttaccaa ttgacagctt 38520gtagaaagtt tccagtctgt agtacaggaa ggagagactc ttatatagct tgccaggctt 38580gagttgagga gatagaagca aaaatttaga gagacaagga ggctagaatt tgaagggtga 38640gtagtaaaag gaagaaagct gcacaaagag ggagacagta gactacagat gtgcagaagg 38700gtccctttca gttaattgag ttctgatctc accattcatg agagatgtct tagtctgttc 38760tgtgtttcta taatggaata gctgacactg ggtaatttat caagaaaaga ggtttatttc 38820aatcatgctt ctggaggttg ggaagtccac aaagcatagc accagaatcc acttggcttc 38880tcgtgagggc ctgtgctgca atagaacatg acaagaagta gaaggggaag cagacagaga 38940tcaaacacaa gaggcacccc actctcctaa gaactaatcc atccctgtga gagctaattc 39000aatcttgtga gagcaagatg gcacttctca caatcttgtg agagtaagaa cccactgacc 39060accgtgagaa tcgcaccaag cttcccatga aggcagaacc ctcatgaccc aaatgtctcc 39120cattagattc cacatcttaa agttccatct cctggcattg ctgcactggg aattaaggtt 39180ccaacatgag ttgtggagga gacactcaaa ccgtagcaag aggcaactat ctgagactgg 39240ggaaagaaat atcagaaaaa agtaagtgaa aaacccatgg accctcacac agggctgcaa 39300ttagtttgtg atcccaaaag aaggaaagga aattgtcata atccaataaa cattgggtag 39360aatattcaga ggagccctgt gttagtaatg aggataaatt agccttaggc taaagactat 39420tctggaccca tcctaacaaa gcttacagga taggatccaa ttgcttccaa ataactgtgt 39480ttcagaaaaa caaaaaacaa acaaaaaaaa actaacatta cttaaagaaa tataacaaaa 39540tccataaatc aaggagcaag tcaagaaata gaaaaagaat cagaaatgat ggagatgctg 39600gaactaacag acaaaaatct aaaactatta taaatattcc ctacatgtcc agtaaggtag 39660aggaaaagat gagcataata aagagaaaaa ttgaagatat taaaaaatac tcaaatggaa 39720cttctagaga aaacaattat aaatgagtga tcaaaaaata aactacaggg ttttatagaa 39780aattggacac tgtaaaagaa atattggtga acttgaacat aaagcaaaag aaaatgaccc 39840caaacaaaca ctgagagtaa aaaaaaaaaa gacaaaaaac ccccagaaaa tcagtgagat 39900atgggaaaat ataattgtta taacctacaa gtaattgaag ttcaggagga gaagtggaga 39960atggaatatt ttgaaataat gatgactaaa agttccaaaa tttgatgaaa atgataaccc 40020aaagactcaa gaatttccat gaacctcaag cagaagaaag gcttttaagc aataaaggaa 40080gctaagaaaa atcatagtaa aattggcagg agagtgggaa gaacagtgaa aaaaacattt 40140tttaagagca accagagaaa aaagataggt tacatggcaa ggaacaaagg tgagaataat 40200gccatccttt ttgtcagaaa ctatttaagc caaataataa taggcatctt taaaatataa 40260aaatgaaaaa aaagttaatc aagaattgtt tatacaatga aaatatcttt caaaaatcaa 40320gtcaaagaca gattttcaga caacaaaagg aggagatgac tcataatcac caagtgtgca 40380cttaaacaaa tattaaaata aattatctag gcagatgaaa aatgataaca ggtggaaaat 40440ttgggcctac acaaaggaat gaagagagaa atgaataata tgtagataaa tgtagaacag 40500attttttatt cttttccagc ctctttaaga gatgaataac tctttaaagt taaaaacaaa 40560aaagaacaaa ttctggagtt tgtgtcatac atagaagtaa aaagcatggc aacctagcac 40620aaaaggttaa ataggaaatg gatggatact gatgcaaggt ccatatacca tgagtgaagt 40680cgtataatat tacatgaagg tgaactgtga taaatttaaa atgcatatgt actgtaaacc 40740tcagaagaac cactaaaaat agttatgtct aacaagacaa tagtaaaaat aaaataaagt 40800aataaaaata actaataaaa ataataacag ggagagagga ataaaaaaca aagagaagac 40860aagtaaatag aaaacaaata accaatatag aagatttaaa accaacagta tcaatagcta 40920cactgcatgt taacagtcta gacacttgaa ttaaatggca gatactggcg ggattggatt 40980aaaaggcaat acccaactat atactgcctg aaatatagta cttaccaagt ggatttttaa 41040aattaataat aaaagaatgg caaaagatat accatgcaaa cactaaccaa aagaaagctg 41100gagtaactat attaatatat gacatcttat agttccaata tttatagttg gaaaattaac 41160acctcaatct cagtaattga tagcaaaagt agacagaaaa atcagtgaag atacagaaga 41220cttgaataac actgtcaatc aacttgacct aattaacatt tatagaacac tccatacaac 41280aagaggaaaa tctacattct ttccaaggtc attcagtaag atagacaata tcctgggtca 41340taaaacaagg ctcaatcaat ttaagagaat taatgtaata caaagtatat tctctgacca 41400caggagaatt aaactagaac tcaataacgc aaatatatct gcagaaaact ccaaatattt 41460ggaaaccaaa ccataggtca acgaggaaat cacaaatgat atcagaaaag attttccctg 41520aatgaaaaca aaacacaata tatcaaaaat tgtggaatgc aactaaagca gtgcttagag 41580aatttatagc attaaatatt tatgttagaa aagaaggctt tcttaaatca atgatctcag 41640cttccacctt agaaaactag aaaaagaaga ggatattaag caaaagttaa aaataaaaat 41700aaaagctacc tttattgaac acttaccagg cattatctta agtgatttat gctaagtgtc 41760ttttccaatc tggtcataac attatgagtt agtcatgatt aatatcccac atttcagatg 41820aggaaattaa atcttgctga acttctgtaa cttccaagtt tatgtagtta accaagagcc 41880agagttatta tttgaactca ggtctctatg ctgttgtaac ttcaacatcc tacagattga 41940gtgtatttat accgttaagc atattttatt atcttcaggt ttgatatttc tttgttgcat 42000atatattata catatatata aatactatat acacatacat acacgaattc ttcatttacc 42060tagaaccaaa aggaccttct cctagcatgc tggagaatgt ctagagacca gacattgcta 42120ttatcatctc tgaaaactgt ggcatcagtg aaatgaccta ccatgaagga tgtcactggg 42180aagtctgtga tggcagtcca tgaataattt gcacttgttc ctgccagtct ttcaagctac 42240atgatctcga gtcatggaga tatgggtgag caactgagta tcacagtgct ctccatggcc 42300accataactc actcaagtct taatatcttc tcgcaaggat aaacccagcc tccttaaaac 42360aaaatcaagc tcatgttctt tacatgagaa gccaaattca tctttctcca agcacaaagt 42420agtaaagagt gctggacatc tgatttctat ttgtagaact gccaggcaat tattgtgtgt 42480cttgggcaag ggacttgatt ttctaaatcc tcagttttct ctgttgcaaa atggaagcaa 42540aaagatctct ccaatgtcct ctccttgttt gctgctttct gcatcttttc tcctacacaa 42600ttgacaattt taactgcctt atcggtataa ctactgaaga atcagttccc aatatccatg 42660aaggtaaaag tcagatatta ttattcatcc actccaaatc ctccaatgac ttcccatttc 42720actaaaataa aaatgtaagt ccttacgatg tcctcacaac atagtttctc ccatccctct 42780gtacagccta ttatttcttt ggctttatct attattcctt ccctctgtat tagtcagctg 42840ggttcccgtg atgaaatacc actgactgag gagcttcaac aacacaaatg tatttattta 42900tttattttat tttattttat tttattttat ttttgagaca aagtctcacc ctgttgccca 42960aactggagtg cagtggcaaa atcttggctc actacaacct ccacctccca ggttcaagca 43020attctcctac ctcagcctcc cgagtagctg ggactacagg catgcaccac catgcccggc 43080taatttttgt atttttagta gagatggagt ttctgtatgt tggccaggct ggtcttgaac 43140tcctgatctc atgatctgcc cacctcagcc tcccaaagtg ctgggattac aggcgtgagc 43200caccatgcct ggccacaaat ttattttctc acagtcctag aggctggaag tctaaaatca 43260aggtgtcagc agatttcatt tcttctgacg cctctctcct tgacttgtag atgactgcct 43320tcttgatgtg tccttacatg gtctttcctc tgtgcacgca catacctggt atctctgtgc 43380atgcccaaat tcccttttct tataaggaca tcagtcagat tggatgaggg cccaacctga 43440aggcctcatt ttaacttaat cacatcgtaa aaggccctat ctccaaggac tcttagatat 43500attagaggtt agggcttcaa tgtgtgaatt tgataagggg agggacataa ttcagcccat 43560aatactctca cttactgtgt tccagctaaa ctggtcttct gcatggtctt caaacacact 43620cttgtctcaa ggcttttgca ctggctattc cttctccctg tgccgctgca aagaacgatc 43680atgtttgccg caatcttgta gttttaagga ccttttcata acctaatgca catgtcaacc 43740catggccaga accctatgta agatttatcc ccaatttttt ttttggcctc cttgctcctc 43800tcttttaatt tgttcccttt ggcttcctta agtattaact ctaacagata acagctttac 43860agtttggctt cccttgtttt attcaactca gtttcaggtt attataatgt cttcatttcc 43920gatgtggccg ccatattgga tggtgctgaa tcacccattc aaaagaaatg tgttaatgcc 43980agtttatgtg ccagtcatcg ttagtatctg gaaatacaca ggaaaatatt agggttagga 44040ttaatgaaga ctaatgaatt cagtagtggt atacacagag tatcatcaga gcccaaaaaa 44100ggaacattta tatgaaagaa tatcaggaag gcgtctggaa agagttggta ctacagctac 44160agtttgaaaa atgagcaact tagccaggta tacagagggg aagagaattt

