Method For Diagnosing The Stage Of A Thyroid Tumor

Abstract

The present invention relates to the use of genes differentially expressed in benign thyroid lesions and malignant thyroid lesions for the diagnosis and staging of thyroid cancer.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. patent application Ser. No. 11/547,995, filed Dec. 21, 2007, which is a national stage filing of PCT Application Serial Number PCT/US2005/012289, filed Apr. 11, 2005, which claims the benefit under 35 U.S.C. .sctn.119(e) of U.S. Provisional Application Ser. No. 60/560,900, filed Apr. 9, 2004, and of U.S. Provisional Application Ser. No. 60/622,643, filed Oct. 26, 2004, all of which are herein incorporated in their entireties by this reference.

TECHNICAL FIELD

[0002] The present invention relates to the use of genes differentially expressed in benign thyroid lesions and malignant thyroid lesions for the diagnosis and staging of thyroid cancer.

BACKGROUND

[0003] It is well known that cancer results from changes in gene expression patterns that are important for cellular regulatory processes such as growth, differentiation, DNA duplication, mismatch repair and apoptosis. It is also becoming more apparent that effective treatment and diagnosis of cancer is dependent upon an understanding of these important processes. Classification of human cancers into distinct groups based on their origin and histopathological appearance has historically been the foundation for diagnosis and treatment. This classification is generally based on cellular architecture, certain unique cellular characteristics and cell-specific antigens only. In contrast, gene expression assays have the potential to identify thousands of unique characteristics for each tumor type (3) (4). Elucidating a genome wide expression pattern for disease states not only could have a enormous impact on the understanding of specific cell biology, but could also provide the necessary link between molecular genetics and clinical medicine (5) (6) (7).

[0004] Thyroid carcinoma represents 1% of all malignant diseases, but 90% of all neuroendocrine malignancies. It is estimated that 5-10% of the population will develop a clinically significant thyroid nodule during their life-time (8). The best available test in the evaluation of a patient with a thyroid nodule is fine needle aspiration biopsy (FNA) (9). Of the malignant FNAs, the majority are from papillary thyroid cancers (PTC) or its follicular variant (FVPTC). These can be easily diagnosed if they have the classic cytologic features including abundant cellularity and enlarged nuclei containing intra-nuclear grooves and inclusions (10). Indeed, one third of the time these diagnoses are clear on FNA. Fine needle aspiration biopsy of thyroid nodules has greatly reduced the need for thyroid surgery and has increased the percentage of malignant tumors among excised nodules (11, 12). In addition, the diagnosis of malignant thyroid tumors, combined with effective therapy, has lead to a marked decrease in morbidity due to thyroid cancer. Unfortunately, many thyroid FNAs are not definitively benign or malignant, yielding an "indeterminate" or "suspicious" diagnosis. The prevalence of indeterminate FNAs varies, but typically ranges from 10-25% of FNAs (13-15). In general, thyroid FNAs are indeterminate due to overlapping or undefined morphologic criteria for benign versus malignant lesions, or focal nuclear atypia within otherwise benign specimens. Of note, twice as many patients are referred for surgery for a suspicious lesion (10%) than for a malignant lesion (5%), an occurrence that is not widely appreciated since the majority of FNAs are benign. Therefore when the diagnosis is unclear on FNA these patients are classified as having a suspicious or indeterminate lesion only. It is well known that frozen section analysis often yields no additional information.

[0005] The question then arises: "Should the surgeon perform a thyroid lobectomy, which is appropriate for benign lesions or a total thyroidectomy, which is appropriate for malignant lesions when the diagnosis is uncertain both preoperatively and intra-operatively?" Thyroid lobectomy as the initial procedure for every patient with a suspicious FNA could result in the patient with cancer having to undergo a second operation for completion thyroidectomy. Conversely, total thyroidectomy for all patients with suspicious FNA would result in a majority of patients undergoing an unnecessary surgical procedure, requiring lifelong thyroid hormone replacement and exposure to the inherent risks of surgery (16).

[0006] Several attempts to formulate a consensus about classification and treatment of thyroid carcinoma based on standard histopathologic analysis have resulted in published guidelines for diagnosis and initial disease management (2). In the past few decades no improvement has been made in the differential diagnosis of thyroid tumors by fine needle aspiration biopsy (FNA), specifically suspicious or indeterminate thyroid lesions, suggesting that a new approach to this should be explored. Thus, there is a compelling need to develop more accurate initial diagnostic tests for evaluating a thyroid nodule.

SUMMARY

[0007] This invention is based in part on the discovery of genes whose expression levels can be correlated to benign or malignant states in a thyroid cell. Thus, the present invention provides differentially expressed genes that can be utilized to diagnose, stage and treat thyroid cancer. These differentially expressed genes are collectively referred to herein as "Differentially Expressed Thyroid" genes ("DET" genes). Examples of these DET genes are provided herein and include C21 or f4 (DET1), Hs.145049 (DET2), Hs.296031 (DET3), KIT (DET4), LSM7 (DET5), SYNGR2 (DET6), C11 or f8 (DET7), CDH11 (DET8), FAM13A1 (DET9), IMPACT (DET10) and KIAA1128 (DET11).

[0008] The present invention provides a gene expression approach to diagnose benign vs malignant thyroid lesions. Identification of differentially expressed genes allows the development of models that can differentiate benign vs. malignant thyroid tumors. Results obtained from these models provide a molecular classification system for thyroid tumors and this in turn provides a more accurate diagnostic tool for the clinician managing patients with suspicious thyroid lesions.

[0009] The present invention also provides a method for classifying a thyroid lesion in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11; b) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid lesion classification is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, in the test cell population and reference cell population, thereby classifying the thyroid lesion in the subject.

[0010] Further provided is a method for classifying a thyroid lesion in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6; b) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid lesion classification is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, in the test cell population and reference cell population, thereby classifying the thyroid lesion in the subject.

[0011] The present invention also provides a method of identifying the stage of a thyroid tumor in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6; b) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, in the test cell population and reference cell population, thereby identifying the stage of the thyroid tumor in the subject.

[0012] Further provided by the present invention is a method of identifying the stage of a thyroid tumor in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11; b) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, in the test cell population and reference cell population, thereby identifying the stage of the thyroid tumor in the subject.

[0013] Also provided by the present invention is a method of identifying an agent for treating a thyroid tumor, the method comprising: a) contacting a population of thyroid tumor cells from a subject for which a tumor stage is known, wherein at least one cell in said population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, with a test agent; b) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6 in the population; c) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and d) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, in the test cell population and reference cell population, such that if there is a difference corresponding to an improvement, a therapeutic agent for treating a thyroid tumor has been identified.

[0014] The present invention also provides a method of identifying an agent for treating a thyroid tumor, the method comprising: a) contacting a population of thyroid tumor cells from a subject for which a tumor stage is known, wherein at least one cell in said population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, with a test agent; b) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11 in the population; c) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and d) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, in the test cell population and reference cell population, such that if there is a difference corresponding to an improvement, a therapeutic agent for treating a thyroid tumor has been identified.

[0015] Also provided by the present invention is a kit comprising one or more reagents for detecting the expression of one or more nucleic acid(s) selected from the group consisting of DET1, DET2, DET3, DET4, DET5, DET6, DET7, DET8, DET9, DET10, DET11.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] FIG. 1 shows PCA (principle component analysis) organization in a three-dimensional space of all samples divided into four groups: hyperplastic-nodule (HN), follicular adenoma (FA), follicular variant of papillary thyroid carcinoma (FVPTC) and papillary thyroid carcinoma (PTC). Each dot represents how that sample is localized in space on the basis of its gene expression profile. The distance between any pair of points is related to the similarity between the two observations in high dimensional space. The principal components are plotted along the various axes (x,y,z). The % indicates the total amount of variance captured by the PCs; the first PC is the one capturing the largest amount of variance, or information, the second PC, the second largest etc. Three PCs were plotted, thus creating a 3D plot.

[0017] FIG. 2 shows PCA organization in a three-dimensional space of all samples divided into two groups: benign (HN-FA) and malignant (FVPTC-PTC). Each dot represents how that sample is localized in-space on the basis of its gene expression profile. The distance between any pair of points is related to the similarity between the two observations in high dimensional space.

[0018] FIG. 3 shows PCA organization in a three-dimensional space of all samples with (A) and without the unknowns (B) based on the gene expressions values of the six most informative genes. It is clear there is a separation of the two groups and that it is possible to predict visually the diagnosis of each unknown. The pathological diagnoses of the unknowns are marked respectively with a + and a * for the benign and the malignant tumor. The red + sign indicates an unknown sample for which pathological diagnosis and predicted diagnosis were discordant. Based on our six gene diagnostic predictor model, this lesion was placed in the malignant group. Upon re-review by the pathologist, this sample was reclassified from benign to a neoplasm of uncertain malignant potential.

[0019] FIG. 4 is a graph showing gene expression profiles of ten unknown samples. On the basis of their profile the predictor model of this invention gave a correct diagnosis in 100% of the cases. The y axis represents the ratio between thyroid tumor mRNA expression level (Cy5 fluorescence intensity) and control thyroid tissue mRNA expression level (Cy3 fluorescence intensity).

[0020] FIG. 5 shows the results of RT-PCR utilizing the 6 gene predictor model. The RT-PCR data using 6 gene's across 42 patient samples demonstrates separation by group.

[0021] FIG. 6 shows immunohistochemical results for expression of KIT and CDH1 in malignant and benign thyroid lesions. These results correlate with the expression data obtained via microarray and RT-PCR.

[0022] FIG. 7 shows the results of RT-PCR utilizing the 10 gene predictor model. The RT-PCR data using 10 genes demonstrates separation by group.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Differentially Expressed Thyroid Genes

[0023] One aspect of the invention relates to genes that are differentially expressed in benign and/or malignant thyroid lesions relative to normal thyroid tissue. These differentially expressed genes are collectively referred to herein as "Differentially Expressed Thyroid" genes ("DET" genes). The corresponding gene products are referred to as "DET products" "DET polypeptides" and/or "DET proteins". The DET genes of the present invention include C21 or f4, Hs.145049, Hs.296031, KIT, LSM7, SYNGR2, C11 or f8, CDH1, FAM13A1, IMPACT and KIAA1128. The following provides a brief description of each DET gene provided herein.

C21 or f4 (DET1)

[0024] C21 or f4 is a gene encoding an integral membrane protein of unknown function, located in the q region of chromosome 21. C21 or f4 was found to be upregulated in benign thyroid lesions and upregulated in malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, C21 or f4 was found to be upregulated in benign tissue as compared to malignant tissue. An example of a nucleic acid encoding C21 or f4 is set forth herein as SEQ ID NO: 40. Nucleic acid sequences for C21 or f4 can also be accessed via GenBank Accession No. AP001717, GenBank Accession No. NM.sub.--006134 and via Unigene No. Hs.433668. All of the information, including any nucleic acid and amino acids sequences provided for C21 or f4 under GenBank Accession No. AP001717, GenBank Accession No. NM.sub.--006134 and Unigene No. Hs.433668 is hereby incorporated in its entirety by this reference.

Hs.145049 (DET2)

[0025] Hs. 145049, formerly known as Hs.24183, is a sodium-D-glucose transporter. The Unigene cluster identified as Unigene NO. Hs. 24183 has been retired and has been replaced by Hs. 145049. Hs. 145049 was found to be upregulated in both benign and malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, Hs.145049 was found to be upregulated in benign tissue as compared to malignant tissue. A nucleic acid encoding Hs. 145049 is set forth herein as SEQ ID NO: 42. Nucleic acid sequences for Hs.145049 can also be accessed via GenBank Accession No. NP.sub.--060265, via GenBank Accession No. AL832414.1 and via Unigene No. Hs.145049. All of the information, including any nucleic acid and amino acids sequences provided for Hs.145049 under GenBank Accession NP.sub.--060265, via GenBank Accession No. AL832414 and via Unigene No. Hs.145049 is hereby incorporated in its entirety by this reference.

Hs.296031 (DET3)

[0026] Hs.296031 is a gene of unknown function. Hs. 296031 was found to be downregulated in benign and comparable to normal in malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, Hs.296031 was found to be upregulated in malignant tissue as compared to benign tissue. A nucleic acid encoding Hs. 296031 is set forth herein as SEQ ID NO: 44. Nucleic acid sequences for Hs.296031 can also be accessed via GenBank Accession No. BC038512 and via Unigene No. Hs.296031. All of the information, including any nucleic acid and amino acids sequences provided for Hs.296031 under GenBank Accession No. BC038512 and Unigene No. Hs.296031 is hereby incorporated in its entirety by this reference.

[0027] c-kit Proto-Oncogene (KIT) (DET4)

[0028] KIT is a protooncogene that functions as a transmembrane receptor tyrosine kinase and is involved in cellular proliferation. See Yarden et al. "Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand" EMBO J. 6(11): 3341-3351 (1987). The Yarden et al. reference is incorporated herein in its entirety for the purpose of describing KIT function as well as for incorporating all KIT protein sequences and nucleic acids encoding KIT provided in the Yarden et al. reference. KIT was found to be downregulated in benign thyroid lesions and downregulated in malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, KIT was found to be upregulated in benign tissue as compared to malignant tissue. Thus, KIT expression decreases during malignancy. A nucleic acid encoding KIT is set forth herein as SEQ ID NO: 45. Nucleic acid sequences for KIT can also be accessed via GenBank Accession Nos. X06182 and NM.sub.--000222 and via Unigene No. Hs.81665. All of the information, including any nucleic acid and amino acids sequences provided for KIT under GenBank Accession No. X06182, GenBank Accession No. NM.sub.--000222 and via Unigene No. Hs.81665 is hereby incorporated in its entirety by this reference.

U6 Small Nuclear RNA Associated Homo sapiens LSM7 Homolog (LSM7) (DET5)

[0029] LSM7 is a U6 small nuclear ribonucleoprotein that is involved in tRNA processing. LSM7 was found to be upregulated in benign thyroid lesions and downregulated in malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, LSM-7 was found to be upregulated in benign tissue as compared to malignant tissue. A nucleic acid sequence encoding LSM7 is set forth herein as SEQ ID NO: 47. Nucleic acid sequences for LSM7 can also be accessed via GenBank Accession No. NM.sub.--016199 and via Unigene No. Hs.512610. All of the information, including any nucleic acid and amino acids sequences provided for LSM7 under GenBank Accession No. NM.sub.--016199 and Unigene No. Hs.512610 is hereby incorporated in its entirety by this reference.

Synaptogyrin 2 (SYNGR2) (DET6)

[0030] SYNGR2 is a synaptic vesicle protein that may play a role in regulating membrane traffic. SYNGR2 was found to be downregulated in benign thyroid lesions and comparable to normal in malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, SYNGR2 was found to be upregulated in malignant tissue as compared to benign tissue. A nucleic acid encoding SYNG2 is set forth herein as SEQ ID NO: 49. Nucleic acid sequences for SYNGR2 can also be accessed via GenBank Accession No. NM.sub.--004710 and via Unigene No. Hs. 433753. All of the information, including any nucleic acid and amino acids sequences provided for LSM7 under GenBank Accession No. NM.sub.--004710 and via Unigene No. Hs. 433753 is hereby incorporated in its entirety by this reference.

C11 or f8 (DET7)

[0031] C11 or f8 is a gene involved in central nervous system development and function. C11 or f8 was found to be downregulated in both benign thyroid lesions and malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, C11 or f8 was found to be upregulated in benign tissue as compared to malignant tissue. A nucleic acid encoding C11 or f8 is set forth herein as SEQ ID NO: 51. Nucleic acid sequences for C11 or f8 can also be accessed via GenBank Accession No. NM.sub.--001584 and via Unigene No. Hs. 432000. All of the information, including any nucleic acid and amino acids sequences provided for LSM7 under GenBank Accession No. NM.sub.--001584 and Unigene No. Hs. 432000 is hereby incorporated in its entirety by this reference.

Cadherin 1, Type 1, E-Cadherin (CDH1) (DET8)

[0032] CDH1 is a cadherin protein involved in cell adhesion, motility, growth and proliferation. CDH1 was found to be upregulated in benign thyroid lesions and downregulated in malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, CDH1 was found to be upregulated in benign tissue as compared to malignant tissue. A nucleic acid encoding CDH1 is set forth herein as SEQ ID NO: 53. Nucleic acid sequences for CDH1 can also be accessed via GenBank Accession No. NM.sub.--004360 and via Unigene No. Hs. 194657. All of the information, including any nucleic acid and amino acids sequences provided for CDH1 under GenBank Accession No. NM.sub.--004360 and Unigene No. Hs. 194657 is hereby incorporated in its entirety by this reference.

Homo sapiens Family with Sequence Similarity 13, Member A1 (FAM13A1) (DET9)

[0033] FAM13A1 is a gene of unknown function. FAM13A1 was found to be upregulated in benign thyroid lesions and downregulated in malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, FAM13A1 was found to be upregulated in benign tissue as compared to malignant tissue. A nucleic acid encoding FAM13A1 is set forth herein as SEQ ID NO: 55. Nucleic acid sequences for FAM13A1 can also be accessed via GenBank Accession No. NM.sub.--014883 and via Unigene No. Hs. 442818. All of the information, including any nucleic acid and amino acids sequences provided for FAM13A1 under GenBank Accession No. NM.sub.--014883 and Unigene No. Hs. 442818 is hereby incorporated in its entirety by this reference.

Homo sapiens Hypothetical Protein IMPACT (IMPACT) (DET10)

[0034] IMPACT is a gene of unknown function. IMPACT was found to be upregulated in benign thyroid lesions and downregulated in malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, IMPACT was found to be upregulated in benign tissue as compared to malignant tissue. A nucleic acid encoding IMPACT is set forth herein as SEQ ID NO: 57. Nucleic acid sequences for IMPACT can also be accessed via GenBank Accession No. NM.sub.--018439 and via Unigene No. Hs. 284245. All of the information, including any nucleic acid and amino acids sequences provided for IMPACT under GenBank Accession No. NM.sub.--018439 and Unigene No. Hs. 284245 is hereby incorporated in its entirety by this reference.

KIAA1128 Protein (KIAA1128) (DET 11)

[0035] KIAA1128 is a gene of unknown function. KIAA 1128 was found to be upregulated in benign thyroid lesions and downregulated in malignant thyroid lesions as compared to normal thyroid tissue. Upon comparing benign tissue with malignant tissue, KIAA1128 was found to be upregulated in benign tissue as compared to malignant tissue. A nucleic acid encoding KIAA1128 is set forth herein as SEQ ID NO: 59. Nucleic acid sequences for KIAA1128 can also be accessed via GenBank Accession Nos. AB032954 and via Unigene No. Hs. 81897. All of the information, including any nucleic acid and amino acids sequences provided for KIAA1128 under GenBank Accession Nos. AB032954 and via Unigene No. Hs. 81897 is hereby incorporated in its entirety by this reference.

Diagnostic Methods

[0036] The present invention provides a method for classifying a thyroid lesion in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11; b) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid lesion classification is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, in the test cell population and reference cell population, thereby classifying the thyroid lesion in the subject.

[0037] The present invention also provides a method for classifying a thyroid lesion in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6; b) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid lesion classification is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, in the test cell population and reference cell population, thereby classifying the thyroid lesion in the subject.

[0038] In the methods of the present invention, "classifying a thyroid lesion" is equivalent to diagnosing a subject with a type of thyroid lesion. These lesions can be benign or malignant. Examples of a benign lesion include, but are not limited to, follicular adenoma, hyperplastic nodule, papillary adenoma, thyroiditis nodule and multinodular goiter. Examples of malignant lesions include, but are not limited to, papillary thyroid carcinoma, follicular variant of papillary thyroid carcinoma, follicular carcinoma, Hurthle cell tumor, anaplastic thyroid cancer, medullary thyroid cancer, thyroid lymphoma, poorly differentiated thyroid cancer and thyroid angiosarcoma.

[0039] In the methods of the present invention, measuring the expression levels of one or more nucleic acids sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, means that the expression of any combination of these sequences can be measured. For example, the expression level of one, two, three, four, five, six, seven, eight, nine or ten sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11 can be measured. Similarly, when measuring the expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, one of skill in the art can measure the expression level of one, two, three, four, five or six sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6.

[0040] In the methods of the present invention, the invention includes providing a test population which includes at least once cell that is capable of expressing one or more of the sequences DET1-11. As utilized herein, "expression" refers to the transcription of a DET gene to yield a DET nucleic acid, such as a DET mRNA. The term "expression" also refers to the transcription and translation of a DET gene to yield the encoded protein, in particular a DET protein or a fragment thereof. Therefore, one of skill in the art can detect the expression of a DET gene by monitoring DET nucleic acid production and/or expression of the DET protein. As utilized herein, "upregulated" refers to an increase in expression and "downregulated" refers to a decrease in expression.

[0041] In the methods of the present invention, the reference cell population can be from normal thyroid tissue, cancerous thyroid tissue or any other type of thyroid tissue for which a classification is known. As used herein, "a cell of a normal subject" or "normal thyroid tissue" means a cell or tissue which is histologically normal and was obtained from a subject believed to be without malignancy and having no increased risk of developing a malignancy or was obtained from tissues adjacent to tissue known to be malignant and which is determined to be histologically normal (non-malignant) as determined by a pathologist.

[0042] Using the sequence information provided herein and the sequences provided by the database entries, the expression of the DET sequences or fragments thereof can be detected, if present, and measured using techniques well known in the art. For example, sequences disclosed herein can be used to construct probes for detecting DET DNA and RNA sequences. The amount of a DET nucleic acid, for example, DET mRNA, in a cell can be determined by methods standard in the art for detecting or quantitating nucleic acid in a cell, such as in situ hybridization, quantitative PCR, Northern blotting, ELISPOT, dot blotting, etc., as well as any other method now known or later developed for detecting or quantitating the amount of a nucleic acid in a cell.

[0043] The presence or amount of a DET protein in or produced by a cell can be determined by methods standard in the art, such as Western blotting, ELISA, ELISPOT, immunoprecipitation, immunofluorescence (e.g., FACS), immunohistochemistry, immunocytochemistry, etc., as well as any other method now known or later developed for detecting or quantitating protein in or produced by a cell.

[0044] As used throughout, by "subject" is meant an individual. Preferably, the subject is a mammal such as a primate, and, more preferably, a human. The term "subject" includes domesticated animals, such as cats, dogs, etc., livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, monkey, rabbit, rat, guinea pig, etc.).

[0045] The present invention also provides for detection of variants of the DET nucleic acids and polypeptides disclosed herein. In general, variants of nucleic acids and polypeptides herein disclosed typically have at least, about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 percent homology to the stated sequence or the native sequence. Those of skill in the art readily understand how to determine the homology of two polypeptides or nucleic acids. For example, the homology can be calculated after aligning the two sequences so that the homology is at its highest level.

[0046] Another way of calculating homology can be performed by published algorithms. Optimal alignment of sequences for comparison may be conducted by the local homology algorithm of Smith and Waterman Adv. Appl. Math. 2: 482 (1981), by the homology alignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48: 443 (1970), by the search for similarity method of Pearson and Lipman, Proc. Natl. Acad. Sci. U.S.A. 85: 2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.; the BLAST algorithm of Tatusova and Madden FEMS Microbiol. Lett. 174: 247-250 (1999) available from the National Center for Biotechnology Information or by inspection. Similarly, the present invention provides for the detection of DET proteins that are homologues of human DET proteins in other species. It would be readily apparent to one of skill in the art that the DET sequences set forth herein and in GenBank can be utilized in sequence comparisons to identify DET sequences in other species.

[0047] The sample of this invention, such as a test cell population or a reference cell population, can be from any organism and can be, but is not limited to, peripheral blood, bone marrow specimens, primary tumors, embedded tissue sections, frozen tissue sections, cell preparations, cytological preparations, exfoliate samples (e.g., sputum), fine needle aspirations, lung fluid, amnion cells, fresh tissue, dry tissue, and cultured cells or tissue. The sample can be from malignant tissue or non-malignant tissue. The sample can be unfixed or fixed according to standard protocols widely available in the art and can also be embedded in a suitable medium for preparation of the sample. For example, the sample can be embedded in paraffin or other suitable medium (e.g., epoxy or acrylamide) to facilitate preparation of the biological specimen for the detection methods of this invention. Furthermore, the sample can be embedded in any commercially available mounting medium, either aqueous or organic.

[0048] The sample can be on, supported by, or attached to, a substrate which facilitates detection. A substrate of the present invention can be, but is not limited to, a microscope slide, a culture dish, a culture flask, a culture plate, a culture chamber, ELISA plates, as well as any other substrate that can be used for containing or supporting biological samples for analysis according to the methods of the present invention. The substrate can be of any material suitable for the purposes of this invention, such as, for example, glass, plastic, polystyrene, mica and the like. The substrates of the present invention can be obtained from commercial sources or prepared according to standard procedures well known in the art.

[0049] Conversely, an antibody or fragment thereof, an antigenic fragment of a DET protein, or DET nucleic acid of the invention can be on, supported by, or attached to a substrate which facilitates detection. Such a substrate can include a chip, a microarray or a mobile solid support. Thus, provided by the invention are substrates including one or more of the antibodies or antibody fragments, antigenic fragments of DET proteins, or DET nucleic acids of the invention.

[0050] The nucleic acids of this invention can be detected with a probe capable of hybridizing to the nucleic acid of a cell or a sample. This probe can be a nucleic acid comprising the nucleotide sequence of a coding strand or its complementary strand or the nucleotide sequence of a sense strand or antisense strand, or a fragment thereof. The nucleic acid can comprise the nucleic acid of a DET gene or fragments thereof. Thus, the probe of this invention can be either DNA or RNA and can bind either DNA or RNA, or both, in the biological sample. The probe can be the coding or complementary strand of a complete DET gene or DET gene fragment.

[0051] The nucleic acids of the present invention, for example, DET1-DET11 nucleic acids and fragments thereof, can be utilized as probes or primers to detect DET nucleic acids. Therefore, the present invention provides DET polynucleotide probes or primers that can be at least 15, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 250, 300, 350 or at least 400 nucleotides in length.

[0052] As used herein, the term "nucleic acid probe" refers to a nucleic acid fragment that selectively hybridizes under stringent conditions with a nucleic acid comprising a nucleic acid set forth in a DET sequence provided herein. This hybridization must be specific. The degree of complementarity between the hybridizing nucleic acid and the sequence to which it hybridizes should be at least enough to exclude hybridization with a nucleic acid encoding an unrelated protein.

[0053] Stringent conditions refers to the washing conditions used in a hybridization protocol. In general, the washing conditions should be a combination of temperature and salt concentration chosen so that the denaturation temperature is approximately 5-20.degree. C. below the calculated T.sub.m of the nucleic acid hybrid under study. The temperature and salt conditions are readily determined empirically in preliminary experiments in which samples of reference DNA immobilized on filters are hybridized to the probe or protein coding nucleic acid of interest and then washed under conditions of different stringencies. The T.sub.m of such an oligonucleotide can be estimated by allowing 2.degree. C. for each A or T nucleotide, and 4.degree. C. for each G or C. For example, an 18 nucleotide probe of 50% G+C would, therefore, have an approximate T.sub.m of 54.degree. C.

[0054] Stringent conditions are known to one of skill in the art. See, for example, Sambrook et al. (2001). An example of stringent wash conditions is 4.times.SSC at 65.degree. C. Highly stringent wash conditions include, for example, 0.2.times.SSC at 65.degree. C.

[0055] As mentioned above, the DET nucleic acids and fragments thereof can be utilized as primers to amplify a DET nucleic acid, such as a DET gene transcript, by standard amplification techniques. For example, expression of a DET gene transcript can be quantified by RT-PCR using RNA isolated from cells, as described in the Examples.

[0056] A variety of PCR techniques are familiar to those skilled in the art. For a review of PCR technology, see White (1997) and the publication entitled "PCR Methods and Applications" (1991, Cold Spring Harbor Laboratory Press), which is incorporated herein by reference in its entirety for amplification methods. In each of these PCR procedures, PCR primers on either side of the nucleic acid sequences to be amplified are added to a suitably prepared nucleic acid sample along with dNTPs and a thermostable polymerase such as Taq polymerase, Pfu polymerase, or Vent polymerase. The nucleic acid in the sample is denatured and the PCR primers are specifically hybridized to complementary nucleic acid sequences in the sample. The hybridized primers are extended. Thereafter, another cycle of denaturation, hybridization, and extension is initiated. The cycles are repeated multiple times to produce an amplified fragment containing the nucleic acid sequence between the primer sites. PCR has further been described in several patents including U.S. Pat. Nos. 4,683,195, 4,683,202 and 4,965,188. Each of these publications is incorporated herein by reference in its entirety for PCR methods. One of skill in the art would know how to design and synthesize primers that amplify a DET sequence or a fragment thereof.