tctagactct 44220gttagcatca tgcatgaaag tatggaagca tgaaacagta tgatacattt acagaaaagc 44280gcatgtagag aagtatgaga taatggggct tgattgatag aaggctagag aataaaaatc 44340atgtgtgcta agataattta tcttgaaagg tccagggagc attttaaaat tcttaacaag 44400ggaatcattt ggtcggatct ccaatttaga acgtttagta ttccatcatt gaagacagtg 44460acatgtaaga gtgagttctg gatgaaggaa gccaggtagg gagttactgt agtaattctt 44520ctatgaagaa atgaggacta gaacaagagc agaggcaaca caaatataat ggaaggtacg 44580gctatatgac acagtaagga aattgaatct atagaattgg tgctgggttt aaacatgaga 44640attgaacgag aagaaaactc taaaataaat cccaggtttc tgggtttggc aaagaaagag 44700atgatgatat tattcatcat tagaagggag agaaacatta acttgcagac acattgagag 44760tagtgaaact tccgtaagag ctgtccagtg aacaggtatt tttatacatt ttgtcaaggg 44820caagaaaatt tcccattgat tggggcctat ttagttgcct tcttcttctt gcaagagtac 44880tatttttctc aacacacctt gtaatcttag gcaaagggaa gaaggctttt atttggagtt 44940gcttttatat gagaccaagt ataactaaaa agatatagca tatcctcaac cccacccagc 45000ccccattcat tgcagcacct cctaaggtgt agatgtcccc tgtatcccaa aaacgtgagt 45060ggtgactaag tgtgatgtgg cacaaacgtt gaccacacta aagtgaccac atagtacttc 45120gctgctccca ctgggaaaca aaacataata caaatataca atgcttcaca gagtagcagg 45180tgattctttt tttttttctt aaagtcagat ttattgaggt atagtttaca ctaaacagtt 45240tactttttgt aacttttaag ttcagaggca tcttttgacc tcaaaaacct agttaagtaa 45300gcaaaggaga actttttttt tgttttcatt tcactgatga ggaagctgat gattaaagag 45360gttaaatgac ttgtcccggg tcatacttag tcttgagtaa gcaagattaa gtcttctgac 45420tcttaattct gctttttcca agatatcaca gaggatcttc cagaacagct tacttagaaa 45480ggacatataa tctgttcctc ataacagttt tatggtaata ggaatttaat cttctaagta 45540atcaactcag gcttttccac ttaccagtga aattgcagga ggaaactata gaacttgaaa 45600cactatcttc cacatttctg tattgatcct gtttgatggt ttgtgatatt aagggaatac 45660atgactatca tctagtgttt caagaccaag cccttcaaag tagagtaagc cacaacataa 45720aaagtgctta gttaccttct tggctctaga gagtcattaa atccaacctt tctcttctgt 45780ctagctgcct aggagtggct tctgttttaa tcatcatcat cattatttgt attagtctgt 45840tctcgcattg ctataaagaa ctacccgaga ctgggtaatt tacaaagaaa agagatttaa 45900ttgactcaca gttccacagg ctgtacaggg agcatggata tggaggcatc aggaaacaca 45960atcatggtgg aaggtgaagg ggaagtaggc acatcttcac atggcagagc aagagagaca 46020gagtgaaggg gaaggtaaca cttttaaaca accagatctc agccgggcgt ggtggctcac 46080acttgcaatc ctagcacttt gggaggccaa ggtgagtaga ttgcctgagc tcaggagtct 46140gagaccagcc tgggcagcat ggtaaaaact cgtgtctact aaaatacaaa aaattagccg 46200agagcggtgg cacatacctg ttatcccagc tactcgggat gctgaggcac aagaattgct 46260tgaacccagg aggcagaggt tgcagtgagt tgacattgtg ctactgcact ccagcctggg 46320taacagggtg agactctctg tttccaaaat atatatacac acacacacac atacacacac 46380acacacacac acacacatac atatatttat ttatttattt atttatttat ttatttgtgt 46440gtgtgtgtgt gtgtgtgtgt gtgtgtatgt gtatctgtat gtgtatgtgt atatatataa 46500acaaccagat ctcgtgagaa ctctataatg agaccgcacc agggagatgg tgctaaacta 46560ttagaaacca cccccatgat tgaatcacct cccgccaggt cccacctcca acaccgcagg 46620ttacaattca acatgagatt tgagtgggga cacagagcca aaccatacca ctattttatc 46680atttctatta agagttccct gcatttcaat ctggcctaga atacctgctg agatcatatt 46740cttatgggta ttaagtgata gtgtcataaa ttaccatctg caaaatacta tttcagaagc 46800tgtaattctc tgtcaagttc tctgttatat tgctacactc tgcagatttt tagaaagtta 46860aatattatat atgtatactt ctgcattaat gactttattt tgattcttgt ggtatctcag 46920gaatgtaata tgcaaagttt gtatagatgt ttttctttag tgtaatgaat tattaggata 46980tgactctttt gtaaaaggga gaaagaacag taatttgaat ccctgcagag atagcaatgt 47040atttggagac aatttgaaat gttttatctt tatctactaa aaattccagg ttgaaaagaa 47100taaaatcacc tcctctctct aaatgcttta ctctggtagt attattatgt aattattcac 47160aaaaaggtgt gttcttgtta cacaatcact accttctcct tggagatttc aaaaataaat 47220agatgagaaa ttatgtccct caaaaaagac cacaaaagtt tatccagaaa actttccctg 47280tattgatttt tctttaataa atgaagctac atgttttcat ttttaagaaa tataaaacct 47340taacttgttc ttctctcttg atacagttta ggaggtcttg catgcattct ctaacctcac 47400ctccttcccc tttctccaac tacactgtcc tctttcagtt cactgaacac tccaagctca 47460ttcatgcctc agggcctttg catatccaga tatctccttc tgctcactcc ttattaccac 47520catggtccat ttgaactgga tcctcccagt tttttctcta tcacttcacc ctattcattt 47580ccttattaca atttacaaaa accaaaaagt gttacttctt atctctcttg ccagctctat 47640cagagctgct accacatctg tgttggatgt catgtataac cagcggctag ttccatgcct 47700ggtacatcat tgcttaatat ctttttgttg aatgaatgaa tgaatggatg aatgacaaaa 47760attcctaatc aaattttctg ttgctacctt ttatacttac aacttaatat tacatcctta 47820tactctaaac tcatacatac ttctataaat aggagaaact ttacctacag aaatagcaca 47880ctaagattgt aagcaggaga aagataactg aagtttttcg aatttagaat ctattctggt 47940cactttctaa tgagttccag aatctatgtt cccatatctt tgggaagcaa ataattgact 48000gttaatagct tttcaaatat gtcatcagaa tggcagatga ggcctgaaat tctcaatgga 48060ttgacaaaaa gcccctgtcc tcttggtaga atgaaatata gtacttgtaa cacttcctta 48120cttcccccaa attacttatt ctttaagtta cagaaaagga attccacaaa ctacaatgaa 48180aactcaaagg aagtaattac tttaggtaat atacaagtta atactatgtc ttttgtttgg 48240tttttcttca gacagaaaat aacccaaact ttttttttaa ttcattcttg aattttagaa 48300accattgtta aagtattaat catttctgag ccatccgtag attgagttta ttcatccttt 48360ctttaagttc ctctcaacaa acttagccat gttttatgat gtataaaaca tgctaaaata 48420tttttaatct aaaccaaaat ggattttggt caggtatgct gaccctgagc agtcagtata 48480tgacagggag accaaaacaa cccaaccagt tctgatttta cacaagttcc ttgccttctc 48540ctttaacata tatcggaatt gctaccttag atggttcagt gttatgggaa gttgacagac 48600agaaaatgca gtattatatt aggtcaaagg ttgacaaact tttcctgtaa agtgaatatt 48660tcagactttg tgagacatgt actcgctgtc acaatgacac aactaagcca tcttagaggg 48720aaagcaatca cagacgatat ataggtgaat atgcataagc aggtgcctta cttcaggctg 48780ctgtcacaaa gtaccataga ctgggtggct tacaaacata tttctcactg ttctggaagc 48840tgaggagtcc taggtcagag tgtctctctt ctcagttaca gactgctgtc ttcttgtatc 48900ctcacatggc aagaagagga caagagagct ctctggagtc cctttcatga ggacattaat 48960cccattcatg agggctaaaa cctcataccc taatcacctc ccaaaggctc taccacctaa 49020taagatcaca ctgggtgcta aaatttcaac atatgaattt tgggaagaac acaaacattc 49080agtccactgc agtgtgctat aataaaactt gatttacaaa agtacactgt aggccagaca 49140tggcttgcag accatagtcc gacaaccttt gaattaggtg atcactacaa catgtaaatg 49200aatatgcatt gtgtcttagt tcaggctgct ataacaaagt accatagaca tggtggttta 49260caaatatgtt tctcacagtt ctggaaacta gggagtccta agtcagagag tccctcttcc 49320cagatataga ctattgtctt tttcttgtat cctcacatgg caaaaagagg ataagagcac 49380gatacctaga tgtatttgtg atggggagtc agccatttta acatttatta aacacccact 49440aaactccaag gtttccagac agtgtcataa ataagcttca caactgatct gtattcagta 49500gatgtgaaaa ttgaaactgc ctggttatta atctgtgtgg ccaggccatg aacccattct 49560cttccgtcag gttcagccct taagcacaca tgccacagag tcaaaaacaa cctaggtttg 49620aatcttgctc agctatttac tgatggtgtg ctgtatggaa aattactaga cctctgtgta 49680tctcagaatc ttcccctatc tcatggagtg gctaggagga ttaagaaata aaccacaaat 49740agcactcgct tagaacagtg ctctctgctc aacgcatgtg gctagctttg accacaattc 49800tgcagacact tcaggttcca gagagttctt tcagaagttc cacaaatgtt tgatttaaat 49860gctgctaaaa aatatttttc actacttaaa ataccttaat aaaaagaaac atatattcat 49920gcaatgtata ccaaattgaa cacatattct cattctatat gttaacttgt gttgtcagtt 49980aacttttaca cagacattga agcaaagctt ttcctgttct tcctgtttat ttaaaaattt 50040tgcagagaat tcaaggtaag ctgataaaaa taattcttac cattgtaacc acttagctgt 50100gtgaatcaga attgtcttga cactgtgcag ctgaagtaaa aacaatctaa aattggaggc 50160tgaggtggac ataagattct catctctaat attgtgttaa tcagaaaaac tttattattc 50220ccattgattg gctttacaat aagtaaatgt tataaatcgg ttttaaagcc tttatatgaa 50280aatgactcac tttttctgtt ttatatattt aaggtttcat gtaaattttc atttggagct 50340aaaaaagaca tttttcagca gaaacattta actagtactt aactagtcaa gatctgcctc 50400tttagattgg ggcttttttt agatcaagac ttgattctta cgtatctttt ttaaaaatta 50460gactctgata attaggtcaa gacaaagagt tacccaagca gagttcttca ttctccttta 50520ctctcctacc cacatcatta tgtcctagtg gccttaatag atattttctc cttagatctt 50580tataataatc ctctgagttt gccaggcagg tgatattagt ctcataaatg aagaaggtga 50640atgagactca aagaatataa atgactccca agggcatatg actaaacaag tggtagggtc 50700aagactcaaa tcagaaggct tctgactact aatcgagagt ttttcccacc cgttttgatg 50760tcaaagatgg ctgagatttt ggggaggggc tttgggagtt cagaggtgac cctttagcca 50820ctgctgaagc tgatagagat gcaagatcag taaacatatc ttattctttg tttgtttttc 50880cataggttgg ctaggctttc tagtgattaa aaaaagcaat gtagacactt gtaaagtgtt 50940ttaatttatt gtcctggact ctgtctcact tgttgcaaga gtcatttgac atgacgcctt 51000gctaagaaat ccacacgtag gtctcaaatt cagtcctggt tgatttccta gggtctatgc 51060tccatgaggg cagggacagt actagatatt tgtgtccaca aacatctaga ggcatccaat 51120tcttatctgt tcataaatat atgatagaat caaccatcat tctatacatt tttctttaga 51180tcttttttcc ttttgctacc attgcttttt ggaccattat tgcaggcata tcataaactt 51240ccttggtaac tcttggcatt ttggtcctgc ctccctcaga tttttttctg cataatctca 51300aagcatccag caatgcttct ccagcgcctc tcagaacaag gcccagatta tcctcctggg 51360attcaagttt cttcatgata tgggcatgcc ttatgaatac accttcgctc tggtctcatc 51420accgtccctg cagtcctctc tctatatggg acatgctcat tgctgctttg tgtctctgcc 51480gttgcttgtc tgtttgccag ctttcatttc tctacacaga tccaaattgt acccatgatt 51540tcctacctaa ttcaactcta attttctatg atccctgccc cagtaatttt agcccataag 51600aatttttata gcacaaattt tgtacttaat gacacttgta ttatttcatg ggttagttag 51660tgcaatctct atgaggctgt aggcaatcaa gtaagatatt taaattgtac ccacattgtc 51720ctaccttccc acactgtaga cacctactaa attggagtaa tgtgtaataa aataatttat 51780agatttaagt aattgaaatc atcccaaggc acagagagaa caaacaaaca tattcctgag 51840acatgtctaa ttcatgtgcc atggttatct tgagataatt ttccactgta cttttaataa 51900aagagacacc taaattattt catagtttgc ttttgttttt cctccttgag cattgccatg 51960gttattgata tttattaaat caaatctgcc actgaagcat atataaccac tcaagaatga 52020attacagcaa atatttaact gcctgcctgc ctttgaattg gttaatcaga atgagtgatg 52080cattagctgg ttcaactcct ttcacctgga aagatggcta tcgattccct ttattgtgat 52140ttaaaagatt tgaggaaagt ctaaaagcat ttcaaaagat ttcaataagt aagacataat 52200tctgcttttc ataaccacta aatgaaaaaa aaaactaaat acaaaaaaga ttcttcgagt 52260aaaattctgt cattctccac tttttattgt gttaaaaaaa tcaactataa tatgagtgaa 52320agtcaagttc tgctggtatg tatgaaatga gaagagaggt gctgtaggtt attaataaca 52380ggggatgttt tgtacctgtt ctggaagatg aatatgcatt tttgtgttgg agccagtcca 52440taagtcaaat tcctttaaaa caggcagagg ccagccttgt tctggctgca gcctgcacgg 52500ccagaaaaac agaggaagaa gcgccttcca ccagcatgaa atgttatcca ctttgatatg 52560taaacattct tccttcacct gaagttgatg tcagggtaac taaaacacaa gaacttggtt 52620gactgagcag aagcaatctg ttgtattctt ctgtttttca aaaccagaga taatcaagga 52680ctgttatgtc agatgctagc tgacctaact tttgagtgga aaacgaacca ggaatctgag 52740ataactggat agtctccgca tatttttaaa aaatcagcat gtctcttgaa actgctcaga 52800cttagctgat ttttgtagtt gttgttgttc tctttatagt tttttttctt ttttctctgt 52860attccagact cctggcattt aatctattgg gtgggaataa atgacgtaaa ttgtactcat 52920atttgcaaaa agcccaaaaa agatgttaag gctgttaaca acagacgtct acgctacagt 52980tgaaatgggc taggtgaatt gagacagaat tctatgaaca ttttatgaag ctttccttaa 53040atttctaatt gaaaattgct actgtttgtg ttactgttga ttcatttcat ttaagtcttg 53100gtcttgtaga ttctattgat accccattct tggggatgaa aaacaatgtt aaatgcgcac 53160atttgttagg aaaatgggct gggtgggaga cggaaggctt tggccgccat cctagggcat 53220tcctgtgcat tgcgatggtc agcatttctg tatctaaaca tcgaaaaagt acaataaaaa 53280tacagtatta taatctggga ccactatcat acacgcagtc tttcttgacc aaaacatcct 53340tatgccgtgc gtggctgtgc tgagaaggag gagcactcgt cctctccaag cacatccaat 53400ttgcctcagt cctcatgact cccgccctgt taccagaact gagctcattt gttattgaag 53460ttgcttttct tatacccagc ccagttttcc attgatgctt ccgcttattc tatgtaggta 53520ttttcattta tcacacaata tccctagtct aagacttcat ttgaggaaag aaaaaaaaaa 53580aaacctctgc tgctaaaaat aatttgaaaa ctcctagaca ataggacctt tcaaatccct 53640tacaattcta acaaccagtg aattcatgct tcacagccat tcagatctat acgtatgaaa 53700tacaagacat atgtgttcaa ctttccttca tcgcctcctt taaactttct tttttctttt 53760ttgagtcagt ccctgcagga acagaccaag tgagcccatt aagagaacag ttcattccca 53820cctgctacct cgagccagcc aacaatctca gcctcaccac tccattcttg attatgtaga 53880accattccaa tcctgagtga caggatttgc aaagacagct gttgggctcc acaaacattt 53940ggaggagggg aaaatgtgag gttggttgct acattctcct acttcttttt actgaaagga 54000acagctgcga tcttcacatg taagatgaag taaacaaaag ctgacaatgc ccagcaccat 54060tcagcagtaa gcattcaaat ggatttttcc tcaccgcgtt tgcaggcccg gcacagtctc 54120agttccccac agcacagaga ggaagcaagg tctttgcatg ccctgttcac ttggccaaac 54180attgccctag atgtgcaatt caacccatat aaagcaagcg taattcaaga gccctgactc 54240tttcaccatt tcatgatggc ttattactcg cacacggcat tgtcaggttc cagcaactct 54300gtgtgcagca ggcagaaatg cagtgtttat ctctgacagg caaacattct taggctcatc 54360ggcatgagta tccacgctga actggctatc ggggaagtag atccctgcat gggaaagtca 54420aggtatgttt agagggactc gatgattcaa ccccattggc tggttcattc cttttgtttc 54480ctctgccttt ttatttgctt acacagaaaa cagagcattc atttatttct tttccctctc 54540tcatctctat taaccactag ggccatctgc ccatctgaaa ctgtctttgg ctgcatggtt 54600gtgaatccag gtgacagtga aaatgaagaa gtggtgattg tccctgcatg ttttctctga 54660agggttaact aaaaaaaaaa aaaaaaaaag cctttgtgtc tgtttcgagt tctccagttg 54720aaatactgta ctcattgaac tgcaagaaat aaaacctgca agtaggcact gtgctaatgt 54780aatagaaatg tgttagacag gggcactatt tcttaaatat gcttgaatta agcaagttct 54840tttaaaaagt gggtgggact tttgatgttt tacatagtta tattttcaat ttcttgtgct 54900cagtttaaaa ctcaagattc tttgtttctg tgtgtgtcat tagggcaggt gttggatgac 54960aagtaaatgc actgaaaaat gaaaaaaaaa gatttgtgcc ctaacctcca tgaatttggt 55020gacttaatat atccatacag atctgacttt taatcaaagg tgctcacagg tggggtaagg 55080gataaggagg aatttgtcta caggatcctt ttatcctaag ttgccttaca acatccaatt 55140gtgttaccgt tttttttttt ttttttacaa acccattgct aggctaagaa gtattgattc 55200catctagtta aacatgtcga gtgagaggaa gtgatcaatg gattacttct tcaaaacatt 55260tatcccccct agtggaatcc tctgattttt ataacattaa agagccaggt ataggagttg 55320ggagaagaat ttaaaatttg aaatgtcttc ttttttcaac tctgttcatg aaaactctag 55380ttaatgcatg tgatttcctg ggtctccctc tctacttccc tccattatca ccaccttttg 55440ttgctgctgg ggctgtgggt gccctgaagg agcatgagat ggccttcctc agatatctgg 55500gttttaaatt cagttcgtat ctcttaagtg aagtgggtag ggccaaaaat gactcactgc 55560ccagtggtgc ctggaaacat tatcagcaaa gacattcacc tagggagaaa ataaacacag 55620aattctcata tgggcccatc tttccaacca tctcctggac tttggtagtc ttttctgagc 55680cagatatctc tctaaagtca cttgctgtca gacctttttg tctcatattt aggaatggct 55740gaagttcttt ataaatccca gatgaaacag gaggaaaact actttgaaat gatcatttcc 55800atgatctcta aaatgcaaca aaccgtattt cttaagatta acggatgcga gcctatgaca 55860ggttcaatgt gggaccaact caagggaaat tgatgaccga attattaaaa ggcattcatt 55920acatcgcagt ttcacctgaa gagggggtgt cccccagtag tgcttctgca gcagaattgc 55980ttagaaactg cagaacatcc acaaggcaag caccccaggc cattgtgtct gactgtcttt 56040caaatagagg aatggctagt tgccatttgc tgagggcatc tcctgcactg agaactgtgt 56100gcatatatgg atgatatcgc cgagactcac aagtatgcaa gatagaaact aggtgcattt 56160ttttcagatt aggaacttga gaatggaaga taaactgaga aggggagcag gggaggatag 56220ggagagattg ggcaacggtt aagaagttac agttaaatag gaataaatcc tggtgctcta 56280ttgcacagca gggtgcctgt ggttgacaac attgcattgt ctatttcaaa gtagatagaa 56340gagaggcttt tgaatgttct caccacaagg atatgataaa tgtttgaggt aatggatatg 56400ctaaatactc tggtttgatt attacatagg gtatgccagt ttcaaagcat cacattttac 56460cccataaata tgtacaacta tcatgtgtca attaaaaata aaattaaaaa aaatttattg 56520ataaaagaat aaaaaatagc atgcttttgg ccactctatt tgataggcat catttaaaaa 56580acataagact ataaggctgg gcatggtggc acatgcacct gtactcccag ctatttagga 56640ggccgagaca agagggctgc ttgagcccag gagttcgaga tcagcctgag caacacagtg 56700agaccctcat ctttaaaaaa tatacgtagt atagatgatg taaaaggacc acctttccaa 56760atgagtcaat ttcttcctta atttaataca ttcctaggta gtaagttttt agagagctaa 56820actaattcct tgctatgtct taggttacca tttataagtg ttcttatggg ggttagcttc 56880attttatgta ctaaacactt atttgaaagg atcgttgcct ttttccatgt gctaatttgt 56940atagagagtt tacgtattgt gggaatttaa tttattcctg cattttatcc aggaaaatag 57000agccagatgc ttttggacac ttgttatttg ctttaaataa gatatcaggt taagataaga 57060aaaatatatt gattggatat tgcgtcttcc tctggagaac gtaaaacctt tcacgtccta 57120catctcatca taccttacaa ctttagaaca gactctaata aaaggaaaat gttttaactg 57180tccctttact tatagagggc agggatggga aagtgcactc aattatacta acagagctct 57240caattaatct aaattcaaag cgaaggctcc tgttgtggat cagggaccct gaataaacat 57300gctttctagg agacttcacc gccaggttcc aagagaggtc acagtactcc tgcactcctg 57360atggcagacc cttggattcc attgcaggca gtgacacacc aagagtaaga ggagctggct 57420tcagccctgt ccacgtgtgt ctgctggctc gcccttctgt ctggcatctc cacgcccctc 57480ctcttccgga ctcccttgca tgaccttcca aacagaatga gctgttcttc caaatatgac 57540cctaactcat tcaacagctg gaggcaagag caaactagag ctcatgcaaa gggtattagc 57600attgagtctt ttttttcccc ctctttctct cagactaata gatatttgga aaattcatct 57660aaaaaccttt tttaaaaaaa tttcattcat aaaaatagcc aaggggtttc tcagagagtt 57720tccttttagc aagtcttttg gaaggaataa atgtctactt tattattttt ccttcctgtg 57780cctgacctcg gagaggatta gagggtctgg gcaaggagag gagcctcaca cccagccacc 57840cacacttttc cttctgacga gacccaccgc catgccatgc tctgtacaag ttctctggag 57900gaacataaga gccaccttat gtgtgaggga ataagaccat gctttgaaga gccagacttt 57960ctccttttac ttgctcttga aattgttttc actctgatct gcaagtcaaa gaaatgatct 58020attatacatg tagggacctc aaaatctgtt tgactctgtg caaataaggt acagtccctg 58080ccttcttcct atagttttct tatcactagg ggacttgaaa aggatttagt tcaacaactg 58140agtcagcatg agctcacaca aaacaaatcg tttcacacca atgtcaattt ctttctttct 58200tcccccccgc ccccactttt ttatttaaat aattcggtca gggaaatccc acatgcttag 58260tatcattttg tcagcaaggt acatgacaac tctggtcaca atagaaagtc gtttagtgaa 58320ttaatgtcaa ctctggaaaa agtggctaat gtgtcttggg gagtttggtc cttgcctgta 58380cacctgcctg aagatcacaa gagtaagaag gacaggtaac acacactgaa tgacaggatc 58440agaggttagc aatatctcag aagcctgcca tatgagccaa acccaataca aaacaattta 58500gcaatattaa gtaattatca cattttgtac ttcaataaaa aatttaatat catgactttg 58560cggtaggaaa ggccaagttt aatgttggtt aaaaatagtt tggagattat atttgtctgt 58620cttcaatatg atgtttcttt caaaatatcc caaataatct gaattaagag tagaaataat 58680atctaccatt tattgagtac ctactatctg ctaaaataac aaatttataa tgaaggtgta 58740actattccca ttttacagat gaaaaaaatg gaggaggtta agtaaccagc actaagtcaa 58800aatggctagc aaagatcaaa accaacatgt tagccaatgt taggcagttc aagtcctttc 58860ctctgtgcct gaaatgaaag aaattttcca ggaattttgc attggttatt catatcaagt 58920ataaaaaatg ttattcattt caatgaacca aaattaagtc aagacactta aggactgtct 58980agaggaaaat gaccaggata ggaaagagtc tggaagccat gcaagaaaag acacagatgg 59040taaatattta acatgaaaaa tagaagattt gtgtgggata taggagatac cttcaaataa 59100tgaagacctg tggtcaactg gggcaaatat tttaacccca aataagttct tcaacaataa 59160cagtttcatt acaaataagg gaagagaaag tgcccaaaat gagcattctc agtcactaga 59220tgcagaatca gaaagccacc tgccagggct gttattgagt gaaattctga