[0057] A detectable label may be included in an amplification reaction. Suitable labels include fluorochromes, e.g. fluorescein isothiocyanate (FITC), rhodamine, Texas Red, phycoerythrin, allophycocyanin, 6-carboxyfluorescein (6-FAM), 2',7'-dimethoxy-4',5'-dichloro-6-carboxyfluorescein (JOE), 6-carboxy-X-rhodamine (ROX), 6-carboxy-2',4',7',4,7-hexachlorofluorescein (HEX), 5-carboxyfluorescein (5-FAM) or N,N,N',N'-tetramethyl-6-carboxyrhodamine (TAMRA), radioactive labels, e.g., .sup.32P, .sup.35S, .sup.3H; etc. The label may be a two stage system, where the amplified DNA is conjugated to biotin, haptens, etc. having a high affinity binding partner, e.g. avidin, specific antibodies, etc., where the binding partner is conjugated to a detectable label. The label may be conjugated to one or both of the primers. Alternatively, the pool of nucleotides used in the amplification is labeled, so as to incorporate the label into the amplification product. The amplification reaction can also include a dual fluorescent probe, as described in the Examples, which hybridizes to and detects the amplification product thus allowing real time quantitation of the amplification product.

[0058] Therefore, expression of the nucleic acid(s) of the present invention can be measured by amplifying the nucleic acid(s) and detecting the amplified nucleic acid with a fluorescent probe.

[0059] For example, DET1 can be amplified utilizing forward primer GCAATCCTCTTACCTCCGCTTT (SEQ ID NO: 7) and reverse primer GGAATCGGAGACAGAAGAGAGCTT (SEQ ID NO: 8). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence CTGGGACCACAGATGTATCCTCCACTCC (SEQ ID NO: 9) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET1 as one of skill in the art would know how to design primers, based on the DET1 nucleic acid sequences provided herein, such as SEQ ID NO: 40 and the nucleic acid sequences provided by the database entries, to amplify a DET1 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET1 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET1 nucleic acid sequences provided herein, such as SEQ ID NO: 40 and the nucleic acid sequences provided by the database entries, to detect a DET2 nucleic acid.

[0060] DET2 can be amplified utilizing forward primer GGCTGACTGGCAAAAAGTCTTG (SEQ ID NO: 1) and reverse primer TTGGTTCCCTTAAGTTCTCAGAGTTT (SEQ ID NO: 2). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence TGGCCCTGTCACTCCCATGATGC (SEQ ID NO: 3) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET2 as one of skill in the art would know how to design primers, based on the DET2 nucleic acid sequences provided herein, such as SEQ ID NO: 42 and the nucleic acid sequences provided by the database entries, to amplify a DET2 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET2 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET2 nucleic acid sequences provided herein, such as SEQ ID NO: 42 and the nucleic acid sequences provided by the database entries, to detect a DET2 nucleic acid.

[0061] DET3 can be amplified utilizing forward primer TGCCAAGGAGCTTTGTTTATAGAA (SEQ ID NO: 19) and reverse primer ATGACGGCATGTACCAACCA (SEQ ID NO: 20). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence TTGGTCCCCTCAGTTCTATGCTGTTGTGT (SEQ ID NO: 21) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET3 as one of skill in the art would know how to design primers, based on the DET3 nucleic acid sequences provided herein, such as SEQ ID NO: 44 and the nucleic acid sequences provided by the database entries, to amplify a DET3 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET3 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET3 nucleic acid sequences provided herein, such as SEQ ID NO: 44 and the nucleic acid sequences provided by the database entries, to detect a DET3 nucleic acid.

[0062] DET4 can be amplified utilizing forward primer GCACCTGCTGAAATGTATGACATAAT (SEQ ID NO: 22) and reverse primer TTTGCTAAGTTGGAGTAAATATGATTGG (SEQ ID NO: 23). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence ATTGTTCAGCTAATTGAGAAGCAGATTTCAGAGAGC (SEQ ID NO: 24) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET4 as one of skill in the art would know how to design primers, based on the DET4 nucleic acid sequences provided herein, such as SEQ ID NO: 45 and the nucleic acid sequences provided by the database entries, to amplify a DET4 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET4 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET4 nucleic acid sequences provided herein, such as SEQ ID NO: 45 and the nucleic acid sequences provided by the database entries, to detect a DET4 nucleic acid.

[0063] DET5 can be amplified utilizing forward primer GACGATCCGGGTAAAGTTCCA (SEQ ID NO: 34) and reverse primer AGGTTGAGGAGTGGGTCGAA (SEQ ID NO: 35) The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence AGGCCGCGAAGCCAGTGGAATC (SEQ ID NO: 36) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET5 as one of skill in the art would know how to design primers, based on the DET5 nucleic acid sequences provided herein, such as SEQ ID NO: 47 and the nucleic acid sequences provided by the database entries, to amplify a DET5 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET5 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET5 nucleic acid sequences provided herein, such as SEQ ID NO: 47 and the nucleic acid sequences provided by the database entries, to detect a DET5 nucleic acid.

[0064] DET6 can be amplified utilizing forward primer GCTGGTGCTCATGGCACTT (SEQ ID NO: 31) and reverse primer CCCTCCCCAGGCTTCCTAA (SEQ ID NO: 32). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence AAGGGCTTTGCCTGACAACACCCA (SEQ ID NO: 33) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET6 as one of skill in the art would know how to design primers, based on the DET6 nucleic acid sequences provided herein, such as SEQ ID NO: 49 and the nucleic acid sequences provided by the database entries, to amplify a DET6 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET6 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET6 nucleic acid sequences provided herein, such as SEQ ID NO: 49 and the nucleic acid sequences provided by the database entries, to detect a DET6 nucleic acid.

[0065] DET7 can be amplified utilizing forward primer CCGGCCCAAGCTCCAT (SEQ ID NO: 13) and reverse primer TTGTGTAACCGTCGGTCATGA (SEQ ID NO: 14). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence TGTTTGGTGGAATCCATGAAGGTTATGGC (SEQ ID NO: 15) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET7 as one of skill in the art would know how to design primers, based on the DET7 nucleic acid sequences provided herein, such as SEQ ID NO: 51 and the nucleic acid sequences provided by the database entries, to amplify a DET7 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET7 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET7 nucleic acid sequences provided herein, such as SEQ ID NO: 51 and the nucleic acid sequences provided by the database entries, to detect a DET7 nucleic acid.

[0066] DET8 can be amplified utilizing forward primer TGAGTGTCCCCCGGTATCTTC (SEQ ID NO: 28) and reverse primer CAGCCGCTTTCAGATTTTCAT (SEQ ID NO: 29). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence CCTGCCAATCCCGATGAAATTGGAAAT (SEQ ID NO: 30) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET8 as one of skill in the art would know how to design primers, based on the DET8 nucleic acid sequences provided herein, such as SEQ ID NO: 53 and the nucleic acid sequences provided by the database entries, to amplify a DET8 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET8 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET8 nucleic acid sequences provided herein, such as SEQ ID NO: 53 and the nucleic acid sequences provided by the database entries, to detect a DET8 nucleic acid.

[0067] DET9 can be amplified utilizing forward primer ATGGCAGTGCAGTCATCATCTT (SEQ ID NO: 10) and reverse primer GCATTCATACAGCTGCTTACCATCT (SEQ ID NO: 11). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence TTTGGTCCCTGCCTAGGACCGGG (SEQ ID NO: 12) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET9 as one of skill in the art would know how to design primers, based on the DET9 nucleic acid sequences provided herein, such as SEQ ID NO: 55 and the nucleic acid sequences provided by the database entries, to amplify a DET9 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET9 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET9 nucleic acid sequences provided herein, such as SEQ ID NO: 55 and the nucleic acid sequences provided by the database entries, to detect a DET9 nucleic acid.

[0068] DET10 can be amplified utilizing forward primer TGAAGAATGTCATGGTGGTAGTATCA (SEQ ID NO: 25) and reverse primer ATGACTCCTCAGGTGAATTTGTGTAG (SEQ ID NO: 26). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence CTGGTATGGAGGGATTCTGCTAGGACCAG (SEQ ID NO: 27) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET10 as one of skill in the art would know how to design primers, based on the DET10 nucleic acid sequences provided herein, such as SEQ ID NO: 57 and the nucleic acid sequences provided by the database entries, to amplify a DET10 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET10 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET10 nucleic acid sequences provided herein, such as SEQ ID NO: 57 and the nucleic acid sequences provided by the database entries, to detect a DET10 nucleic acid.

[0069] DET11 can be amplified utilizing forward primer GAGAGCGTGATCCCCCTACA (SEQ ID NO: 16) and reverse primer ACCAAGAGTGCACCTCAGTGTCT (SEQ ID NO: 17). The nucleic acid amplified by these primers can be detected with a probe comprising the nucleic acid sequence TCACTTCCAAATGTTCCTGTAGCATAAATGGTG (SEQ ID NO: 18) linked to a fluorescent label. These primers are merely exemplary for the amplification of DET11 as one of skill in the art would know how to design primers, based on the DET11 nucleic acid sequences provided herein, such as SEQ ID NO: 59 and the nucleic acid sequences provided by the database entries, to amplify a DET11 nucleic acid. Similarly, the probe sequences provided herein are merely exemplary for the detection of a DET11 nucleic acid, as one of skill in the art would know how to design a probe, based on the DET11 nucleic acid sequences provided herein, such as SEQ ID NO: 59 and the nucleic acid sequences provided by the database entries, to detect a DET11 nucleic acid.

[0070] The sample nucleic acid, e.g. amplified fragment, can be analyzed by one of a number of methods known in the art. The nucleic acid can be sequenced by dideoxy or other methods. Hybridization with the sequence can also be used to determine its presence, by Southern blots, dot blots, etc.

[0071] The DET nucleic acids of the invention can also be used in polynucleotide arrays. Polynucleotide arrays provide a high throughput technique that can assay a large number of polynucleotide sequences in a single sample. This technology can be used, for example, as a diagnostic tool to identify samples with differential expression of DET nucleic acids as compared to a reference sample.

[0072] To create arrays, single-stranded polynucleotide probes can be spotted onto a substrate in a two-dimensional matrix or array. Each single-stranded polynucleotide probe can comprise at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or 30 or more contiguous nucleotides selected from the nucleotide sequences of DET1-DET11. The substrate can be any substrate to which polynucleotide probes can be attached, including but not limited to glass, nitrocellulose, silicon, and nylon. Polynucleotide probes can be bound to the substrate by either covalent bonds or by non-specific interactions, such as hydrophobic interactions. Techniques for constructing arrays and methods of using these arrays are described in EP No. 0 799 897; PCT No. WO 97/29212; PCT No. WO 97/27317; EP No. 0 785 280; PCT No. WO 97/02357; U.S. Pat. Nos. 5,593,839; 5,578,832; EP No. 0 728 520; U.S. Pat. No. 5,599,695; EP No. 0 721 016; U.S. Pat. No. 5,556,752; PCT No. WO 95/22058; and U.S. Pat. No. 5,631,734. Commercially available polynucleotide arrays, such as Affymetrix GeneChip.TM., can also be used. Use of the GeneChip.TM. to detect gene expression is described, for example, in Lockhart et al., Nature Biotechnology 14:1675 (1996); Chee et al., Science 274:610 (1996); Hacia et al., Nature Genetics 14:441, 1996; and Kozal et al., Nature Medicine 2:753, 1996.

[0073] Tissue samples can be treated to form single-stranded polynucleotides, for example by heating or by chemical denaturation, as is known in the art. The single-stranded polynucleotides in the tissue sample can then be labeled and hybridized to the polynucleotide probes on the array. Detectable labels which can be used include but are not limited to radiolabels, biotinylated labels, fluorophors, and chemiluminescent labels. Double stranded polynucleotides, comprising the labeled sample polynucleotides bound to polynucleotide probes, can be detected once the unbound portion of the sample is washed away. Detection can be visual or with computer assistance.

[0074] The present invention also provides methods of detecting and measuring a DET protein or fragment thereof. An amino acid sequence for a C21 or f4 (DET1) protein is set forth herein as SEQ ID NO: 41. An amino acid sequence for a Hs. 145049 (DET2) protein is set forth herein as SEQ ID NO: 43. An amino acid sequence for a KIT (DET4) protein is set forth herein as SEQ ID NO: 46. An amino acid sequence for a LSM7 (DET5) protein is set forth herein SEQ ID NO: 48. An amino acid sequence for a SYNGR2 (DET6) protein is set forth herein as SEQ ID NO: 50. An amino acid sequence for a C11 or f8 (DET7) protein is provided herein as SEQ ID NO: 52. An amino acid sequence for a CDH1 (DET8) protein is set forth herein as SEQ ID NO: 54. An amino acid sequence for a FAM13A1 (DET9) protein is set forth herein as SEQ ID NO: 56. An amino acid sequence for IMPACT (DET10) protein is provided herein as SEQ ID NO: 58. An amino acid sequence for KIAA1128 (DET11) protein is set forth herein as SEQ ID NO: 60. Therefore, the present invention provides antibodies that bind to the DET protein sequences or fragments thereof set forth herein. The antibody utilized to detect a DET polypeptide, or fragment thereof, can be linked to a detectable label either directly or indirectly through use of a secondary and/or tertiary antibody; thus, bound antibody, fragment or molecular complex can be detected directly in an ELISA or similar assay.

[0075] The sample can be on, supported by, or attached to, a substrate which facilitates detection. A substrate of the present invention can be, but is not limited to, a microscope slide, a culture dish, a culture flask, a culture plate, a culture chamber, ELISA plates, as well as any other substrate that can be used for containing or supporting biological samples for analysis according to the methods of the present invention. The substrate can be of any material suitable for the purposes of this invention, such as, for example, glass, plastic, polystyrene, mica and the like. The substrates of the present invention can be obtained from commercial sources or prepared according to standard procedures well known in the art.

[0076] Conversely, an antibody or fragment thereof, an antigenic fragment of a DET protein can be on, supported by, or attached to a substrate which facilitates detection. Such a substrate can be a mobile solid support. Thus, provided by the invention are substrates including one or more of the antibodies or antibody fragments, or antigenic fragments of a DET polypeptide.

[0077] In the methods of the present invention, once the expression levels of one or more DET nucleic acids is measured, these expression levels are comparing to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid lesion classification is known. Once this comparison is performed, a difference in expression levels, if present, is identified by one of skill in the art.

[0078] A difference or alteration in expression of one or more DET nucleic acids in the test cell population, as compared to the reference cell population, indicates that the test cell population is different from the reference cell population. By "difference" or "alteration" is meant that the expression of one or more DET nucleic acid sequences is either increased or decreased as compared to the expression levels of the reference cell population. If desired, but not necessary, relative expression levels within the test and reference cell populations can be normalized by reference to the expression level of a nucleic acid sequence that does not vary according to thyroid cancer stage in the subject. The absence of a difference or alteration in expression of one or more DET nucleic acids in the test cell population, as compared to the reference cell population, indicates that the test cell population is similar to the reference cell population. As an example, if the reference cell population is from normal thyroid tissue, a similar DET gene expression profile in the test cell population indicates that the test cell population is also normal whereas a different profile indicates that the test cell population is not normal. By "similar" is meant that an expression pattern does not have to be exactly like the expression pattern but similar enough such that one of skill in the art would know that the expression pattern is more closely associated with one type of tissue than with another type of tissue. In another example, if the reference cell population is from malignant thyroid tissue, a similar DET gene expression profile in the test cell population indicates that the test cell population is also malignant whereas a different profile indicates that the test cell population is not malignant. Similarly, if the reference cell population is from benign thyroid tissue, a similar DET gene expression profile in the test cell population indicates that the test cell population is also benign whereas a different profile indicates that the test cell population is not benign.

[0079] Upon observing a difference between the test cell population and a normal reference cell population, one of skill in the art can classify the test cell population as benign or malignant by comparing the expression pattern to known expression patterns for benign and malignant cells. This comparison can be done by comparing the expression pattern of the test cell population to the expression pattern obtained from a plurality of reference cells used as a control while measuring expression levels in the test cell population. One of skill in the art can also compare the expression pattern of the test cell population with a database of expression patterns corresponding to normal, benign and malignant cells and subcategories thereof. For example, upon observing a difference between the test cell population and a reference cell population from normal thyroid tissue, one of skill in the art can compare the expression pattern of the test cell population with a database of expression patterns corresponding to normal, benign and malignant cells. One of skill in the art would then determine which expression pattern in the database is most similar to the expression pattern obtained for the test cell population and classify the test cell population as benign or malignant, as well as classify the test cell population as a type of benign or malignant lesion. For example, if the test cell population is classified as being from a benign lesion, this population can be further classified as being from a follicular adenoma, hyperplastic nodule or papillary adenoma or any other type of benign thyroid lesion. If the test cell population is classified as being from a malignant lesion, this population can be further classified as being from papillary thyroid carcinoma, follicular variant of papillary thyroid carcinoma, follicular carcinoma, Hurthle cell tumor, anaplastic thyroid cancer, medullary thyroid cancer, thyroid lymphoma, poorly differentiated thyroid cancer and thyroid angiosarcoma or any other type of malignant thyroid lesion. Therefore, utilizing the methods of the present invention, one of skill in the art can diagnose a benign or malignant lesion in a subject, as well as the type of benign or malignant lesion in the subject.

Staging of Thyroid Cancer

[0080] Once a subject has been diagnosed with a malignant lesion or thyroid tumor, the stage of thyroid malignancy can also be determined by the methods of the present invention. Staging of a thyroid malignancy or tumor can be useful in prescribing treatment as well as in determining a prognosis for the subject.

[0081] Therefore, also provided by the present invention is a method of identifying the stage of a thyroid tumor in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11; b) comparing the expression of said nucleic acid sequences to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, in the test cell population and reference cell population, thereby identifying the stage of the thyroid tumor in the subject.

[0082] Also provided by the present invention is a method of identifying the stage of a thyroid tumor in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6; b) comparing the expression of said nucleic acid sequences to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, in the test cell population and reference cell population, thereby identifying the stage of the thyroid tumor in the subject.

[0083] Also provided by the present invention is a method of determining a prognosis for subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET1 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11; b) comparing the expression of said nucleic acid sequences to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, in the test cell population and reference cell population, thereby determining the prognosis for the subject.

[0084] Also provided by the present invention is a method of determining the prognosis for a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6 in a test cell population, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6; b) comparing the expression of said nucleic acid sequences to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, in the test cell population and reference cell population, thereby determining the prognosis for the subject.

[0085] In staging a thyroid tumor, once the expression levels of one or more DET nucleic acids is measured, these expression levels are comparing to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a stage of thyroid tumor is known. Once this comparison is performed, a difference in expression levels, if present, is identified by one of skill in the art.

[0086] A difference or alteration in expression of one or more DET nucleic acids in the test cell population, as compared to the reference cell population, indicates that the test cell population is at a different stage than the stage of the reference cell population. By "difference" or "alteration" is meant that the expression of one or more DET nucleic acid sequences is either increased or decreased as compared to the expression levels of the reference cell population. If desired, but not necessary, relative expression levels within the test and reference cell populations can be normalized by reference to the expression level of a nucleic acid sequence that does not vary according to thyroid cancer stage in the subject. The absence of a difference or alteration in expression of one or more DET nucleic acids in the test cell population, as compared to the reference cell population, indicates that the test cell population is at the same stage as that of the reference cell population. As an example, if the reference cell population is from an early stage thyroid tumor, a similar DET gene expression profile in the test cell population indicates that the test cell population is also from an early stage thyroid tumor whereas a different profile indicates that the test cell population is not from an early stage thyroid tumor. By "similar" is meant that an expression pattern does not have to be exactly like the expression pattern but similar enough such that one of skill in the art would know that the expression pattern is more closely associated with one stage than with another stage.

[0087] In order to establish a database of stages of thyroid cancer, one skilled in the art can measure DET nucleic acid levels and/or DET polypeptide levels in numerous subjects in order to establish expression patterns that correspond to clinically defined stages such as, for example, 1) normal, 2) at risk of developing thyroid cancer, 3) pre-cancerous or 4) cancerous as well as other substages defined within each of these stages. These stages are not intended to be limiting as one of skill in the art may define other stages depending on the type of sample, type of cancer, age of the subject and other factors. This database can then be used to compare an expression pattern from a test sample and make clinical decisions. Upon correlation of a DET expression pattern with a particular stage of thyroid cancer, the skilled practitioner can administer a therapy suited for the treatment of cancer. The present invention also allows the skilled artisan to correlate a DET expression pattern with a type of thyroid lesion and correlate the expression pattern with a particular stage of thyroid cancer. The subjects of this invention undergoing anti-cancer therapy can include subjects undergoing surgery, chemotherapy, radiotherapy, immunotherapy or any combination thereof. Examples of chemotherapeutic agents include cisplatin, 5-fluorouracil and S-1. Immunotherapeutics methods include administration of interleukin-2 and interferon-.alpha..

[0088] In determining the prognosis for a subject, once the expression levels of one or more DET nucleic acids is measured, these expression levels are comparing to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a prognosis is known. Once this comparison is performed, a difference in expression levels, if present, is identified by one of skill in the art.

[0089] One skilled in the art can measure DET nucleic acid levels and/or DET polypeptide levels in order to determine a prognosis for a subject. One of skill in the art can measure DET nucleic acid levels and/or DET polypeptide levels in numerous subjects with varying prognoses in order to establish reference expression patterns that correspond to prognoses for subjects. As utilized herein, "prognosis" means a prediction of probable development and/or outcome of a disease. These reference expression patterns or a database of reference expression patterns can then be used to compare an expression pattern from a test sample and determine what the prognosis for a subject is. These expression patterns can also be used to compare an expression pattern from a test sample from a subject and determine whether or not a subject can recover from the disease. Upon correlation of a DET expression pattern with a particular prognosis, the skilled practitioner can then determine if a therapy suited for the treatment of cancer is applicable.

[0090] The present invention provides a computer system comprising a) a database including records comprising a plurality of reference DET gene expression profiles or patterns for benign, malignant and normal tissue samples and associated diagnosis and therapy data; and b) a user interface capable of receiving a selection of one or more test gene expression profiles for use in determining matches between the test expression profiles and the reference DET gene expression profiles and displaying the records associated with matching expression profiles. The database can also include DET gene expression profiles for subclasses of benign tissue samples such as follicular adenoma, hyperplastic nodule, papillary adenoma, thyroiditis nodule and multinodular goiter. The database can also include DET gene expression profiles for subclasses of malignant tissue samples such as papillary thyroid carcinoma, follicular variant of papillary thyroid carcinoma, follicular carcinoma, Hurthle cell tumor, anaplastic thyroid cancer, medullary thyroid cancer, thyroid lymphoma, poorly differentiated thyroid cancer and thyroid angiosarcoma. The database can also include DET gene expression profiles for stages of thyroid cancer as well as DET gene expression profiles that correspond to prognoses for subjects.

[0091] It will be appreciated by those skilled in the art that the DET gene expression profiles provided herein as well as the DET expression profiles identified from samples and subjects can be stored, recorded, and manipulated on any medium which can be read and accessed by a computer. As used herein, the words "recorded" and "stored" refer to a process for storing information on a computer medium. A skilled artisan can readily adopt any of the presently known methods for recording information on a computer readable medium to generate a list of DET gene expression profiles comprising one or more of the DET expression profiles of the invention. Another aspect of the present invention is a computer readable medium having recorded thereon at least 2, 5, 10, 15, 20, 25, 30, 50, 100, 200, 250, 300, 400, 500, 1000, 2000, 3000, 4000 or 5000 expression profiles of the invention or expression profiles identified from subjects.

[0092] Computer readable media include magnetically readable media, optically readable media, electronically readable media and magnetic/optical media. For example, the computer readable media may be a hard disc, a floppy disc, a magnetic tape, CD-ROM, DVD, RAM, or ROM as well as other types of other media known to those skilled in the art.

[0093] Embodiments of the present invention include systems, particularly computer systems which contain the DET gene expression information described herein. As used herein, "a computer system" refers to the hardware components, software components, and data storage components used to store and/or analyze the DET gene expression profiles of the present invention or other DET gene expression profiles. The computer system preferably includes the computer readable media described above, and a processor for accessing and manipulating the DET gene expression data.

[0094] Preferably, the computer is a general purpose system that comprises a central processing unit (CPU), one or more data storage components for storing data, and one or more data retrieving devices for retrieving the data stored on the data storage components. A skilled artisan can readily appreciate that any one of the currently available computer systems are suitable.

[0095] In one particular embodiment, the computer system includes a processor connected to a bus which is connected to a main memory, preferably implemented as RAM, and one or more data storage devices, such as a hard drive and/or other computer readable media having data recorded thereon. In some embodiments, the computer system further includes one or more data retrieving devices for reading the data stored on the data storage components. The data retrieving device may represent, for example, a floppy disk drive, a compact disk drive, a magnetic tape drive, a hard disk drive, a CD-ROM drive, a DVD drive, etc. In some embodiments, the data storage component is a removable computer readable medium such as a floppy disk, a compact disk, a magnetic tape, etc. containing control logic and/or data recorded thereon. The computer system may advantageously include or be programmed by appropriate software for reading the control logic and/or the data from the data storage component once inserted in the data retrieving device. Software for accessing and processing the expression profiles of the invention (such as search tools, compare tools, modeling tools, etc.) may reside in main memory during execution.

[0096] In some embodiments, the computer system may further comprise a program for comparing expression profiles stored on a computer readable medium to another test expression profile on a computer readable medium. An "expression profile comparer" refers to one or more programs which are implemented on the computer system to compare an expression profile with other expression profiles.

[0097] Accordingly, one aspect of the present invention is a computer system comprising a processor, a data storage device having stored thereon a DET gene expression profile of the invention, a data storage device having retrievably stored thereon reference DET gene expression profiles to be compared with test or sample sequences and an expression profile comparer for conducting the comparison. The expression profile comparer may indicate a similarity between the expression profiles compared or identify a difference between the two expression profiles.

[0098] Alternatively, the computer program may be a computer program which compares a test expression profile(s) from a subject or a plurality of subjects to a reference expression profile (s) in order to determine whether the test expression profile(s) differs from or is the same as a reference expression profile.

[0099] This invention also provides for a computer program that correlates DET gene expression profiles with a type of cancer and/or a stage of cancer and/or a prognosis. The computer program can optionally include treatment options or drug indications for subjects with DET gene expression profiles associated with a type of cancer and/or stage of cancer.

Screening Methods

[0100] Further provided by the present invention is a method of identifying an agent for treating a thyroid tumor, the method comprising: a) contacting a population of thyroid tumor cells from a subject for which a tumor stage is known, wherein at least one cell in said population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, with a test agent; b) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11 in the cell population; c) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and d) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11, in the test cell population and reference cell population, such that if there is a difference corresponding to an improvement, a therapeutic agent for treating thyroid tumor has been identified.

[0101] Further provided by the present invention is a method of identifying an agent for treating a thyroid tumor, the method comprising: a) contacting a population of thyroid tumor cells from a subject for which a tumor stage is known, wherein at least one cell in said test population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, with a test agent; b) measuring the expression of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6 in the cell population; c) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and d) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET1, DET2, DET3, DET4, DET5 and DET6, in the cell population and reference cell population, such that if there is a difference corresponding to an improvement, a therapeutic agent for treating thyroid tumor has been identified.

[0102] The test agents used in the methods described herein can be made by methods standard in the art and include, but are not limited to, chemicals, small molecules, antisense molecules, siRNAs, drugs, antibodies, peptides and secreted proteins.

[0103] By "improvement" is meant that the treatment leads to a shift in a thyroid tumor stage to a less advanced stage. As mentioned above, the expression pattern obtained for the test cell population can be compared to expression patterns in a database before and after contacting the test cell population with a test agent to determine the stage of the test cell population before and after treatment.