ctttgaaaac 59280atttggccta tacgagggat tcttaatctg atatccatgg aagaacttta ggtaaagtct 59340ttgaatccct ggaaattata tgaaaaattg tatatgtgtt tttttttctt gggaaatggt 59400ggatatattt cttcaaatcc tcaaagcaat tctacaatat tggtggggca gtgaaaggaa 59460atcacttcca attctacaat tctgttttgt aaaagtagtc ttacccttca cagaggtgca 59520cccaagagaa ctgtgtgatt gatttaatat taggggtgaa tgaacataaa caattgaaga 59580aaacttcaag gtttttagcc ttgtaactaa gatgttcata caatttttaa aaatctttaa 59640taaaagagaa gcaaatttag tggaagataa ttaagtagaa ataaataggc aaactgaagc 59700ctgtctaaga ttccagtact gagagtactg agtacgtaat tcaaatattc ttttacatca 59760tggcagaaaa atgctgaaat ctagggatat atgctgacta gtaactgagt cttatataaa 59820taattttttt aaagccactt gaactttaga accataaaat gttataacac taactgttct 59880agagactact tacttcagtc tcctaatgtt acaactgaag aaatcatgtc tcagaaaaac 59940taagagacat attctggatt ctggggcctg gttcctgatt cacgtctctg tctgcaaatt 60000taaggaaaaa aaattctaaa acattcaaat ctggaataaa cctatgcatt tttcaagaag 60060aaaatatata tataaaaact agtcttaact acatataata cacaaaggtc cactttgtta 60120tggtataagg caagaccgta aggaggtctt atgcctcctt atgaggcata agattgcccc 60180ttacgagttt taaagtatga attccacacg tcagcatgct ctgggatgtt ttcacagtat 60240ttttaacatt ggtcctcata gtcttaattt acctctggaa atttccatgg atgattaaac 60300tatgaagaac aaagaagcac atggctgtgt tatttagagt ttagtgaatt aggtctgcaa 60360gtctgttggt ttccttttag atgttgtctt gtccgtttct aagatcagag ggagaccagc 60420tccaggagtg ctcatgaatg catcagtggt cttccatacc atctgatgaa aagattcatt 60480ctgtgtctca aaaggatatt ccagatccag ttctgagtca gcaggtcttt ggtgtatata 60540tatatatata tatatatata taaatttttc cactgcttta tttttttaaa ttcatctgac 60600aaggtcaagg tgggattgag acaagaaaaa tttggaacta gtcccatttg agacttattt 60660ccttaaaaaa ggaactgttt tttaataatc tgaaagttta cataattttg acatgcaagt 60720tatatacgtg tgtgtgtacg tttgcatgct tgtgtgtatg ttcatttttt ttaaagagac 60780tcaaactaaa taaaattttg attgggggtg ttgctgaaag gactatagtg tcagctgtta 60840taacttcagc tttaaacact aaaccaaaac atgggctaca tgttccaatt catactgaag 60900ctttataata tatggcctta gagtagaagt ataatgatct cttgggagag gcaagatcca 60960attaaaattc agtttgctgt cttttggaaa gacataagca gttatatatc ctttgagacg 61020gtcttaagaa atacacacct gagctttaaa tggccactca tttgactgtg aagttgaatt 61080tcaattcatc tgggagtcag agcacaagaa agaattcaaa taacaacact ctgatatttc 61140ctggtgtgtt accagggaga aaagagctcc tggaaaatga acgccttaca catttgcaga 61200tattaccaac cacttataaa aacaaggcta ttgttatgca taaaagtcat tccttttagg 61260ggaagcctaa gagtgaattg aaatgtggct gacatttcta ccacaagata aaatgttttt 61320ttaatatcat gtttaagttc tcttagttaa aaaagagaaa agggaaaaaa agaagaagaa 61380agaaaaatat ctataatcca gtattcagaa gcaattccag acacttcacc catgaaataa 61440ctcactggaa gacattacat ttctaaacac aaaagctatt agcagccttt tctaattctc 61500ttttagttca ataagggaat tattgaccgt attttgcaat cccacatgtt tttaaaagac 61560aaaaaacata gtacattgaa cagaaaacat acgaatgctt tctatttaat ttattagttc 61620atgactaaga tgaaacactc caacatatac aataacctcc ccacccccac ttcactctga 61680ggttcttttg gttacttctt ttttacaaca aaggtttgat gtattcttta aaatataaaa 61740agaaaaagcc actatattgc ctcagaacta ctccatctca ctgcctcact ttaaattctg 61800attgactgta atgagaccac agacagattg atgaaataaa tttagatact aaatagcatt 61860gtacttgggg tgatttagtt atatagctca tttatttctt caacaaattt gttgaacagc 61920agtattagtt aaggcaatgc aagctgatgt cataaataaa cccccaaatc acaatggcct 61980aaaaccttaa aggtgcaatt tttattcatg gaagcagggc aatgtaagta actacaggat 62040tcaggcagcc agaattcttt catcctgtgt ttccatcatc ttctagagct tcaaagtctt 62100ctgcatttat ccaagataag agaaaagaaa tttgagaagg tgtacctgtt tttagccatc 62160ttctgctcac ttgctcttgg aattaacaaa tcacacaacc atacctaagt gcaaagtggt 62220tgagaaatgt atttcctgat gggacaacca ccttccagtg ataacttcac actctgaaag 62280ggctcagctg caacacctgt aataatactg tgctggacat tgtggaattt tctaaaagaa 62340acaaaactgg gaccttgtct tccacgagca tgcacgttag caattttttg caaggaattt 62400attcccttac caataataat agttaatata tatataaagt ttgttatgta tcaggctcat 62460tattggacca gaggctgtgt gggtggtatt tcaggactca aaccctggta tctgcgctgt 62520ccaaattcat gctcttgcct cctgccctcc gtagacttct aatcacttaa ggcaagagac 62580tcaagtctag ttctcttaga agttcctacc acagggcaga gcccacacca gacagtgaag 62640gaatgtggat tatactaaac aaaaccctag gatcgattgt ataggtaact gttggcaata 62700aattagagct caattccaac tcataaaaag ctgtactcca aaatacaatt caccataaat 62760gaaagctttt taaagatatg agttgcctat actataaata ttgatttttt ttcatctgag 62820tcaattgaga tgcaaatgct aatttgagta gatgagcata tgagcattag tggaaaaact 62880cacctaaaaa ggtacaagag agagcaagat gcccaagata gattaacaca acactttaac 62940cagaatgttc tatcattttc tttctgcaca tacaccttct aacttgcaaa tctgtcttgc 63000ttcacatgat ctcttcccat ctaatttgat gggtttttct ctgaaagaaa tgaagggagg 63060attcctccag ttcttgtttt ctatggtaat tatcctaagt tttaggggaa gaattttaaa 63120agaggaattc taggcacttc tcaacttgga gcagaataga gatgtattcc agtaaggaat 63180atagttcatg ggcataagtg acttgaatat gaggtagaat tgggggtaaa taacctatga 63240aatgtataga tgatattcta tcagacaaga gatattacct atagttttac aaaagaaata 63300aacttttagc taggcctttt agaaacatgt aaaattaact gagtttacca agtatagaaa 63360aaataggaaa ttgtcattta gaagggcatg atctattcag ctagccaacc aagaaatatg 63420tcgagtgctc cgatgcaagg tagggtatga agagcagtgg ggagaagggg gcagtgaaaa 63480gtgcaagaca acacctattc ccatataggt cagcagctaa gagcaacaac aaaagagaac 63540aatgggcatg tacagtgcat ccacctgtac caggtaacat gccaggtgaa ttattcaaat 63600tatctcattt ggcactaatg catgtaaagt acatagcaag gtgcctgtca cagaaagaat 63660gtacaataag tgatagctgt gatttaaatg ccagttttat gtggaggtta ttatctgttt 63720tcaaattaaa gaaagtgagg catggtgagg ctatgtgatg ctataaactg aatgttttta 63780tccccacaaa atttatatgt tggaacctaa tcacgaaagt aatcgtgagg ccccgtaaag 63840gtagggtctt tgggggttga ttaggtcatg aaaactccac cttcatgaat gctgttataa 63900taataataat tagtactctt ataagagagg actgggggag ctcatttgtc ccttctacta 63960tgtgaggatg tagcaacaaa gtaccatctt tgaagcagag agtgagctct catcagacat 64020tgaatctgtc agtacattga tcttggactt cccagcctcc aggaccgtaa gcaataaatt 64080tctgttgttt ataaattatc ccatctgagg tattttctta cagtaggcta agatagatga 64140tatatccaaa gccccttagc tggagaaacc agacatacac gcatggaaag ttcaataaca 64200atgagattct ttgtgaaagt tgctctcctg gcagttctat tttactagta gaatattcat 64260cttagttcat gggttgttat tcctcaatct ggctgctgag tgccctttgg gtgtttatga 64320ttttaactgc ctgcccctgg ttctagttgc ctgggttagg caatgagggt attttgtgca 64380aattgtgtcc tgagtgccta tgctgcagct ccccatgagt cttccattct aattctaatc 64440aacttccagc tatctatctt aagcagagta ccttttagga cagggtgata gggggagcct 64500agaggtcaca tgcgaggcct cccatctgtg gaggtttagt tggagagagc tgacaatgag 64560atgattcctg tgcagcagta gtcatgaacc tggggcagga atgagagcac catgctatct 64620cccagggccc agagagtgtg gccctgagag acagatcagt gaaatctcta aagagcaatg 64680cgccagattg atgagattat cttgggggta cttgctagtc tctttggctt cggaggggcg 64740tggagggagg ggaacagata ggctcagatc ctctctgccc ttgaggctgg tcaaacatat 64800tgcaggtttg tagagaagtg tcttctcctt gtacttgtac agatgatttg ctaaccggac 64860ctgaaactgt cctatctccc tccattccag tgactcaagt gtcctcagag ctaatccagg 64920taactagagc caggggcagg cagttaaaat cataaacacc caaagggaac ccagcagcca 64980gattgaggaa taacaacaac ccatgcccca agatgaacat tctactagta aaatagaact 65040tccagaagaa acagatgaca actttaacaa agaatcaaaa gtatacttac aaaaattgaa 65100aaatagcatt aaaataactt tccagcattc aaaaacatgg cttttcaatt aaaaacatca 65160attcagttaa ggaaaggatg gcctaggatg agacagactc acttgcaata taagacatta 65220tagggtaaat accaaatgag tcgttttgat tctcaggtgg aattgaccat tagactcacc 65280tgttaaaaac acagacttca acttacccag ccctaataaa tcaggaactc tggaagccga 65340gccaatgaaa gtgcattttg gttggaagtg gccactggtt ttgggcactg gttatggggg 65400ctgtggaaac tggcagtaca tgttgaatga gttatcaggg tgagagatca ctgggtctgc 65460agggatggtg gtaaggaccg cgggagagag atgagaactg aaatgagcat gagaggtggg 65520tagagtttat tgatagtgac ctaaaaatat gaaacaagga ttgatgaatg ttttgtctgc 65580atgatcccaa gttttcacca gatttagaca caaatacttg tcacacccgt agatcaaata 65640gcaagtctaa aattttttaa agtttagctt taaataatat aatacacatc agataaataa 65700gaagttgaag tatcgcgatt ttgcaaatgt ttaggaagct tgtgttcatc cggttcacat 65760ttccttcact ctatgtgtgc atgtttgaaa ctgaaatata caagttaaat ctttagtctt 65820acttttttaa ccactgacaa tgatgatggt ccatttatct cccaatgttc catttcaaga 65880cagatggatc agtttgtcaa ggtctgagta ggaataaatg gagtgctcca aaggcaaatc 65940tgtagtggtg tgttcaattt gataaaatca cgcttgcata tttttttcct aaatttcctg 66000aaccactcca ctaagggaga caacctagta cttcttggtt tttttctctt caaatggctg 66060cttctgagtc acagatgtga aataacagga atcaaaggat tcatggatca agaaaaatga 66120ctcctgatca tttccagtag gttatttcct tggagctgtt ctgctctgcc cccaggaggt 66180gtaatggatt tgaactaaat gtaatcaaaa attttcacct gcatccttat ttcctgaaag 66240tagctcagtc ccatgaagct gaactttctg cagctgtgag acccacggca tggctgcttc 66300cttaggggaa ataaactcga tgtttctctg agtcagaacc acagaacaac agtctcatga 66360aatgctctat gccaaacaaa aagcactctg cactcagatt tgggatgaga ttcacatgcc 66420atcagctctc agagggtgat agagcacatc caagcttctg gagcccctgc agcagagaaa 66480tcattttatt cataactctc tgtaacttag tcacttgtat tcatttttga gtgctgcctt 66540aacaaagtaa caactgggta gtttagacaa cagaaatgta ttgtctcaca gttccagagg 66600ctagaagttc aaagtcaaag tgttggcagc tctgtcccaa gcttccctcc ttggcttgta 66660gatggctgat ttcatgttca cagggcattc tccccatata ggtgtctatc tccaaattcc 66720atctgtttgc aaagacacca gtcatagtgg attagagtcc atctaacgac ttcattttaa 66780cttgattacc tctgtaaaga ccctatctcc acataaggtc acattctgag gtactgaggt 66840ttagaactta catctgaatt tgaggaggga gatgtaattc aactgattat accactgaat 66900cctttttttc ccatgtcatc tattaacagc ctgaagaaca cgtttagagg gatgttactg 66960tggcttcaca gataccatgc tcttcctcaa tggttcccaa atgccatttg cagaatatat 67020gcagaatcac tgggagtgct ttttagaatt ctaaatctgc caggcatggt ggctaacacc 67080tgtaatccca gtactttggg agaccaaggc aggcagatcg cttgagccca ggagttcgag 67140accagcctgg gcaacatggt gaaaccccat ccctactaaa aatacaaaaa attagctggg 67200tgttgtggca tgcacctgta gtcccagcta cttgagaagg ttaggctgca atgagccatg 67260agcccatgat cctccactgc actccagcct gggcaagaag agtgaaacct gtcaaaaaaa 67320aaaaagaaga attatagatt cttgggtctc acctccacaa attaaaatcc actggatcta 67380aggaggaact caggaatttg caatttacaa agttgcccag aacattctga tgcatcacca 67440ggttggagtt ccacagccag ttagtgctcc cttattattt tttagacttg atttgggcca 67500taaatcttat aatagctacc taagaagtac acttcttctt taaacaatat gaacatagaa 67560ttgttttctc atctctgttt ttattacatc ttctatcttc ctccactgca gtacaaacca 67620cttgatgtgc atagattctg ccttactcat ctttttattc tcagtgtgta ccagagaatc 67680cacacataaa taacattcaa taagcgttta ttgaagaaat aaatacctcc agcaacacag 67740gcaaactgta caattgtttc atcatttaaa gaagttcctg gccgggcgca gtggctcatg 67800cctgtatccc agcactttag gaggccaaga caggtggatc tcttaagctc aggagttcga 67860gaccagcctg gccaacatgg tgaaacctca tctctattaa aaatacaaaa aaaaaggtag 67920ctgggcatgg tggtgtgcac ctgtggtccc agctactcag gtgattgagg caggagaatt 67980acttgaacct gggaggcaga ggttgcagtg agctgagatc acgtcactgc actccagcct 68040gggcaacaga gtgagactcc atctaaaaaa aaaaaaaaga aaaagaaaaa aagaaaaaga 68100aaaaagaaga aaaatgttat tgacattgac atatctttat acttgagaga attcagctac 68160tcttaagagt ttaacccgtg cagccatgcc cgctgtcctg actcattttt actcctgcca 68220tgatagctta cctgtggttt caggacacat ctttcttttt ccagcctcaa ggatcttttg 68280cacatgctat tttggaactc ttctgcctac cctctttctc caccccatcc ccagttgcca 68340cgactatttc caaatgaata tttgttctgc ccttcaaatt agaagtggtg cccctgttaa 68400acgttttcat aatgcttcat tttttttccc atggagacac tgatcatgct tgtaatgaat 68460agttcaatgg ttgctctctc tgacaaactc taatctacat gtaggcaggc ttcatgtctg 68520ttgtgttcat ttttgaagcc acagaaactt gaacagagta ggaactcaaa tattaattga 68580gtcgttatgc gctttaccat gattatgtgt tttttcccac cattaaactg ggagcttctc 68640tacagcaggg actagattta atttattttt ctatttttgg cacctggcac agtgcctgga 68700aggcagaaca agcacaataa attttcttaa aatttgtaag gtttttgttt atttgaatgg 68760ttgtttagtt tttgccttga tgaaagcctg ggatagaaat ttagaacaag gttggatgtt 68820ggtgatcata taaaaataga tttgttcttt tttgtcatta gagcccaaac ttaaaaaata 68880tgtcaaataa aaaaataaac tagaataaca gggaacattt aatggaacca aggcacctca 68940aacagctgac atacttctaa aaagcagaaa gtaatagtaa gggagataat agcatacgag 69000ttagttttcc aattgccaaa agatcacttc aaatacagct cttggcagtc atcttcttat 69060ggagaaactg caacacttat ggaatggcaa ttccaccaat cccctttttc taacagcaga 69120aaaacctgaa ggagacaagc ccagctatag tccagctggg acctgtggca ataacctgac 69180ctaaagttac ataagtgatc aggaccgtat gtggtccgta cccctctgcc tgaggatgct 69240acgcagctgt ttaactctct caaacatttt gttcttttac tgacaaccca ctgcagtcaa 69300gttgtctatt cccataatat ggaatattgg gtctatagta atttcctatt cctatttcta 69360ggcaatcatg taagataagg ggaatgggca cctatttctc tggggaaggt ataaatgtgt 69420cttttatctc tttccagtat ccccactgtg tagagctggt ccacaatgga gaggaggaaa 69480agttttgcat tggaccaaat cactgcctta gaaggaaaga gattgcaatc ccattcattt 69540ttaagatctg caatgggttg ggatgatacc catttaaaaa agaaaaaaaa agaggttacc 69600tctttggcct ctttggcaaa ggatatgaac tagtaataaa gcctcagcat caaggcttgg 69660gagtctggct caaagtggct aagactagaa gcatcttcta acataaatat ggcagcatta 69720ggaaaatagc ttggccttta gagagaccca gattatcttc accttaaaaa ctaccaagac 69780cctggtccag caagaccacc atcacagcag taaatacata gccaccaact tcacagaagg 69840ttttccactg agacattgtg aaaaccacaa tccattaccg gtggatgagt cccagctctc 69900ttactacctg gagcttccaa gcaagactta cctgtccttt gttccagatt ggttcctggg 69960atcctggacc aacacaaaga gaagaggaaa gcctcaaggg aaataaaagt gaaggtttca 70020gtgatagttt aaatatatat ttttaaatgt tagctttttt ttaaatactt cacagtgatg 70080gatggagtat ttcaaccaca atggcaaaga atgaattacc ggcagtgtca gagtttcttg 70140ttgctgtggg aagacagctg ccatgttgag aggtgccttg tggagaggct catgtggcga 70200ggaactgaga ctggcttcta tccaacaacc agtgaggaac taaggcccta aagtcctata 70260gtccacaagg aactaaatcc taccaacaac tacatgagtg agcctggaat ctgattttcc 70320ccagtgggga cttaaggtac ctacaacctg gctgttatgg gctaaactgc atcctgccca 70380aatttatatg tttgagtctt aactcccagc acttcagaac atggttttgt ttggagacat 70440agtcattaaa gaggtaatga agttaaaatg aggtcattag gatgagtcct aatccaatag 70500gactggtgtt cttatatgaa gaggaaattt gaacacagac acatatacag gaaagaccat 70560gcgaagaaga cacagagagg aaacggccat ctacaatcca aggagagagg cctcagaaca 70620agccaaccct gcagatacct tgatctaggc atccagaatt gtatgaaaat acatttttgt 70680tatttaagct acccagtctg tggtgctttg ttatggcaat cccagaaaac taattaacta 70740attgactgca gccttgcaag ggaccctgaa ccagaggacc cagttaagcc atgtgcagat 70800tcctgactca cagaactagg agataacaaa tgtttgttgt tctaaggtgc taaatgttgg 70860gaaaatatgt tatgtggcta tgttgttttg cacatgtgcc acataatgat gttttggtca 70920acaacagacc acacatatga tggtgggccc ataagattgt aatactgtgt ttctattatg 70980cattctctat ttatagatac acaaatactt gccactgtgt tacaattgcc tactgtcttc 71040agtactgtaa catgctgtac aggtttgtag cccagaagca atagactata ccatacagtc 71100tgggtgtgta gtaggctata ccatctatgt ttgtgaagta cactctatga tgttcacata 71160attatgaagt tgcctagtga tgcatttctc agaatgcatg cccgacatta agtgacactt 71220ggctttatgt ctatcatgca tttaagatat tgcaatatag ttaacttatg ttttaataca 71280cctcttaatt ctgttttgat cccacaccaa ccaagatgca aaactaattt tttcgcccat 71340ttccataaaa aacacaatta caatgggcct aatgtggttt atgtcatttt ccctgaagat 71400ttgtggtggt ataggaagca gtcacagcac cctgtataaa gctcttccat ggcctgcccc 71460cttttcgcag tcacctctat tatttgaagg aatggtccaa ccaacctcaa agctctggaa 71520atttgcccca aaataatttt accctgaagc cattgaagct taagtttcag accccagttt 71580cacattcctg tgagttctgc aagtcactgg gagctataga gtcttctacg tagatttggg 71640aaacaaggtg aaaatacctc aagaaatctc agaagccagg ggcctgcatc tccaagcctc 71700tggcaatttt cttgtggttt ctatcctcac tctagatatt tgcttttgag actgattttg 71760aattcagaat tttatattct ctcaaaaaga gaattctcca aattctataa gcttcaggct 71820ctacaaaact tgtctattct gcctaactag atttatcata gcacgtacca aagatggccc 71880tgcctcatga ggacttttca tatcagaccc ttagataata atattccctc atgtaagtaa 71940taatatttcc gcatgtagtt atgtatgaat aattttcatt catctatatc atgttggcca 72000tagtcagtgt ccatgtccaa tttatttttt gtgtccttgg tgctcagaaa gttaccagat 72060gttcagtcag aattttattt aaaatatttt gatgaactag atttaaagat agattaaatt 72120aattcctaca catgatttaa tttaatggat aaaataaggg actgagcatt agcctgaact 72180gtgtacttgc attagccctg atgttcccca gagggaataa tatgtgaaga atactgcata 72240ggctgaaaaa caagagttcc cagcagacca atattctttc tttctgcaag ctgtgagaca 72300cctggggaaa gttctccaca tttggttttt cagctactcc acccatgact agaaggaaga 72360ttttatttta ttattttatt ttattgtatt ttttaacagt aaaagaaaaa ttattgttat 72420tttaatgaaa aagaaccacc tggaaagtct agtgacattt ttgaaggcag ggaccacttt 72480ttccagggat ttgtttccct atgctagtgc tccattcacc cttgcaccac ttcagcaaag 72540cacatagtag gtgtagcagg gagatgttaa gatggaaact tggccctgac cataggccaa 72600gccagggtgt ctagtcggga tttatccata aacatcaata tttatcacta gatgatatat 72660tgatttctta tctgcctcct atacctattg atctattttt cacagcttat agtggggagg 72720gtcatgttca gttattatcc ttaaaccaaa acaatctctt cttgaaaaat aggatgctat 72780gctctgatgt ttgcagaggc caggaaattc ttgctctgag agttccagaa aaaaagattt 72840gtccagattt gaactaattt cagaaaaaca aaacaaaaac aaaaaaccat ccaaggttaa 72900gaggtgactt ctgactcaca gaatgaacaa gaaggcaggg gaaaaaataa gtcccccaag 72960attcaggtca aaggaaatga acagaaggat gatggagtgg cccagaggag gatcacgtga 73020cagaaaagtc aagataaatt agtggcagga cagaggaaaa gaactaaaga cctgcaggat 73080cctgaaagaa agaatgaaag gaagcagatg aagattctag agcccagctg aatagccagg 73140ccgcctgagg gtaaagaggg agagaaagag gaagcagtga atcaaatcaa aaaaggatag 73200aaaaatacag agaaacaagc cagggcacgg tggctctcac ctgtaatccc agcactttgg 73260gatgacaagg aaggcggatc acatgaggcc aggaatttga gaccacgctg gccaacatgg 73320caaaaccctg tctctactag aaaaatatgg aggaatgttt gagagattgt gcactgccag 73380gggtgaggac ataaatttat ttgctatgtg aatgtttttt gagactcatc tagttccttt 73440acaattttaa tttagaattt ctttagctcc aaatcaggat cattagctgg gagttcttat 73500aaatcaaaag caaaacaaag ctattgcaaa caagtgggag ttctcataac cttaatcaga 73560aaggcttgag ttgcatttcc aaatcctgtc tctagagacc atgagttttt aatgatagta 73620tttccatgaa agcccaattg aatacaatca ccacccagac caaagtgtag gggaaatcat 73680aaagctactt tcaaatccga gtcttctttg aaatttaaaa ttatattcca tgataatggt 73740tctcataaac cttaatgcaa gggaaaaaaa aaaaactaca gcagaataaa gaagatttaa 73800aaagaagcag gataggaaaa aagacaagcc agaggctagc tatatctttt cataaagcac 73860acctggtctc ataagcacat gagagctagg cccagaagtt tcgagccttg gagactcact 73920tcaaacaaat tccagggaaa gacactcaat taagtgttca ggacaattgt atatccccag 73980tgcactcatg tactggaagt gcttaaactc tgccctcagt ggtcaataaa atggtattaa 74040gtcacagaca acccattgcc attggtattg gctgatgtct ctggtagttt atgtgatgac 74100aaacattagc cttaacagca gagccttcct ttctttgatt tccgtgtgaa attctgtggc 74160tgggagatgt ttatgttcac atgaacataa ctgtaagcaa accatcttat ggtagacatc 74220tctccagaaa aagcaaattc catcttttta aatagaaaaa aaaaacagca gcaaaatgaa 74280attaatgcct ttggctcatt gtgttgtaaa attatccttg aagttatttc

acactgccct 74340aaaaaatcat tgaattcaga ttataacaca gctcttatga agctgttagg cagttgcatc 74400tttaatgagg ctgagtaggt aagaggaaca gatactctag attgaaagcc atcgcaaaaa 74460atgtgaaaca actgtattaa atttaattta atttaaccaa tgggtgtatt tattccctgc 74520cttcttccag aaaggattta gggagcttag gtaatgtgga ggtctgaagg tgtagatact 74580catgaaagcc tcagattaat atctagaaca tataatgtgt ccagatagtt ttcaattatc 74640aatgcattaa tctaagcttg gaaaggactt ttaaactgca atgaaacctc aactagtttc 74700aaacctgcat tttttagtaa gctattttgt catttggaga cccacacaaa aaacctattg 74760ttcctttaaa aaggagagag agaaaaaaag aaaaacaacc tgctggtgtt gctttgttca 74820tcttatcacc ttatcattca gcagcctatt caggatcaaa tgtgggaaag tctgtgtgtg 74880agattaagcc ctatactcag cacaggaatt tcttggataa atgtctttct taaatggata 74940gctatgtaaa aaacagaaga gaaactctat tattacaatg cagttgggtt tttttgtttg 75000gtatgtttca aatctaatat ttaaaattaa gaaaattcaa agcaaaccat ctgtgtggat 75060gttttcatac tccatttttg tgacaatagc ttgcttaacc gagattatta gtggattctt 75120tcaataagag gaagagagta ccatcattaa gatggtatgc ctccactagc ctttattttt 75180gagattaaag aatgacaaaa atatttatat atattttttc attattaaga cggagtctca 75240ctctatcgcc aaggctggag tgcagtggcg ccatcttggc tcactgcaac ctctgcctcc 75300caggttcaag caattctccc acttcggcct cctgagtagc tgggatcaca ggcacccgcc 75360accacacctg gctaattttt gtatttttag tagagatggg gtttcaccac attgcccagg 75420ctggtctcaa attcctgacc tcaagtgatc cgcctgcctc agcatcccac agtgctggga 75480ttacaggcat gagccaccac aactagccaa aaaatatata ttttctttaa aaaaaagtta 75540ttttctgcct aattacttca atatttcatg aacattgtgg gggaaagaat attcatacag 75600ttctctaaat atatcagtga gttgaggtac caaatacaga attctattga attctaattg 75660caacactgaa gcagacttac tctaagatcc tgctacctgg actaaccaca gactataccc 75720agattccatc tgcaagatgt agtggagcca aacatcacat cactgaggaa tatttattat 75780atatctttct gtagaggtga gagagtattt atagatataa caaacaattg gtcagatact 75840actggagatt tggaagcttc actaggtttt tcactaaatt tgttgatagc caactctaaa 75900gctcattcta ctactactag ccatcttccc ttggacaatt tcatgggcat cgcttcactg 75960aaaagaaaaa tgagtaagta taatctcact agtacatgaa taactattat aaacacaata 76020ctttctacaa ggtttattac taatctatgt catttaagtt ctagatttta cagtattttg 76080gagtgatgaa taaatagcat gctgttcttc tatagctagc aaacaagact cagctttgga 76140gacaagaaga aggaatacag gagatgtttc cttgaatgag tcttcttcct aaactctgct 76200agaagtatgt cagaaagcga aggttacctc agtctccaag tcatgaaaac atgaggtctt 76260tctgttttct agggaaagta tttcatcatt tcctagtgtg gctttttgca caccccagaa 76320ggaggaagac aagccatcgt gtcaccttta catggtagtt gagatgcttc acatttgtac 76380ataacatctt atatgatcga aagaggaact caaactcgac aggggagaat aaggaaatac 76440atctaaaact gacaattatg ttaatccctc aattccctgg gcccccaaaa tagtctcctc 76500tatttgccat ttcaaaatag ctaatgagag ggtaattgga catgtagaca ctgaatttcc 76560actgctcatg gtttccttcc ctgggctccc agtcacccgg aaggccccgg attacctcaa 76620atgtcataac gggttcatcg cattacgaat tacctccttc tgccaataaa ctacaagttc 76680tttgaggaca gaaactgtga tttatgggca tttgtatccc cagagattca aagagtgcct 76740gatacagagt ggtgatagat gattttatca tcttatcatc atcatcctca tcatcgttgt 76800acctaaatag aggttacttc ctgtttcttt tatttaacaa taacctatta taatatatac 76860tatgcatttt taatgcactt tacaaatatt gtcctcattt aatccctgta aggtgaatac 76920tattattggc tccattttgc agataagaca ctgagtcgtg aaaaggctaa gtacctcaca 76980caagatcaca cagccagtga cagaactagg atttggctgg actcttaaag actctggttt 77040gccatttaaa ggtacgctga gctccacaac actgccttag aacttgctca gagcaattgt 77100catattacta tggtaggttt ccctgtctcc cttaagactt aaagcttctg gagatcagaa 77160actgtattgt ttacttgcaa aatcatgggc ttaggagcca gaaagatctc gatctaagtc 77220ctgcctcatc tgcttcttct tcatgggatt agtagactga ttttcccctt gcttagccat 77280gcagtttgaa tggaattcac cccattctca gctacaacca cggatcttgt ttgctttaaa 77340ccaatcatca ctgcccaatt ttctggcctt tgattgattt aaaggtgaac acatgaccgc 77400tttggaccaa tgaggctcag gtggtatttt gtgagggtct ctggaataga aaatcatttc 77460tcttctgaca gaactacaag gcaaggcgca atcactgatg gtgaaagata aagatcatta 77520tattaggaac tgttggctgt catactgcta atgtgaggtg agttagcctt agaaagagga 77580tgctaccttg aaaggcaggg cagatctatg gaaataaact gagtttgtgg tgacattgat 77640agccacttta gttcatcagc tgaatcccaa tctacttggt tttttcagct ctgtaagcca 77700acaaataccc tgctagtgtt ttagcctatg ccagttgttt tttctgctgc ttgttaataa 77760gacacataca gtcttggaca aattatataa aaatatgaat ctttggccag gcatggaggc 77820tcacgcctgt aatcccaaca ctttgggagg ccgaagcggt cggatcacag ggtcaggagt 77880tcgagaccag cctggccaat atggtgaaac cccgtctcta ctaaaaatac aaaaattagc 77940tggatgtggt ggcacatgcc tgttgtccca gctactcagg aggctgaggc agaagaatcg 78000cttgaacccg ggaggcagag gttgcagtga gctgagatca tgccactgaa ctccagcctg 78060ggagacagaa tgacactcgg tctcaaaaaa aaaaaaaaat tctgaatctt tgaatgttat 78120cgtatagctt tttaaaagac tagattaagc tatggatgta agcaccaatg cattttttta 78180aaagtatatt ggatgaatga gttaaagtct aagtgaattc agcaagtttg taacccttga 78240gctcttgtga gctcaatctg ccctcaatca tctgagaatg aacaaaacag actcaaccat 78300tttgtgtcat ccagatgaat agaaagggcc tgaatatatt ctttttttat attttttgtc 78360ataggcccta gcgttttcat ctgctcagtt tttgagtgtg cttgttaggg ctttaatgct 78420aaactcaatg taagctgggt ttatgtaatt tagtggtttc tagacttagg cttcctaaat 78480gttccattag acaagaagac aaaatatgaa acaaaataac atcaaactac cattaacaat 78540tagcattgtc agagtcagta aaaactgttt tgaaataaag cagcttttca ggccagtatt 78600tgagaactaa tgatagagtt tttttgtagg caatgaatga agtgttgtgg aacaaatgtg 78660gatttggact ttcaagacca acttgaacca gagtcttgaa tctgcaactt tactagctgt 78720ggcttctttt taattgatta actttctttt tctgtaaaat gggaataatg attcctacct 78780cttacaagcg ttgtggtagg aggtattcca aatgagataa atatgtgaaa tcactaaaac 78840ttccagaata catggaaata atatatgtct gtattggcaa attatgagtg tagtaatgag 78900ggatttacat ggacacattt acattcttta gttcagactc cctttgacga cacataacaa 78960acacacacaa gaatatttgc cctgtgtcca gcactctttt gagaatttct ctcttctcct 79020ccttctgata tcccaaccaa ccaaccagta ggaatgtgcc ctagaaacta tgttttacag 79080ctcagtccac atcttttcac cttacaaatt acttattgtt agtttcttgg gaaagtaaaa 79140ttgagatatt aagattctat gaaattggtt ggtggtattg aagactgtgc tgctgctgct 79200gctactgctc cagaactcta gtggagatat tacaaatggg agcagaaaaa gtgagaaggt 79260ggtctgtaga gacagagcac agcacagagg tagaaaggtt gagataaaga aacaatgcag 79320tgagagaagg agagaacaca gacatagaaa cagagacata aaggcaccag acacgagagc 79380agagataatt taataaggcc gtagtttctc ttggatttcc agttccttct tttagtcaat 79440tctgatattt agcacactgc actgcaccag atatcttgtc gccttcaaat aaagtatttt 79500tcccccttaa acatgctaat ttgggcttgt attatttgca atcaatagaa ttgagaaaaa 79560cactctatgt catatctgaa ctagtatatc agaatggttt tctgccattg gtaacagaga 79620cccagctcaa tggcttaaac acacaagggt ttatcctgtc acattaacaa aaaaaaaagt 79680gcagagtagc agtccggggt tagctttttt ttaaatactt cacagtgatg gatggagtat 79740ttcaaccaca atggcaaaga atgaattacc ggcagtgtca gagtttcttg ttgctgtggg 79800aagacagctg ccatgttgag aggtgccttg tggagaggct catgtggcga ggaactgaga 79860ctggcttcta tccaacaacc agtgaggaac taaggcccta aagtcctata gtccacaagg 79920aactaaatcc taccaacaac tacatgagtg agcctggaat ctgattttcc ccagtgggga 79980cttaaggtac ctacaacctg gctgttatgg gctaaactgc atcctgccca aatttatatg 80040tttgagtctt aactcccagc acttcagaac atggttttgt ttggagacat agtcattaaa 80100gaggtaatga agttaaaatg aggtcattag gatgagtcct aatccaatag gactggtgtt 80160cttatatgaa gaggaaattt gaacacagac acatatacag gaaagaccat gcgaagaaga 80220cacagagagg aaacggccat ctacaatcca aggagagagg cctcagaaca agccaaccct 80280gcagatacct tgatctaggc atccagaatt gtatgaaaat acatttttgt tatttaagct 80340acccagtctg tggtgctttg ttatggcaat cccagaaaac taattaacta attgactgca 80400gccttgcaag ggaccctgaa ccagaggacc cagttaagcc atgtgcagat tcctgactca 80460cagaactagg agataacaaa tgtttgttgt tctaaggtgc taaatgttgg gaaaatatgt 80520tatgtggcta tgttgttttg cacatgtgcc acataatgat gttttggtca acaacagacc 80580acacatatga tggtgggccc ataagattgt aatactgtgt ttctattatg cattctctat 80640ttatagatac acaaatactt gccactgtgt tacaattgcc tactgtcttc agtactgtaa 80700catgctgtac aggtttgtag cccagaagca atagactata ccatacagtc tgggtgtgta 80760gtaggctata ccatctatgt ttgtgaagta cactctatga tgttcacata attatgaagt 80820tgcctagtga tgcatttctc agaatgcatg cccgacatta agtgacactt ggctttatgt 80880ctatcatgca tttaagatat tgcaatatag ttaacttatg ttttaataca cctcttaatt 80940ctgttttgat cccacaccaa ccaagatgca aaactaattt tttcgcccat ttccataaaa 81000aacacaatta caatgggcct aatgtggttt atgtcatttt ccctgaagat ttgtggtggt 81060ataggaagca gtcacagcac cctgtataaa gctcttccat ggcctgcccc cttttcgcag 81120tcacctctat tatttgaagg aatggtccaa ccaacctcaa agctctggaa atttgcccca 81180aaataatttt accctgaagc cattgaagct taagtttcag accccagttt cacattcctg 81240tgagttctgc aagtcactgg gagctataga gtcttctacg tagatttggg aaacaaggtg 81300aaaatacctc aagaaatctc agaagccagg ggcctgcatc tccaagcctc tggcaatttt 81360cttgtggttt ctatcctcac tctagatatt tgcttttgag actgattttg aattcagaat 81420tttatattct ctcaaaaaga gaattctcca aattctataa gcttcaggct ctacaaaact 81480tgtctattct gcctaactag atttatcata gcacgtacca aagatggccc tgcctcatga 81540ggacttttca tatcagaccc ttagataata atattccctc atgtaagtaa taatatttcc 81600gcatgtagtt atgtatgaat aattttcatt catctatatc atgttggcca tagtcagtgt 81660ccatgtccaa tttatttttt gtgtccttgg tgctcagaaa gttaccagat gttcagtcag 81720aattttattt aaaatatttt gatgaactag atttaaagat agattaaatt aattcctaca 81780catgatttaa tttaatggat aaaataaggg actgagcatt agcctgaact gtgtacttgc 81840attagccctg atgttcccca gagggaataa tatgtgaaga atactgcata ggctgaaaaa 81900caagagttcc cagcagacca atattctttc tttctgcaag ctgtgagaca cctggggaaa 81960gttctccaca tttggttttt cagctactcc acccatgact agaaggaaga ttttatttta 82020ttattttatt ttattgtatt ttttaacagt aaaagaaaaa ttattgttat tttaatgaaa 82080aagaaccacc tggaaagtct agtgacattt ttgaaggcag ggaccacttt ttccagggat 82140ttgtttccct atgctagtgc tccattcacc cttgcaccac ttcagcaaag cacatagtag 82200gtgtagcagg gagatgttaa gatggaaact tggccctgac cataggccaa gccagggtgt 82260ctagtcggga tttatccata aacatcaata tttatcacta gatgatatat tgatttctta 82320tctgcctcct atacctattg atctattttt cacagcttat agtggggagg gtcatgttca 82380gttattatcc ttaaaccaaa acaatctctt cttgaaaaat aggatgctat gctctgatgt 82440ttgcagaggc caggaaattc ttgctctgag agttccagaa aaaaagattt gtccagattt 82500gaactaattt cagaaaaaca aaacaaaaac aaaaaaccat ccaaggttaa gaggtgactt 82560ctgactcaca gaatgaacaa gaaggcaggg gaaaaaataa gtcccccaag attcaggtca 82620aaggaaatga acagaaggat gatggagtgg cccagaggag gatcacgtga cagaaaagtc 82680aagataaatt agtggcagga cagaggaaaa gaactaaaga cctgcaggat cctgaaagaa 82740agaatgaaag gaagcagatg aagattctag agcccagctg aatagccagg ccgcctgagg 82800gtaaagaggg agagaaagag gaagcagtga atcaaatcaa aaaaggatag aaaaatacag 82860agaaacaagc cagggcacgg tggctctcac ctgtaatccc agcactttgg gatgacaagg 82920aaggcggatc acatgaggcc aggaatttga gaccacgctg gccaacatgg caaaaccctg 82980tctctactag aaaaatatgg aggaatgttt gagagattgt gcactgccag gggtgaggac 83040ataaatttat ttgctatgtg aatgtttttt gagactcatc tagttccttt acaattttaa 83100tttagaattt ctttagctcc aaatcaggat cattagctgg gagttcttat aaatcaaaag 83160caaaacaaag ctattgcaaa caagtgggag ttctcataac cttaatcaga aaggcttgag 83220ttgcatttcc aaatcctgtc tctagagacc atgagttttt aatgatagta tttccatgaa 83280agcccaattg aatacaatca ccacccagac caaagtgtag gggaaatcat aaagctactt 83340tcaaatccga gtcttctttg aaatttaaaa ttatattcca tgataatggt tctcataaac 83400cttaatgcaa gggaaaaaaa aaaaactaca gcagaataaa gaagatttaa aaagaagcag 83460gataggaaaa aagacaagcc agaggctagc tatatctttt cataaagcac acctggtctc 83520ataagcacat gagagctagg cccagaagtt tcgagccttg gagactcact tcaaacaaat 83580tccagggaaa gacactcaat taagtgttca ggacaattgt atatccccag tgcactcatg 83640tactggaagt gcttaaactc tgccctcagt ggtcaataaa atggtattaa gtcacagaca 83700acccattgcc attggtattg gctgatgtct ctggtagttt atgtgatgac aaacattagc 83760cttaacagca gagccttcct ttctttgatt tccgtgtgaa attctgtggc tgggagatgt 83820ttatgttcac atgaacataa ctgtaagcaa accatcttat ggtagacatc tctccagaaa 83880aagcaaattc catcttttta aatagaaaaa aaaaacagca gcaaaatgaa attaatgcct 83940ttggctcatt gtgttgtaaa attatccttg aagttatttc acactgccct aaaaaatcat 84000tgaattcaga ttataacaca gctcttatga agctgttagg cagttgcatc tttaatgagg 84060ctgagtaggt aagaggaaca gatactctag attgaaagcc atcgcaaaaa atgtgaaaca 84120actgtattaa atttaattta atttaaccaa tgggtgtatt tattccctgc cttcttccag 84180aaaggattta gggagcttag gtaatgtgga ggtctgaagg tgtagatact catgaaagcc 84240tcagattaat atctagaaca tataatgtgt ccagatagtt ttcaattatc aatgcattaa 84300tctaagcttg gaaaggactt ttaaactgca atgaaacctc aactagtttc aaacctgcat 84360tttttagtaa gctattttgt catttggaga cccacacaaa aaacctattg ttcctttaaa 84420aaggagagag agaaaaaaag aaaaacaacc tgctggtgtt gctttgttca tcttatcacc 84480ttatcattca gcagcctatt caggatcaaa tgtgggaaag tctgtgtgtg agattaagcc 84540ctatactcag cacaggaatt tcttggataa atgtctttct taaatggata gctatgtaaa 84600aaacagaaga gaaactctat tattacaatg cagttgggtt tttttgtttg gtatgtttca 84660aatctaatat ttaaaattaa gaaaattcaa agcaaaccat ctgtgtggat gttttcatac 84720tccatttttg tgacaatagc ttgcttaacc gagattatta gtggattctt tcaataagag 84780gaagagagta ccatcattaa gatggtatgc ctccactagc ctttattttt gagattaaag 84840aatgacaaaa atatttatat atattttttc attattaaga cggagtctca ctctatcgcc 84900aaggctggag tgcagtggcg ccatcttggc tcactgcaac ctctgcctcc caggttcaag 84960caattctccc acttcggcct cctgagtagc tgggatcaca ggcacccgcc accacacctg 85020gctaattttt gtatttttag tagagatggg gtttcaccac attgcccagg ctggtctcaa 85080attcctgacc tcaagtgatc cgcctgcctc agcatcccac agtgctggga ttacaggcat 85140gagccaccac aactagccaa aaaatatata ttttctttaa aaaaaagtta ttttctgcct 85200aattacttca atatttcatg aacattgtgg gggaaagaat attcatacag ttctctaaat 85260atatcagtga gttgaggtac caaatacaga attctattga attctaattg caacactgaa 85320gcagacttac tctaagatcc tgctacctgg actaaccaca gactataccc agattccatc 85380tgcaagatgt agtggagcca aacatcacat cactgaggaa tatttattat atatctttct 85440gtagaggtga gagagtattt atagatataa caaacaattg gtcagatact actggagatt 85500tggaagcttc actaggtttt tcactaaatt tgttgatagc caactctaaa gctcattcta 85560ctactactag ccatcttccc ttggacaatt tcatgggcat cgcttcactg aaaagaaaaa 85620tgagtaagta taatctcact agtacatgaa taactattat aaacacaata ctttctacaa 85680ggtttattac taatctatgt catttaagtt ctagatttta cagtattttg gagtgatgaa 85740taaatagcat gctgttcttc tatagctagc aaacaagact cagctttgga gacaagaaga 85800aggaatacag gagatgtttc cttgaatgag tcttcttcct aaactctgct agaagtatgt 85860cagaaagcga aggttacctc agtctccaag tcatgaaaac atgaggtctt tctgttttct 85920agggaaagta tttcatcatt tcctagtgtg gctttttgca caccccagaa ggaggaagac 85980aagccatcgt gtcaccttta catggtagtt gagatgcttc acatttgtac ataacatctt 86040atatgatcga aagaggaact caaactcgac aggggagaat aaggaaatac atctaaaact 86100gacaattatg ttaatccctc aattccctgg gcccccaaaa tagtctcctc tatttgccat 86160ttcaaaatag ctaatgagag ggtaattgga catgtagaca ctgaatttcc actgctcatg 86220gtttccttcc ctgggctccc agtcacccgg aaggccccgg attacctcaa atgtcataac 86280gggttcatcg cattacgaat tacctccttc tgccaataaa ctacaagttc tttgaggaca 86340gaaactgtga tttatgggca tttgtatccc cagagattca aagagtgcct gatacagagt 86400ggtgatagat gattttatca tcttatcatc atcatcctca tcatcgttgt acctaaatag 86460aggttacttc ctgtttcttt tatttaacaa taacctatta taatatatac tatgcatttt 86520taatgcactt tacaaatatt gtcctcattt aatccctgta aggtgaatac tattattggc 86580tccattttgc agataagaca ctgagtcgtg aaaaggctaa gtacctcaca caagatcaca 86640cagccagtga cagaactagg atttggctgg actcttaaag actctggttt gccatttaaa 86700ggtacgctga gctccacaac actgccttag aacttgctca gagcaattgt catattacta 86760tggtaggttt ccctgtctcc cttaagactt aaagcttctg gagatcagaa actgtattgt 86820ttacttgcaa aatcatgggc ttaggagcca gaaagatctc gatctaagtc ctgcctcatc 86880tgcttcttct tcatgggatt agtagactga ttttcccctt gcttagccat gcagtttgaa 86940tggaattcac cccattctca gctacaacca cggatcttgt ttgctttaaa ccaatcatca 87000ctgcccaatt ttctggcctt tgattgattt aaaggtgaac acatgaccgc tttggaccaa 87060tgaggctcag gtggtatttt gtgagggtct ctggaataga aaatcatttc tcttctgaca 87120gaactacaag gcaaggcgca atcactgatg gtgaaagata aagatcatta tattaggaac 87180tgttggctgt catactgcta atgtgaggtg agttagcctt agaaagagga tgctaccttg 87240aaaggcaggg cagatctatg gaaataaact gagtttgtgg tgacattgat agccacttta 87300gttcatcagc tgaatcccaa tctacttggt tttttcagct ctgtaagcca acaaataccc 87360tgctagtgtt ttagcctatg ccagttgttt tttctgctgc ttgttaataa gacacataca 87420gtcttggaca aattatataa aaatatgaat ctttggccag gcatggaggc tcacgcctgt 87480aatcccaaca ctttgggagg ccgaagcggt cggatcacag ggtcaggagt tcgagaccag 87540cctggccaat atggtgaaac cccgtctcta ctaaaaatac aaaaattagc tggatgtggt 87600ggcacatgcc tgttgtccca gctactcagg aggctgaggc agaagaatcg cttgaacccg 87660ggaggcagag gttgcagtga gctgagatca tgccactgaa ctccagcctg ggagacagaa 87720tgacactcgg tctcaaaaaa aaaaaaaaat tctgaatctt tgaatgttat cgtatagctt 87780tttaaaagac tagattaagc tatggatgta agcaccaatg cattttttta aaagtatatt 87840ggatgaatga gttaaagtct aagtgaattc agcaagtttg taacccttga gctcttgtga 87900gctcaatctg ccctcaatca tctgagaatg aacaaaacag actcaaccat tttgtgtcat 87960ccagatgaat agaaagggcc tgaatatatt ctttttttat attttttgtc ataggcccta 88020gcgttttcat ctgctcagtt tttgagtgtg cttgttaggg ctttaatgct aaactcaatg 88080taagctgggt ttatgtaatt tagtggtttc tagacttagg cttcctaaat gttccattag 88140acaagaagac aaaatatgaa acaaaataac atcaaactac cattaacaat tagcattgtc 88200agagtcagta aaaactgttt tgaaataaag cagcttttca ggccagtatt tgagaactaa 88260tgatagagtt tttttgtagg caatgaatga agtgttgtgg aacaaatgtg gatttggact 88320ttcaagacca acttgaacca gagtcttgaa tctgcaactt tactagctgt ggcttctttt 88380taattgatta actttctttt tctgtaaaat gggaataatg attcctacct cttacaagcg 88440ttgtggtagg aggtattcca aatgagataa atatgtgaaa tcactaaaac ttccagaata 88500catggaaata atatatgtct gtattggcaa attatgagtg tagtaatgag ggatttacat 88560ggacacattt acattcttta gttcagactc cctttgacga cacataacaa acacacacaa 88620gaatatttgc cctgtgtcca gcactctttt gagaatttct ctcttctcct ccttctgata 88680tcccaaccaa ccaaccagta ggaatgtgcc ctagaaacta tgttttacag ctcagtccac 88740atcttttcac cttacaaatt acttattgtt agtttcttgg gaaagtaaaa ttgagatatt 88800aagattctat gaaattggtt ggtggtattg aagactgtgc tgctgctgct gctactgctc 88860cagaactcta gtggagatat tacaaatggg agcagaaaaa gtgagaaggt ggtctgtaga 88920gacagagcac agcacagagg tagaaaggtt gagataaaga aacaatgcag tgagagaagg 88980agagaacaca gacatagaaa cagagacata aaggcaccag acacgagagc agagataatt 89040taataaggcc gtagtttctc ttggatttcc agttccttct tttagtcaat tctgatattt 89100agcacactgc actgcaccag atatcttgtc gccttcaaat aaagtatttt tcccccttaa 89160acatgctaat ttgggcttgt attatttgca atcaatagaa ttgagaaaaa cactctatgt 89220catatctgaa ctagtatatc agaatggttt tctgccattg gtaacagaga cccagctcaa 89280tggcttaaac acacaagggt ttatcctgtc acattaacaa aaaaaaaagt gcagagtagc 89340agtccggggt tggaataggg tccacaaagt catctggggc caggcttcat