[0104] The reference cell population can be from normal thyroid tissue. For example, if the cell population from the subject is from an early stage thyroid tumor, and after treatment, the expression pattern of the cell population when compared to the reference cell population from normal thyroid tissue, is similar to that of the reference cell population, the agent is effective in treating a thyroid tumor. By "similar" is meant that the expression pattern does not have to be exactly like the expression pattern from normal thyroid tissue but similar enough such that one of skill in the art would know that the treatment leads to expression patterns more closely associated with normal thyroid tissue. As an another example, if both the cell population from the subject and the reference cell population are from an early stage thyroid tumor, and after treatment, the expression pattern of the cell population is similar to the reference cell population, the agent is not effective in treating a thyroid tumor. By "similar" is meant that the expression pattern does not have to be exactly like the expression pattern from the early stage thyroid tumor cell population but similar enough such that one of skill in the art would know that the treatment does not lead to an expression pattern corresponding to a less advanced thyroid tumor stage. As another example, if both the cell population from the subject and the reference cell population are from an early stage thyroid tumor, and after treatment, the expression pattern of the cell population is different from the reference cell population, and correlates with a less advanced thyroid tumor stage, the agent is effective in treating a thyroid tumor. These examples are not intended to be limiting with regard to the types of thyroid tumor populations that can be contacted with an agent, the types of agents that can be utilized, the type of reference cell population that can be utilized or the effects observed as there are numerous variations known to one of skill in the art for performing these methods.

Treatment Methods

[0105] Also provided by the present invention is a method of treating malignant thyroid lesions or thyroid cancer in a subject suffering from or at risk of developing thyroid cancer comprising administering to the subject an agent that modulates the expression of one or more DET sequences. By "at risk for developing" is meant that the subject's prognosis is less favorable and that the subject has an increased likelihood of developing thyroid cancer. Administration of the agent can be prophylactic or therapeutic.

[0106] My "modulation" is meant that the expression of one or more DET sequences can be increased or decreased.

[0107] For example, KIT (DET4), LSM7 (DET5), FAM13A1 (DET9), C11 or f8 (DET7), KIAA1128 (DET11), IMPACT (DET10) and CDH1 (DET8) were all downregulated or underexpressed in malignant thyroid lesions as compared to normal thyroid tissue. Therefore, a subject can be treated with an effective amount of an agent that increases the amount of the downregulated or underexpressed nucleic acids in the subject. Administration can be systemic or local, e.g. in the immediate vicinity of the subject's cancerous cells. This agent can be for example, the protein product of a downregulated or underexpressed DET gene or a biologically active fragment thereof, a nucleic acid encoding a downregulated or underexpressed DET gene and having expression control sequences permitting expression in the thyroid cancer cells or an agent which increases the endogenous level of expression of the gene.

[0108] With regard to genes that are upregulated or overexpressed as compared to normal thyroid tissue, C21 or f4 (DET1), Hs.145049 (DET2) were upregulated or overexpressed in malignant thyroid lesions as compared to normal thyroid tissue. Therefore, a subject can be treated with an effective amount of an agent that decreases the amount of the upregulated or overexpressed nucleic acids in the subject. Administration can be systemic or local, e.g. in the immediate vicinity of the subject's cancerous cells. The agent can be, for example, a nucleic acid that inhibits or antagonizes the expression of the overexpressed DET gene, such as an antisense nucleic acid or an siRNA. The agent can also be an antibody that binds to a DET protein that is overexpressed.

[0109] In the treatment methods of the present invention, the subject can be treated with one or more agents which decrease the expression of overexpressed DET sequences alone or in combination with one or more agents which increase the expression of DET sequences that are downregulated or underexpressed in thyroid cancer. The subject can also be treated with one or more agents which increase the expression of DET sequences alone or in combination with one or more agents which decrease the expression of overexpressed DET sequences.

[0110] These treatment methods can be combined with other anti-cancer treatments such as surgery, chemotherapy, radiotherapy, immunotherapy or any combination thereof. Examples of chemotherapeutic agents include cisplatin, 5-fluorouracil and S-1. Immunotherapeutics methods include administration of interleukin-2 and interferon-.alpha..

Identification of Differentially Expressed Thyroid Genes

[0111] The present invention also provides a method of identifying differentially expressed genes and/or expression patterns for such genes in other types of benign and malignant lesions. As set forth in the Examples, one of skill in the art can utilize gene expression profiling and supervised machine learning algorithms to construct a molecular classification scheme for other types of thyroid tumors. These include any type of benign lesion such as papillary adenoma, multinodular goiter or thyroiditis nodule, and any type of malignant lesion, such as papillary thyroid carcinoma, follicular carcinoma, Hurthle cell tumor, anaplastic thyroid cancer, medullary thyroid cancer, thyroid lymphoma, poorly differentiated thyroid cancer and thyroid angiosarcoma. Those genes and expression patterns identified via these method can be utilized in the methods of the present invention to diagnose, stage and treat cancer.

Kits

[0112] The present invention also provides for a kit comprising one or more reagents for detecting one or more nucleic acid sequences selected from the group consisting of DET1-DET11. In various embodiments the expression of one or more of the sequences represented by DET1-DET11 are measured. The kit can identify the DET nucleic acids by having homologous nucleic acid sequences, such as oligonucleotide sequences, complimentary to a portion of the recited nucleic acids, or antibodies to proteins encoded by the DET nucleic acids. The kit can also include amplification primers for performing RT-PCR, such as those set forth in Table 4 and probes, such as those set forth in Table 4, that can be fluorescently labeled for detecting amplification products in, for example, a Taqman assay. The kits of the present invention can optionally include buffers, enzymes, detectable labels and other reagents for the detecting expression of DET sequences described herein.

[0113] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the antibodies, polypeptides, nucleic acids, compositions, and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for.

EXAMPLES

[0114] DNA microarrays allow quick and complete evaluation of a cell's transcriptional activity.

[0115] Expression genomics is very powerful in that it can generate expression data for a large number of genes simultaneously across multiple samples. In cancer research, an intriguing application of expression arrays includes assessing the molecular components of the neoplastic process and in cancer classification (1). Classification of human cancers into distinct groups based on their molecular profile rather than their histological appearance can be more relevant to specific cancer diagnoses and cancer treatment regimes. Several attempts to formulate a consensus about classification and treatment of thyroid carcinoma based on standard histopathologic analysis have resulted in published guidelines for diagnosis and initial disease management (2). In the past few decades no improvement has been made in the differential diagnosis of thyroid tumors by fine needle aspiration biopsy (FNA), specifically suspicious or indeterminate thyroid lesions, suggesting that a new approach to this should be explored. Therefore in this study a gene expression approach was developed to diagnose benign vs malignant thyroid lesions in 73 patients with thyroid tumors. A 10 gene and 6 gene model were developed to be able to differentiate benign vs. malignant thyroid tumors. These results provide a molecular classification system for thyroid tumors and this in turn provides a more accurate diagnostic tool for the clinician managing patients with suspicious thyroid lesions.

[0116] It is well known that cancer results from changes in gene expression patterns that are important for cellular regulatory processes such as growth, differentiation, DNA duplication, mismatch repair and apoptosis. It is also becoming more apparent that effective treatment and diagnosis of cancer is dependent upon an understanding of these important processes. Classification of human cancers into distinct groups based on their origin and histopathological appearance has historically been the foundation for diagnosis and treatment. This classification is generally based on cellular architecture, certain unique cellular characteristics and cell-specific antigens only. In contrast, gene expression assays have the potential to identify thousands of unique characteristics for each tumor type (3) (4). Elucidating a genome wide expression pattern for disease states not only could have a enormous impact on our understanding of specific cell biology, but could also provide the necessary link between molecular genetics and clinical medicine (5) (6) (7).

[0117] Thyroid carcinoma represents 1% of all malignant diseases, but 90% of all neuroendocrine malignancies. It is estimated that 5-10% of the population will develop a clinically significant thyroid nodule during their life-time (8). The best available test in the evaluation of a patient with a thyroid nodule is fine needle aspiration biopsy (FNA) (9). Of the malignant FNAs, the majority are from papillary thyroid cancers (PTC) or its follicular variant (FVPTC). These can be easily diagnosed if they have the classic cytologic features including abundant cellularity and enlarged nuclei containing intra-nuclear grooves and inclusions (10). Indeed, one third of the time these diagnoses are clear on FNA. Fine needle aspiration biopsy of thyroid nodules has greatly reduced the need for thyroid surgery and has increased the percentage of malignant tumors among excised nodules (11, 12). In addition, the diagnosis of malignant thyroid tumors, combined with effective therapy, has lead to a marked decrease in morbidity due to thyroid cancer. Unfortunately, many thyroid FNAs are not definitively benign or malignant, yielding an "indeterminate" or "suspicious" diagnosis. The prevalence of indeterminate FNAs varies, but typically ranges from 10-25% of FNAs (13-15). In general, thyroid FNAs are indeterminate due to overlapping or undefined morphologic criteria for benign versus malignant lesions, or focal nuclear atypia within otherwise benign specimens. Of note, twice as many patients are referred for surgery for a suspicious lesion (10%) than for a malignant lesion (5%), an occurrence that is not widely appreciated since the majority of FNAs are benign. Therefore when the diagnosis is unclear on FNA these patients are classified as having a suspicious or indeterminate lesion only. It is well known that frozen section analysis often yields no additional information.

[0118] The question then arises: "Should the surgeon perform a thyroid lobectomy, which is appropriate for benign lesions or a total thyroidectomy, which is appropriate for malignant lesions when the diagnosis is uncertain both preoperatively and intra-operatively?" Thyroid lobectomy as the initial procedure for every patient with a suspicious FNA could result in the patient with cancer having to undergo a second operation for completion thyroidectomy. Conversely, total thyroidectomy for all patients with suspicious FNA would result in a majority of patients undergoing an unnecessary surgical procedure, requiring lifelong thyroid hormone replacement and exposure to the inherent risks of surgery (16).

[0119] There is a compelling need to develop more accurate initial diagnostic tests for evaluating a thyroid nodule. Recent studies suggest that gene expression data from cDNA microarray analysis holds promise for improving tumor classification and for predicting response to therapy among cancer patients (17) (18) (19). No clear consensus exists regarding which computational tool is optimal for the analysis of large gene expression profiling datasets, especially when they are used to predict outcome (20).

[0120] This invention describes the use of gene expression profiling and supervised machine learning algorithms to construct a molecular classification scheme for thyroid tumors (22). The gene expression signatures provided herein include new tumor related genes whose encoded proteins can be useful for improving the diagnosis of thyroid tumors.

Tissue Samples

[0121] Thyroid tissues collected under John Hopkins University Hospital Institutional Review Board-approved protocols were snap-frozen in liquid nitrogen and stored at -80.degree. C. until use. The specimens were chosen based on their tumor type: papillary thyroid carcinoma (PTC n=17), follicular variant of PTC (FVPTC n=15), follicular adenoma (FA n=16) and hyperplastic nodule (HN n=15). All diagnoses were made by the Surgical Pathology Department at Johns Hopkins.

Tissue Processing and Isolation of RNA

[0122] Frozen sections of 100-300 mg of tissue were collected in test tubes containing 1 ml of Trizol. Samples were transferred to FastRNA tubes containing mini beads and homogenized in a FastPrep beater (Bio101Savant, Carlsbad, Calif.) for 1.5 min at speed 6. The lysate was transferred to a new tube and total RNA was extracted according to the Trizol protocol (Molecular Research Center, Inc. Cincinnati, Ohio). Approximately 12 ug of total RNA was obtained from each tumor sample. The total RNA was then subjected to two rounds of amplification following the modified Eberwine method (23) (24) resulting in approximately 42.mu.g of messenger RNA (mRNA). The quality of the extracted RNA was tested by spectrophotometry and by evaluations on minichips (BioAnalyzer, Agilent Technologies, Palo Alto, Calif.).

Microarray Analysis

[0123] Hybridization was performed on 10 k human cDNA microarrays, Hs-UniGem2, produced by the NCl/NIH (ATC, Gaithersburg, Md.). Comparisons were made for each tumor with the same control which consisted of amplified RNA extracted from normal thyroid tissue and provided by Ambion Inc (Austin, Tex.). Fluorescent marker dyes (Cy5 and Cy3) were used to label the test and control samples, respectively. The respective dyes and samples were also switched in order to test for any labeling bias. The mixture of the two populations of RNA species was then hybridized to the same microarray and incubated for 16 hr at 42.degree. C. cDNA microarrays were then washed and scanned using the GenePix.TM. 4000B (Axon Instruments Inc., Calif.) and images were analyzed with GenePix software version 3.0. For each sample a file containing the image of the array and an Excel file containing the expression ratio values for each gene was uploaded onto the MadbArray web-site (National Center for Biotechnology Information/NIH) http://nciarray.nci.nih.gov for further analysis. To accurately compare measurements from different experiments, the data was normalized and the ratio (Signal Cy5/Signal Cy3) was calculated so that the median (Ratio) was 1.0.

Immunohistochemistry

[0124] Immunohistochemistry studies utilizing antibodies to two gene products in the predictor models have also been performed and this data correlates with the expression data. Taqman analysis was performed for CHD1 and KIT. Both KIT and CDH1 expression decreased in malignancy, which correlates with the microarray data. As shown in FIG. 6, immunohistochemical results show that both KIT and CDH1 expression decrease in malignancy which correlates with the expression results obtained via microarray and Taqman analysis.

Statistical Analysis

[0125] Data from the 73 thyroid tumors was used to build a benign (FA and HN) vs. malignant (PTC and FVPTC) expression ratio-based model, capable of predicting the diagnosis (benign vs malignant) of each sample. After normalization, a file containing the gene expression ratio values from all 73 samples was imported into a statistical analysis software package (Partek Inc., Mo.). Samples were divided in two sets: one set (63 samples) was used to train the diagnosis predictor model and a second set (10) was used as a validation set to test the model. These 10 samples were not previously used to do any other analysis. As a first step, the data from the 63 samples was subjected to Principal Component Analysis (PCA) to perform an exploratory analysis and to view the overall trend of the data. PCA is an exploratory technique that describes the structure of high dimensional data by reducing its dimensionality. It is a linear transformation that converts n original variables (gene expression ratio values) into n new variables or principal components (PC) which have three important properties: they 1) are ordered by the amount of variance explained; 2) are uncorrelated and; 3) they explain all variation in the data. The new observations (each array) are represented by points in a three dimensional space. The distance between any pair of points is related to the similarity between the two observations in high dimensional space. Observations that are near each other are similar for a large number of variables and conversely, the ones that are far apart are different for a large number of variables.

[0126] An Anova test with Bonferroni correction was then used to identify genes that were statistically different between the two groups. The resulting significant genes were used to build a diagnosis-predictor model. Variable (gene) selection analysis with cross-validation was performed different times, each time testing a different number of gene combinations. For cross-validation the "leave-one-out" method was used to estimate the accuracy of the output class prediction rule: the whole dataset was divided into different parts and each part was individually removed from the data set. The remaining data set was used to train a class prediction rule; and the resulting rule was applied to predict the class of the "held-out" sample.

[0127] Anova test with Bonferroni correction was used on 9100 genes to identify ones that were statistically different among the 4 groups. PCA analysis of the 63 samples (FIG. 1) using the statistically significant genes showed a clear organization of the samples based on diagnosis. The same analysis (Anova test with Bonferroni correction) was performed on the dataset organized, this time, in benign (HN-FA) and malignant (PTC-FVPTC). For this analysis, 47 genes were found to be significantly different between the benign and the malignant group (Table 1). PCA analysis also separated the data clearly into two groups (FIG. 2).

[0128] For the purpose of this invention, attention was focused on the analysis of the dataset separating benign from malignant. These 47 genes were used to build a diagnostic predictor model. Variable (gene) selection analysis with cross validation was performed with a different number of gene combinations. After cross-validation the model was 87.1% accurate in predicting benign versus malignant with an error rate of 12.9% (Table 2). This suggested that it was possible to use the data to create a diagnostic predictor model.

[0129] The most accurate results were obtained with a combination of 6 to 10 genes. This combination of genes constituted a predictor model and a validation set of 10 additional thyroid samples was used to confirm the accuracy of this model (Table 3). The pathologic diagnosis for each sample was kept blinded to researchers at the time of the analysis. When the blind was broken, it was found that 9 of the samples were diagnosed in concordance with the pathologic diagnosis by our model. One sample that was originally diagnosed as a benign tumor by standard histologic criteria, was diagnosed as malignant by our model. This sample was re-reviewed by the Pathology Department at The Johns Hopkins Hospital and was subsequently found to be a neoplasm of uncertain malignant potential. The diagnosis was changed by pathology after review for clinical reasons, not because of the gene profiling. What is so extraordinary about this is that this was not discovered until the genotyping suggested that the lesion might be malignant and the pathology report examined a second time. By that time the report had been amended and it suggested that the tumor had undetermined malignant potential. Regarding the other tumors, all were examined a second time before array analysis to be certain that the tissue was representative and consistent with the pathology report. Therefore, this model was correct in assigning the diagnosis in all 10 cases.

[0130] PCA analysis using only the six most informative genes was conducted on all the samples with and without the 10 unknown samples (FIG. 3A-B). It is clear from the PCA organization that the six genes strongly distinguish benign from malignant. In addition, these same genes can be used for diagnosis with respect to the four subcategories of thyroid lesion. Between the two-predictor models 11 genes are informative.

[0131] The identification of markers that can determine a specific type of tumor, predict patient outcome or the tumor response to specific therapies is currently a major focus of cancer research. This invention provides the use of gene expression profiling to build a predictor model able to distinguish a benign thyroid tumor from a malignant one. Such a model, when applied to FNA cytology, could greatly impact the clinical management of patients with suspicious thyroid lesions. To build the predictor model four types of thyroid lesions, papillary thyroid carcinoma (PTC), follicular variant of papillary thyroid carcinoma (FVPTC), follicular adenoma (FA) and hyperplastic nodules (FIN) were used. Taken together, these represent the majority of thyroid lesions that often present as "suspicious". The choice of the appropriate control for comparative array experiments is often the subject of much discussion. In this case, in order to construct a predictive diagnostic algorithm based on a training set of samples, it was necessary to have a "common" reference standard to which all individual samples are compared. In this way, differences between each, and in fact all, samples could be analyzed. Had each tumor been compared to the adjacent normal thyroid tissue from the same patient, it would only be possible to comment on gene changes within each patient. A source of RNA from normal thyroid tissue was chosen since the source was replenishable and could be used for all of our future experiments once the diagnostic predictor algorithm was validated.

[0132] The mRNA extracted from each sample was amplified. It was found that the quality of the arrays and the data derived from them is superior when mRNA has been amplified from total RNA. Of note, all samples and all reference controls were amplified in the same fashion. Analysis of the overall gene expression profiles revealed that the benign lesions (FA, HN) could be distinguished from the malignant lesions (PTC, FVPTC). Furthermore, although not statistically significant, the 4 tumor sub-types appeared to have different gene profiles. The use of a powerful statistical analysis program (Partek) helped discover a group of 11 genes that were informative enough to create a predictor model. Two combinations were created out of these 11 genes, a combination of six genes and a combination of 10 genes. PCA analysis of the six most informative genes resulted in a nearly perfect distinction between the two groups (FIG. 3A-B). In general, PCA analysis describes similarities between samples and is not a commonly employed tool for predicting diagnosis. However, in this study the distinction was so powerful that it was possible to visually make a correct diagnosis for each of the 10 unknown samples (FIG. 3A-B). The predictor model determines the kind of tumor with a specific probability value diagnosis of all 10 unknown samples was correctly predicted, with a more accurate prediction using the six-gene combination (Table 3, see probabilities). It is clear from the graph in FIG. 4 how the combination of gene expression values gives a distinctly different profile between the benign and malignant lesions. However, within each tumor group there are differences among the profiles of the five samples tested. This could be explained by the fact that each tumor, even if of the same type, could be at a different stage of progression.

[0133] Of the 11 genes that were informative for the diagnosis, five genes are known genes and for the other six genes no functional studies are yet available. The genes that were identified are the ones that the model has determined best group the known samples into their correct diagnosis. Those genes identified are the ones that consistently grouped the samples into the categories and subcategories described herein. This type of pattern assignment is based on the analysis of thousands of genes and the recognition by the computer software that certain patterns are associated repeatedly with certain diagnostic groups. This type of analysis derives it power (and significance) by the number of genes that are analyzed, rather than the degree of up or down regulation of any particular gene. With respect to the specific genes identified, the computer is not biased by the knowledge of previously identified associated with thyroid cancer. The genes it identifies are those that best differentiate the varied diagnoses of the known samples. This occurs during the "training" phase of establishing the algorithm. Once the computer is trained with data from comparisons of RNA from known diagnoses to a standard reference, unknowns can be tested and fit to the diagnostic groups predicted during the training. For the purposes of such an approach, individual genes are less important. A specific gene which is found in a univariate study to be associated with thyroid cancer, may not turn out to be the best multivariate predictor of a diagnosis in an analysis such as the one presented here.

TaqMan Assay Utilizing 6 Gene Predictor Model and 10 Gene Predictor Model

[0134] Utilizing the information obtained for these differentially expressed genes TaqMan Real Time PCR analysis for the group of 6 genes and the group of 10 genes that are diagnostic for benign versus malignant thyroid lesions from total RNA extracted from thyroid tissue as well as RNA from control normal thyroids was performed. TaqMan Real Time PCR analysis was also performed for the group of 10 genes that are diagnostic for benign versus malignant thyroid lesions.

[0135] Thyroid samples were collected under Johns Hopkins University Hospital Institutional Review Board-approved protocols. The samples were snap-frozen in liquid nitrogen and stored at -80.degree. C. until use. The specimens were chosen based on their tumor type: papillary thyroid cancer (PTC); follicular variant of papillary thyroid cancer (FVPTC); follicular adenoma (FA); and hyperplastic nodule (HN). All diagnoses were made using standard clinical criteria by the Surgical Pathology Department at Johns Hopkins University Hospital.

Tissue Processing and Isolation of RNA

[0136] Frozen sections of 100-300 mg of tissue were collected in test tubes containing 1 ml of Trizol. Samples were transferred to FastRNA.TM. tubes containing mini beads and homogenized in a FastPrep beater (Bio101Savant.TM., Carlsbad, Calif.) for 1.5 min at speed 6. The lysate was transferred to a new tube and total RNA was extracted according to the Trizol protocol in a final volume of 40 .mu.l Rnase-free water (Molecular Research Center, Inc., Cincinnati, Ohio). The quality of the extracted RNA was tested by spectrophotometry and by evaluation on minichips (BioAnalyzer; Agilent Technologies, Palo Alto, Calif.). Minimal criteria for a successful total RNA run were the presence of two ribosomal peaks and one marker peak. Normal human thyroid RNA (Clontech, BD Biosciences) served as a reference control. The total RNA extracted from tissue samples and normal thyroid was then used as the template for one round of reverse transcription to generate cDNA. Eight microliters of purified total RNA (containing up to 3.mu.g of total RNA) was added to a mix containing 3 .mu.g/l .mu.l of random hexamer primers, 4 .mu.l of 1.times. reverse transcription buffer, 2 .mu.l of DTT, 2 .mu.l of dNTPs, 1 .mu.l of Rnase inhibitor, and 2 .mu.l of SuperScript II reverse transcriptase (200 U/.mu.l) in a 20 .mu.l reaction volume (all purchased from Invitrogen, Carlsbad, Calif.). Reverse transcription was performed according to the SuperScript First-Strand Synthesis System instructions (Invitrogen, Carlsbad, Calif.). Following the reverse transcription reaction, the SuperScript II enzyme was heat inactivated, and degradation of the original template RNA was performed using 2 U/l .mu.l of RNAse H (Invitrogen, Carlsbad, Calif.) for 20 minutes at 37.degree. C. The final volume of the mixture was brought to 500 .mu.l using Rnase free water and stored at -20.degree. C. until use.

Quantitative Real-Time PCR

[0137] For the quantitative analysis of mRNA expression, ABI Prism 7500 Sequence Detection System (Applied Biosystems) was used and the data analyzed using the Applied Biosystems 7500 System SDS Software Version 1.2.2. Primers and probes for the genes of interest and for G3PDH were designed using the Primer Express software (version 2.0; Applied Biosystems). Each primer was designed to produce an approximately 70-150 by amplicon. Primer and probe sequences that can be utilized in the 6 gene predictor model and the 10 gene predictor model are listed in Table 4. Table 4 lists the forward and reverse primer for each gene as well as the fluorescent probe sequence that was dual labeled. Table 4 also provides the GenBank Accession No. corresponding to each gene and the location of the primer and probe sequences within the full-length nucleotide sequences provided under the GenBank Accession Nos. Table 4 also provides the InCytePD clone number for each gene (if available), a Unigene identification number for each gene (if available), the chromosomal location for each gene, and additional information about the primers and probes. The primer and probe sequences set forth in Table 4 are examples of the primers and probes that can be utilized to amplify and detect DET1-11. These examples should not be limiting as one of skill in the art would know that other primer sequences for DET1-DET11 including primers comprising the sequences set forth in Table 4 and fragments thereof can be utilized to amplify DET1-DET11. Similarly, other probes which specifically detect DET1-DET11 can be utilized such as probes that comprise the probe sequences set forth in Table 4 and fragments thereof.

[0138] Primers and probes were synthesized by Sigma (sequences shown in Table 4; Sigma, The Woodlands, Tex.). Probes were labeled at the 5' end with the reporter dye FAM (emission wavelength, 518 nm) and at the 3' end with the quencher dye TAMRA (emission wavelength, 582 nm). Standards were created for the six genes using gel-extracted PCR products (Qiagen, Valencia, Calif.). The G3PDH standard was created using a plasmid construct containing the relevant G3PDH sequence (kind gift of Dr. Tetsuya Moriuchi, Osaka University.sup.12). For PCR, 12.5 .mu.l TaqMan Universal PCR Master Mix, 0.5 .mu.l per well each of 0.5 .mu.l forward and reverse primers, and 0.5 .mu.l per well of 10 .mu.l dual labelled fluorescent probe were combined and adjusted to a total volume of 20 .mu.l with Rnase-free water. Finally, 5 .mu.l cDNA per well was added to a total reaction volume of 25 .mu.l. The PCR reaction was performed for 40 cycles of a two-step program: denaturation at 95.degree. C. for 15 seconds, annealing and extension at 60.degree. C. for 1 minute. The fluorescence was read at the completion of the 60.degree. C. step. For each experiment, a no-template reaction was included as a negative control. Each cDNA sample was tested in triplicate, and the mean values were calculated. Triplicate values varied by no more than 10% from the mean. We used the standard curve absolute quantification technique to quantify copy number. A standard curve was generated using a ten-fold dilution series of four different known concentrations of the standards. The number of PCR cycles required for the threshold detection of the fluorescence signal (cycle threshold or Ct) was determined for each sample. Ct values of the standard samples were determined and plotted against the log amount of standard. Ct values of the unknown samples were then compared with the standard curve to determine the amount of target in the unknown sample. Standard curves from each experiment were compared to insure accurate, precise and reproducible results. Each plate contained duplicate copies of serial dilutions of known standards and G3PDH, triplicate copies of cDNA from each sample and normal thyroid cDNA for amplification of G3PDH and the gene of interest.

Statistical Analysis

[0139] Data from 41 of the thyroid tumors was used to build a benign (FA, n=15; HN, n=10) versus malignant (PTC, n=9; FVPTC, n=7) expression ratio-based model, capable of predicting the diagnosis (benign versus malignant) of each sample. Ten additional samples were provided as blinded specimens, processed as described above and used as a validation set to test the model. These ten samples were not previously used to do any other analysis. Expression values of all six genes in all samples and normal thyroid were standardized to the expression of G3PDH, a common housekeeping gene chosen to serve as a reference control. The ratio of the expression values for each gene in each sample was then compared to the ratio in normal thyroid, and converted to log 2 to generate a gene expression ratio value for all 41 samples. A file containing the gene expression ratio values from all 51 samples (41 known, 10 unknown) was imported into a statistical analysis software package (Partek, Inc., St. Charles, Mo.).

[0140] As a first step, the data from the 41 samples were subjected to principal component analysis (PCA) to provide a three-dimensional visualization of the data. All six genes were used to build a diagnosis-predictor model called a class prediction rule. This resulting rule was applied to predict the class of the ten samples in the validation set. The same analysis was then performed on a second set of data from 47 of the thyroid tumors to build a benign (FA, n=15; HN, n=11) versus malignant (PTC, n=9; FVPTC, n=12) expression ratio-based model. Ten additional unstudied samples were provided as blinded specimens for this second training set.

[0141] Principal Component Analysis (PCA) of the 41 samples using the gene expression values for all six genes showed a clear organization of the samples based on diagnosis. PCA was then conducted on all of the 41 samples with the 10 unknown samples. This combination of genes constituted a first predictor model and the validation set of 10 additional thyroid samples was used to confirm the accuracy of the model. The pathological diagnosis for each sample was kept blinded until after the analysis was completed. When the blind was broken, it was found that 8 of the 10 unknown samples were diagnosed by this model in concordance with the pathological diagnosis determined by standard pathologic criteria. One sample that was originally diagnosed as a benign follicular adenoma by standard histological criteria was diagnosed as malignant by the six gene predictor model set forth herein; one sample that was originally diagnosed as a papillary thyroid carcinoma by standard histological criteria was diagnosed as benign by the six gene predictor model set forth herein.