ctatctttct 89400cttacatcac aagtgacttc tgtctacaag gcccctcatg gtccacaatt gattgttttt 89460acaacagctt tccaaagagc agaaagaaaa acaagtagaa gagcttgtac tttcttttct 89520atttatgtca cctctgctta catctcacta gccagatata gacatatggc cccatctacc 89580tgcacagaaa tctcagaaat gtaatttttc agcttggcca ttgcccaggg ttctgttact 89640agggaagaag 8965062260DNAHomo sapiens 6atttgaattg gtgaacttag taaagcagac ggctctcacc aataagggca ggcatcatcc 60aatctgtcga aagcttgaat aaaacaaaaa gaggaaggga aaatttgctt cttttcttct 120tgatctagta tatcatcttc tcctgccctt ggatgtgagt gggccttcag acttaaacca 180ggagttacac ctttggcttc cctggttctc agttctttgg acttggactg aattacactg 240ccaggtttcc tggttctcca gcttgcagat ggcagatcat gggacttctt ggcctccata 300attgttttca tatctccagg cctttcattg ggtcaggttg gcatttcgct gccctttatg 360tgtgtgacaa gtgaaaataa ggaaagaaaa aaactcaagt gaagaaaatc agaatctgcg 420cagcagttcc tgggcgtttc agctgcttcc cacatcacct gcctcatcaa gccccagcat 480ccatctcctt gctcatctta caccctgtgt gcatgacagg cccaccattc atttatcaga 540gcaaaggctc tcccactatt ctggttcacc cccctactta gccagatata caagaatatc 600tgcacggatg acctgcctca cctgggagct cagaggagct cagattccat tactatcgca 660ccaaggacag atctcccagc aagaatgaca gaaaagacta actgccccca aaatctccct 720tccaaaacac agttctctta attctcccaa gaaaccagaa tgtgactgct cacctctcta 780aggacctgaa aacaactggc catttcagct atttaaatca actttaaaaa atccaaccgc 840caaaatatta aaccattttg gttggaatga taacataact aacctgctga cagctgcttc 900tgctaggtgc aaaaatggaa aaaaaaatac ttctaatcag gtcaaatcac tctacctttg 960ggattctaaa tttactcata ttctcaaaga aatatattca gtcatagtgg ggaaaatagg 1020attattcctt tagctcgata agcaaccaga agttcttcct tcaaatcttg acatttaatc 1080aatcagaaat tgatttttgg aaaactgttt cctatgaagc tatctctgcc tgaaggattt 1140ttcttttaca atccagacta tagaaggaaa ttcacaacct ggactttcac ctccattggt 1200cagagtttta ctgaccaatt cccacctctg ccttacacct aacggaagtt tatgcctgtt 1260ttctcttcac ataccccaac agttacaaat ggttgttatt attaagcatc ttttattttg 1320tggcctctga ttacatggtc ccctaaattt tgacctaatc acaaaagatt ggtaaaattt 1380cttaacatat taataatatt ttgtttatgt gtcaatatct tagcatgtat caattaagac 1440agaggtctta acgttctctt tttgaaagag aatattagga ttcagagata ttaagagatt 1500ctcccaggat cacagttagg taacagagct ggattttagt ccaggtctgt ctacagctct 1560aacgtatata caccctttgt ataacatgtc acgaattcag cataaaggga tcttcagtga 1620tctaagtcag gggtcagcaa ccttttctaa aaaggaccaa atagtaatat ttcaggcttt 1680gtggacccta tggtctctat cataactgtt caaatcacca tgtagtgtaa aaggagccat 1740aagcaaaata taaactaacg aatgtggctg ttttatggga ttttttttta actctttatt 1800tacaaaagca ggtggcagat cagaactcac ttatgggcca tagttctctg acccctgacc 1860tgagaaaatc ttatatttat ggacaacatt tagactgtga cttgccaagt aagaacaaga 1920agctctgtca actgaaggtc aaggctggag ttctgaaagc aaagagctgt ctggtgttaa 1980tgataagtga aatagttaaa gttagaagat cccagttata agaagcacaa agaataatga 2040ccatagactc ctgaacaaga atgtctggac ttctggctta ggcactcttg ttgtatggtc 2100caggccaagt tacctaatct ctccaggcct ccattttctt atcattaaat gaagataata 2160aaagtatttt cctcagagag ctgtaagaat aaactgagct aacccatgtc aagcacatag 2220aatagggccc agcctatatt aatttatcaa taaatgccag 226072817DNAHomo sapiens 7atttgaattg gtgaacttag taaagcagac ggctctcacc aataagggca ggcatcatcc 60aatctgtcga aagcttgaat aaaacaaaaa gaggaaggga aaatttgctt cttttcttct 120tgatctagta tatcatcttc tcctgccctt ggatgtgagt gggccttcag acttaaacca 180ggagttacac ctttggcttc cctggttctc agttctttgg acttggactg aattacactg 240ccaggtttcc tggttctcca gcttgcagat ggcagatcat gggacttctt ggcctccata 300attgtgggca aaaaggaaag agacaaaaca gcatgaaatg atgagaccaa gtgatgaaaa 360ttcattcaca atgattgctt tcaagagtaa tttctcttgg gtaattcagc agcctgttac 420tatggctctc tggagtgata gctaatgtaa atgaagcctc taaaagtgga ttatcctgac 480aagaatatac tcagccaata atgcaacaga aatccattca aagcattcgg gaaaaattca 540aaagaataaa tattcttttt ttttttttaa agttaatgac ctacgatcca tttcttccct 600gactaacaag cagcaagcac ttaaaaatat ccagccagga tgaaatagaa acccacctga 660cttgttaata tttttgtttg gtcccaggga ctcagattct aagccaaatt ctttgaatga 720tcttggcaaa tgtctcgaat tatttttgcc aacttttctt tatcttggaa aaaaagtttc 780atgaatgggt gtcaaaattg attagtttta aaaacctttc ttgcagatac gtatggcacc 840ctaaaactgt attagaaaaa aatttcatat ctccaggcct ttcattgggt caggttggca 900tttcgctgcc ctttatgtgt gtgacaagtg aaaataagga aagaaaaaaa ctcaagtgaa 960gaaaatcaga atctgcgcag cagttcctgg gcgtttcagc tgcttcccac atcacctgcc 1020tcatcaagcc ccagcatcca tctccttgct catcttacac cctgtgtgca tgacaggccc 1080accattcatt tatcagagca aaggctctcc cactattctg gttcaccccc ctacttagcc 1140agatatacaa gaatatctgc acggatgacc tgcctcacct gggagctcag aggagctcag 1200attccattac tatcgcacca aggacagatc tcccagcaag aatgacagaa aagactaact 1260gcccccaaaa tctcccttcc aaaacacagt tctcttaatt ctcccaagaa accagaatgt 1320gactgctcac ctctctaagg acctgaaaac aactggccat ttcagctatt taaatcaact 1380ttaaaaaatc caaccgccaa aatattaaac cattttggtt ggaatgataa cataactaac 1440ctgctgacag ctgcttctgc taggtgcaaa aatggaaaaa aaaatacttc taatcaggtc 1500aaatcactct acctttggga ttctaaattt actcatattc tcaaagaaat atattcagtc 1560atagtgggga aaataggatt attcctttag ctcgataagc aaccagaagt tcttccttca 1620aatcttgaca tttaatcaat cagaaattga tttttggaaa actgtttcct atgaagctat 1680ctctgcctga aggatttttc ttttacaatc cagactatag aaggaaattc acaacctgga 1740ctttcacctc cattggtcag agttttactg accaattccc acctctgcct tacacctaac 1800ggaagtttat gcctgttttc tcttcacata ccccaacagt tacaaatggt tgttattatt 1860aagcatcttt tattttgtgg cctctgatta catggtcccc taaattttga cctaatcaca 1920aaagattggt aaaatttctt aacatattaa taatattttg tttatgtgtc aatatcttag 1980catgtatcaa ttaagacaga ggtcttaacg ttctcttttt gaaagagaat attaggattc 2040agagatatta agagattctc ccaggatcac agttaggtaa cagagctgga ttttagtcca 2100ggtctgtcta cagctctaac gtatatacac cctttgtata acatgtcacg aattcagcat 2160aaagggatct tcagtgatct aagtcagggg tcagcaacct tttctaaaaa ggaccaaata 2220gtaatatttc aggctttgtg gaccctatgg tctctatcat aactgttcaa atcaccatgt 2280agtgtaaaag gagccataag caaaatataa actaacgaat gtggctgttt tatgggattt 2340ttttttaact ctttatttac aaaagcaggt ggcagatcag aactcactta tgggccatag 2400ttctctgacc cctgacctga gaaaatctta tatttatgga caacatttag actgtgactt 2460gccaagtaag aacaagaagc tctgtcaact gaaggtcaag gctggagttc tgaaagcaaa 2520gagctgtctg gtgttaatga taagtgaaat agttaaagtt agaagatccc agttataaga 2580agcacaaaga ataatgacca tagactcctg aacaagaatg tctggacttc tggcttaggc 2640actcttgttg tatggtccag gccaagttac ctaatctctc caggcctcca ttttcttatc 2700attaaatgaa gataataaaa gtattttcct cagagagctg taagaataaa ctgagctaac 2760ccatgtcaag cacatagaat agggcccagc ctatattaat ttatcaataa atgccag 281781970DNAHomo sapiens 8atttgaattg gtgaacttag taaagcagac ggctctcacc aataagggca ggcatcatcc 60aatctgtcga aagcttgaat aaaacaaaaa gaggaaggga aaatttgctt cttttcttct 120tgatctagta tatcatcttc tcctgccctt ggatgtgagt gggccttcag acttaaacca 180ggagttacac ctttggcttc cctggttctc agttctttgg acttggactg aattacactg 240ccaggtttcc tggttctcca gcttgcagat ggcagatcat gggacttctt ggcctccata 300attgtgtatc cccactgtgt agagctggtc cacaatggag aggaggaaaa gttttgcatt 360ggaccaaatc actgccttag aaggaaagag attgcaatcc cattcatttt taagatctgc 420aatgggttgg gatgataccc atttaaaaaa gaaaaaaaaa gaggttacct ctttggcctc 480tttggcaaag gatatgaact agtaataaag cctcagcatc aaggcttggg agtctggctc 540aaagtggcta agactagaag catcttctaa cataaatatg gcagcattag gaaaatagct 600tggcctttag agagacccag attatcttca ccttaaaaac taccaagacc ctggtccagc 660aagaccacca tcacagcagt aaatacatag ccaccaactt cacagaaggt tttccactga 720gacattgtga aaaccacaat ccattaccgg tggatgagtc ccagctctct tactacctgg 780agcttccaag caagacttac ctgtcctttg ttccagattg gttcctggga tcctggacca 840acacaaagag aagaggaaag cctcaaggga aataaaagtg aaggtttcag tgatagttta 900aatatatatt tttaaatgtt agcttttttt taaatacttc acagtgatgg atggagtatt 960tcaaccacaa tggcaaagaa tgaattaccg gcagtgtcag agtttcttgt tgctgtggga 1020agacagctgc catgttgaga ggtgccttgt ggagaggctc atgtggcgag gaactgagac 1080tggcttctat ccaacaacca gtgaggaact aaggccctaa agtcctatag tccacaagga 1140actaaatcct accaacaact acatgagtga gcctggaatc tgattttccc cagtggggac 1200ttaaggtacc tacaacctgg ctgttatggg ctaaactgca tcctgcccaa atttatatgt 1260ttgagtctta actcccagca cttcagaaca tggttttgtt tggagacata gtcattaaag 1320aggtaatgaa gttaaaatga ggtcattagg atgagtccta atccaatagg actggtgttc 1380ttatatgaag aggaaatttg aacacagaca catatacagg aaagaccatg cgaagaagac 1440acagagagga aacggccatc tacaatccaa ggagagaggc ctcagaacaa gccaaccctg 1500cagatacctt gatctaggca tccagaattg tatgaaaata catttttgtt atttaagcta 1560cccagtctgt ggtgctttgt tatggcaatc ccagaaaact aattaactaa ttgactgcag 1620ccttgcaagg gaccctgaac cagaggaccc agttaagcca tgtgcagatt cctgactcac 1680agaactagga gataacaaat gtttgttgtt ctaaggtgct aaatgttggg aaaatatgtt 1740atgtggctat gttgttttgc acatgtgcca cataatgatg ttttggtcaa caacagacca 1800cacatatgat ggtgggccca taagattgta atactgtgtt tctattatgc attctctatt 1860tatagataca caaatacttg ccactgtgtt acaattgcct actgtcttca gtactgtaac 1920atgctgtaca ggtttgtagc ccagaagcaa tagactatac catacagtca 197091989DNAHomo sapiens 9tttgcaggcc cggcacagtc tcagttcccc acagcacaga gaggaagcaa ggtctttgca 60tgccctgttc acttggccaa acattgccct agatgtgcaa ttcaacccat ataaagcaag 120cgtaattcaa gagccctgac tctttcacca tttcatgatg gcttattact cgcacacggc 180attgtcaggt tccagcaact ctgtgtgcag caggcagaaa tgcagtgttt atctctgaca 240ggcaaacatt cttaggctca tcggcatgag tatccacgct gaactggcta tcggggaagt 300agatccctgc atgggaaagt caaggtatcc ccactgtgta gagctggtcc acaatggaga 360ggaggaaaag ttttgcattg gaccaaatca ctgccttaga aggaaagaga ttgcaatccc 420attcattttt aagatctgca atgggttggg atgataccca tttaaaaaag aaaaaaaaag 480aggttacctc tttggcctct ttggcaaagg atatgaacta gtaataaagc ctcagcatca 540aggcttggga gtctggctca aagtggctaa gactagaagc atcttctaac ataaatatgg 600cagcattagg aaaatagctt ggcctttaga gagacccaga ttatcttcac cttaaaaact 660accaagaccc tggtccagca agaccaccat cacagcagta aatacatagc caccaacttc 720acagaaggtt ttccactgag acattgtgaa aaccacaatc cattaccggt ggatgagtcc 780cagctctctt actacctgga gcttccaagc aagacttacc tgtcctttgt tccagattgg 840ttcctgggat cctggaccaa cacaaagaga agaggaaagc ctcaagggaa ataaaagtga 900aggtttcagt gatagtttaa atatatattt ttaaatgtta gctttttttt aaatacttca 960cagtgatgga tggagtattt caaccacaat ggcaaagaat gaattaccgg cagtgtcaga 1020gtttcttgtt gctgtgggaa gacagctgcc atgttgagag gtgccttgtg gagaggctca 1080tgtggcgagg aactgagact ggcttctatc caacaaccag tgaggaacta aggccctaaa 1140gtcctatagt ccacaaggaa ctaaatccta ccaacaacta catgagtgag cctggaatct 1200gattttcccc agtggggact taaggtacct acaacctggc tgttatgggc taaactgcat 1260cctgcccaaa tttatatgtt tgagtcttaa ctcccagcac ttcagaacat ggttttgttt 1320ggagacatag tcattaaaga ggtaatgaag ttaaaatgag gtcattagga tgagtcctaa 1380tccaatagga ctggtgttct tatatgaaga ggaaatttga acacagacac atatacagga 1440aagaccatgc gaagaagaca cagagaggaa acggccatct acaatccaag gagagaggcc 1500tcagaacaag ccaaccctgc agataccttg atctaggcat ccagaattgt atgaaaatac 1560atttttgtta tttaagctac ccagtctgtg gtgctttgtt atggcaatcc cagaaaacta 1620attaactaat tgactgcagc cttgcaaggg accctgaacc agaggaccca gttaagccat 1680gtgcagattc ctgactcaca gaactaggag ataacaaatg tttgttgttc taaggtgcta 1740aatgttggga aaatatgtta tgtggctatg ttgttttgca catgtgccac ataatgatgt 1800tttggtcaac aacagaccac acatatgatg gtgggcccat aagattgtaa tactgtgttt 1860ctattatgca ttctctattt atagatacac aaatacttgc cactgtgtta caattgccta 1920ctgtcttcag tactgtaaca tgctgtacag gtttgtagcc cagaagcaat agactatacc 1980atacagtca 1989101955DNAHomo sapiens 10tttcatatct ccaggccttt cattgggtca ggttggcatt tcgctgccct ttatgtgtgt 60gacaagtgaa aataaggaaa gaaaaaaact caagtgaaga aaatcagaat ctgcgcagca 120gttcctgggc gtttcagctg cttcccacat cacctgcctc atcaagcccc agcatccatc 180tccttgctca tcttacaccc tgtgtgcatg acaggcccac cattcattta tcagagcaaa 240ggctctccca ctattctggt tcacccccct acttagccag atatacaaga atatctgcac 300ggatgacctg cctcacctgg gagctcagag gagctcagat tccattacta tcgcaccaag 360gacagatctc ccagcaagaa tgacagaaaa gactaactgc ccccaaaatc tcccttccaa 420aacacagttc tcttaattct cccaagaaac cagaatgtga ctgctcacct ctctaaggac 480ctgaaaacaa ctggccattt cagctattta aatcaacttt aaaaaatcca accgccaaaa 540tattaaacca ttttggttgg aatgataaca taactaacct gctgacagct gcttctgcta 600ggtgcaaaaa tggaaaaaaa aatacttcta atcaggtcaa atcactctac ctttgggatt 660ctaaatttac tcatattctc aaagaaatat attcagtcat agtggggaaa ataggattat 720tcctttagct cgataagcaa ccagaagttc ttccttcaaa tcttgacatt taatcaatca 780gaaattgatt tttggaaaac tgtttcctat gaagctatct ctgcctgaag gatttttctt 840ttacaatcca gactatagaa ggaaattcac aacctggact ttcacctcca ttggtcagag 900ttttactgac caattcccac ctctgcctta cacctaacgg aagtttatgc ctgttttctc 960ttcacatacc ccaacagtta caaatggttg ttattattaa gcatctttta ttttgtggcc 1020tctgattaca tggtccccta aattttgacc taatcacaaa agattggtaa aatttcttaa 1080catattaata atattttgtt tatgtgtcaa tatcttagca tgtatcaatt aagacagagg 1140tcttaacgtt ctctttttga aagagaatat taggattcag agatattaag agattctccc 1200aggatcacag ttaggtaaca gagctggatt ttagtccagg tctgtctaca gctctaacgt 1260atatacaccc tttgtataac atgtcacgaa ttcagcataa agggatcttc agtgatctaa 1320gtcaggggtc agcaaccttt tctaaaaagg accaaatagt aatatttcag gctttgtgga 1380ccctatggtc tctatcataa ctgttcaaat caccatgtag tgtaaaagga gccataagca 1440aaatataaac taacgaatgt ggctgtttta tgggattttt ttttaactct ttatttacaa 1500aagcaggtgg cagatcagaa ctcacttatg ggccatagtt ctctgacccc tgacctgaga 1560aaatcttata tttatggaca acatttagac tgtgacttgc caagtaagaa caagaagctc 1620tgtcaactga aggtcaaggc tggagttctg aaagcaaaga gctgtctggt gttaatgata 1680agtgaaatag ttaaagttag aagatcccag ttataagaag cacaaagaat aatgaccata 1740gactcctgaa caagaatgtc tggacttctg gcttaggcac tcttgttgta tggtccaggc 1800caagttacct aatctctcca ggcctccatt ttcttatcat taaatgaaga taataaaagt 1860attttcctca gagagctgta agaataaact gagctaaccc atgtcaagca catagaatag 1920ggcccagcct atattaattt atcaataaat gccag 1955119458DNAHomo sapiens 11atttgaattg gtgaacttag taaagcagac ggctctcacc aataagggca ggcatcatcc 60aatctgtcga aagcttgaat aaaacaaaaa gaggaaggga aaatttgctt cttttcttct 120tgatctagta tatcatcttc tcctgccctt ggatgtgagt gggccttcag acttaaacca 180ggagttacac ctttggcttc cctggttctc agttctttgg acttggactg aattacactg 240ccaggtttcc tggttctcca gcttgcagat ggcagatcat gggacttctt ggcctccata 300attgtgtgag tcaatttcca ttttatttac atatccagtt atgcattgct taacaatgga 360gacaggttct gagaaatgca ttgttaagtg atttcatcat tgtgcaaaca tcatagagtg 420taactacaca aacctggaca gcatagacta ctacacatct aggctacatg gtgtagcttg 480taacctcatg ataagtatgt ataacatcat gataagtatg tatgtatcta ccatatctaa 540atgtagaaaa ggtacagtaa aaatatggta taatcttatg ggatcaccat catatatgca 600atcctttgta gactgaaatg tcattgtgta gtgcatgact gtatacgcac acatacacaa 660acacacacaa atatactatt ggttcttttt ctctgaagag ccctaataca atatgttata 720catttatatt gactctattt caaaatttat ggttttggtg aaacatatgt ggagatgggg 780cataggtgtg tgaactggga tagtgtcctg ctgatgaatg ggtgggaggc atcatttggg 840acaagcccag ggcatcagct tatagatatc aagagctcaa caagagcact ttatggcaaa 900acctcccaca agacctctca gaagttgaga aactgctaaa agtttcttta tgacagatga 960catttatgga taaaataggg attagcagga ttctttaaat actttcgaac actaaccttc 1020atttctacca ggcagtgggg ccccaagtgc agggccatag gaagtacaag tctgggagat 1080actaggctgc actgtctgta gagaatctga aaaaataata gagtcactga aatgcagttt 1140ggtataatta ttgccatgca tcataattct aaatcatact agtggtcaaa tactcttccc 1200tgaaaaaaca ttttcttggt ttgaattcta aataattgtt gtggtcacca ctgagctttt 1260aaatatataa atactttcaa gtttgcatat ttttattacc tgttccttaa caaacattga 1320attcaacatg aaaatgatta tgggaaacat tcgggtatac agtccctgac tcttaaggac 1380tcaggtaaat acttagggta tttcatggcc ctagtctttg gggtaccaca tgtttcttct 1440tcaaatcaca gattcaaaat caagaatgat aacacagtga ttgtgtagac aaaataagtg 1500aaccaaaatt gcttgcttct gtcattctat ggaaccactg agagttttta cttgtgctta 1560aaattttgaa tagtaaaaca gagtgtcaac ttcatgctgg aatatttttg gctttttaga 1620cacaatttta agtacatgaa gtatttttac aagactaagt aacatcactg aaattacagc 1680tttcttcttt ttaaaactgg tatttgttat aaaactaaag agcgaatcaa gaaaagcata 1740attattactg attattacag gattattact gaaaaagaaa tgtacggaat agaggaggaa 1800ggagttaaca aatgatccac tctgggtgtt gaaaacacca ataagcctgc ttccaggaag 1860tgcctaagac agagctggct cagcttgctg ggtcacagca tgtaaggaaa ctgctgggct 1920acatgccacc atcctcagtt gtccagatag ataatcccat agccccatgg ggaaataatc 1980tttaattatg atatagctga caccattcaa agcactatgc taagtccttt atgtgaatta 2040acttttgtca aatttatttt tcataaataa cccaaatatg tataccacta ttatcctacc 2100ttaaagagga gaaactgagc tcctaaagtt taaatatcta acccaagtta agactgctag 2160tcaccctagg ctattaactc aggcagtcta actcaggtat aataacatta tgctactgtt 2220tgcagctttg actatgcctg aattataacg tcatgctatc taactaaaaa gctaagggaa 2280ataaaatgag ccatagggct caatttcata aaaggagaga aaatactggg gaaaagtgat 2340aatgcagagt ttaaaatatt tttgtaaaag tgccagagat tgagtataac aagtgtgacc 2400aaaaaaaaaa aaaaaaaaaa aaaaggaaga aggtaaaaaa aagagggagg tctgagaaat 2460agaaatatca gaggaaggaa ataaaggagg gtgagagtaa attctctttt agcattcaga 2520ttccacagat tccacaaatc acatttcttt ttttaccaac taaggaaaaa taacacttga 2580cctaacattt cattgcagtt agctaaagga tgctagaaaa actatgttgc agtggtttgc 2640tctaatttct tcaggaatag agaaaagtga caaaaagatc agagaagaga agaaaggaaa 2700ctatcagaaa aatacagaat tggagtagga tataacatat ttgggttgaa ggtaaaattt 2760tatattgtaa tcttaagtat cttgctactt cagtttggtc cctggaacag cagcatcaga 2820atctgccgag ggcttgttaa aaaggcagaa tctcaggtcc catcccagac tcactgaatc 2880agaatataaa tactgacaag atgccccggg attcatatgc acagtagagc tggcgaagtt 2940ccattgtagc ctgtgattgt tttctgcaac ttagtatttc tgagttttcc caaggaagaa 3000aacccaggcc ttagcttctg gcagacttgt gtttctcctt tacttactag ctgcatgact 3060catgagcaag gaaatcaaac tttatgtgcc tgagtttcct catctataaa atggagacta 3120taataatcat ctcctaggct tgttttgagg atgttcaaca aatgctcctt tcattcctct 3180atttacagac ctgccgcaga caattctgct agcagccttt gtgctattat ctgttttcta 3240aacttagtaa ttgagtgtga tctggagact aactctgaaa taaataagct gattatttat 3300ttattttctc aaaacaacag aatacgattt agcaaattac ttcttaagat attattttac 3360atttctatat tctcctaccc tgagttgatg tgtgagcaat atgtcacttt cataaagcca 3420ggtatacatt atggacaggt aagtaaaaaa catattattt attctacgtt tttgtccaaa 3480aattttaaat ttcaactgtt gcgcgtgtgt tggtaatgta

aaacaaactc agtacagtag 3540tattcagtac agtatttaag cccctgtact taaacatatt cctcgtacca atgaagttac 3600atgaaaagca aatttgtgtg agatatcgta gatggaagta aattagtctt tatgttcccc 3660acaaattgaa atgcatttca aaaactctgt gtgtgtatgt gtgtgtgtga cagagtgtgt 3720gtgagagaga gacagagaga tacgctttgg ttgcctccat aagctggctg ctatgattaa 3780taagaccaag ttttctaaag aaaatgagat cataacaaaa gccctcttta tgactatctt 3840ttatcagggg caaaaaggaa agagacaaaa cagcatgaaa tgatgagacc aagtgatgaa 3900aattcattca caatgattgc tttcaagagt aatttctctt gggtaattca gcagcctgtt 3960actatggctc tctggagtga tagctaatgt aaatgaagcc tctaaaagtg gattatcctg 4020acaagaatat actcagccaa taatgcaaca gaaatccatt caaagcattc gggaaaaatt 4080caaaagaata aatattcttt tttttttttt aaagttaatg acctacgatc catttcttcc 4140ctgactaaca agcagcaagc acttaaaaat atccagccag gatgaaatag aaacccacct 4200gacttgttaa tatttttgtt tggtcccagg gactcagatt ctaagccaaa ttctttgaat 4260gatcttggca aatgtctcga attatttttg ccaacttttc tttatcttgg aaaaaaagtt 4320tcatgaatgg gtgtcaaaat tgattagttt taaaaacctt tcttgcagat acgtatggca 4380ccctaaaact gtattagaaa aaaagtaagt actctgtagt gtgaaaaatt cttaaaggac 4440accctctttt acaaactcac aaaaacagcc tttggaatac ccacatgaag tagctgttgt 4500tattgctttc tatataccta catcttgtct attataaaaa gactggtttt tggcaggtgt 4560ggtggctcac acctgtaatt ccagcacttt gggaggccaa ggcgggcgga tcacctgaga 4620tcaggagttc aggaccagcc tgatcaatat ggtgaaaccc agtctttact gaaaatacaa 4680aaatcacccg ggtgtggtga cgggcgcctg tagtcccagc tactcgggta gctgaggcag 4740gagaatcact tgaactcagg agtcagaggt tgcagtgagc tgagatcatg ccactgcact 4800ccagcctggg tgacagagca agactccatc tcaaaaaaaa aaaaaaaaaa gactggtttt 4860tcaacagcta ttcccacccc tctgcatgga aatattcacc cagtcaattg ttttcctagt 4920ttgggtaatg gccctctggg caggactgga gtggggcaca caggagaagc tgcaaactat 4980gtttagaagc atgtctggga aatgtcatgc aagaaaagac atatttaaag gtaggctttg 5040catgaatgga aaaggagagt aattctatgt agagcagagc ctcttacttg cagtgagaga 5100agcaaaagtg gggaagcaag aggaattatg cttttcatca gccaaatttg caggtaggag 5160gattggctca gtcatcttgg ctgaggctca tgaaaccagg tgtaaagaaa gtggactaga 5220ttaatttcat ccattacagg aagaggagcc gtgaaagata atccagaaat cattgggatt 5280tgatggtaga aggtattttg ggactattcc atttgaaatg agaaggtacc tgacattctt 5340tgaattcctt tcaagcaaag gattaaattt acccatgagt tgactcagaa aaaacataaa 5400aagtattgtt gctctgctca gagttttatc taactcattc tcacttctta ttccatgatg 5460aaatgacata aatgaggttt tttattgttg ttgttgttgt tttctggaca caaggcaagg 5520tagctacctg ggcagagctg ttttatttct ctatgccgtg gagagaaatt ggttaattgg 5580ccatggaagg cagtcattaa gatgttccca tgcgagtgaa ctttccaggg ttcccagctt 5640ctgcatcctt ccctgtccct caattccatt gttggtgatg acaatgtctc tcccatcagc 5700ctcatgaagt tctctctcat ttattaaaat ttgctttcag gaaaaatttt gaaaatgtgt 5760ccagtaatgc ctgattggcc ccttatccta aaggcttaaa ctggaggaag gaagctaaac 5820tgagaaatct tgcaaatcat tgagccaaaa acgtattaat agcaagatct atcatttatt 5880gactagtatg tggcaggcag tgccctttta tttaggcagg gagagttgat ggggggggcg 5940gggttcacac atcttaaaga ggtgctatct cctcctatat aaatcatgta agtcaagaga 6000gtaaggaatt gtctttgttt ggttatattc aggggattag agtatacagt agaagatccc 6060aagaaacctt gggatcattt tagactaaga aatgccaata ccgccgggcg cggtggctca 6120cgcctgtaat cccagcactt tgagaggccg aggtgggcgg atcacaaggt caggagattg 6180agaccgtcct ggctaacgtg gtgaaaccct gtctctacta aaaatacaaa aaattagccg 6240ggcgtggtgg cgggcgcctg tagtcccagc tactcgggag gcggaggcag gagaatggtg 6300tgaactcagg aggcggagct tgcagtcagc cgagattgcc ccaatgcact ccagcctggg 6360cgacagaacg agactccgtc tcagaacaaa acaaaaggaa atgccaatac cagcagaaat 6420agagccaaat catgaacata agctaaacaa atgttggcag tgtagcctag tggttaagag 6480agcagactct taactagaac actgcactcc atgtcctcac tgtagaccct cactgtgggg 6540ttctaattaa cccctgttac ttaccagtgg cagtcttaag gcattcctta agttcgttgt 6600gccccaattt gttcatctgt agaaggggta ggatgacagt agtgtttact ttataggctt 6660actgtgagca ttaaatgagt tactactgta tttgtaaagt gcttaaaatg ctgctccaaa 6720agagtttgtt aaacacttaa gaactgattt acttgcatct aaactgacag ctctcaataa 6780ctggaaatga tcaagcatag gccctggaat ataagcaggt ctacatgaag gcaaaaatgt 6840tcgtttcttt tgttcagccc tgtgcctaga tcaatatcta gtgatcatgc tcaagaaata 6900ttgttgaatg aatcaatgaa cctaccgagg tagttacata aaagagttct gcatgagtac 6960aaatctgggc aaagtgacct ccaaggaaat ttccactttt agattctgtg atttccttaa 7020ggaactgata aattggtgtg atacaatgta aaaaaatgtg cctatatgat ttgagaaaaa 7080cttattttct ctccctcttt tttccttcct tccttcctcc ctcccttcct tccttcctcc 7140ctcccttcct tcctccctcc ctcccttcct tccttctctt tcttcttttc tttctttctt 7200tctttctttc tttctttctt tctttctttc tttctttctt ctcttctctt tcctttcttt 7260cttcctttct ttgtgccttt ctttctttct ttctttcttc tctgtccttt ctttcttcct 7320ttctttcttt ctgcctttct ttctctttgt ttttctttct ttccttcttt tttcctttaa 7380gcagaccatg tctgttagat gaatgccttt ttctagttaa aaggttaaac aggaaagtga 7440agcacaatta tcaagggtct ccagtcatct ccacatgttc ttaatcatta tcttctttta 7500cagtttcata tctccaggcc tttcattggg tcaggttggc atttcgctgc cctttatgtg 7560tgtgacaagt gaaaataagg aaagaaaaaa actcaagtga agaaaatcag aatctgcgca 7620gcagttcctg ggcgtttcag ctgcttccca catcacctgc ctcatcaagc cccagcatcc 7680atctccttgc tcatcttaca ccctgtgtgc atgacaggcc caccattcat ttatcagagc 7740aaaggctctc ccactattct ggttcacccc cctacttagc cagatataca agaatatctg 7800cacggatgac ctgcctcacc tgggagctca gaggagctca gattccatta ctatcgcacc 7860aaggacagat ctcccagcaa gaatgacaga aaagactaac tgcccccaaa atctcccttc 7920caaaacacag ttctcttaat tctcccaaga aaccagaatg tgactgctca cctctctaag 7980gacctgaaaa caactggcca tttcagctat ttaaatcaac tttaaaaaat ccaaccgcca 8040aaatattaaa ccattttggt tggaatgata acataactaa cctgctgaca gctgcttctg 8100ctaggtgcaa aaatggaaaa aaaaatactt ctaatcaggt caaatcactc tacctttggg 8160attctaaatt tactcatatt ctcaaagaaa tatattcagt catagtgggg aaaataggat 8220tattccttta gctcgataag caaccagaag ttcttccttc aaatcttgac atttaatcaa 8280tcagaaattg atttttggaa aactgtttcc tatgaagcta tctctgcctg aaggattttt 8340cttttacaat ccagactata gaaggaaatt cacaacctgg actttcacct ccattggtca 8400gagttttact gaccaattcc cacctctgcc ttacacctaa cggaagttta tgcctgtttt 8460ctcttcacat accccaacag ttacaaatgg ttgttattat taagcatctt ttattttgtg 8520gcctctgatt acatggtccc ctaaattttg acctaatcac aaaagattgg taaaatttct 8580taacatatta ataatatttt gtttatgtgt caatatctta gcatgtatca attaagacag 8640aggtcttaac gttctctttt tgaaagagaa tattaggatt cagagatatt aagagattct 8700cccaggatca cagttaggta acagagctgg attttagtcc aggtctgtct acagctctaa 8760cgtatataca ccctttgtat aacatgtcac gaattcagca taaagggatc ttcagtgatc 8820taagtcaggg gtcagcaacc ttttctaaaa aggaccaaat agtaatattt caggctttgt 8880ggaccctatg gtctctatca taactgttca aatcaccatg tagtgtaaaa ggagccataa 8940gcaaaatata aactaacgaa tgtggctgtt ttatgggatt tttttttaac tctttattta 9000caaaagcagg tggcagatca gaactcactt atgggccata gttctctgac ccctgacctg 9060agaaaatctt atatttatgg acaacattta gactgtgact tgccaagtaa gaacaagaag 9120ctctgtcaac tgaaggtcaa ggctggagtt ctgaaagcaa agagctgtct ggtgttaatg 9180ataagtgaaa tagttaaagt tagaagatcc cagttataag aagcacaaag aataatgacc 9240atagactcct gaacaagaat gtctggactt ctggcttagg cactcttgtt gtatggtcca 9300ggccaagtta cctaatctct ccaggcctcc attttcttat cattaaatga agataataaa 9360agtattttcc tcagagagct gtaagaataa actgagctaa cccatgtcaa gcacatagaa 9420tagggcccag cctatattaa tttatcaata aatgccag 945812552DNAHomo sapiens 12attatgtaga accattccaa tcctgagtga caggatttgc aaagacagct gttgggctcc 60acaaacattt ggaggagggg aaaatgtgag gttggttgct acattctcct acttcttttt 120actgaaagga acagctgcga tcttcacatg taagatgaag taaacaaaag ctgacaatgc 180ccagcaccat tcagcagtaa gcattcaaat ggatttttcc tcaccgcgtt tgcaggcccg 240gcacagtctc agttccccac agcacagaga ggaagcaagg tctttgcatg ccctgttcac 300ttggccaaac attgccctag atgtgcaatt caacccatat aaagcaagcg taattcaaga 360gccctgactc tttcaccatt tcatgatggc ttattactcg cacacggcat tgtcaggttc 420cagcaactct gtgtgcagca ggcagaaatg cagtgtttat ctctgacagg caaacattct 480taggctcatc ggcatgagta tccacgctga actggctatc ggggaagtag atccctgcat 540gggaaagtca ag 55213305DNAHomo sapiens 13atttgaattg gtgaacttag taaagcagac ggctctcacc aataagggca ggcatcatcc 60aatctgtcga aagcttgaat aaaacaaaaa gaggaaggga aaatttgctt cttttcttct 120tgatctagta tatcatcttc tcctgccctt ggatgtgagt gggccttcag acttaaacca 180ggagttacac ctttggcttc cctggttctc agttctttgg acttggactg aattacactg 240ccaggtttcc tggttctcca gcttgcagat ggcagatcat gggacttctt ggcctccata 300attgt 30514307DNAHomo sapiens 14atttgaattg gtgaacttag taaagcagac ggctctcacc aataagggca ggcatcatcc 60aatctgtcga aagcttgaat aaaacaaaaa gaggaaggga aaatttgctt cttttcttct 120tgatctagta tatcatcttc tcctgccctt ggatgtgagt gggccttcag acttaaacca 180ggagttacac ctttggcttc cctggttctc agttctttgg acttggactg aattacactg 240ccaggtttcc tggttctcca gcttgcagat ggcagatcat gggacttctt ggcctccata 300attgtgt 30715557DNAHomo sapiens 15gggcaaaaag gaaagagaca aaacagcatg aaatgatgag accaagtgat gaaaattcat 60tcacaatgat tgctttcaag agtaatttct cttgggtaat tcagcagcct gttactatgg 120ctctctggag tgatagctaa tgtaaatgaa gcctctaaaa gtggattatc ctgacaagaa 180tatactcagc caataatgca acagaaatcc attcaaagca ttcgggaaaa attcaaaaga 240ataaatattc tttttttttt tttaaagtta atgacctacg atccatttct tccctgacta 300acaagcagca agcacttaaa aatatccagc caggatgaaa tagaaaccca cctgacttgt 360taatattttt gtttggtccc agggactcag attctaagcc aaattctttg aatgatcttg 420gcaaatgtct cgaattattt ttgccaactt ttctttatct tggaaaaaaa gtttcatgaa 480tgggtgtcaa aattgattag ttttaaaaac ctttcttgca gatacgtatg gcaccctaaa 540actgtattag aaaaaaa 557161955DNAHomo Sapiens 16tttcatatct ccaggccttt cattgggtca ggttggcatt tcgctgccct ttatgtgtgt 60gacaagtgaa aataaggaaa gaaaaaaact caagtgaaga aaatcagaat ctgcgcagca 120gttcctgggc gtttcagctg cttcccacat cacctgcctc atcaagcccc agcatccatc 180tccttgctca tcttacaccc tgtgtgcatg acaggcccac cattcattta tcagagcaaa 240ggctctccca ctattctggt tcacccccct acttagccag atatacaaga atatctgcac 300ggatgacctg cctcacctgg gagctcagag gagctcagat tccattacta tcgcaccaag 360gacagatctc ccagcaagaa tgacagaaaa gactaactgc ccccaaaatc tcccttccaa 420aacacagttc tcttaattct cccaagaaac cagaatgtga ctgctcacct ctctaaggac 480ctgaaaacaa ctggccattt cagctattta aatcaacttt aaaaaatcca accgccaaaa 540tattaaacca ttttggttgg aatgataaca taactaacct gctgacagct gcttctgcta 600ggtgcaaaaa tggaaaaaaa aatacttcta atcaggtcaa atcactctac ctttgggatt 660ctaaatttac tcatattctc aaagaaatat attcagtcat agtggggaaa ataggattat 720tcctttagct cgataagcaa ccagaagttc ttccttcaaa tcttgacatt taatcaatca 780gaaattgatt tttggaaaac tgtttcctat gaagctatct ctgcctgaag gatttttctt 840ttacaatcca gactatagaa ggaaattcac aacctggact ttcacctcca ttggtcagag 900ttttactgac caattcccac ctctgcctta cacctaacgg aagtttatgc ctgttttctc 960ttcacatacc ccaacagtta caaatggttg ttattattaa gcatctttta ttttgtggcc 1020tctgattaca tggtccccta aattttgacc taatcacaaa agattggtaa aatttcttaa 1080catattaata atattttgtt tatgtgtcaa tatcttagca tgtatcaatt aagacagagg 1140tcttaacgtt ctctttttga aagagaatat taggattcag agatattaag agattctccc 1200aggatcacag ttaggtaaca gagctggatt ttagtccagg tctgtctaca gctctaacgt 1260atatacaccc tttgtataac atgtcacgaa ttcagcataa agggatcttc agtgatctaa 1320gtcaggggtc agcaaccttt tctaaaaagg accaaatagt aatatttcag gctttgtgga 1380ccctatggtc tctatcataa ctgttcaaat caccatgtag tgtaaaagga gccataagca 1440aaatataaac taacgaatgt ggctgtttta tgggattttt ttttaactct ttatttacaa 1500aagcaggtgg cagatcagaa ctcacttatg ggccatagtt ctctgacccc tgacctgaga 1560aaatcttata tttatggaca acatttagac tgtgacttgc caagtaagaa caagaagctc 1620tgtcaactga aggtcaaggc tggagttctg aaagcaaaga gctgtctggt gttaatgata 1680agtgaaatag ttaaagttag aagatcccag ttataagaag cacaaagaat aatgaccata 1740gactcctgaa caagaatgtc tggacttctg gcttaggcac tcttgttgta tggtccaggc 1800caagttacct aatctctcca ggcctccatt ttcttatcat taaatgaaga taataaaagt 1860attttcctca gagagctgta agaataaact gagctaaccc atgtcaagca catagaatag 1920ggcccagcct atattaattt atcaataaat gccag 1955171253DNAHomo Sapiens 17tatccccact gtgtagagct ggtccacaat ggagaggagg aaaagttttg cattggacca 60aatcactgcc ttagaaggaa agagattgca atcccattca tttttaagat ctgcaatggg 120ttgggatgat acccatttaa aaaagaaaaa aaaagaggtt acctctttgg cctctttggc 180aaaggatatg aactagtaat aaagcctcag catcaaggct tgggagtctg gctcaaagtg 240gctaagacta gaagcatctt ctaacataaa tatggcagca ttaggaaaat agcttggcct 300ttagagagac ccagattatc ttcaccttaa aaactaccaa gaccctggtc cagcaagacc 360accatcacag cagtaaatac atagccacca acttcacaga aggttttcca ctgagacatt 420gtgaaaacca caatccatta ccggtggatg agtcccagct ctcttactac ctggagcttc 480caagcaagac ttacctgtcc tttgttccag attggttcct gggatcctgg accaacacaa 540agagaagagg aaagcctcaa gggaaataaa agtgaaggtt tcagtgatag tttaaatata 600tatttttaaa tgttagcttt tttttaaata cttcacggtg atggatggag tatttcaacc 660acaatggcaa agaatgaatt accggcagtg tcagagtttc ttgttgctgt gggaagacag 720ctgccatgtt gagaggtgcc ttgtggagag gctcatgtgg cgaggaactg agactggctt 780ctatccaaca accagtgagg aactaaggcc ctaaagtcct atagtccaca aggaactaaa 840tcctaccaac aactacatga gtgagcctgg aatctgattt tccccagtgg ggacttaagg 900tacctacaac ctggctgtta tgggctaaac tgcatcctgc ccaaatttat atgtttgagt 960cttaactccc agcacttcag aacatggttt tgtttggaga catagtcatt aaagaggtaa 1020tgaagttaaa atgaggtcat taggatgagt cctaatccaa taggactggt gttcttatat 1080gaagaggaaa tttgaacaca gacacatata caggaaagac catgcgaaga agacacagag 1140aggaaacggc catctacaat ccaaggagag aggcctcaga acaagccaac cctgcagata 1200ccttgatcta ggcatccaga attgtatgaa aatacatttt tgttatttaa gct 125318366DNAHomo sapiens 18atgttcaaca aatgctcctt tcattcctct atttacagac ctgccgcaga caattctgct 60agcagccttt gtgctattat ctgttttcta aacttagtaa ttgagtgtga tctggagact 120aactctgaaa taaataagct gattatttat ttattttctc aaaacaacag aatacgattt 180agcaaattac ttcttaagat attattttac atttctatat tctcctaccc tgagttgatg 240tgtgagcaat atgtcacttt cataaagcca ggtatacatt atggacaggt aagtaaaaaa 300catattattt attctacgtt tttgtccaaa aattttaaat ttcaactgtt gcgcgtgtgt 360tggtaa 3661921RNAHomo sapiens 19aauaagggca ggcaucaucc a 212021RNAHomo sapiens 20aauuacacug ccagguuucc u 212121RNAHomo sapiens 21aauucauuca caaugauugc u 212221RNAHomo sapiens 22aauuucucuu ggguaauuca g 212321RNAHomo sapiens 23aaaaucagaa ucugcgcagc a 212421RNAHomo sapiens 24aaugaugaug ggaagaagga a 212521RNAHomo sapiens 25aaacuuagua auugagugug a 212621RNAHomo sapiens 26aauaugucac uuucauaaag c 212721RNAHomo sapiens 27aaugaugaug ggaagaagga a 212821RNAHomo sapiens 28aaacuaugag auuucagaag g 212914DNAHomo sapiensprimer_bind(0)...(0)Exon overlapping oligonucleotide primer F26 29agacggctct cacc 143021DNAHomo sapiensprimer_bind(0)...(0)Exon overlapping oligonucleotide primer FDP5 30cacttgtcac acacataaag g 213121DNAHomo sapiensprimer_bind(0)...(0)cDNA oligonucleotide primer FDP5 31cctttatgtg tgtgacaagt g 213222DNAHomo sapiensprimer_bind(0)...(0)cDNA oligonucleotide primer F10 32atccagccag gatgaaatag aa 223320DNAHomo sapiensprimer_bind(0)...(0)upstream primer human VH family leader sequence VH1 33ccatggactg gacctggagg 203421DNAHomo sapiensprimer_bind(0)...(0)upstream primer human VH family leader sequence VH2 34atggacatac tttgttccag c 213520DNAHomo sapiensprimer_bind(0)...(0)upstream primer human VH family leader sequence VH3 35ccatggagtt tgggctgagc 203620DNAHomo sapiensprimer_bind(0)...(0)upstream primer human VH family leader sequence VH4 36atgaaacacc tgtggttctt 203720DNAHomo sapiensprimer_bind(0)...(0)upstream primer human VH family leader sequence VH5 37atggggtcaa ccgcgatcct 203820DNAHomo sapiensprimer_bind(0)...(0)upstream primer human VH family leader sequence VH6 38atgtctgtct ccttcctcat 203921DNAHomo sapiensprimer_bind(0)...(0)down stream primer C1 39gaggctcagc gggaagacct t 214021DNAHomo sapiensprimer_bind(0)...(0)down stream primer C 2 40ggggaagacc gatgggcccc t 214120DNAHomo sapiensprimer_bind(0)...(0)northern blot primer 41tcacctggga gctcagagga 204220DNAHomo sapiensprimer_bind(0)...(0)northern blot primer 42gtgatcctgg gagaatctct 204325DNAHomo sapiensprimer_bind(0)...(0)RACE antisence primer 43tacattacca acacacgcgc aacag 25