[0142] Further to the analysis above, the G3PDH standard was redesigned and processing of all tissue for total RNA extraction was standardized. Following these two modifications, Principal Component Analysis (PCA) was performed on the second training set of 47 samples and on ten new unknown samples using the gene expression values for all six genes. Again, PCA demonstrated a clear organization of the samples based on diagnosis. The pathological diagnosis for these ten new unknowns was also kept blinded until after the analysis. When the blind was broken, it was found that 9 of the samples were diagnosed in concordance with the pathological diagnosis by the six gene predictor model set forth herein. One sample that was diagnosed as a benign hyperplastic nodule by standard histological criteria was diagnosed as malignant by our model.

[0143] The results of the Taqman assays correlated with the microarray data. As shown in FIG. 5, the Taqman data utilizing the 6 gene model (DET1, DET2, DET3, DET4, DET5, DET6) demonstrates the ability to classify a thyroid sample as benign or malignant. Similar to results obtained via microarray, c21 or f4, Hs.145049, KIT and LSM-7 were upregulated in benign samples as compared to malignant samples. In other words, the expression of c21 or f4, Hs.145049, KIT and LSM7 decreases during malignancy. Hs.296031 and SYNGR2 were upregulated in malignant samples as compared to benign samples. In other words, expression of Hs.296031 and SYNGR2 increases during malignancy. The same analysis was performed with the 10 gene model utilizing the primers and probes set forth in Table 4 for DET1, DET2, DET3, DET4, DET6, DET7, DET8, DET9, DET10 and DET11. As shown in FIG. 7, similar to results obtained via microarray, c21 or f4, Hs.145049 (Hs. 24183), KIT, FAM13A1, C11 or f8, KIAA 1128, IMPACT and CDH1 were upregulated in benign samples as compared to malignant samples. In other words, the expression of c21 or f4, Hs.145049, KIT, FAM13A1, C11 or f8, KIAA1128, IMPACT and CDH1 decreases during malignancy. Hs.296031 and SYNGR2 were upregulated in malignant samples as compared to benign samples. In other words, expression of Hs.296031 and SYNGR2 increases during malignancy. Therefore, it is clear that this pattern of differences between malignant and benign samples can be utilized to classify thyroid lesions utilizing the 6 gene model and the 10 gene model. In addition to classification, the Real Time PCR Taqman assay can also be used for staging thyroid cancer and in identifying agents that treat thyroid tumors.

[0144] Analysis of the 6 gene expression and the 10 gene expression profiles revealed that the benign lesions could be distinguished from the malignant lesions, and that this profile could be used to diagnose unknown samples against the current "gold standard" of pathologic criteria with a high degree of accuracy. Of the six genes in the six gene model, downregulation of kit was seen in both benign and malignant thyroid tissue when compared to normal control. The magnitude of this downregulation was much greater in malignant thyroid tissue. Kit is a well-known protooncogene.

[0145] As to the other five genes in the six gene model, for three of these no functional studies are yet available. Of the remaining two genes, SYNGR2 has been characterized as an integral vesicle membrane protein. LSM7 likewise has been described in the family of Sm-like proteins, possibly involved in pre-mRNA splicing. The interaction of LSM7 with the TACC1 complex may participate in breast cancer oncogenesis. However, the role of LSM7 in thyroid oncogenesis has not yet been explored.

[0146] The six gene model determined the accurate diagnosis of 17 out of 20 unknown samples tested. Accuracy was based on a comparison to the "gold standard" pathologic diagnosis as determined by clinical pathologists. Therefore, this strategy demonstrates the power of genomic analysis as a technique for studying the underlying pathways responsible for the pathophysiology of neuroendocrine tumors. Further evaluation and linkage of clinical data to molecular profiling allows for a better understanding of tumor pathogenesis, or even normal thyroid function and development. In addition, the use of qRT-PCR can lead to incorporation of this model and/or the 10 gene model into preoperative decision making for patients with thyroid nodules.

[0147] The present invention is a clear example of how gene-expression profiling can provide highly useful diagnostic information. It is likely that gene expression profiling will be used in the future for clinical decision-making. For this purpose adequate reporting of DNA-microarray data to clinicians will be necessary. Gene-expression profiles may be more reproducible and clinically applicable than well-established but highly subjective techniques, such as histopathology. The small number of genes for which RNA expression levels are diagnostically and prognostically relevant could lead to a robust, affordable, commercially available testing system. To this end, the present invention provides a useful method for classifying thyroid nodules as benign or malignant and therefore helps facilitate appropriate, and eliminate unnecessary, operations in patients with suspicious thyroid tumors.

[0148] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0149] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

TABLE-US-00001 TABLE 1 Table 1. Two tail Anova analysis with Bonferroni correction resulted in 47 genes significantly different (p = <0.05) between the malignant and the benign group. Gene Bonferroni p-value Mean(benign) S.D. +/- Mean(malignant) S.D. +/- C21orf4 <0.0001 1.54 0.36 0.92 0.36 KIT <0.0001 1.20 0.66 0.38 0.32 FLJ20477 <0.0001 1.16 0.28 0.76 0.22 MGC4276 0.0001 1.02 0.37 0.54 0.22 KIAA0062 0.001 1.03 0.51 0.46 0.25 CDH1 0.001 1.51 0.46 0.87 0.45 LSM7 0.001 1.28 0.53 0.69 0.27 ACYP1 <0.01 2.11 0.91 1.09 0.51 SYNGR2 <0.01 0.75 0.41 1.67 1.05 XPA <0.01 2.29 0.84 1.31 0.58 AD-017 <0.01 1.57 0.63 0.84 0.44 DP1 <0.01 1.59 0.69 0.84 0.39 IDI1 <0.01 1.37 0.61 0.74 0.29 RODH <0.01 1.36 0.93 0.45 0.36 ID4 <0.01 1.10 0.56 0.48 0.37 Hs.24183 <0.01 2.05 0.70 1.30 0.42 HTCD37 <0.01 1.22 0.37 0.78 0.30 DUSP5 <0.01 0.97 0.60 3.93 3.15 Hs.87327 <0.01 1.54 0.53 1.01 0.26 CRNKL1 0.01 1.33 0.49 0.79 0.34 LOC54499 0.01 1.33 0.50 0.83 0.26 RAP140 0.01 1.60 0.58 1.00 0.35 MAPK4 0.01 0.66 0.38 0.30 0.16 Hs.296031 0.01 1.13 0.63 2.28 1.12 ATP6V1D 0.01 1.71 0.75 0.94 0.46 TXNL 0.01 1.19 0.66 0.57 0.28 FAM13A1 0.02 1.35 0.60 0.71 0.43 GUK1 0.02 0.87 0.43 1.56 0.66 Hs.383203 0.02 1.55 0.57 0.91 0.45 C11orf8 0.02 0.81 0.43 0.36 0.30 DENR 0.02 1.54 0.42 1.02 0.42 PRDX1 0.02 1.36 0.40 0.84 0.44 FLJ20534 0.02 1.94 0.92 1.08 0.40 DI02 0.02 1.95 1.37 0.70 0.52 C21orf51 0.02 1.01 0.40 0.63 0.22 KIAA1128 0.03 1.76 0.87 0.90 0.52 IMPACT 0.03 1.32 0.48 0.86 0.27 KIAA0089 0.03 1.43 0.63 0.76 0.49 HSD1784 0.03 1.45 0.57 0.88 0.36 MAP4K5 0.04 1.59 0.61 0.97 0.44 ELF3 0.04 0.82 0.24 1.45 0.72 ALDH7A1 0.04 1.61 0.52 0.96 0.58 BET1 0.04 1.38 0.55 0.82 0.39 GTF2H2 0.04 1.80 0.54 1.23 0.44 DC6 0.04 1.19 0.34 0.81 0.29 CDH1 0.04 1.31 0.49 0.82 0.34 The genes are listed from the most to the least significant. In bold are all the genes that combined together created the best predictor model.

TABLE-US-00002 TABLE 2 Table 2. Results of the cross validation analysis using the "leave- one-out" method (see materials and methods). # per Class # Correct # Error % Correct % Error Benign 31 27 4 87.1 12.9 Malignant 32 28 4 87.5 12.5 Total 63 55 8 87.3 12.7 Normalized 87.3 12.7 The predictor model was able to correctly predict 87% of the diagnoses. The outcome is called a confusion matrix.

TABLE-US-00003 TABLE 3 DIAGNOSIS PREDICTOR MODEL 31 benign tumors 32 malignant tumors Table 3. In this table the two predictor model of 10 and 6 genes is shown with their gene expression values, the predicted diagnosis, the percentage probability of the diagnosis being correct and the pathologic diagnosis. 10 gene diagnose cross validation % % ma- Pre- Patho- predictor model of 83% IM- benign lignant dicted logic C11orf8 C21orf4 CDH1 FAM13A1 Hs.24183 Hs.288031 PACT KIAA1128 KIT SYNGR2 prob. prob. Diagnosis Diagnosis 0.4561 1.35 1.53 0.76 1.81 1.55 1.02 1.21 2.03 1.12 0.99 0.01 benign FA 0.4988 0.82 0.83 0.45 1.67 1.74 0.93 1.27 0.27 0.54 0.02 0.98 malignant FVPTC 1.311 0.78 2.13 1.13 1.39 0.65 1.36 1.19 1.70 1.04 0.91 0.09 benign HN 0.5143 1.05 0.62 0.85 0.95 1.56 1.16 0.86 0.80 0.78 0.43 0.57 malignant PTC 0.3786 2.07 0.64 1.44 1.84 1.51 0.48 1.14 1.32 2.65 0.94 0.06 benign FA 0.7376 1.81 0.85 1.85 1.34 0.55 0.91 1.56 1.83 2.70 1.00 0.00 benign FA 0.1206 0.57 0.50 0.55 0.86 1.94 0.61 0.99 0.25 4.88 0.00 1.00 malignant PTC 0.026 1.27 0.46 0.59 1.22 1.19 0.91 0.56 0.11 4.69 0.00 1.00 malignant PTC 0.1097 0.70 2.17 1.01 1.24 0.82 0.96 0.93 1.59 3.69 0.05 0.95 malignant HN 1.0368 1.37 1.24 1.50 1.23 1.74 0.94 1.82 2.82 1.38 1.00 0.00 benign HN 6 gene diagnose predictor model cross validation of 87% % benign % malignant Predicted Pathologic C21orf4 Hs.24183 Hs.296031 KIT LSM7 SYNGR2 prob. prob. Diagnosis Diagnosis 1.3518 1.81 1.55 2.03 2.40 1.12 1.00 0.00 benign FA 0.819 1.67 1.74 0.27 0.56 0.54 0.15 0.85 malignant FVPTC 0.7822 1.39 0.65 1.70 1.33 1.04 0.94 0.06 benign HN 1.0457 0.95 1.56 0.80 0.85 0.79 0.33 0.67 malignant PTC 2.0723 1.84 1.51 1.32 1.05 2.65 0.06 0.14 benign FA 1.8053 1.34 0.65 1.83 1.47 2.70 0.96 0.04 benign FA 0.5555 0.85 1.94 0.25 0.66 4.88 0.00 1.00 malignant PTC 1.2698 1.22 1.19 0.11 0.43 4.69 0.00 1.00 malignant PTC 0.698 1.24 0.82 1.69 1.60 3.69 0.10 0.90 malignant HN 1.3677 1.23 1.74 2.92 1.04 1.38 0.99 0.01 benign HN FA = follicular adenoma, HN = hyperplastic nodules, FVPTC = follicular variant papillary thyroid carcinoma and PTC = papillary thyroid carcinoma. The square indicates the unknown sample for which there was discordance between the predicted and the pathologic diagnosis. The percentage diagnosis probability for both 6 and 10 gene combinations strongly suggested that this was a malignant sample. The sample was re-reviewed by the pathologist and the pathologic diagnosis was in-fact changed to a neoplasm with uncertain malignant potential.

TABLE-US-00004 TABLE 4 Table 4. This table shows the primer and probe sequences that can be utilized in the 6 gene predictor model and the 10 gene predictor model. Table 4 Thyroid Primer/Probes InCyta Oligo Name Length Sequence(5'-3') Tm Residues PO_Clone Hs.24183-Forward SEQ ID NO. 1 22 ggcgactggcaaaagag 2438-2457 2123020 Hs.24183-Reverse SEQ ID NO. 2 26 2530-2506 2123020 Hs.24183-Probe SEQ ID NO. 3 23 ( )TggCCTgTCACTCCCATgATgC(Tamra) 2462-2484 2123020 globulin-forward SEQ ID NO. 4 18 aagggctcgcatgcaag 59 2036-2053 globulin-reverse SEQ ID NO. 5 25 cacagtagcactcg 60 2157-2133 globulin-probe SEQ ID NO. 6 33 ( )TTTgTCCCTgCTTgTACTAgTgAgg(Tamra) 69 2088-2120 c21orf4-forward SEQ ID NO. 7 22 gctatcctcttacctcccgt 2822-2643 1710736 c21orf4-reverse SEQ ID NO. 8 25 gga 2743-2712 1710736 c21orf4-Probe SEQ ID NO. 9 28 ( )CTgcgACACAgATgTATCCTCCACTCC(Tamra) 2652-2679 1710736 fam13a1-forward SEQ ID NO. 10 22 2931-2952 1458358 fam13a1-reverse SEQ ID NO. 11 25 gca 3058-3034 1458388 fam13a1-Probe SEQ ID NO. 12 23 ( )TgTTTgTggAATCCATgAAggTTATggC(Tamra) 2992-3014 1458388 c11orf8-forward SEQ ID NO. 13 16 ccggcccagc 849-864 4117578 c11orf8-reverse SEQ ID NO. 14 21 gtg 916-896 4117578 c11orf8-Probe SEQ ID NO. 15 29 ( )TgTTTggTggAATCCATgAAggTTATggC(Tamra) 866-894 4117578 kiaa1128-forward SEQ ID NO. 16 20 gagagcg 5980-5999 1428225 kiaa1128-reverse SEQ ID NO. 17 23 6083-8041 1428225 kiaa1128-probe SEQ ID NO. 18 33 ( )TCACTTCCAAATgTTCCTgTAgCATAAATggTg(Tamra) 6004-6036 1428225 Hs.298031-forward SEQ ID NO. 19 24 gcaaaggag 4271-4294 29557644 Hs.298031-reverse SEQ ID NO. 20 20 atgacggcatg 4353-4334 29557644 Hs.298031-probe SEQ ID NO. 21 29 ( )TTggTCCCCTCAgTTCTATgCTgTTgTgT(Tamra) 4301-4329 29557644 -forward SEQ ID NO. 22 26 gcactgc 2704-2129 2358031/ 1572225 -reverse SEQ ID NO. 23 28 2643-2816 2358031/ 1572225 -probe SEQ ID NO. 24 36 ( )ATTgTTCAgCTAATTgAgAAgCAgATTTCAgAgAgC(Tamra) 2779-2814 2358031/ 1572225 impact-forward SEQ ID NO. 25 26 gaagaa 809-864 983008 impact-reverse SEQ ID NO. 26 25 atgc 943-918 983008 impact-probe SEQ ID NO. 27 29 ( )CTggTATggAgggATTCTgCTAggACCAg(Tamra) 837-865 983008 cdh1-forward SEQ ID NO. 28 21 gagtg 2499-2519 1911913/ 2060560 cdh1-reverse SEQ ID NO. 29 21 cagccgccag 2579-2559 1911913/ 2060560 cdh1-probe SEQ ID NO. 30 27 ( )CCTgCCAATCCCgATgAAATTggAAAT(Tamra) 2525-2551 1911913/ 2060560 syngr2-forward SEQ ID NO. 31 18 gctgg 1255-1273 syngr2-reverse SEQ ID NO. 32 19 ccct 1374-1356 syngr2-probe SEQ ID NO. 33 24 ( )aagggcttgcctgaca (Tamra) 1303-1328 lsm7-forward SEQ ID NO. 34 21 gacg 72-82 lsm7-reverse SEQ ID NO. 35 20 agg 148-127 lsm7-probe SEQ ID NO. 36 22 ( )aggcccg (Tamra) 95-117 G3PDH-Forward SEQ ID NO. 37 22 TCACCAGGGCTGCTTTTAACTC 128-149 G3PDH-Reverse SEQ ID NO. 38 25 GGAATCATATTGGAACATGTAAACCA 228-203 G3PDH-probe SEQ ID NO. 39 27 FAM-TTGCCATCAATGACCCCTTCATTGACC-TAMRA 167-193 normal thyroid Coated Lot 63100784 paded 65 autopsy sample patients Table 4 Thyroid Primer/Probes CM Paper TAOman Primer/Probe Oligo Name Unigene GenBank/RefSeq GenBank/RefSeq Chromosome Details Hs.24183-Forward Hs.24183 KP060255 ALB32414.1 21 used later part of sequence Hs.24183-Reverse Hs.24183 KP060255 ALB32414.1 Hs.24183-Probe Hs.24183 KP060255 ALB32414.1 globulin-forward NM_033235 NM_003235 used with Exon9 globulin-reverse NM_033235 NM_003235 globulin-probe NM_033235 NM_003235 c21orf4-forward (Hs.284142-rel)Hs.433668 AP001717 NM_006134.4 21q22.11 spans Exon7-8 c21orf4-reverse (Hs.284142-rel)Hs.433668 AP001717 NM_006134.4 c21orf4-Probe (Hs.284142-rel)Hs.433668 AP001717 NM_006134.4 fam13a1-forward (Hs.177644-removed)Hs.442818 (NM0148883)fromA8020721 (NM014883)fromAB020721 4q22.1 used later part of seg-exon19 fam13a1-reverse (Hs.177644-removed)Hs.442818 (NM0148883)fromA8020721 (NM014883)fromAB020721 fam13a1-Probe (Hs.177644-removed)Hs.442818 (NM0148883)fromA8020721 (NM014883)fromAB020721 c11orf8-forward (Hs.45638-rel)Hs.432000 NM001584 NM001584 11p13 spans Exon5-8 c11orf8-reverse (Hs.45638-rel)Hs.432000 NM001584 NM001584 c11orf8-Probe (Hs.45638-rel)Hs.432000 NM001584 NM001584 kiaa1128-forward Hs.81897 AB032914.1-this is AB032954.1 10q23.2 used later actually AB032954.1 part of sequence kiaa1128-reverse Hs.81897 AB032914.1-this is AB032954.1 actually AB032954.1 kiaa1128-probe Hs.81897 AB032914.1-this is AB032954.1 actually AB032954.1 Hs.298031-forward Hs.296031 BC38512.1 BC38512.1 X used later part of sequence Hs.298031-reverse Hs.296031 BC38512.1 BC38512.1 Hs.298031-probe Hs.296031 BC38512.1 BC38512.1 -forward Hs.81665 X05182.1 X05182.1 4q11-q12 spans Exon 19-20 -reverse Hs.81665 X05182.1 X05182.1 -probe Hs.81665 X05182.1 X05182.1 impact-forward Hs.284245 NM018439 NM018439 18q11.2-q12.1 spans Exon 10-11 impact-reverse Hs.284245 NM018439 NM018439 impact-probe Hs.284245 NM018439 NM018439 cdh1-forward HS 194857 NM004350 NM004350 16q22.1 spans Exon 15-18 cdh1-reverse HS 194857 NM004350 NM004350 cdh1-probe HS 194857 NM004350 NM004350 syngr2-forward (Hs.5097-rel) Hs.433753 NM004710.2 NM004710.2 17q25.3 used later sequence syngr2-reverse (Hs.5097-rel) Hs.433753 NM004710.2 NM004710.2 syngr2-probe (Hs.5097-rel) Hs.433753 NM004710.2 NM004710.2 lsm7-forward (Hs.70830-rel)Hs.512610 NM0151991.1 NM0151991.1 19p13.3 used later sequence lsm7-reverse (Hs.70830-rel)Hs.512610 NM0151991.1 NM0151991.1 lsm7-probe (Hs.70830-rel)Hs.512610 NM0151991.1 NM0151991.1 G3PDH-Forward NM_002048 from Takahashi paper G3PDH-Reverse NM_002048 G3PDH-probe NM_002048 normal thyroid 650-424-8222 sample indicates data missing or illegible when filed

Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 60 <210> SEQ ID NO 1 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 1 ggctgactgg caaaaagtct tg 22 <210> SEQ ID NO 2 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 2 ttggttccct taagttctca gagttt 26 <210> SEQ ID NO 3 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 3 tggccctgtc actcccatga tgc 23 <210> SEQ ID NO 4 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 4 aagggctcgc atgcaaag 18 <210> SEQ ID NO 5 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 5 cacagtagca ctctgagttg aagca 25 <210> SEQ ID NO 6 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 6 tttgtccctg cttgtactag tgagg 25 <210> SEQ ID NO 7 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 7 gcaatcctct tacctccgct tt 22 <210> SEQ ID NO 8 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 8 ggaatcggag acagaagaga gctt 24 <210> SEQ ID NO 9 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 9 ctgggaccac agatgtatcc tccactcc 28 <210> SEQ ID NO 10 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 10 atggcagtgc agtcatcatc tt 22 <210> SEQ ID NO 11 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 11 gcattcatac agctgcttac catct 25 <210> SEQ ID NO 12 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 12 tttggtccct gcctaggacc ggg 23 <210> SEQ ID NO 13 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 13 ccggcccaag ctccat 16 <210> SEQ ID NO 14 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 14 ttgtgtaacc gtcggtcatg a 21 <210> SEQ ID NO 15 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 15 tgtttggtgg aatccatgaa ggttatggc 29 <210> SEQ ID NO 16 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 16 gagagcgtga tccccctaca 20 <210> SEQ ID NO 17 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 17 accaagagtg cacctcagtg tct 23 <210> SEQ ID NO 18 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 18 tcacttccaa atgttcctgt agcataaatg gtg 33 <210> SEQ ID NO 19 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 19 tgccaaggag ctttgtttat agaa 24 <210> SEQ ID NO 20 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 20 atgacggcat gtaccaacca 20 <210> SEQ ID NO 21 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 21 ttggtcccct cagttctatg ctgttgtgt 29 <210> SEQ ID NO 22 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 22 gcacctgctg aaatgtatga cataat 26 <210> SEQ ID NO 23 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 23 tttgctaagt tggagtaaat atgattgg 28 <210> SEQ ID NO 24 <211> LENGTH: 36 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 24 attgttcagc taattgagaa gcagatttca gagagc 36 <210> SEQ ID NO 25 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 25 tgaagaatgt catggtggta gtatca 26 <210> SEQ ID NO 26 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 26 atgactcctc aggtgaattt gtgtag 26 <210> SEQ ID NO 27 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 27 ctggtatgga gggattctgc taggaccag 29 <210> SEQ ID NO 28 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 28 tgagtgtccc ccggtatctt c 21 <210> SEQ ID NO 29 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 29 cagccgcttt cagattttca t 21 <210> SEQ ID NO 30 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 30 cctgccaatc ccgatgaaat tggaaat 27 <210> SEQ ID NO 31 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 31 gctggtgctc atggcactt 19 <210> SEQ ID NO 32 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 32 ccctccccag gcttcctaa 19 <210> SEQ ID NO 33 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 33 aagggctttg cctgacaaca ccca 24 <210> SEQ ID NO 34 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 34 gacgatccgg gtaaagttcc a 21 <210> SEQ ID NO 35 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 35 aggttgagga gtgggtcgaa 20 <210> SEQ ID NO 36 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 36 aggccgcgaa gccagtggaa tc 22 <210> SEQ ID NO 37 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 37 tcaccagggc tgcttttaac tc 22 <210> SEQ ID NO 38 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 38 ggaatcatat tggaacatgt aaacca 26 <210> SEQ ID NO 39 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 39 ttgccatcaa tgaccccttc attgacc 27 <210> SEQ ID NO 40 <211> LENGTH: 3084 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C21orf4 <400> SEQUENCE: 40 gctcccgggg ctgaggtgga gccgcgggac gccggcaggg ttgtggcgca gcagtctcct 60 tcctgcgcgc gcgcctgaag tcggcgtggg cgtttgagga agctgggata cagcatttaa 120 tgaaaaattt atgcttaaga agtaaaaatg gcaggcttcc tagataattt tcgttggcca 180 gaatgtgaat gtattgactg gagtgagaga agaaatgctg tggcatctgt tgtcgcaggt 240 atattgtttt ttacaggctg gtggataatg attgatgcag ctgtggtgta tcctaagcca 300 gaacagttga accatgcctt tcacacatgt ggtgtatttt ccacattggc tttcttcatg 360 ataaatgctg tatccaatgc tcaggtgaga ggtgatagct atgaaagcgg ctgtttagga 420 agaacaggtg ctcgagtttg gcttttcatt ggtttcatgt tgatgtttgg gtcacttatt 480 gcttccatgt ggattctttt tggtgcatat gttacccaaa atactgatgt ttatccggga 540 ctagctgtgt tttttcaaaa tgcacttata ttttttagca ctctgatcta caaatttgga 600 agaaccgaag agctatggac ctgagatcac ttcttaagtc acattttcct tttgttatat 660 tctgtttgta gataggtttt ttatctctca gtacacattg ccaaatggag tagattgtac 720 attaaatgtt ttgtttcttt acatttttat gttctgagtt ttgaaatagt tttatgaaat 780 ttctttattt ttcattgcat agactgttaa tatgtatata atacaagact atatgaattg 840 gataatgagt atcagttttt tattcctgag atttagaact tgatctactc cctgagccag 900 ggttacatca tcttgtcatt ttagaagtaa ccactcttgt ctctctggcc gggcacggtg 960 gctcatgcct gtaatcccag cactttggga ggccgaggcg ggccgattgc ttgaggtcaa 1020 gtgttttgag accagcctgg ccaacatggc gaaaccccat ctactaaaaa tacaaaaatt 1080 agccaggcat ggtggtgggt gcctgtaatc ccaactacct aggaggctga ggcaggagaa 1140 tcgcttgaac ccggggggca gaggttgtag tgagctgagt ttgcgccact gcactctagc 1200 ctgggggaga aagtgaaact ccctctcaaa aaaaagaagg accactctca gtatctgatt 1260 tctgaagatg tacaaaaaaa tatagcttca tatatctaga atgagcactg agccataaaa 1320 ggttttcagc aagttgtaac ttattttggc ctaaaaatga ggtttttttg gtaaagaaaa 1380 aatatttgtt cttatgtatt gaagaagtgt acttttatat aatgattttt taaatgccca 1440 aaggactagt ttgaaagctt cttttaaaaa gaattcctct aatatgactt tatgtgagaa 1500 gggataatac atgatcaaat aaactcagtt ttttatggtt actgtaaaaa gactgtgtaa 1560 ggcagctcag caccatgctt ctcgtaaaag cagcttcaaa tatccactgg ggttatcttt 1620 tgacgacttg ccattatctg atgttacaca attcaatagc aagcaagttt gagacaatcg 1680 cagtttaaaa gcatgaacca tttaacaaaa agtggaataa ttaaagataa agcacttctt 1740 cccaaaggga attatcacct agtgaaaaat tatgcatttc atctactcag ttaccgactg 1800 caagtctctc ctcgctctag ctctcaagct ttgggtgaat attcctgtga aatatatctt 1860 caacttgaaa gttcatactc caatcaaaaa ctccttttac tgagtttgca gtactgtatt 1920 tgcactgttt gtattcctct gggcccttat tgctactttt gctttccttt gttacacaga 1980 ttttgtgttg cactttttct ccagaggggt gttgtagagc cttggttgta tgaataatac 2040 cagtggtagt gtccacggct ctaatgtaag cccatttggc atcactcctc tcctctctct 2100 tgagaggatt tcttgtgcac agagtatgaa gcagttgtgg agcgctgtgc ctttgtcaag 2160 ataccatctt gtttgatgac ttctttcttt gctgtttttt tcttcaaaat gttagtaagc 2220 tctgtcatgc ttctagcaaa ttgtaagact aattatttgt ttccacctca taacctgttg 2280 caataaatat tacttctcat acagtttaat attgttgttt gttggagaaa atgaaccata 2340 aaaattgatt tgctgttcag ttttcaatta ttcaagtata cccaattaaa gatgcagtta 2400 tgtttataaa ataagaagaa atagacttgt aaaatgctta tgtgagggtt attgaaggtt 2460 tccctgaaga ctgactggaa atggtggctg tttttttcta tttctgactc tgccatgaat 2520 tttttttttt tttttttaaa gacaatatct cactctgttg cctaggctgg agtgcagtgg 2580 tgcaaccaca gctcactgca ccttcaaatg ctggagctca ggcaatcctc ttacctccgc 2640 tttccaagca gctgggacca cagatgtatc ctccactcct cgctggccac catcctgctg 2700 cccaacagaa gaagctcttc tgtctccgat ttcctgaacg gtctaaggac caggaagaaa 2760 caggctcctg ccagcaccga cagcaacgaa aatgttccca cggagatcag gatgacttgc 2820 tgaagctcag tggaggctaa aaagaggaca cgaaagtgaa cagaatgatc ttcctacgca 2880 caacacaaac atcagttaat gttccatcca tgctgcttaa agagcattcc tgtcctagta 2940 aaatgggcaa gtccctctac cccccaccct cacctggtat gcttacatta atagctaaag 3000 tcaatcctgt aatgaaataa agcaagtggt agctgtctgg tagcctccac tactgcaaat 3060 ctcaagaaaa aaaaaaaaaa aaaa 3084 <210> SEQ ID NO 41 <211> LENGTH: 158 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: c21orf4 <400> SEQUENCE: 41 Met Ala Gly Phe Leu Asp Asn Phe Arg Trp Pro Glu Cys Glu Cys Ile 1 5 10 15 Asp Trp Ser Glu Arg Arg Asn Ala Val Ala Ser Val Val Ala Gly Ile 20 25 30 Leu Phe Phe Thr Gly Trp Trp Ile Met Ile Asp Ala Ala Val Val Tyr 35 40 45 Pro Lys Pro Glu Gln Leu Asn His Ala Phe His Thr Cys Gly Val Phe 50 55 60 Ser Thr Leu Ala Phe Phe Met Ile Asn Ala Val Ser Asn Ala Gln Val 65 70 75 80 Arg Gly Asp Ser Tyr Glu Ser Gly Cys Leu Gly Arg Thr Gly Ala Arg 85 90 95 Val Trp Leu Phe Ile Gly Phe Met Leu Met Phe Gly Ser Leu Ile Ala 100 105 110 Ser Met Trp Ile Leu Phe Gly Ala Tyr Val Thr Gln Asn Thr Asp Val 115 120 125 Tyr Pro Gly Leu Ala Val Phe Phe Gln Asn Ala Leu Ile Phe Phe Ser 130 135 140 Thr Leu Ile Tyr Lys Phe Gly Arg Thr Glu Glu Leu Trp Thr 145 150 155 <210> SEQ ID NO 42 <211> LENGTH: 2822 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Hs.145049 <400> SEQUENCE: 42 gtttctctga atagcagagg catcaaattt tggtggggaa tgagaggagt attaggggaa 60 agtttgaaaa tagctctcct ggagatggag ggcacacaga gtggtcctca ggctcacctt 120 gactgagttg attcacagtt atcctgcatc agaccattag atttctttag tgctatgatt 180 ataataggga tttttgaatc accaaaaaca gtttttagat gtttatgttc tttgttttac 240 tatcaatgtt gtgctggtta agggagagaa aagttcaaga agatcttaca tatttgaaag 300 gaaattggta ctcttgaagg ctatgcaaca tgagtctttg aacaagaatt ccttgctact 360 ttgattcatt catcaaatac tgagtgcctg tgtgccaggc acaggtgaac tctggggatt 420 caggggtaac taaaacagat tgcaaccctg cccttgtgaa gctttcagtc tagaagggag 480 acgtgaaaca aattttagct tcaaaagcaa catctatttt tgcctgttag catgcattta 540 ttttaaaagt catattagag ttacctggtt ccgcttcaga gcagactggg aaaatcaggc 600 ttacaatgga atcagatgct gtgggcctaa aacagctctt taaaaatcta tttttttagg 660 ccaggtgcgt tggctcacac ctgtaatccc agcactttgg gaggccaagg tgggtggata 720 tgaggtcagg aggtcgagac cagcctggtc aatatgatga aaccttacct ctactaaaaa 780 taaaaaatta gccgggcatg gtggcacatg cctgtagtcc cagctactcg ggaaactgag 840 gcagaagaat cgcttgaacc cgggaggcgg aggttgcagt gagccgggat cacgtcactg 900 tactccagcc tgggcaagag tgagacaccg tctcaaaaaa aaaaaaaatt tttttttaaa 960 tggaatcaga gaaaccaaca aaatatgtaa catgtataaa tgcctgagga gatcagttat 1020 tgagaaatcc atttacaatg ctggaggaga ggggatggcc aggaaagaag tgcaacaaat 1080 aaatggaaga tgaccctaaa aatgcaccag tgacagtcag tcaatccatc agaccacctc 1140 acatgcaggg tagaaacatg gagtgtgcgg cagcatcctc ctcacatccc tttgtgagca 1200 cggctgctcc ggaatactga ccatctgggc tagcacgact tagcagaggg ttctgcagga 1260 tgtgctattt taaagcagct gggtgcaact tgtgaaaacg ggaatctaga gcagaacatg 1320 taatcagcga tggctgggat tggtggacag gattgacagg agtatttgag gctctaccag 1380 gcctgtctac aggacagctt catcaaaggg acatttttta acctgttatt ttaaatgcca 1440 catatatgtt gtaatgctga agcatacagg tagaatttct ggatcgtaac tactagtgac 1500 ttctgaggtt tacagttaga aaatgttctc aaaggtttat cagttatgta ttgatgattg 1560 gtaatctaga ccctctggag gctgtagaat gtgaaaagat acagctgagc tgacaagttt 1620 tagggcacta tcttctggaa tgaaatcggc caagaaaatg gttcaagggc atgggggtta 1680 gagaatgttt cttttaccta aaaatgttaa gccaactatg gaagattggg gtcgtggggg 1740 catgaaatac aaaattatga taatttatac agaactaggt ttctttatgt tctgcaagaa 1800 ggtttttatt agctaatttg gggagggggg catgctgcag tatttttttt cctgggaaca 1860 tgcatttctg atgggaagtt attttgttta caagagttgg ttttacacac aaccctgaat 1920 gaatgtgtct atggcctaaa aatggtagac ctgtatttcc ttcccgaggc aggctgattc 1980 gtttcctgat tccttctgtc tgagattacc tgatgctgac cagacttatt tttcctttcc 2040 tgaatcttca cagctgagtt tatggcaccc atccaagacc ttcccatttg aatgactaga 2100 tttctattct atccccgatc atccttttga aatagttcta gtgataaact cagagaaatt 2160 caatatattg attgaatttt attttttcgc tttgtatcta caacagaaat tgatttgttc 2220 atttttattt caaatctctt catggcaagt tgggctaatg gactttgcac tcaagaaagg 2280 tttgtttacc agttttgtag ccatgtttgg caaatcttag caactagaaa ccccgtcctt 2340 tcttttcctt ctttatatgt tcttgcagtt actcttgtat tgcaagattt tctgacttta 2400 agctttgaga ctactgcatc ttaaaagaag aactaggctg actggcaaaa agtcttgcca 2460 gtggccctgt cactcccatg atgctttggt tttgagagtt gggaaaactc tgagaactta 2520 agggaaccaa actcaggaat cccaaaattg gtggcattgt gccattcgtt taggggctga 2580 acataggacc tgtctgaaac tgagtgagct agatgcattt gggtttgaat ttttgtcaca 2640 tactgaaatg taagtcagcc ctaaataatc aaaacacttt attttatttt tcttttttta 2700 aataggaact ttctgaagaa aaagtggtgt gtaaaacatt tgatatttaa gacaataaag 2760 tttttatcat aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaagaaaaa aaaaaaaaaa 2820 aa 2822 <210> SEQ ID NO 43 <211> LENGTH: 152 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Hs.145049 <400> SEQUENCE: 43 Met Val His Ser Pro Arg Ser Leu Val Ala Asn Pro Ser Gln Val Leu 1 5 10 15 Phe Phe Leu Ser Phe Leu Phe Phe Phe Phe Leu Arg Gln Ser Phe Ala 20 25 30 Leu Val Ala Gln Ala Gly Val Gln Trp Arg Asn Leu Gly Ser Leu Gln 35 40 45 Pro Pro Pro Pro Gly Phe Lys Gln Phe Ser Cys Leu Ser Leu Leu Ser 50 55 60 Ser Trp Asp Tyr Arg His Ala Pro Pro Cys Pro Ala Tyr Phe Val Phe 65 70 75 80 Leu Val Asp Met Gly Phe Pro His Val Gly Gln Thr Gly Leu Glu Leu 85 90 95 Leu Thr Ser Gly Asp Pro Pro Ala Ser Ala Ser Gln Ser Ala Gly Ile 100 105 110 Thr Gly Gly Ser His Arg Ala Gln Pro Thr Ser Ser Asn Pro Tyr Gly 115 120 125 Ile Val Phe Phe Phe Leu Pro Val Lys Thr Phe Ser Gly Met Ser Gln 130 135 140 Glu Ala Gly Asp Cys Arg Glu Thr 145 150 <210> SEQ ID NO 44 <211> LENGTH: 4597 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Hs.296031 <400> SEQUENCE: 44 aatggtacga ttgagagatg agtgctatgg agaaaaatcc agccagaaag ggagatgcag 60 aagatagcac cagatcttct caatgttgtt ttcatcatgg acaggtgcgt tccttagaag 120 atgaagtgtt agtgattcct gagtttttct caccttcacg tcgattgatc tgaatttgga 180 gagtctgttt tctgtgtctg gctctgcact caactttgta ggggaccctg tcgaggtccc 240 cacactgtgg cttcaggtag acagagcaga tgggagccca tttcagttca ttgtcttgct 300 gaccaatggg gaactgtggt caggtgagag gaggcagctt ttacaatcag acttcattga 360 atagtgtggg ctgctgtttc cttgtaacaa aaccccataa tgatggcagt ttccggatgt 420 gtctttttag gacttcagaa cttattattt gaatagaagt ttaaagcatc tggatgatga 480 tgctgtagct aaaacagctg cttgtcagaa gagaccctat ttaacacttc taaacttgtt 540 tcagaggtgg aggaaaggat aatctgggaa ggcctccctc tcaagtccac aggttggtat 600 cagctgtgtt catcccccaa aaggaaaata aaatgacaac aatattttgg tcacagaatt 660 cctgagaaac ctctgtttct atcttcatgt ctttaagata gggacatgaa ttccccatga 720 tctgggtgat agggttagag tggccaggac actgttactt tgtgtgtgac acaggtggct 780 cctcatgaca gttcctccat gccttagaac atgttgtctg tctggtcatc cctgggggta 840 gagctgagtg acccagcagt gggagattta acaactggag aagaagatgg gatgtgttta 900 attatcccca gaggtagggc caatttgtca ccctttaaat agacttattt gcatataaac 960 taaagcacct tagggcatca ttaccgaaag tgtctaagca aatgtctgat atagttacgt 1020 gcctgcatta aaagaaagca gcccccttat cttgccttaa tatccttaca gtgttttaat 1080 aagttcataa tgcatcctgt atgtgcattt tttggtataa aacaccgaaa ggtggagaat 1140 tgacttcagt tctctccatc ctttcccctt aagtgttggt ggcgctgcag gggcaacgtg 1200 cctcccattg gaagtggtga cttcctcttt gatagaggtt tgcctgtctc ttgaaaatga 1260 aaagaagcgg agattgatct ctggagtccc atggtccagt ttggactatt gggaatattt 1320 tttatgggat gttaaaaaca atattagaga cgtgagatag taaatttgtg gtaataccgg 1380 atccaggaag cttacagtga agagtatgaa cttaacctga aaagtatttc tctgttctat 1440 aaatctctca gtgacatttg gattaatcaa gcataattaa atgtagttag atttttgtca 1500 gattgtagtt caaaataata ttcatctatg gagagggtaa tatattatgt agaaatttta 1560 ttaagcactt tagttaagca aacactaagg agaacaaaat caacctcagg aaggttaatt 1620 actaaaaaaa tcacaaagta tagtagatta tgtaaatcat tttaattttg aataccatgg 1680 cttgagcttt aatttacata gagacgtatt ttggatttgt ttttcacatt atattttcta 1740 gtacaggatt gcaattgcat tcttgaaaag ttctactcat tttaggattc cattaagttt 1800 gcttaacttt tttcatgtta taatttccaa aagcaaagaa ttacaattgt attctagcta 1860 attattttaa tgtttcacta actttgtgtg tattgtaaga ccatattttt atttctatac 1920 aaatgatgat tttaagagaa gtatcaggag agagaatgta tatgaaagca tcgcgtccac 1980 gcctggcttt gcaataagtg ttcatttaaa agaaagacat ttacaaaggt aaaacataag 2040 agtttagact atagcgataa atctttttat tttagtaatt tctttaaagg gaaaagtaaa 2100 gagatcaaaa tgattttata tgtatttttt ttgtactcag agaattacat tttcactacc 2160 cccgcctgtc tcagggaata gcctttgata agaatcccat ggagatctct ggaactctat 2220 tacagtgtgt tcagatttgt tagttcatat gtaaatttca gagctagagc ttcaaaacta 2280 gagtattgta atctcaggaa cataagatta tccaagaagc ctgaaccttg ctcttttcat 2340 gataaatgac atccaaattt cctttgtcta ggagataagc atagatccct tttatcatgc 2400 ttctctgaga ttttcacaga acaaccctgc aatttgattt tgtttgataa ttttgctttt 2460 tggcttttca gtgaggactc tattttccat tggaactgac tcctttgggg ataataagct 2520 ttcacttaaa agaacattcc attagatagt tctaacttca atgaacctaa aagtggcttc 2580 ttaatttgaa taatctggat aacttttgca aatgggtcaa aacagcacaa gtatcaacaa 2640 tcacgtatgt actgagtaat atttgccctc cagttagcaa agtcaagaaa tgtctaactc 2700 tggcacacag cactggtttt aactactctt tagttcatct ttgccttcca aattggttga 2760 aaatggcaag cttagaatgg aatgcatatt aataacagaa ccacttaatg ttttaaaata 2820 ttcatacctt gagattcttt ttgagagaaa aaagaaatct taacatccaa ttctagttgt 2880 tttggctttt cacatatgct agacatgaaa aaggcagtta caaaagtgaa atccgattgg 2940 aagtcagtgg tgtccgccat tgagccgtgc taaatgtcgt gtcacaaaag gagtttgtga 3000 aaacaggatg agtagaaaat gttatactgt tgtttctatc gtggcaccgc tttcttataa 3060 attccatttg ctttttgtca tctgaactgt tacaaccatg ggaaacctca gtccatattt 3120 ttaaaagcac tatatactta caggaaaaac cgacttatgc cttcattgaa aaaatgttga 3180 agttaatatc ccaaatgttt aatgagcatg ttttagaata tttacagcta aagtctgtca 3240 ctttagggat ttgacaaaac ttgagactgc ctgccaccga agagggacca ggcagaatct 3300 tctcagcctt gtaaccagcg ttaaaaaaat ataaggggct tgatgagatc ctagatctgc 3360 tccttttctc ctaggtgcct gggtaactcc tggggaaagc atcatattaa gtccttttca 3420 agcaaggtgt gtgattttga ccaatgaatt gagctgatat gtgattttga ccaatgaatt 3480 gtgcatctat ttaaaaatta ccaagtgtat cttgactctt gagtggacag tcaaggcaaa 3540 gtttacttag gaaatgtaaa gtatggagtg ttttaaaaaa ttcaaattga gtttattcac 3600 tgttggagga attgaattct attgcctccc tcatttcaat tatgttcatt gttacaattg 3660 tgctgctctg ttctcattgt gatgcttagt tctcgtgtag aactgagtgc tacattgtga 3720 ttagaaactg gagttgtgct tgagtcagtc ctggaaaaca ggacccattt ttaagaagaa 3780 cggaacatac cactttggca ttctggctga ccctaatttc tgcagagttc cttggtgtta 3840 aaatcatttg aggtcatagt tgctgcttat ggtttatata cacaccatct gctgctctaa 3900 gttcacatcc tctcaaaagc atgcaagtgc ttgaaattta aatatttccc agatctaaaa 3960 caacttgtga ctacctaaga aatgcttgaa ccaaataaga aacagcactg tggaataaaa 4020 tataccattg tgaacatatc tgatgctgca atgaaatgta aagttcctta ctttgctgat 4080 ttttcatcat aactccttga ctcataaaag cggtgtctaa actgggaaca gctgctaata 4140 gggtaaaagt attatacatc aaataaaagt tcattacaat atttgtactc ataagtcaaa 4200 atctgacctg gttcgctttg tgcctctgtc agcctactta cagtgataaa tgtacacaca 4260 agtccagtgt tgccaaggag ctttgtttat agaaagaagc ttggtcccct cagttctatg 4320 ctgttgtgtg gcctggttgg tacatgccgt catgatgaag gatgactttg gtttgagata 4380 atttgtcact ccacattcca tggagaaaag tgtttcattt tgatgttgga aaaacatgac 4440 cagagaagca tgtgactcag ataatgttcc ccggaagttg cagagcaatc tgtggtgtct 4500 gtcatagccc aactagtcct ggagcacatg gacaattctg taccccaata atcagaacaa 4560 taaaatggta gttgtgattc aaaaaaaaaa aaaaaaa 4597 <210> SEQ ID NO 45 <211> LENGTH: 5084 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: KIT <400> SEQUENCE: 45 gatcccatcg cagctaccgc gatgagaggc gctcgcggcg cctgggattt tctctgcgtt 60 ctgctcctac tgcttcgcgt ccagacaggc tcttctcaac catctgtgag tccaggggaa 120 ccgtctccac catccatcca tccaggaaaa tcagacttaa tagtccgcgt gggcgacgag 180 attaggctgt tatgcactga tccgggcttt gtcaaatgga cttttgagat cctggatgaa 240 acgaatgaga ataagcagaa tgaatggatc acggaaaagg cagaagccac caacaccggc 300 aaatacacgt gcaccaacaa acacggctta agcaattcca tttatgtgtt tgttagagat 360 cctgccaagc ttttccttgt tgaccgctcc ttgtatggga aagaagacaa cgacacgctg 420 gtccgctgtc ctctcacaga cccagaagtg accaattatt ccctcaaggg gtgccagggg 480 aagcctcttc ccaaggactt gaggtttatt cctgacccca aggcgggcat catgatcaaa 540 agtgtgaaac gcgcctacca tcggctctgt ctgcattgtt ctgtggacca ggagggcaag 600 tcagtgctgt cggaaaaatt catcctgaaa gtgaggccag ccttcaaagc tgtgcctgtt 660 gtgtctgtgt ccaaagcaag ctatcttctt agggaagggg aagaattcac agtgacgtgc 720 acaataaaag atgtgtctag ttctgtgtac tcaacgtgga aaagagaaaa cagtcagact 780 aaactacagg agaaatataa tagctggcat cacggtgact tcaattatga acgtcaggca 840 acgttgacta tcagttcagc gagagttaat gattctggag tgttcatgtg ttatgccaat 900 aatacttttg gatcagcaaa tgtcacaaca accttggaag tagtagataa aggattcatt 960 aatatcttcc ccatgataaa cactacagta tttgtaaacg atggagaaaa tgtagatttg 1020 attgttgaat atgaagcatt ccccaaacct gaacaccagc agtggatcta tatgaacaga 1080 accttcactg ataaatggga agattatccc aagtctgaga atgaaagtaa tatcagatac 1140 gtaagtgaac ttcatctaac gagattaaaa ggcaccgaag gaggcactta cacattccta 1200 gtgtccaatt ctgacgtcaa tgctgccata gcatttaatg tttatgtgaa tacaaaacca 1260 gaaatcctga cttacgacag gctcgtgaat ggcatgctcc aatgtgtggc agcaggattc 1320 ccagagccca caatagattg gtatttttgt ccaggaactg agcagagatg ctctgcttct 1380 gtactgccag tggatgtgca gacactaaac tcatctgggc caccgtttgg aaagctagtg 1440 gttcagagtt ctatagattc tagtgcattc aagcacaatg gcacggttga atgtaaggct 1500 tacaacgatg tgggcaagac ttctgcctat tttaactttg catttaaagg taacaacaaa 1560 gagcaaatcc atccccacac cctgttcact cctttgctga ttggtttcgt aatcgtagct 1620 ggcatgatgt gcattattgt gatgattctg acctacaaat atttacagaa acccatgtat 1680 gaagtacagt ggaaggttgt tgaggagata aatggaaaca attatgttta catagaccca 1740 acacaacttc cttatgatca caaatgggag tttcccagaa acaggctgag ttttgggaaa 1800 accctgggtg ctggagcttt cgggaaggtt gttgaggcaa ctgcttatgg cttaattaag 1860 tcagatgcgg ccatgactgt cgctgtaaag atgctcaagc cgagtgccca tttgacagaa 1920 cgggaagccc tcatgtctga actcaaagtc ctgagttacc ttggtaatca catgaatatt 1980 gtgaatctac ttggagcctg caccattgga gggcccaccc tggtcattac agaatattgt 2040 tgctatggtg atcttttgaa ttttttgaga agaaaacgtg attcatttat ttgttcaaag 2100 caggaagatc atgcagaagc tgcactttat aagaatcttc tgcattcaaa ggagtcttcc 2160 tgcagcgata gtactaatga gtacatggac atgaaacctg gagtttctta tgttgtccca 2220 accaaggccg acaaaaggag atctgtgaga ataggctcat acatagaaag agatgtgact 2280 cccgccatca tggaggatga cgagttggcc ctagacttag aagacttgct gagcttttct 2340 taccaggtgg caaagggcat ggctttcctc gcctccaaga attgtattca cagagacttg 2400 gcagccagaa atatcctcct tactcatggt cggatcacaa agatttgtga ttttggtcta 2460 gccagagaca tcaagaatga ttctaattat gtggttaaag gaaacgctcg actacctgtg 2520 aagtggatgg cacctgaaag cattttcaac tgtgtataca cgtttgaaag tgacgtctgg 2580 tcctatggga tttttctttg ggagctgttc tctttaggaa gcagccccta tcctggaatg 2640 ccggtcgatt ctaagttcta caagatgatc aaggaaggct tccggatgct cagccctgaa 2700 cacgcacctg ctgaaatgta tgacataatg aagacttgct gggatgcaga tcccctaaaa 2760 agaccaacat tcaagcaaat tgttcagcta attgagaagc agatttcaga gagcaccaat 2820 catatttact ccaacttagc aaactgcagc cccaaccgac agaagcccgt ggtagaccat 2880 tctgtgcgga tcaattctgt cggcagcacc gcttcctcct cccagcctct gcttgtgcac 2940 gacgatgtct gagcagaatc agtgtttggg tcacccctcc aggaatgatc tcttcttttg 3000 gcttccatga tggttatttt cttttctttc aacttgcatc caactccagg atagtgggca 3060 ccccactgca atcctgtctt tctgagcaca ctttagtggc cgatgatttt tgtcatcagc 3120 caccatccta ttgcaaaggt tccaactgta tatattccca atagcaacgt agcttctacc 3180 atgaacagaa aacattctga tttggaaaaa gagagggagg tatggactgg gggccagagt 3240 cctttccaag gcttctccaa ttctgcccaa aaatatggtt gatagtttac ctgaataaat 3300 ggtagtaatc acagttggcc ttcagaacca tccatagtag tatgatgata caagattaga 3360 agctgaaaac ctaagtcctt tatgtggaaa acagaacatc attagaacaa aggacagagt 3420 atgaacacct gggcttaaga aatctagtat ttcatgctgg gaatgagaca taggccatga 3480 aaaaaatgat ccccaagtgt gaacaaaaga tgctcttctg tggaccactg catgagcttt 3540 tatactaccg acctggtttt taaatagagt ttgctattag agcattgaat tggagagaag 3600 gcctccctag ccagcacttg tatatacgca tctataaatt gtccgtgttc atacatttga 3660 ggggaaaaca ccataaggtt tcgtttctgt atacaaccct ggcattatgt ccactgtgta 3720 tagaagtaga ttaagagcca tataagtttg aaggaaacag ttaataccat tttttaagga 3780 aacaatataa ccacaaagca cagtttgaac aaaatctcct cttttagctg atgaacttat 3840 tctgtagatt ctgtggaaca agcctatcag cttcagaatg gcattgtact caatggattt 3900 gatgctgttt gacaaagtta ctgattcact gcatggctcc cacaggagtg ggaaaacact 3960 gccatcttag tttggattct tatgtagcag gaaataaagt ataggtttag cctccttcgc 4020 aggcatgtcc tggacaccgg gccagtatct atatatgtgt atgtacgttt gtatgtgtgt 4080 agacaaatat ttggaggggt atttttgccc tgagtccaag agggtccttt agtacctgaa 4140 aagtaacttg gctttcatta ttagtactgc tcttgtttct tttcacatag ctgtctagag 4200 tagcttacca gaagcttcca tagtggtgca gaggaagtgg aaggcatcag tccctatgta 4260 tttgcagttc acctgcactt aaggcactct gttatttaga ctcatcttac tgtacctgtt 4320 ccttagacct tccataatgc tactgtctca ctgaaacatt taaattttac cctttagact 4380 gtagcctgga tattattctt gtagtttacc tctttaaaaa caaaacaaaa caaaacaaaa 4440 aactcccctt cctcactgcc caatataaaa ggcaaatgtg tacatggcag agtttgtgtg 4500 ttgtcttgaa agattcaggt atgttgcctt tatggtttcc cccttctaca tttcttagac 4560 tacatttaga gaactgtggc cgttatctgg aagtaaccat ttgcactgga gttctatgct 4620 ctcgcacctt tccaaagtta acagattttg gggttgtgtt gtcacccaag agattgttgt 4680 ttgccatact ttgtctgaaa aattcctttg tgtttctatt gacttcaatg atagtaagaa 4740 aagtggttgt tagttataga tgtctaggta cttcaggggc acttcattga gagttttgtc 4800 ttgccatact ttgtctgaaa aattcctttg tgtttctatt gacttcaatg atagtaagaa 4860 aagtggttgt tagttataga tgtctaggta cttcaggggc acttcattga gagttttgtc 4920 aatgtctttt gaatattccc aagcccatga gtccttgaaa atatttttta tatatacagt 4980 aactttatgt gtaaatacat aagcggcgta agtttaaagg atgttggtgt tccacgtgtt 5040 ttattcctgt atgttgtcca attgttgaca gttctgaaga attc 5084 <210> SEQ ID NO 46 <211> LENGTH: 976 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: KIT <400> SEQUENCE: 46 Met Arg Gly Ala Arg Gly Ala Trp Asp Phe Leu Cys Val Leu Leu Leu 1 5 10 15 Leu Leu Arg Val Gln Thr Gly Ser Ser Gln Pro Ser Val Ser Pro Gly 20 25 30 Glu Pro Ser Pro Pro Ser Ile His Pro Gly Lys Ser Asp Leu Ile Val 35 40 45 Arg Val Gly Asp Glu Ile Arg Leu Leu Cys Thr Asp Pro Gly Phe Val 50 55 60 Lys Trp Thr Phe Glu Ile Leu Asp Glu Thr Asn Glu Asn Lys Gln Asn 65 70 75 80 Glu Trp Ile Thr Glu Lys Ala Glu Ala Thr Asn Thr Gly Lys Tyr Thr 85 90 95 Cys Thr Asn Lys His Gly Leu Ser Asn Ser Ile Tyr Val Phe Val Arg 100 105 110 Asp Pro Ala Lys Leu Phe Leu Val Asp Arg Ser Leu Tyr Gly Lys Glu 115 120 125 Asp Asn Asp Thr Leu Val Arg Cys Pro Leu Thr Asp Pro Glu Val Thr 130 135 140 Asn Tyr Ser Leu Lys Gly Cys Gln Gly Lys Pro Leu Pro Lys Asp Leu 145 150 155 160 Arg Phe Ile Pro Asp Pro Lys Ala Gly Ile Met Ile Lys Ser Val Lys 165 170 175 Arg Ala Tyr His Arg Leu Cys Leu His Cys Ser Val Asp Gln Glu Gly 180 185 190 Lys Ser Val Leu Ser Glu Lys Phe Ile Leu Lys Val Arg Pro Ala Phe 195 200 205 Lys Ala Val Pro Val Val Ser Val Ser Lys Ala Ser Tyr Leu Leu Arg 210 215 220 Glu Gly Glu Glu Phe Thr Val Thr Cys Thr Ile Lys Asp Val Ser Ser 225 230 235 240 Ser Val Tyr Ser Thr Trp Lys Arg Glu Asn Ser Gln Thr Lys Leu Gln 245 250 255 Glu Lys Tyr Asn Ser Trp His His Gly Asp Phe Asn Tyr Glu Arg Gln 260 265 270 Ala Thr Leu Thr Ile Ser Ser Ala Arg Val Asn Asp Ser Gly Val Phe 275 280 285 Met Cys Tyr Ala Asn Asn Thr Phe Gly Ser Ala Asn Val Thr Thr Thr 290 295 300 Leu Glu Val Val Asp Lys Gly Phe Ile Asn Ile Phe Pro Met Ile Asn 305 310 315 320 Thr Thr Val Phe Val Asn Asp Gly Glu Asn Val Asp Leu Ile Val Glu 325 330 335 Tyr Glu Ala Phe Pro Lys Pro Glu His Gln Gln Trp Ile Tyr Met Asn 340 345 350 Arg Thr Phe Thr Asp Lys Trp Glu Asp Tyr Pro Lys Ser Glu Asn Glu 355 360 365 Ser Asn Ile Arg Tyr Val Ser Glu Leu His Leu Thr Arg Leu Lys Gly 370 375 380 Thr Glu Gly Gly Thr Tyr Thr Phe Leu Val Ser Asn Ser Asp Val Asn 385 390 395 400 Ala Ala Ile Ala Phe Asn Val Tyr Val Asn Thr Lys Pro Glu Ile Leu 405 410 415 Thr Tyr Asp Arg Leu Val Asn Gly Met Leu Gln Cys Val Ala Ala Gly 420 425 430 Phe Pro Glu Pro Thr Ile Asp Trp Tyr Phe Cys Pro Gly Thr Glu Gln 435 440 445 Arg Cys Ser Ala Ser Val Leu Pro Val Asp Val Gln Thr Leu Asn Ser 450 455 460 Ser Gly Pro Pro Phe Gly Lys Leu Val Val Gln Ser Ser Ile Asp Ser 465 470 475 480 Ser Ala Phe Lys His Asn Gly Thr Val Glu Cys Lys Ala Tyr Asn Asp 485 490 495 Val Gly Lys Thr Ser Ala Tyr Phe Asn Phe Ala Phe Lys Gly Asn Asn 500 505 510 Lys Glu Gln Ile His Pro His Thr Leu Phe Thr Pro Leu Leu Ile Gly 515 520 525 Phe Val Ile Val Ala Gly Met Met Cys Ile Ile Val Met Ile Leu Thr 530 535 540 Tyr Lys Tyr Leu Gln Lys Pro Met Tyr Glu Val Gln Trp Lys Val Val 545 550 555 560 Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu 565 570 575 Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly 580 585 590 Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val Val Glu Ala Thr Ala 595 600 605 Tyr Gly Leu Ile Lys Ser Asp Ala Ala Met Thr Val Ala Val Lys Met 610 615 620 Leu Lys Pro Ser Ala His Leu Thr Glu Arg Glu Ala Leu Met Ser Glu 625 630 635 640 Leu Lys Val Leu Ser Tyr Leu Gly Asn His Met Asn Ile Val Asn Leu 645 650 655 Leu Gly Ala Cys Thr Ile Gly Gly Pro Thr Leu Val Ile Thr Glu Tyr 660 665 670 Cys Cys Tyr Gly Asp Leu Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser 675 680 685 Phe Ile Cys Ser Lys Gln Glu Asp His Ala Glu Ala Ala Leu Tyr Lys 690 695 700 Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser Asp Ser Thr Asn Glu 705 710 715 720 Tyr Met Asp Met Lys Pro Gly Val Ser Tyr Val Val Pro Thr Lys Ala 725 730 735 Asp Lys Arg Arg Ser Val Arg Ile Gly Ser Tyr Ile Glu Arg Asp Val 740 745 750 Thr Pro Ala Ile Met Glu Asp Asp Glu Leu Ala Leu Asp Leu Glu Asp 755 760 765 Leu Leu Ser Phe Ser Tyr Gln Val Ala Lys Gly Met Ala Phe Leu Ala 770 775 780 Ser Lys Asn Cys Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu 785 790 795 800 Thr His Gly Arg Ile Thr Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp 805 810 815 Ile Lys Asn Asp Ser Asn Tyr Val Val Lys Gly Asn Ala Arg Leu Pro 820 825 830 Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn Cys Val Tyr Thr Phe 835 840 845 Glu Ser Asp Val Trp Ser Tyr Gly Ile Phe Leu Trp Glu Leu Phe Ser 850 855 860 Leu Gly Ser Ser Pro Tyr Pro Gly Met Pro Val Asp Ser Lys Phe Tyr 865 870 875 880 Lys Met Ile Lys Glu Gly Phe Arg Met Leu Ser Pro Glu His Ala Pro 885 890 895 Ala Glu Met Tyr Asp Ile Met Lys Thr Cys Trp Asp Ala Asp Pro Leu 900 905 910 Lys Arg Pro Thr Phe Lys Gln Ile Val Gln Leu Ile Glu Lys Gln Ile 915 920 925 Ser Glu Ser Thr Asn His Ile Tyr Ser Asn Leu Ala Asn Cys Ser Pro 930 935 940 Asn Arg Gln Lys Pro Val Val Asp His Ser Val Arg Ile Asn Ser Val 945 950 955 960 Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu Val His Asp Asp Val 965 970 975 <210> SEQ ID NO 47 <211> LENGTH: 489 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LSM7 <400> SEQUENCE: 47 cgcgacaaga tggcggataa ggagaagaag aaaaaggaga gcatcttgga cttgtccaag 60 tacatcgaca agacgatccg ggtaaagttc cagggaggcc gcgaagccag tggaatcctg 120 aagggcttcg acccactcct caaccttgtg ctggacggca ccattgagta catgcgagac 180 cctgacgacc agtacaagct cacggaggac acccggcagc tgggcctcgt ggtgtgccgg 240 ggcacgtccg tggtgctaat ctgcccgcag gacggcatgg aggccatccc caaccccttc 300 atccagcagc aggacgccta gcctggccgg gggcgcgggg ggtgcagggc aggcccgagc 360 agctcggttt cccgcggact tggctgctgc tcccaccgca gtaccgcctc ctggaacgga 420 agcatttctc ctttttgtat aggttgaatt tttgttttct taataaaatt gcaaacctca 480 aaaaaaaaa 489 <210> SEQ ID NO 48 <211> LENGTH: 103 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LSM7 <400> SEQUENCE: 48 Met Ala Asp Lys Glu Lys Lys Lys Lys Glu Ser Ile Leu Asp Leu Ser 1 5 10 15 Lys Tyr Ile Asp Lys Thr Ile Arg Val Lys Phe Gln Gly Gly Arg Glu 20 25 30 Ala Ser Gly Ile Leu Lys Gly Phe Asp Pro Leu Leu Asn Leu Val Leu 35 40 45 Asp Gly Thr Ile Glu Tyr Met Arg Asp Pro Asp Asp Gln Tyr Lys Leu 50 55 60 Thr Glu Asp Thr Arg Gln Leu Gly Leu Val Val Cys Arg Gly Thr Ser 65 70 75 80 Val Val Leu Ile Cys Pro Gln Asp Gly Met Glu Ala Ile Pro Asn Pro 85 90 95 Phe Ile Gln Gln Gln Asp Ala 100 <210> SEQ ID NO 49 <211> LENGTH: 1694 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: SYNGR2 <400> SEQUENCE: 49 ggcggcggca gcggcggcga cggcgacatg gagagcgggg cctacggcgc ggccaaggcg 60 ggcggctcct tcgacctgcg gcgcttcctg acgcagccgc aggtggtggc gcgcgccgtg 120 tgcttggtct tcgccttgat cgtgttctcc tgcatctatg gtgagggcta cagcaatgcc 180 cacgagtcta agcagatgta ctgcgtgttc aaccgcaacg aggatgcctg ccgctatggc 240 agtgccatcg gggtgctggc cttcctggcc tcggccttct tcttggtggt cgacgcgtat 300 ttcccccaga tcagcaacgc cactgaccgc aagtacctgg tcattggtga cctgctcttc 360 tcagctctct ggaccttcct gtggtttgtt ggtttctgct tcctcaccaa ccagtgggca 420 gtcaccaacc cgaaggacgt gctggtgggg gccgactctg tgagggcagc catcaccttc 480 agcttctttt ccatcttctc ctggggtgtg ctggcctccc tggcctacca gcgctacaag 540 gctggcgtgg acgacttcat ccagaattac gttgacccca ctccggaccc caacactgcc 600 tacgcctcct acccaggtgc atctgtggac aactaccaac agccaccctt cacccagaac 660 gcggagacca ccgagggcta ccagccgccc cctgtgtact gagcggcggt tagcgtggga 720 agggggacag agagggccct cccctctgcc ctggactttc ccatgagcct cctggaactg 780 ccagcccctc tctttcacct gttccatcct gtgcagctga cacacagcta aggagcctca 840 tagcctggcg ggggctggca gagccacacc ccaagtgcct gtgcccagag ggcttcagtc 900 agccgctcac tcctccaggg cacttttagg aaagggtttt tagctagtgt ttttcctcgc 960 ttttaatgac ctcagccccg cctgcagtgg ctagaagcca gcaggtgccc atgtgctact 1020 gacaagtgcc tcagcttccc cccggcccgg gtcaggccgt gggagccgct attatctgcg 1080 ttctctgcca aagactcgtg ggggccatca cacctgccct gtgcagcgga gccggaccag 1140 gctcttgtgt cctcactcag gtttgcttcc cctgtgccca ctgctgtatg atctgggggc 1200 caccaccctg tgccggtggc ctctgggctg cctcccgtgg tgtgagggcg gggctggtgc 1260 tcatggcact tcctccttgc tcccacccct ggcagcaggg aagggctttg cctgacaaca 1320 cccagcttta tgtaaatatt ctgcagttgt tacttaggaa gcctggggag ggcaggggtg 1380 ccccatggct cccagactct gtctgtgccg agtgtattat aaaatcgtgg gggagatgcc 1440 cggcctggga tgctgtttgg agacggaata aatgttttct cattcagtct ccagtcattg 1500 gttgagccac agcctagggg ttggaggaag actccactct gggtacaccc ttaggggctg 1560 gctttatgga acttgtagtt tgaacaaggc agtggcaatc cgccccctcc agcctgcctg 1620 gctggccccc ttccctctgt ctggggtcgc attccgcaca agcctttcat caacatctta 1680 aaatagtaac tgtg 1694 <210> SEQ ID NO 50 <211> LENGTH: 224 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: SYNGR2 <400> SEQUENCE: 50 Met Glu Ser Gly Ala Tyr Gly Ala Ala Lys Ala Gly Gly Ser Phe Asp 1 5 10 15 Leu Arg Arg Phe Leu Thr Gln Pro Gln Val Val Ala Arg Ala Val Cys 20 25 30 Leu Val Phe Ala Leu Ile Val Phe Ser Cys Ile Tyr Gly Glu Gly Tyr 35 40 45 Ser Asn Ala His Glu Ser Lys Gln Met Tyr Cys Val Phe Asn Arg Asn 50 55 60 Glu Asp Ala Cys Arg Tyr Gly Ser Ala Ile Gly Val Leu Ala Phe Leu 65 70 75 80 Ala Ser Ala Phe Phe Leu Val Val Asp Ala Tyr Phe Pro Gln Ile Ser 85 90 95 Asn Ala Thr Asp Arg Lys Tyr Leu Val Ile Gly Asp Leu Leu Phe Ser 100 105 110 Ala Leu Trp Thr Phe Leu Trp Phe Val Gly Phe Cys Phe Leu Thr Asn 115 120 125 Gln Trp Ala Val Thr Asn Pro Lys Asp Val Leu Val Gly Ala Asp Ser 130 135 140 Val Arg Ala Ala Ile Thr Phe Ser Phe Phe Ser Ile Phe Ser Trp Gly 145 150 155 160 Val Leu Ala Ser Leu Ala Tyr Gln Arg Tyr Lys Ala Gly Val Asp Asp 165 170 175 Phe Ile Gln Asn Tyr Val Asp Pro Thr Pro Asp Pro Asn Thr Ala Tyr 180 185 190 Ala Ser Tyr Pro Gly Ala Ser Val Asp Asn Tyr Gln Gln Pro Pro Phe 195 200 205 Thr Gln Asn Ala Glu Thr Thr Glu Gly Tyr Gln Pro Pro Pro Val Tyr 210 215 220 <210> SEQ ID NO 51 <211> LENGTH: 2272 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: c11orf8 <400> SEQUENCE: 51 aatgcacagc ggtattgatg agtagatcct tggattcaga ggttggctga aacgcaccat 60 gcctgcttcc atcttttgct ctgtaaagtt gtgaattgct catgcctata gggaggaagg 120 atggcacatg ggattccttc tcaaggcaaa gttaccataa cggtggatga gtacagctca 180 aaccccaccc aggcattcac gcactacaac atcaaccaga gcagattcca gcctccacat 240 gtacatatgg tcgaccccat cccatatgac actccaaaac cagcgggcca cacgcggttt 300 gtctgcatct cagacacaca ctccagaaca gatggtatcc agatgcctta tggggacatc 360 cttctccaca caggcgattt caccgagctg ggactgccct cagaggttaa gaagtttaat 420 gactggttag gaaacctgcc atatgaatat aaaatagtga ttgctgggaa tcatgaactg 480 acatttgata aggaattcat ggcagacctt gttaaacagg actactaccg tttcccctct 540 gtgtccaaat tgaaaccaga ggactttgac aatgttcagt ccctcctgac aaacagtatt 600 tacttacaag attcggaggt aacagtgaag ggattcagga tatacggtgc accttggacc 660 ccgtggttta atggatgggg ctttaaccta cccagaggtc agtctctgct ggacaagtgg 720 aacctcatcc ctgagggcat tgacatactc atgacacatg gacctcctct aggttttcga 780 gactgggttc caaaggagct tcaaagagtg ggctgtgtgg agctgttaaa cacggttcag 840 aggcgagtcc ggcccaagct ccatgtgttt ggtggaatcc atgaaggtta tggcatcatg 900 accgacggtt acacaacgta catcaatgcc tcgacgtgta cagtcagctt tcaaccgacc 960 aaccctccaa ttatatttga ccttccaaac ccacagggtt cctgaagctc taaatgccct 1020 attggaatgt gagggaaggt ctataaactg ccatttttct aattataaac ttacattctc 1080 ttacttattt acaaaccctg tgagttcttt ttgtaaattg ttggaacaca aatgatgcta 1140 gaggttgtgc ttcttatttt attttatttt aaatggggca tccatttgaa atcagaggaa 1200 cattgtgaat ttgtaaaatg acttctgttt tctcaaaggc catgccattg taaattgtta 1260 gtgttcgcca aaggacagcc aagctttctt ttaaaaagtg ataaaagtct tattttaata 1320 tgctttaagc tgaaagaaaa aaaaataaga aacaggcagt gttttaaaaa ccaacacaga 1380 tttgcacaac tgtttaagag tattgtttga aatattttaa ttttcaatgt tttgttgttg 1440 ttgttttctt ggtaatgctt cttttttgca gatgtggtcc caatttatag caatcttctc 1500 aacagaagta ggcatggaaa agacttcttt tcatactctc actataaaga aagctgcatt 1560 gagaagaaaa tggctgtcat ttaaaggatg gtttaactag tgagattcct attgtggtta 1620 tacaaggtct cattgtttgt ttgtttcttt taaattattt cagctttaaa aatacagaaa 1680 tggaatctgt caagagcagg tatttcatac ggttaaaaaa atgaacatgc agactccttt 1740 tcaatatggg tttatatata taagtatttt ttgtgtatta tgactacgtt aggagtttaa 1800 tattgtcaag gacagtacaa ctgcaaaggg atgctgtata gcagcacatc agaagtcgga 1860 aggaactgac acattctctc agagctcaag gtcttaaaga gcttgagtta aatctaggta 1920 cagttacagg catgtataga cttaaatgga tgcaatggaa gctaactaaa ataaggctta 1980 gttgtccttt ctatttaaat accccaagtt gtcttcttac ttcctctccc ctctcccatt 2040 ttgcactgtg tgtcgatgca atcttcgcta gcacaaaata ttgtcgctaa tagtcatttc 2100 tgttttccca ttgtaaatgc tgttgagctt tattctattt tatgttactt tgttaatgaa 2160 atttaggaaa gcagttgttt ctttaaattt attgtgatat tctatatcta gcggccttta 2220 tatgcaaata aaattgcaag atttttaaaa aaaaaaaaaa aaaaaaaaaa aa 2272 <210> SEQ ID NO 52 <211> LENGTH: 294 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: c11orf8 <400> SEQUENCE: 52 Met Ala His Gly Ile Pro Ser Gln Gly Lys Val Thr Ile Thr Val Asp 1 5 10 15 Glu Tyr Ser Ser Asn Pro Thr Gln Ala Phe Thr His Tyr Asn Ile Asn 20 25 30 Gln Ser Arg Phe Gln Pro Pro His Val His Met Val Asp Pro Ile Pro 35 40 45 Tyr Asp Thr Pro Lys Pro Ala Gly His Thr Arg Phe Val Cys Ile Ser 50 55 60 Asp Thr His Ser Arg Thr Asp Gly Ile Gln Met Pro Tyr Gly Asp Ile 65 70 75 80 Leu Leu His Thr Gly Asp Phe Thr Glu Leu Gly Leu Pro Ser Glu Val 85 90 95 Lys Lys Phe Asn Asp Trp Leu Gly Asn Leu Pro Tyr Glu Tyr Lys Ile 100 105 110 Val Ile Ala Gly Asn His Glu Leu Thr Phe Asp Lys Glu Phe Met Ala 115 120 125 Asp Leu Val Lys Gln Asp Tyr Tyr Arg Phe Pro Ser Val Ser Lys Leu 130 135 140 Lys Pro Glu Asp Phe Asp Asn Val Gln Ser Leu Leu Thr Asn Ser Ile 145 150 155 160 Tyr Leu Gln Asp Ser Glu Val Thr Val Lys Gly Phe Arg Ile Tyr Gly 165 170 175 Ala Pro Trp Thr Pro Trp Phe Asn Gly Trp Gly Phe Asn Leu Pro Arg 180 185 190 Gly Gln Ser Leu Leu Asp Lys Trp Asn Leu Ile Pro Glu Gly Ile Asp 195 200 205 Ile Leu Met Thr His Gly Pro Pro Leu Gly Phe Arg Asp Trp Val Pro 210 215 220 Lys Glu Leu Gln Arg Val Gly Cys Val Glu Leu Leu Asn Thr Val Gln 225 230 235 240 Arg Arg Val Arg Pro Lys Leu His Val Phe Gly Gly Ile His Glu Gly 245 250 255 Tyr Gly Ile Met Thr Asp Gly Tyr Thr Thr Tyr Ile Asn Ala Ser Thr 260 265 270 Cys Thr Val Ser Phe Gln Pro Thr Asn Pro Pro Ile Ile Phe Asp Leu 275 280 285 Pro Asn Pro Gln Gly Ser 290 <210> SEQ ID NO 53 <211> LENGTH: 4828 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: CDH1 <400> SEQUENCE: 53 agtggcgtcg gaactgcaaa gcacctgtga gcttgcggaa gtcagttcag actccagccc 60 gctccagccc ggcccgaccc gaccgcaccc ggcgcctgcc ctcgctcggc gtccccggcc 120 agccatgggc ccttggagcc gcagcctctc ggcgctgctg ctgctgctgc aggtctcctc 180 ttggctctgc caggagccgg agccctgcca ccctggcttt gacgccgaga gctacacgtt 240 cacggtgccc cggcgccacc tggagagagg ccgcgtcctg ggcagagtga attttgaaga 300 ttgcaccggt cgacaaagga cagcctattt ttccctcgac acccgattca aagtgggcac 360 agatggtgtg attacagtca aaaggcctct acggtttcat aacccacaga tccatttctt 420 ggtctacgcc tgggactcca cctacagaaa gttttccacc aaagtcacgc tgaatacagt 480 ggggcaccac caccgccccc cgccccatca ggcctccgtt tctggaatcc aagcagaatt 540 gctcacattt cccaactcct ctcctggcct cagaagacag aagagagact gggttattcc 600 tcccatcagc tgcccagaaa atgaaaaagg cccatttcct aaaaacctgg ttcagatcaa 660 atccaacaaa gacaaagaag gcaaggtttt ctacagcatc actggccaag gagctgacac 720 accccctgtt ggtgtcttta ttattgaaag agaaacagga tggctgaagg tgacagagcc 780 tctggataga gaacgcattg ccacatacac tctcttctct cacgctgtgt catccaacgg 840 gaatgcagtt gaggatccaa tggagatttt gatcacggta accgatcaga atgacaacaa 900 gcccgaattc acccaggagg tctttaaggg gtctgtcatg gaaggtgctc ttccaggaac 960 ctctgtgatg gaggtcacag ccacagacgc ggacgatgat gtgaacacct acaatgccgc 1020 catcgcttac accatcctca gccaagatcc tgagctccct gacaaaaata tgttcaccat 1080 taacaggaac acaggagtca tcagtgtggt caccactggg ctggaccgag agagtttccc 1140 tacgtatacc ctggtggttc aagctgctga ccttcaaggt gaggggttaa gcacaacagc 1200 aacagctgtg atcacagtca ctgacaccaa cgataatcct ccgatcttca atcccaccac 1260 gtacaagggt caggtgcctg agaacgaggc taacgtcgta atcaccacac tgaaagtgac 1320 tgatgctgat gcccccaata ccccagcgtg ggaggctgta tacaccatat tgaatgatga 1380 tggtggacaa tttgtcgtca ccacaaatcc agtgaacaac gatggcattt tgaaaacagc 1440 aaagggcttg gattttgagg ccaagcagca gtacattcta cacgtagcag tgacgaatgt 1500 ggtacctttt gaggtctctc tcaccacctc cacagccacc gtcaccgtgg atgtgctgga 1560 tgtgaatgaa gcccccatct ttgtgcctcc tgaaaagaga gtggaagtgt ccgaggactt 1620 tggcgtgggc caggaaatca catcctacac tgcccaggag ccagacacat ttatggaaca 1680 gaaaataaca tatcggattt ggagagacac tgccaactgg ctggagatta atccggacac 1740 tggtgccatt tccactcggg ctgagctgga cagggaggat tttgagcacg tgaagaacag 1800 cacgtacaca gccctaatca tagctacaga caatggttct ccagttgcta ctggaacagg 1860 gacacttctg ctgatcctgt ctgatgtgaa tgacaacgcc cccataccag aacctcgaac 1920 tatattcttc tgtgagagga atccaaagcc tcaggtcata aacatcattg atgcagacct 1980 tcctcccaat acatctccct tcacagcaga actaacacac ggggcgagtg ccaactggac 2040 cattcagtac aacgacccaa cccaagaatc tatcattttg aagccaaaga tggccttaga 2100 ggtgggtgac tacaaaatca atctcaagct catggataac cagaataaag accaagtgac 2160 caccttagag gtcagcgtgt gtgactgtga aggggccgcc ggcgtctgta ggaaggcaca 2220 gcctgtcgaa gcaggattgc aaattcctgc cattctgggg attcttggag gaattcttgc 2280 tttgctaatt ctgattctgc tgctcttgct gtttcttcgg aggagagcgg tggtcaaaga 2340 gcccttactg cccccagagg atgacacccg ggacaacgtt tattactatg atgaagaagg 2400 aggcggagaa gaggaccagg actttgactt gagccagctg cacaggggcc tggacgctcg 2460 gcctgaagtg actcgtaacg acgttgcacc aaccctcatg agtgtccccc ggtatcttcc 2520 ccgccctgcc aatcccgatg aaattggaaa ttttattgat gaaaatctga aagcggctga 2580 tactgacccc acagccccgc cttatgattc tctgctcgtg tttgactatg aaggaagcgg 2640 ttccgaagct gctagtctga gctccctgaa ctcctcagag tcagacaaag accaggacta 2700 tgactacttg aacgaatggg gcaatcgctt caagaagctg gctgacatgt acggaggcgg 2760 cgaggacgac taggggactc gagagaggcg ggccccagac ccatgtgctg ggaaatgcag 2820 aaatcacgtt gctggtggtt tttcagctcc cttcccttga gatgagtttc tggggaaaaa 2880 aaagagactg gttagtgatg cagttagtat agctttatac tctctccact ttatagctct 2940 aataagtttg tgttagaaaa gtttcgactt atttcttaaa gctttttttt ttttcccatc 3000 actctttaca tggtggtgat gtccaaaaga tacccaaatt ttaatattcc agaagaacaa 3060 ctttagcatc agaaggttca cccagcacct tgcagatttt cttaaggaat tttgtctcac 3120 ttttaaaaag aaggggagaa gtcagctact ctagttctgt tgttttgtgt atataatttt 3180 ttaaaaaaaa tttgtgtgct tctgctcatt actacactgg tgtgtccctc tgcctttttt 3240 ttttttttta agacagggtc tcattctatc ggccaggctg gagtgcagtg gtgcaatcac 3300 agctcactgc agccttgtcc tcccaggctc aagctatcct tgcacctcag cctcccaagt 3360 agctgggacc acaggcatgc accactacgc atgactaatt ttttaaatat ttgagacggg 3420 gtctccctgt gttacccagg ctggtctcaa actcctgggc tcaagtgatc ctcccatctt 3480 ggcctcccag agtattggga ttacagacat gagccactgc acctgcccag ctccccaact 3540 ccctgccatt ttttaagaga cagtttcgct ccatcgccca ggcctgggat gcagtgatgt 3600 gatcatagct cactgtaacc tcaaactctg gggctcaagc agttctccca ccagcctcct 3660 ttttattttt ttgtacagat ggggtcttgc tatgttgccc aagctggtct taaactcctg 3720 gcctcaagca atccttctgc cttggccccc caaagtgctg ggattgtggg catgagctgc 3780 tgtgcccagc ctccatgttt taatatcaac tctcactcct gaattcagtt gctttgccca 3840 agataggagt tctctgatgc agaaattatt gggctctttt agggtaagaa gtttgtgtct 3900 ttgtctggcc acatcttgac taggtattgt ctactctgaa gacctttaat ggcttccctc 3960 tttcatctcc tgagtatgta acttgcaatg ggcagctatc cagtgacttg ttctgagtaa 4020 gtgtgttcat taatgtttat ttagctctga agcaagagtg atatactcca ggacttagaa 4080 tagtgcctaa agtgctgcag ccaaagacag agcggaacta tgaaaagtgg gcttggagat 4140 ggcaggagag cttgtcattg agcctggcaa tttagcaaac tgatgctgag gatgattgag 4200 gtgggtctac ctcatctctg aaaattctgg aaggaatgga ggagtctcaa catgtgtttc 4260 tgacacaaga tccgtggttt gtactcaaag cccagaatcc ccaagtgcct gcttttgatg 4320 atgtctacag aaaatgctgg ctgagctgaa cacatttgcc caattccagg tgtgcacaga 4380 aaaccgagaa tattcaaaat tccaaatttt ttcttaggag caagaagaaa atgtggccct 4440 aaagggggtt agttgagggg tagggggtag tgaggatctt gatttggatc tctttttatt 4500 taaatgtgaa tttcaacttt tgacaatcaa agaaaagact tttgttgaaa tagctttact 4560 gtttctcaag tgttttggag aaaaaaatca accctgcaat cactttttgg aattgtcttg 4620 atttttcggc agttcaagct atatcgaata tagttctgtg tagagaatgt cactgtagtt 4680 ttgagtgtat acatgtgtgg gtgctgataa ttgtgtattt tctttggggg tggaaaagga 4740 aaacaattca agctgagaaa agtattctca aagatgcatt tttataaatt ttattaaaca 4800 attttgttaa accataaaaa aaaaaaaa 4828 <210> SEQ ID NO 54 <211> LENGTH: 882 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: CDH1 <400> SEQUENCE: 54 Met Gly Pro Trp Ser Arg Ser Leu Ser Ala Leu Leu Leu Leu Leu Gln 1 5 10 15 Val Ser Ser Trp Leu Cys Gln Glu Pro Glu Pro Cys His Pro Gly Phe 20 25 30 Asp Ala Glu Ser Tyr Thr Phe Thr Val Pro Arg Arg His Leu Glu Arg 35 40 45 Gly Arg Val Leu Gly Arg Val Asn Phe Glu Asp Cys Thr Gly Arg Gln 50 55 60 Arg Thr Ala Tyr Phe Ser Leu Asp Thr Arg Phe Lys Val Gly Thr Asp 65 70 75 80 Gly Val Ile Thr Val Lys Arg Pro Leu Arg Phe His Asn Pro Gln Ile 85 90 95 His Phe Leu Val Tyr Ala Trp Asp Ser Thr Tyr Arg Lys Phe Ser Thr 100 105 110 Lys Val Thr Leu Asn Thr Val Gly His His His Arg Pro Pro Pro His 115 120 125 Gln Ala Ser Val Ser Gly Ile Gln Ala Glu Leu Leu Thr Phe Pro Asn 130 135 140 Ser Ser Pro Gly Leu Arg Arg Gln Lys Arg Asp Trp Val Ile Pro Pro 145 150 155 160 Ile Ser Cys Pro Glu Asn Glu Lys Gly Pro Phe Pro Lys Asn Leu Val 165 170 175 Gln Ile Lys Ser Asn Lys Asp Lys Glu Gly Lys Val Phe Tyr Ser Ile 180 185 190 Thr Gly Gln Gly Ala Asp Thr Pro Pro Val Gly Val Phe Ile Ile Glu 195 200 205 Arg Glu Thr Gly Trp Leu Lys Val Thr Glu Pro Leu Asp Arg Glu Arg 210 215 220 Ile Ala Thr Tyr Thr Leu Phe Ser His Ala Val Ser Ser Asn Gly Asn 225 230 235 240 Ala Val Glu Asp Pro Met Glu Ile Leu Ile Thr Val Thr Asp Gln Asn 245 250 255 Asp Asn Lys Pro Glu Phe Thr Gln Glu Val Phe Lys Gly Ser Val Met 260 265 270 Glu Gly Ala Leu Pro Gly Thr Ser Val Met Glu Val Thr Ala Thr Asp 275 280 285 Ala Asp Asp Asp Val Asn Thr Tyr Asn Ala Ala Ile Ala Tyr Thr Ile 290 295 300 Leu Ser Gln Asp Pro Glu Leu Pro Asp Lys Asn Met Phe Thr Ile Asn 305 310 315 320 Arg Asn Thr Gly Val Ile Ser Val Val Thr Thr Gly Leu Asp Arg Glu 325 330 335 Ser Phe Pro Thr Tyr Thr Leu Val Val Gln Ala Ala Asp Leu Gln Gly 340 345 350 Glu Gly Leu Ser Thr Thr Ala Thr Ala Val Ile Thr Val Thr Asp Thr 355 360 365 Asn Asp Asn Pro Pro Ile Phe Asn Pro Thr Thr Tyr Lys Gly Gln Val 370 375 380 Pro Glu Asn Glu Ala Asn Val Val Ile Thr Thr Leu Lys Val Thr Asp 385 390 395 400 Ala Asp Ala Pro Asn Thr Pro Ala Trp Glu Ala Val Tyr Thr Ile Leu 405 410 415 Asn Asp Asp Gly Gly Gln Phe Val Val Thr Thr Asn Pro Val Asn Asn 420 425 430 Asp Gly Ile Leu Lys Thr Ala Lys Gly Leu Asp Phe Glu Ala Lys Gln 435 440 445 Gln Tyr Ile Leu His Val Ala Val Thr Asn Val Val Pro Phe Glu Val 450 455 460 Ser Leu Thr Thr Ser Thr Ala Thr Val Thr Val Asp Val Leu Asp Val 465 470 475 480 Asn Glu Ala Pro Ile Phe Val Pro Pro Glu Lys Arg Val Glu Val Ser 485 490 495 Glu Asp Phe Gly Val Gly Gln Glu Ile Thr Ser Tyr Thr Ala Gln Glu 500 505 510 Pro Asp Thr Phe Met Glu Gln Lys Ile Thr Tyr Arg Ile Trp Arg Asp 515 520 525 Thr Ala Asn Trp Leu Glu Ile Asn Pro Asp Thr Gly Ala Ile Ser Thr 530 535 540 Arg Ala Glu Leu Asp Arg Glu Asp Phe Glu His Val Lys Asn Ser Thr 545 550 555 560 Tyr Thr Ala Leu Ile Ile Ala Thr Asp Asn Gly Ser Pro Val Ala Thr 565 570 575 Gly Thr Gly Thr Leu Leu Leu Ile Leu Ser Asp Val Asn Asp Asn Ala 580 585 590 Pro Ile Pro Glu Pro Arg Thr Ile Phe Phe Cys Glu Arg Asn Pro Lys 595 600 605 Pro Gln Val Ile Asn Ile Ile Asp Ala Asp Leu Pro Pro Asn Thr Ser 610 615 620 Pro Phe Thr Ala Glu Leu Thr His Gly Ala Ser Ala Asn Trp Thr Ile 625 630 635 640 Gln Tyr Asn Asp Pro Thr Gln Glu Ser Ile Ile Leu Lys Pro Lys Met 645 650 655 Ala Leu Glu Val Gly Asp Tyr Lys Ile Asn Leu Lys Leu Met Asp Asn 660 665 670 Gln Asn Lys Asp Gln Val Thr Thr Leu Glu Val Ser Val Cys Asp Cys 675 680 685 Glu Gly Ala Ala Gly Val Cys Arg Lys Ala Gln Pro Val Glu Ala Gly 690 695 700 Leu Gln Ile Pro Ala Ile Leu Gly Ile Leu Gly Gly Ile Leu Ala Leu 705 710 715 720 Leu Ile Leu Ile Leu Leu Leu Leu Leu Phe Leu Arg Arg Arg Ala Val 725 730 735 Val Lys Glu Pro Leu Leu Pro Pro Glu Asp Asp Thr Arg Asp Asn Val 740 745 750 Tyr Tyr Tyr Asp Glu Glu Gly Gly Gly Glu Glu Asp Gln Asp Phe Asp 755 760 765 Leu Ser Gln Leu His Arg Gly Leu Asp Ala Arg Pro Glu Val Thr Arg 770 775 780 Asn Asp Val Ala Pro Thr Leu Met Ser Val Pro Arg Tyr Leu Pro Arg 785 790 795 800 Pro Ala Asn Pro Asp Glu Ile Gly Asn Phe Ile Asp Glu Asn Leu Lys 805 810 815 Ala Ala Asp Thr Asp Pro Thr Ala Pro Pro Tyr Asp Ser Leu Leu Val 820 825 830 Phe Asp Tyr Glu Gly Ser Gly Ser Glu Ala Ala Ser Leu Ser Ser Leu 835 840 845 Asn Ser Ser Glu Ser Asp Lys Asp Gln Asp Tyr Asp Tyr Leu Asn Glu 850 855 860 Trp Gly Asn Arg Phe Lys Lys Leu Ala Asp Met Tyr Gly Gly Gly Glu 865 870 875 880 Asp Asp <210> SEQ ID NO 55 <211> LENGTH: 5858 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: FAM13A1 <400> SEQUENCE: 55 ccttccagcc atgtgggttc agcggaaaga gaagcaaaac cactcttcct aaaatgttag 60 aagctgctct tcgcttacct tggggccttt gcattgggag ctgtttttca catcaaagaa 120 tatgtgctga atggaatttt agtattttgc tgtcgtttta atattttcgt ctggtcttcc 180 tcagttcttc cagacgcttt ctgagagaat gggggcagga gctctagcca tctgtcaaag 240 taaagcagcg gttcggctga aagaagacat gaaaaagata gtggcagtgc cattaaatga 300 acagaaggat tttacctatc agaagttatt tggagtcagt ctccaagaac ttgaacggca 360 ggggctcacc gagaatggca ttccagcagt agtgtggaat atagtggaat atttgacgca 420 gcatggactt acccaagaag gtctttttag ggtgaatggt aacgtgaagg tggtggaaca 480 acttcgactg aagttcgaga gtggagtgcc cgtggagctc gggaaggacg gtgatgtctg 540 ctcagcagcc agtctgttga agctgtttct gagggagctg cctgacagtc tgatcacctc 600 agcgttgcag cctcgattca ttcaactctt tcaggatggc agaaatgatg ttcaggagag 660 tagcttaaga gacttaataa aagagctgcc agacacccac tactgcctcc tcaagtacct 720 ttgccagttc ttgacaaaag tagccaagca tcatgtgcag aatcgcatga atgttcacaa 780 tctcgccact gtatttgggc caaattgctt tcatgtgcca cctgggcttg aaggcatgaa 840 ggaacaggac ctgtgcaaca agataatggc taaaattcta gaaaattaca ataccctgtt 900 tgaagtagag tatacagaaa atgatcatct gagatgtgaa aacctggcta ggcttatcat 960 agtaaaagag gtctattata agaactccct gcccatcctt ttaacaagag gcttagaaag 1020 agacatgcca aaaccacctc caaaaaccaa gatcccaaaa tccaggagtg agggatctat 1080 tcaggcccac agagtactgc aaccagagct atctgatggc attcctcagc tcagcttgcg 1140 gctaagttat agaaaagcct gcttggaaga catgaattca gcagagggtg ctattagtgc 1200 caagttggta cccagttcac aggaagatga aagacctctg tcacctttct atttgagtgc 1260 tcatgtaccc caagtcagca atgtgtctgc aaccggagaa ctcttagaaa gaaccatccg 1320 atcagctgta gaacaacatc tttttgatgt taataactct ggaggtcaaa gttcagagga 1380 ctcagaatct ggaacactat cagcatcttc tgccacatct gccagacagc gccgccgcca 1440 gtccaaggag caggatgaag ttcgacatgg gagagacaag ggacttatca acaaagaaaa 1500 tactccttct gggttcaacc accttgatga ttgtattttg aatactcagg aagtcgaaaa 1560 ggtacacaaa aatacttttg gttgtgctgg agaaaggagc aagcctaaac gtcagaaatc 1620 cagtactaaa ctttctgagc ttcatgacaa tcaggacggt cttgtgaata tggaaagtct 1680 caattccaca cgatctcatg agagaactgg acctgatgat tttgaatgga tgtctgatga 1740 aaggaaagga aatgaaaaag atggtggaca cactcagcat tttgagagcc ccacaatgaa 1800 gatccaggag catcccagcc tatctgacac caaacagcag agaaatcaag atgccggtga 1860 ccaggaggag agctttgtct ccgaagtgcc ccagtcggac ctgactgcat tgtgtgatga 1920 aaagaactgg gaagagccta tccctgcttt ctcctcctgg cagcgggaga acagtgactc 1980 tgatgaagcc cacctctcgc cgcaggctgg gcgcctgatc cgtcagctgc tggacgaaga 2040 cagcgacccc atgctctctc ctcggttcta cgcttatggg cagagcaggc aatacctgga 2100 tgacacagaa gtgcctcctt ccccaccaaa ctcccattct ttcatgaggc ggcgaagctc 2160 ctctctgggg tcctatgatg atgagcaaga ggacctgaca cctgcccagc tcacacgaag 2220 gattcagagc cttaaaaaga agatccggaa gtttgaagat agattcgaag aagagaagaa 2280 gtacagacct tcccacagtg acaaagcagc caatccggag gttctgaaat ggacaaatga 2340 ccttgccaaa ttccggagac aacttaaaga atcaaaacta aagatatctg aagaggacct 2400 aactcccagg atgcggcagc gaagcaacac actccccaag agttttggtt cccaacttga 2460 gaaagaagat gagaagaagc aagagctggt ggataaagca ataaagccca gtgttgaagc 2520 cacattggaa tctattcaga ggaagctcca ggagaagcga gcggaaagca gccgccctga 2580 ggacattaag gatatgacca aagaccagat tgctaatgag aaagtggctc tgcagaaagc 2640 tctgttatat tatgaaagca ttcatggacg gccggtaaca aagaacgaac ggcaggtgat 2700 gaagccacta tacgacaggt accggctggt caaacagatc ctctcccgag ctaacaccat 2760 acccatcatt ggttccccct ccagcaagcg gagaagccct ttgctgcagc caattatcga 2820 gggcgaaact gcttccttct tcaaggagat aaaggaagaa gaggaggggt cagaagacga 2880 tagcaatgtg aagccagact tcatggtcac tctgaaaacc gatttcagtg cacgatgctt 2940 tctggaccaa ttcgaagatg acgctgatgg atttatttcc ccaatggatg ataaaatacc 3000 atcaaaatgc agccaggaca cagggctttc aaatctccat gctgcctcaa tacctgaact 3060 cctggaacac ctccaggaaa tgagagaaga aaagaaaagg attcgaaaga aacttcggga 3120 ttttgaagac aactttttca gacagaatgg aagaaatgtc cagaaggaag accgcactcc 3180 tatggctgaa gaatacagtg aatataagca cataaaggcg aaactgaggc tcctggaggt 3240 gctcatcagc aagagagaca ctgattccaa gtccatgtga ggggcatggc caagcacagg 3300 gggctggcag ctgcggtgag agtttactgt ccccagagaa agtgcagctc tggaaggcag 3360 ccttggggct ggccctgcaa agcatgcagc ccttctgcct ctagaccatt tggcatcggc 3420 tcctgtttcc attgcctgcc ttagaaactg gctggaagaa gacaatgtga cctgacttag 3480 gcattttgta attggaaagt caagactgca gtatgtgcac atgcgcacgc gcatgcacgc 3540 acacacacac acagtagtgg agctttccta acactagcag agattaatca ctacattaga 3600 caacactcat ctacagagaa tatacactgt tcttccctgg ataactgaga aacaagagac 3660 cattctctgt ctaactgtga taaaaacaag ctcaggactt tattctatag agcaaacttg 3720 ctgtggaggg ccatgctctc cttggaccca gttaactgca aacgtgcatt ggagccctat 3780 ttgctgccgc tgccattcta gtgacctttc cacagagctg cgccttcctc acgtgtgtga 3840 aaggttttcc ccttcagccc tcaggtagat ggaagctgca tctgcccacg atggcagtgc 3900 agtcatcatc ttcaggatgt ttcttcagga cttcctcagc tgacaaggaa ttttggtccc 3960 tgcctaggac cgggtcatct gcagaggaca gagagatggt aagcagctgt atgaatgctg 4020 attttaaaac caggtcatgg gagaagagcc tggagattct ttcctgaaca ctgactgcac 4080 ttaccagtct gattttatcg tcaaacacca agccaggcta gcatgctcat ggcaatctgt 4140 ttggggctgt tttgttgtgg cactagccaa acataaaggg gcttaagtca gcctgcatac 4200 agaggatcgg ggagagaagg ggcctgtgtt ctcagcctcc tgagtactta ccagagttta 4260 atttttttaa aaaaaatctg cactaaaatc cccaaactga caggtaaatg tagccctcag 4320 agctcagccc aaggcagaat ctaaatcaca ctattttcga gatcatgtat aaaaagaaaa 4380 aaaagaagtc atgctgtgtg gccaattata atttttttca aagactttgt cacaaaactg 4440 tctatattag acattttgga gggaccagga aatgtaagac accaaatcct ccatctcttc 4500 agtgtgcctg atgtcacctc atgatttgct gttacttttt taactcctgc gccaaggaca 4560 gtgggttctg tgtccacctt tgtgctttgc gaggccgagc ccaggcatct gctcgcctgc 4620 cacggctgac cagagaaggt gcttcaggag ctctgcctta gacgacgtgt tacagtatga 4680 acacacagca gaggcaccct cgtatgtttt gaaagttgcc ttctgaaagg gcacagtttt 4740 aaggaaaaga aaaagaatgt aaaactatac tgacccgttt tcagttttaa agggtcgtga 4800 gaaactggct ggtccaatgg gatttacagc aacattttcc attgctgaag tgaggtagca 4860 gctctcttct gtcagctgaa tgttaaggat ggggaaaaag aatgccttta agtttgctct 4920 taatcgtatg gaagcttgag ctatgtgttg gaagtgccct ggttttaatc catacacaaa 4980 gacggtacat aatcctacag gtttaaatgt acataaaaat atagtttgga attctttgct 5040 ctactgttta cattgcagat tgctataatt tcaaggagtg agattataaa taaaatgatg 5100 cactttagga tgtttcctat ttttgaaatc tgaacatgaa tcattcacat gaccaaaaat 5160 tgtgtttttt taaaaataca tgtctagtct gtcctttaat agctctctta aataagctat 5220 gatattaatc agatcattac cagttagctt ttaaagcaca tttgtttaag actatgtttt 5280 tggaaaaata cgctacagaa ttttttttta agctacaaat aaatgagatg ctactaattg 5340 ttttggaatc tgttgtttct gccaaaggta aattaactaa agatttattc aggaatcccc 5400 atttgaattt gtatgattca ataaaagaaa acaccaagta agttatataa aataaattgt 5460 gtatgagatg ttgtgttttc ctttgtaatt tccactaact aactaactaa cttatattct 5520 tcatggaatg gagcccagaa gaaatgagag gaagcccttt tcacactaga tcttatttga 5580 agaaatgttt gttagtcagt cagtcagtgg tttctggctc tgccgaggga gatgtgttcc 5640 ccagcaacca tttctgcagc ccagaatctc aaggcactag aggcggtgtc ttaattaatt 5700 ggcttcacaa agacaaaatg ctctggactg ggatttttcc tttgctgtgt tgggaatatg 5760 tgtttattaa ttagcacatg ccaacaaaat aaatgtcaag agttatttca taagtgtaag 5820 taaacttaag aattaaagag tgcagactta taattttc 5858 <210> SEQ ID NO 56 <211> LENGTH: 1023 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: FAM13A1 <400> SEQUENCE: 56 Met Gly Ala Gly Ala Leu Ala Ile Cys Gln Ser Lys Ala Ala Val Arg 1 5 10 15 Leu Lys Glu Asp Met Lys Lys Ile Val Ala Val Pro Leu Asn Glu Gln 20 25 30 Lys Asp Phe Thr Tyr Gln Lys Leu Phe Gly Val Ser Leu Gln Glu Leu 35 40 45 Glu Arg Gln Gly Leu Thr Glu Asn Gly Ile Pro Ala Val Val Trp Asn 50 55 60 Ile Val Glu Tyr Leu Thr Gln His Gly Leu Thr Gln Glu Gly Leu Phe 65 70 75 80 Arg Val Asn Gly Asn Val Lys Val Val Glu Gln Leu Arg Leu Lys Phe 85 90 95 Glu Ser Gly Val Pro Val Glu Leu Gly Lys Asp Gly Asp Val Cys Ser 100 105 110 Ala Ala Ser Leu Leu Lys Leu Phe Leu Arg Glu Leu Pro Asp Ser Leu 115 120 125 Ile Thr Ser Ala Leu Gln Pro Arg Phe Ile Gln Leu Phe Gln Asp Gly 130 135 140 Arg Asn Asp Val Gln Glu Ser Ser Leu Arg Asp Leu Ile Lys Glu Leu 145 150 155 160 Pro Asp Thr His Tyr Cys Leu Leu Lys Tyr Leu Cys Gln Phe Leu Thr 165 170 175 Lys Val Ala Lys His His Val Gln Asn Arg Met Asn Val His Asn Leu 180 185 190 Ala Thr Val Phe Gly Pro Asn Cys Phe His Val Pro Pro Gly Leu Glu 195 200 205 Gly Met Lys Glu Gln Asp Leu Cys Asn Lys Ile Met Ala Lys Ile Leu 210 215 220 Glu Asn Tyr Asn Thr Leu Phe Glu Val Glu Tyr Thr Glu Asn Asp His 225 230 235 240 Leu Arg Cys Glu Asn Leu Ala Arg Leu Ile Ile Val Lys Glu Val Tyr 245 250 255 Tyr Lys Asn Ser Leu Pro Ile Leu Leu Thr Arg Gly Leu Glu Arg Asp 260 265 270 Met Pro Lys Pro Pro Pro Lys Thr Lys Ile Pro Lys Ser Arg Ser Glu 275 280 285 Gly Ser Ile Gln Ala His Arg Val Leu Gln Pro Glu Leu Ser Asp Gly 290 295 300 Ile Pro Gln Leu Ser Leu Arg Leu Ser Tyr Arg Lys Ala Cys Leu Glu 305 310 315 320 Asp Met Asn Ser Ala Glu Gly Ala Ile Ser Ala Lys Leu Val Pro Ser 325 330 335 Ser Gln Glu Asp Glu Arg Pro Leu Ser Pro Phe Tyr Leu Ser Ala His 340 345 350 Val Pro Gln Val Ser Asn Val Ser Ala Thr Gly Glu Leu Leu Glu Arg 355 360 365 Thr Ile Arg Ser Ala Val Glu Gln His Leu Phe Asp Val Asn Asn Ser 370 375 380 Gly Gly Gln Ser Ser Glu Asp Ser Glu Ser Gly Thr Leu Ser Ala Ser 385 390 395 400 Ser Ala Thr Ser Ala Arg Gln Arg Arg Arg Gln Ser Lys Glu Gln Asp 405 410 415 Glu Val Arg His Gly Arg Asp Lys Gly Leu Ile Asn Lys Glu Asn Thr 420 425 430 Pro Ser Gly Phe Asn His Leu Asp Asp Cys Ile Leu Asn Thr Gln Glu 435 440 445 Val Glu Lys Val His Lys Asn Thr Phe Gly Cys Ala Gly Glu Arg Ser 450 455 460 Lys Pro Lys Arg Gln Lys Ser Ser Thr Lys Leu Ser Glu Leu His Asp 465 470 475 480 Asn Gln Asp Gly Leu Val Asn Met Glu Ser Leu Asn Ser Thr Arg Ser 485 490 495 His Glu Arg Thr Gly Pro Asp Asp Phe Glu Trp Met Ser Asp Glu Arg 500 505 510 Lys Gly Asn Glu Lys Asp Gly Gly His Thr Gln His Phe Glu Ser Pro 515 520 525 Thr Met Lys Ile Gln Glu His Pro Ser Leu Ser Asp Thr Lys Gln Gln 530 535 540 Arg Asn Gln Asp Ala Gly Asp Gln Glu Glu Ser Phe Val Ser Glu Val 545 550 555 560 Pro Gln Ser Asp Leu Thr Ala Leu Cys Asp Glu Lys Asn Trp Glu Glu 565 570 575 Pro Ile Pro Ala Phe Ser Ser Trp Gln Arg Glu Asn Ser Asp Ser Asp 580 585 590 Glu Ala His Leu Ser Pro Gln Ala Gly Arg Leu Ile Arg Gln Leu Leu 595 600 605 Asp Glu Asp Ser Asp Pro Met Leu Ser Pro Arg Phe Tyr Ala Tyr Gly 610 615 620 Gln Ser Arg Gln Tyr Leu Asp Asp Thr Glu Val Pro Pro Ser Pro Pro 625 630 635 640 Asn Ser His Ser Phe Met Arg Arg Arg Ser Ser Ser Leu Gly Ser Tyr 645 650 655 Asp Asp Glu Gln Glu Asp Leu Thr Pro Ala Gln Leu Thr Arg Arg Ile 660 665 670 Gln Ser Leu Lys Lys Lys Ile Arg Lys Phe Glu Asp Arg Phe Glu Glu 675 680 685 Glu Lys Lys Tyr Arg Pro Ser His Ser Asp Lys Ala Ala Asn Pro Glu 690 695 700 Val Leu Lys Trp Thr Asn Asp Leu Ala Lys Phe Arg Arg Gln Leu Lys 705 710 715 720 Glu Ser Lys Leu Lys Ile Ser Glu Glu Asp Leu Thr Pro Arg Met Arg 725 730 735 Gln Arg Ser Asn Thr Leu Pro Lys Ser Phe Gly Ser Gln Leu Glu Lys 740 745 750 Glu Asp Glu Lys Lys Gln Glu Leu Val Asp Lys Ala Ile Lys Pro Ser 755 760 765 Val Glu Ala Thr Leu Glu Ser Ile Gln Arg Lys Leu Gln Glu Lys Arg 770 775 780 Ala Glu Ser Ser Arg Pro Glu Asp Ile Lys Asp Met Thr Lys Asp Gln 785 790 795 800 Ile Ala Asn Glu Lys Val Ala Leu Gln Lys Ala Leu Leu Tyr Tyr Glu 805 810 815 Ser Ile His Gly Arg Pro Val Thr Lys Asn Glu Arg Gln Val Met Lys 820 825 830 Pro Leu Tyr Asp Arg Tyr Arg Leu Val Lys Gln Ile Leu Ser Arg Ala 835 840 845 Asn Thr Ile Pro Ile Ile Gly Ser Pro Ser Ser Lys Arg Arg Ser Pro 850 855 860 Leu Leu Gln Pro Ile Ile Glu Gly Glu Thr Ala Ser Phe Phe Lys Glu 865 870 875 880 Ile Lys Glu Glu Glu Glu Gly Ser Glu Asp Asp Ser Asn Val Lys Pro 885 890 895 Asp Phe Met Val Thr Leu Lys Thr Asp Phe Ser Ala Arg Cys Phe Leu 900 905 910 Asp Gln Phe Glu Asp Asp Ala Asp Gly Phe Ile Ser Pro Met Asp Asp 915 920 925 Lys Ile Pro Ser Lys Cys Ser Gln Asp Thr Gly Leu Ser Asn Leu His 930 935 940 Ala Ala Ser Ile Pro Glu Leu Leu Glu His Leu Gln Glu Met Arg Glu 945 950 955 960 Glu Lys Lys Arg Ile Arg Lys Lys Leu Arg Asp Phe Glu Asp Asn Phe 965 970 975 Phe Arg Gln Asn Gly Arg Asn Val Gln Lys Glu Asp Arg Thr Pro Met 980 985 990 Ala Glu Glu Tyr Ser Glu Tyr Lys His Ile Lys Ala Lys Leu Arg Leu 995 1000 1005 Leu Glu Val Leu Ile Ser Lys Arg Asp Thr Asp Ser Lys Ser Met 1010 1015 1020 <210> SEQ ID NO 57 <211> LENGTH: 3683 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: IMPACT <400> SEQUENCE: 57 cctggcaggc ggcggctgca gggcaggtcc aggggccaca tggctgaggg ggacgcaggg 60 agcgaccaga ggcagaatga ggaaattgaa gcaatggcag ccatttatgg cgaggagtgg 120 tgtgtcattg atgactgtgc caaaatattt tgtattagaa ttagcgacga tatagatgac 180 cccaaatgga cactttgctt gcaggtgatg ctgccgaatg aatacccagg tacagctcca 240 cctatctacc agttgaatgc tccttggctt aaagggcaag aacgtgcgga tttatcaaat 300 agccttgagg aaatatatat tcagaatatc ggtgaaagta ttctttacct gtgggtggag 360 aaaataagag atgttcttat acaaaaatct cagatgacag aaccaggccc agatgtaaag 420 aagaaaactg aagaggaaga tgttgaatgt gaagatgatc tcattttagc atgtcagccg 480 gaaagttcgg ttaaagcatt ggattttgat atcagtgaaa ctcggacaga agtagaagta 540 gaagaattac ctccgattga tcatggcatt cctattacag accgaagaag tacttttcag 600 gcacacttgg ctccagtggt ttgtcccaaa caggtgaaaa tggttctttc caaattgtat 660 gagaataaga aaatagctag tgccacccac aacatctatg cctacagaat atattgtgag 720 gataaacaga ccttcttaca ggattgtgag gatgatgggg aaacagcagc tggtgggcgt 780 cttcttcatc tcatggagat tttgaatgtg aagaatgtca tggtggtagt atcacgctgg 840 tatggaggga ttctgctagg accagatcgc tttaaacata tcaacaactg tgccagaaac 900 atactagtgg aaaagaacta cacaaattca cctgaggagt catctaaggc tttgggaaag 960 aacaaaaaag taagaaaaga caagaagagg aatgaacatt aatacctgaa actataggaa 1020 aggttaattt gcctataatt atatatacat tccatagtca tcaaggaata tattgtgcag 1080 agagagtatc cttgactgct taagtcagcc agttcagcat ggataccaac attagctttt 1140 cttcttggtt atatcatctg ccaaaaatag agaacttatg atctattcat gtgtgtttca 1200 ggcttatttg ggagaactaa tttgaactta atcaccactt catctaattt tagcaaggta 1260 acagttgccc agggcagtac ctgaattaac tgtccatttc agtacatgtc aagtgccttt 1320 gttaggtgga gaagaaatgt ctctagagga atataaatac ctgatttctt gtcatcgaga 1380 ttcttgtact gttaaatgaa tattgccttt tactgctctt tatggcttat tggaatagga 1440 gctcatttaa gattgatctt ggagagtttc ttcttgtgat tttagttcat aagtatgtca 1500 cctttcattt tatagtgttc atcattgagt aatggattaa gtgaaaatcc aggagtatcc 1560 atctgcagtt atgtgctgag gtgataattc atccaacata tttgttagca taaatattat 1620 gcttcagttt ctgttgcaaa ttggtgattg tgaaattaca gaaagtgatt ttctagtctg 1680 ctttttttgt ttaattcttg taatgtaagc aataaatatg gagtgtcagt agtctccttc 1740 caccccagaa atgtgttggt gtaacattct cgtttctttt aacaacctgg aagtaccttt 1800 cttgtgatct tcactgagga attagaacta tgatagaagt taggctgtgg caaatgggac 1860 attcgtagag tgggatagag gtggcagaat gaacctggtg tagggcagga gtatgttgtg 1920 tagttacatc aatttgatgc atgctttcca tctgcactcc agacggcttt ctcagttcca 1980 agattttgca gagagaagga gcaaaccttt tcattggaaa aacagaaaca accctccccc 2040 ccattttttc ccctctattc atcaaacctt tatgtatctt tcatcttcca gttacctcta 2100 ggcatttaga tagtgaaatt tacctttgag atataacaat aagtgattaa ctgttcactt 2160 tcagatgtaa tggcaaacaa ttgttaaaag ttattaactg atcacagatt tgcctggact 2220 tcccttccca gggagggaac agaagttagg aggcaacttt gggatggtgc tagagcatgg 2280 aaagcacaga gaattggaca aacaggtctt tttctctttt ctctgatgtt ttacctttaa 2340 aagatccaac atccttaccg ttggtatttt tagtaaggtt atagtaaata gctttacacc 2400 aggatggatt ctgaaatata aattctaaat tatatttgtt ataactatat tttatgttgt 2460 atgttatcag gagccatcag agaatgacct ttttgtgttt ggaacacttg gttccatgaa 2520 aagtatgctt tgtgttttaa ctgttaaaat aatttaaaaa ttaattattt tacataatta 2580 aagaagttaa aaactattaa cattaaataa tttcacaatt tcaacatgtc aaacctatga 2640 agggagatag gaaacaatga gaaacttact tttgctcctt tatacagaat tattaactat 2700 attttactaa ctaaaaaact ctagtattct ttacctaaag tcaattggct ggtaagaggg 2760 agagatgcaa aattctccag ctctgaactt ggagctactt cacactctac tcttaatgga 2820 aacttgaact aatgatagat agtatttttt tcctctattt aaaatttttg tcttgattag 2880 gagatttttc agttctccat ataataattt tctacaatca gatctatgct gtggcatatt 2940 ttgctttatt taaaaatttt tttttagaga tgagttcttg ctctgtcacc taggctggag 3000 tgcagtggca tgatcatggc tcactgcagc cttgaccttc cagcctgcca agtagctggg 3060 attacagaca ggcatgtgct attacacctg gctaattttt aaagtttttt ttgtaaagat 3120 agggtctttc tatgttgccc aggctcgtct tgagctcctg gcctcaatcg atcttcctgc 3180 caaggttttg gaattacagg tgtgagccac catgcctggc ctgctttgac atattttata 3240 gtgtgttaat tacaaatagt cttcatatgc cagaatataa gagcaagtgt tatctacttt 3300 ttagatggga attgcagaag ctgcatcaaa agtatgcttt gaggtatata tagtgaaaca 3360 gagcctttct gaagagaatt atatcaaact aattacaacc aagaaataat agtatgaagc 3420 ggatgctgtt tggaggacag gaaaatttat cgggaaaatt acataatccc tctgattcca 3480 ctatccagag atagccatta ttattaatat ttggtatgta catccttata ttattttttt 3540 tttatgcatg attttgtata tatggttatt tttctttcca taaaaatggt attaaactgt 3600 atatactgtt ttgtagccta catatttcat atagaagtat attgttaaca ttttccatgt 3660 caataaatat tctatggctt tct 3683 <210> SEQ ID NO 58 <211> LENGTH: 320 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: IMPACT <400> SEQUENCE: 58 Met Ala Glu Gly Asp Ala Gly Ser Asp Gln Arg Gln Asn Glu Glu Ile 1 5 10 15 Glu Ala Met Ala Ala Ile Tyr Gly Glu Glu Trp Cys Val Ile Asp Asp 20 25 30 Cys Ala Lys Ile Phe Cys Ile Arg Ile Ser Asp Asp Ile Asp Asp Pro 35 40 45 Lys Trp Thr Leu Cys Leu Gln Val Met Leu Pro Asn Glu Tyr Pro Gly 50 55 60 Thr Ala Pro Pro Ile Tyr Gln Leu Asn Ala Pro Trp Leu Lys Gly Gln 65 70 75 80 Glu Arg Ala Asp Leu Ser Asn Ser Leu Glu Glu Ile Tyr Ile Gln Asn 85 90 95 Ile Gly Glu Ser Ile Leu Tyr Leu Trp Val Glu Lys Ile Arg Asp Val 100 105 110 Leu Ile Gln Lys Ser Gln Met Thr Glu Pro Gly Pro Asp Val Lys Lys 115 120 125 Lys Thr Glu Glu Glu Asp Val Glu Cys Glu Asp Asp Leu Ile Leu Ala 130 135 140 Cys Gln Pro Glu Ser Ser Val Lys Ala Leu Asp Phe Asp Ile Ser Glu 145 150 155 160 Thr Arg Thr Glu Val Glu Val Glu Glu Leu Pro Pro Ile Asp His Gly 165 170 175 Ile Pro Ile Thr Asp Arg Arg Ser Thr Phe Gln Ala His Leu Ala Pro 180 185 190 Val Val Cys Pro Lys Gln Val Lys Met Val Leu Ser Lys Leu Tyr Glu 195 200 205 Asn Lys Lys Ile Ala Ser Ala Thr His Asn Ile Tyr Ala Tyr Arg Ile 210 215 220 Tyr Cys Glu Asp Lys Gln Thr Phe Leu Gln Asp Cys Glu Asp Asp Gly 225 230 235 240 Glu Thr Ala Ala Gly Gly Arg Leu Leu His Leu Met Glu Ile Leu Asn 245 250 255 Val Lys Asn Val Met Val Val Val Ser Arg Trp Tyr Gly Gly Ile Leu 260 265 270 Leu Gly Pro Asp Arg Phe Lys His Ile Asn Asn Cys Ala Arg Asn Ile 275 280 285 Leu Val Glu Lys Asn Tyr Thr Asn Ser Pro Glu Glu Ser Ser Lys Ala 290 295 300 Leu Gly Lys Asn Lys Lys Val Arg Lys Asp Lys Lys Arg Asn Glu His 305 310 315 320 <210> SEQ ID NO 59 <211> LENGTH: 6737 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: KIAA1128 <400> SEQUENCE: 59 gctgtggatc ttacaaagcc ttatcagaac caacagctat ccattagagt gcctctacgg 60 tcaagtatgc taacaagaaa ttcccggcag ccagaagtac tcaatgggaa tgaacatttg 120 gggtatggat ttaataggcc ttatgctgct ggtggaaaga agttggcttt accaaatggc 180 ccaggtgtaa cttctacttt aggttataga atggttcatc cctctctact gaaatctagc 240 cgatctccat tttctgggac tatgacagtt gatggaaata aaaattcacc tgctgacaca 300 tgtgtagagg aagatgctac agttttggct aaggacagag ctgctaataa ggaccaagaa 360 ctgattgaaa atgaaagtta tagaacaaaa aacaaccaga ccatgaaaca tgatgctaaa 420 atgagatacc tgagtgatga tgtggatgac atttccttgt cgtctttgtc atcttctgat 480 aagaatgatt taagtgaaga ctttagtgat gattttatag atatagaaga ctccaacaga 540 actagaataa ctccagagga aatgtctctc aaagaagaga aacatgaaaa tgggccacca 600 caggatatgt ttgattcccc caaggaaaat gaaaaagcct tcagtaaaac tgatgaatgg 660 atagatataa gtgtctctga caggagtgaa tgtacaaaac atacttctgg gaataatttg 720 gtttcaccag atacagacta cagagctggt tcttcgtttg aactctctcc atctgatagc 780 tctgatggaa catacatgtg ggatgaagaa ggcttggaac ccattggaaa tgtccatcca 840 gttgggagct atgagtcctc tgaaatgaac agcatagata ttttgaataa tcttgaatca 900 tgtgaccttg aggatgatga tcttatgctt gatgtggatc tgcctgagga tgcacctctt 960 gaaaatgtgg agtgtgacaa tatgaaccgc tttgaccgac cagacagaaa tgttcggcag 1020 cctcaggaag gtttttggaa aaggccaccc cagaggtgga gtggacagga gcattaccac 1080 ctcagccacc ctgaccacta tcatcaccat ggaaaaagtg acttgagcag aggctctccc 1140 tatagagaat ctcctttggg tcattttgaa agctatggag ggatgccctt tttccaggct 1200 cagaagatgt ttgttgatgt accagaaaat acagtgatac tggatgagat gacccttcgg 1260 cacatggttc aggattgcac tgctgtaaaa actcagttac tcaaactgaa acgtctcctg 1320 catcagcatg atggaagtgg ttcattgcat gatattcaac tgtcattgcc atccagtcca 1380 gaaccagaag atggtgataa agtatataag aatgaagatt tattaaatga aataaaacaa 1440 cttaaagacg aaataaagaa aaaagatgaa aagatccaac tattagaact tcagcttgca 1500 actcagcata tctgccacca aaaatgtaaa gaggaaaaat gcacttatgc tgataaatat 1560 acccaaacac cctggagacg aattcctggt gggtattctg ctccctcctt ctctccttgg 1620 cagggctcct tccaggggat cccacggact gttccaccgc accgcagaca gacctcaagt 1680 actacagcct tccagcagcc ttcccagacc cacagatcac acccagggaa aactaataaa 1740 gccacaacgt atcgaggccc gcagtgaatg ctcaatccaa gacatgcatc agggcggtgc 1800 acatccggaa gaaagcttta cacacgtctt gcaccaagaa agcaactatg gtttggaaga 1860 gcagcctttt tcatcaggcc cacaattaac aatggatgtg gctaagagta caccttctga 1920 agcaaactta aacattactg taaatgctca agagccttat catttggcaa acaatcaaat 1980 tagtgacatg cagtttatac ccacttctct tcagacacct cccgagtcaa gtacagtaga 2040 ccaggctaag agagttggaa gaaatcagtc tccgccagtg ggttatatgt ctcagcccaa 2100 gtccttgcag cttttaaagc catccatatt gagttctttg gtaccgcctc cagtttctga 2160 atcatctcca agtaggactc ccacttgtaa aaagtcacca ataatcacaa catgtaattc 2220 agcaaaactt cagccaacat ctagtcaaac aaatcttgca aataatcaga atctgaaagc 2280 atctaagctc cgccccccct caggctcttt caaacaaaaa caaacaaaca gcccccaact 2340 agagcctcaa agcttccagg ccaagacaag catcccaagg ccactaacac aacgaaaaga 2400 aatcatgcag aatccaaatg gcaatttgca ttctggggat tgtttggcct ctaatcgata 2460 ttctcgtctt cctaaaccaa agatacatta agtacatagc catcacctgc caatttgttt 2520 cttaaaaaca atctcttctg taatagcttt atgtgcagct tgcagcttgc tactgtggtg 2580 gaggttccat tgaaagcctg caaatcttaa attaaaatgt ggaagcttct actagtttgg 2640 ctccttcatt ttatatcctg gttgaagtac atgccatttg agcataatta tctcaggtaa 2700 acacgaaagt ttgcttaccc atttcagagg cctgccaaag gcccaaatca tgttatccat 2760 ccctctccag gtcagaaaat tcataatatt ttactgagca ggcaagaagt gtgctttgct 2820 ggtttagtcc tattaaggtc tgtatttatt gtggttgtca gaacctcacc ccttttcact 2880 tgtctctcct gtgaatatgg ctactatttt aactaaagat atggtgataa tggaagatgg 2940 tagtctgtaa gcagagttct ggccagtgtt ttgtatattt aaaaggtcta tgcaaaagct 3000 ttgtgatgaa taaaggagat taggctttta atggaaagtc tatgtaagtt ttatttttcc 3060 ttgccagggt cagtcagcta atgttactgt tgattcattt cccaaattcc ccagactgaa 3120 aatgtttctt attacatata aatcagttat atattccttt acatcttgtt ttacaaacac 3180 atgtgcatgc acacacacac atacacacac ataccattta tgtttgtatt tgttactggg 3240 taaattttgg agcgcttgag atacaccttg aaacctgtac ctaaagatgt attcatttgt 3300 aacatatgtt ggtgctagag ttttgctggt aattcaggtt tgaaccctta ggcttgtgga 3360 tccatgatag ccattttaag gttccacagc attatgtctt taattgtaat atttatattt 3420 attgattttc tgctaatatc tgaagactga aataatgaac ttgaaacatt tgcacaaaac 3480 tttgatgggg tataaatata ccatatatag ggattgtaaa ctattttcta tagcaaaaca 3540 agttaaaata ttttgagaaa aataacaaat ttaaataaga ctatcttgag aaagctggag 3600 ttcataatat tctccccctc ccccatctcc agtctcctag gtttcccttt tctgtgtttt 3660 ttgttttttt ctgtttgttt tttgagacag agtcttgctc cattgcccag gctggattac 3720 agtggcgcaa tctcggctca ctgcaacttc tgcctcccgg gttcaagcga ttctcctgcc 3780 tcagcctcct gagtagctgg gactacaggc atgtgccacc atgcctggct aatttttttg 3840 tatttttagt agagatgagg tttcaccttg ttggtcaggc tggtctcgaa ctcctgacct 3900 caagtgatcc acccacctcg tctatggtgt atttttgaaa gacaattttt taaaggtaga 3960 tttgggaaaa aaatagaatt gaagatggga aattttgttt tattaaaaag gtgctagaag 4020 atgtttcaaa gacaatattc ttattttaat acgctgtaga aggtaggtgt ggaacctcca 4080 tgctaccatg tgcacaaacc taattatgct ttgggtcact tgtcagttca gtaaatctgc 4140 cttcctcttc tcccaaatca tgtcatcttt aggttgttca cctgcagctg ctttaaatga 4200 attagtatct ttcagataga taaccttaca aggagaatgt ttgttttgag cagctgacca 4260 aaaatatatc aaacaggatt atggccaaaa agtcactcaa atttctagag attcctttaa 4320 aagatgtatg ttgatgaaat tgccccttta taagaaaaac aacagcaagt cttttagtag 4380 aaatttgaaa gaagtgtttg ctaccatttt gacccattat tcccttacct atcagatgaa 4440 tttgccattc actggataga aaccattctt ggatttggta agaggtgagc aagacaaatc 4500 ttgtaccata ctcttatgta ccagcacttc tgatggagaa gcagtgaagt tcagaacgtt 4560 cttcacatag tccagatact gttagagtca ggcaaatcag caaagcactt tgttatggag 4620 atgacccatg atggctgcag ttgtaagtgg gcatacatgt tctatcattt tgaaggagaa 4680 agaaaaccgt tctcacatgt cgcaaatatg tgaatcatac tatattcccc taaagtaaaa 4740 ccagtgactt agtggttttt ggtttattta gaagttggtt tagaccctta tgaaacatta 4800 tttacgagtt ggccttatcc ttaagggaaa agttctaaat ttttaaattt atttttaatt 4860 ccctagtctg agggaaatgt ctttattgtc cattacataa aaatgttgac tccagtaatt 4920 tatttttctc tattttttcc tccatgtatt tactccattt ttctctattt tttccttccc 4980 tgatggattt gcagaaatgt taaccaatta gctcaacttt tctctacctt tgttgagtct 5040 taatctttta gaagataggc ttaccgtata tttatgaagc ataatatatt aaaagaaaac 5100 aaatctagga tgcttgcatg acataaagta tttgcctgca gttttcatta aaaactgcaa 5160 gaatatcatg cttgtctgct tcttagtaaa tgttaagtct gaaatggaag tgaggatgta 5220 actctactga ataatcaaag atcatcttag atttggcttg atctgtgttt attgcttcta 5280 ttaatgtaaa tcaactctgt gccaaatcct cctccacaaa ccatttattg tcttagttct 5340 agtggtatca atgaagatag ttacagtata tgaattctaa gtcctgagga agaaatttta 5400 tggggtttgt taagtttcac attcgtgaaa gaggaaatta gtagagtatt cagactttga 5460 tatttggctg ttaatgggat gcatatcaaa tttttaaaag aaggcttggc ctaaggagtt 5520 tattggtaca ggtgcagatg attttaaggc attaaaggat tatagagtta tgtcatttag 5580 actgtttcta ataactgaga ccatctaaca tttttctttt ggagtctcat ttttatttgt 5640 gcaatatttt caggcatata ggctactgtt cattgtattt atatatatat tagaatttac 5700 taagtacttt aacaagtaaa aatctgaata tgaaagaaaa tatcagattt gcactttaaa 5760 tgagcttaat tgcttgaagt tgtgcctgaa atatcgaatt gcctcctatt gggtgtggct 5820 ttgttgaaat aaatttgtaa ttgttgctgt ttgaagatat cagtacagct gttcacagaa 5880 atatattccc agcatgtcac ttttccatta aagcactaag ttttctttga atgttccatt 5940 gttccgataa gtattttact tttttctcag tacatcagag agagcgtgat ccccctacag 6000 ctgtcacttc caaatgttcc tgtagcataa atggtgttac agacactgag gtgcactctt 6060 ggtttctgag cagagttgtc atactggttt cctggtctct agggcactgg ggatgtactt 6120 tgaaatcacc gaacaggctt gcaattaaga tcaataaggc tgcagcacca tttcaattta 6180 ctttccatct tacccagtag tttttgtgtt tttaaattcg tttgggtggt tatgtttgca 6240 tgcttaagca cacatttgaa aattaattat agctgtacta cccgatgttt ttccttgggg 6300 atgatggcct tgttcctttt taaattctga tgcttgaatt ctattttcta gtgatttttc 6360 acatctccct ttaagttttt gctgcagcaa tttgagagag tacttttgat taaatgattc 6420 tgatggtggg caccaatcta caactatgtc attaactgaa gatacatgtt ttaatcttgt 6480 tgggaataag cttacccact ttctccttgg taaagcgttt acttaacaaa ataatacccg 6540 agaatgtaag gtctctaagt cattactaac aaagagcaaa aataatatct gcagtattgt 6600 ttttcccatt gattttaagt cagtttagag tacaaactgt atattagaat ttgcctgtaa 6660 aatgaattct aaaaagcaga tgtaaagtct ctcctgaaaa tgttggcata gtaaataaaa 6720 ataaagttca taattat 6737 <210> SEQ ID NO 60 <211> LENGTH: 588 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: KIAA1128 <400> SEQUENCE: 60 Ala Val Asp Leu Thr Lys Pro Tyr Gln Asn Gln Gln Leu Ser Ile Arg 1 5 10 15 Val Pro Leu Arg Ser Ser Met Leu Thr Arg Asn Ser Arg Gln Pro Glu 20 25 30 Val Leu Asn Gly Asn Glu His Leu Gly Tyr Gly Phe Asn Arg Pro Tyr 35 40 45 Ala Ala Gly Gly Lys Lys Leu Ala Leu Pro Asn Gly Pro Gly Val Thr 50 55 60 Ser Thr Leu Gly Tyr Arg Met Val His Pro Ser Leu Leu Lys Ser Ser 65 70 75 80 Arg Ser Pro Phe Ser Gly Thr Met Thr Val Asp Gly Asn Lys Asn Ser 85 90 95 Pro Ala Asp Thr Cys Val Glu Glu Asp Ala Thr Val Leu Ala Lys Asp 100 105 110 Arg Ala Ala Asn Lys Asp Gln Glu Leu Ile Glu Asn Glu Ser Tyr Arg 115 120 125 Thr Lys Asn Asn Gln Thr Met Lys His Asp Ala Lys Met Arg Tyr Leu 130 135 140 Ser Asp Asp Val Asp Asp Ile Ser Leu Ser Ser Leu Ser Ser Ser Asp 145 150 155 160 Lys Asn Asp Leu Ser Glu Asp Phe Ser Asp Asp Phe Ile Asp Ile Glu 165 170 175 Asp Ser Asn Arg Thr Arg Ile Thr Pro Glu Glu Met Ser Leu Lys Glu 180 185 190 Glu Lys His Glu Asn Gly Pro Pro Gln Asp Met Phe Asp Ser Pro Lys 195 200 205 Glu Asn Glu Lys Ala Phe Ser Lys Thr Asp Glu Trp Ile Asp Ile Ser 210 215 220 Val Ser Asp Arg Ser Glu Cys Thr Lys His Thr Ser Gly Asn Asn Leu 225 230 235 240 Val Ser Pro Asp Thr Asp Tyr Arg Ala Gly Ser Ser Phe Glu Leu Ser 245 250 255 Pro Ser Asp Ser Ser Asp Gly Thr Tyr Met Trp Asp Glu Glu Gly Leu 260 265 270 Glu Pro Ile Gly Asn Val His Pro Val Gly Ser Tyr Glu Ser Ser Glu 275 280 285 Met Asn Ser Ile Asp Ile Leu Asn Asn Leu Glu Ser Cys Asp Leu Glu 290 295 300 Asp Asp Asp Leu Met Leu Asp Val Asp Leu Pro Glu Asp Ala Pro Leu 305 310 315 320 Glu Asn Val Glu Cys Asp Asn Met Asn Arg Phe Asp Arg Pro Asp Arg 325 330 335 Asn Val Arg Gln Pro Gln Glu Gly Phe Trp Lys Arg Pro Pro Gln Arg 340 345 350 Trp Ser Gly Gln Glu His Tyr His Leu Ser His Pro Asp His Tyr His 355 360 365 His His Gly Lys Ser Asp Leu Ser Arg Gly Ser Pro Tyr Arg Glu Ser 370 375 380 Pro Leu Gly His Phe Glu Ser Tyr Gly Gly Met Pro Phe Phe Gln Ala 385 390 395 400 Gln Lys Met Phe Val Asp Val Pro Glu Asn Thr Val Ile Leu Asp Glu 405 410 415 Met Thr Leu Arg His Met Val Gln Asp Cys Thr Ala Val Lys Thr Gln 420 425 430 Leu Leu Lys Leu Lys Arg Leu Leu His Gln His Asp Gly Ser Gly Ser 435 440 445 Leu His Asp Ile Gln Leu Ser Leu Pro Ser Ser Pro Glu Pro Glu Asp 450 455 460 Gly Asp Lys Val Tyr Lys Asn Glu Asp Leu Leu Asn Glu Ile Lys Gln 465 470 475 480 Leu Lys Asp Glu Ile Lys Lys Lys Asp Glu Lys Ile Gln Leu Leu Glu 485 490 495 Leu Gln Leu Ala Thr Gln His Ile Cys His Gln Lys Cys Lys Glu Glu 500 505 510 Lys Cys Thr Tyr Ala Asp Lys Tyr Thr Gln Thr Pro Trp Arg Arg Ile 515 520 525 Pro Gly Gly Tyr Ser Ala Pro Ser Phe Ser Pro Trp Gln Gly Ser Phe 530 535 540 Gln Gly Ile Pro Arg Thr Val Pro Pro His Arg Arg Gln Thr Ser Ser 545 550 555 560 Thr Thr Ala Phe Gln Gln Pro Ser Gln Thr His Arg Ser His Pro Gly 565 570 575 Lys Thr Asn Lys Ala Thr Thr Tyr Arg Gly Pro Gln 580 585

1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 60 <210> SEQ ID NO 1 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 1 ggctgactgg caaaaagtct tg 22 <210> SEQ ID NO 2 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 2 ttggttccct taagttctca gagttt 26 <210> SEQ ID NO 3 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 3 tggccctgtc actcccatga tgc 23 <210> SEQ ID NO 4 <211> LENGTH: 18 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 4 aagggctcgc atgcaaag 18 <210> SEQ ID NO 5 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 5 cacagtagca ctctgagttg aagca 25 <210> SEQ ID NO 6 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 6 tttgtccctg cttgtactag tgagg 25 <210> SEQ ID NO 7 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 7 gcaatcctct tacctccgct tt 22 <210> SEQ ID NO 8 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 8 ggaatcggag acagaagaga gctt 24 <210> SEQ ID NO 9 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 9 ctgggaccac agatgtatcc tccactcc 28 <210> SEQ ID NO 10 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 10 atggcagtgc agtcatcatc tt 22 <210> SEQ ID NO 11 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 11 gcattcatac agctgcttac catct 25 <210> SEQ ID NO 12 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 12 tttggtccct gcctaggacc ggg 23 <210> SEQ ID NO 13 <211> LENGTH: 16 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 13 ccggcccaag ctccat 16 <210> SEQ ID NO 14 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 14 ttgtgtaacc gtcggtcatg a 21 <210> SEQ ID NO 15 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 15 tgtttggtgg aatccatgaa ggttatggc 29 <210> SEQ ID NO 16 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 16 gagagcgtga tccccctaca 20 <210> SEQ ID NO 17 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 17 accaagagtg cacctcagtg tct 23 <210> SEQ ID NO 18 <211> LENGTH: 33 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 18 tcacttccaa atgttcctgt agcataaatg gtg 33 <210> SEQ ID NO 19 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 19