Claims

1-41. (canceled)

42. A nucleotide sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18 for use as a medicament.

43. A transcriptional product selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11 for use as a medicament.

44. An amino acid sequence selected from the group consisting of: i) an amino acid sequence of SEQ ID NO: 3, ii) an amino acid sequence having at least 60% sequence identity compared to the full length sequence of SEQ ID NO: 3 iii) a fragment of SEQ ID NO: 3 having at least 60% sequence identity compared to the full length sequence of SEQ ID NO: 3 for use in a diagnostic method for a subtype of B-CLL having a poor prognosis.

45. An amino acid sequence according to claim 44, said amino acid sequence being a polypeptide having interleukin or cytokine activity.

46. The amino acid sequence according to any one of claims 44 or 45, which folds as a 4-helical cytokine.

47. Use of an amino acid sequence as defined in any one of claims 44-46 for the preparation of a medicament for the treatment of cancer.

48. Use according to claim 47, wherein the cancer is B-CLL.

49. A method of immunisation of a patient in need thereof against B-CLL, wherein said immunisation generates an immune response in said patient which recognises a translational product of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11.

50. A method for producing an antibody with specificity against an isolated polypeptide selected from i) an amino acid sequence of SEQ ID NO: 3, ii) an amino acid sequence having at least 60% sequence identity with the full length SEQ ID NO: 3, iii) a fragment of SEQ ID NO: 3 having at least 60% sequence identity compared to full length SEQ ID NO: 3.

51. The method of claim 50 wherein said isolated polypeptide has interleukin or cytokine activity.

52. The method of claim 50 wherein the isolated polypeptide folds as a 4-helical cytokine.

53. An antibody obtainable by the method of claim 50.

54. An antibody with specificity against an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: i) an amino acid sequence of SEQ ID NO: 3, ii) an amino acid sequence having at least 60% sequence identity compared to the full length sequence of SEQ ID NO:3 iii) a fragment of SEQ ID NO:3 having at least 60% sequence identity compared to the full length sequence of SEQ ID NO:3.