tgccaaggag ctttgtttat agaa 24 <210> SEQ ID NO 20 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 20 atgacggcat gtaccaacca 20 <210> SEQ ID NO 21 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 21 ttggtcccct cagttctatg ctgttgtgt 29 <210> SEQ ID NO 22 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 22 gcacctgctg aaatgtatga cataat 26 <210> SEQ ID NO 23 <211> LENGTH: 28 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 23 tttgctaagt tggagtaaat atgattgg 28 <210> SEQ ID NO 24 <211> LENGTH: 36 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 24 attgttcagc taattgagaa gcagatttca gagagc 36 <210> SEQ ID NO 25 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 25 tgaagaatgt catggtggta gtatca 26 <210> SEQ ID NO 26 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 26 atgactcctc aggtgaattt gtgtag 26 <210> SEQ ID NO 27 <211> LENGTH: 29 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 27 ctggtatgga gggattctgc taggaccag 29 <210> SEQ ID NO 28 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 28 tgagtgtccc ccggtatctt c 21 <210> SEQ ID NO 29 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 29 cagccgcttt cagattttca t 21 <210> SEQ ID NO 30 <211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 30 cctgccaatc ccgatgaaat tggaaat 27 <210> SEQ ID NO 31 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 31 gctggtgctc atggcactt 19 <210> SEQ ID NO 32 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 32 ccctccccag gcttcctaa 19 <210> SEQ ID NO 33 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 33 aagggctttg cctgacaaca ccca 24 <210> SEQ ID NO 34 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 34 gacgatccgg gtaaagttcc a 21 <210> SEQ ID NO 35 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 35 aggttgagga gtgggtcgaa 20 <210> SEQ ID NO 36 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 36 aggccgcgaa gccagtggaa tc 22 <210> SEQ ID NO 37 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 37 tcaccagggc tgcttttaac tc 22 <210> SEQ ID NO 38 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 38 ggaatcatat tggaacatgt aaacca 26 <210> SEQ ID NO 39

<211> LENGTH: 27 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence:/note = Synthetic Construct <400> SEQUENCE: 39 ttgccatcaa tgaccccttc attgacc 27 <210> SEQ ID NO 40 <211> LENGTH: 3084 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: C21orf4 <400> SEQUENCE: 40 gctcccgggg ctgaggtgga gccgcgggac gccggcaggg ttgtggcgca gcagtctcct 60 tcctgcgcgc gcgcctgaag tcggcgtggg cgtttgagga agctgggata cagcatttaa 120 tgaaaaattt atgcttaaga agtaaaaatg gcaggcttcc tagataattt tcgttggcca 180 gaatgtgaat gtattgactg gagtgagaga agaaatgctg tggcatctgt tgtcgcaggt 240 atattgtttt ttacaggctg gtggataatg attgatgcag ctgtggtgta tcctaagcca 300 gaacagttga accatgcctt tcacacatgt ggtgtatttt ccacattggc tttcttcatg 360 ataaatgctg tatccaatgc tcaggtgaga ggtgatagct atgaaagcgg ctgtttagga 420 agaacaggtg ctcgagtttg gcttttcatt ggtttcatgt tgatgtttgg gtcacttatt 480 gcttccatgt ggattctttt tggtgcatat gttacccaaa atactgatgt ttatccggga 540 ctagctgtgt tttttcaaaa tgcacttata ttttttagca ctctgatcta caaatttgga 600 agaaccgaag agctatggac ctgagatcac ttcttaagtc acattttcct tttgttatat 660 tctgtttgta gataggtttt ttatctctca gtacacattg ccaaatggag tagattgtac 720 attaaatgtt ttgtttcttt acatttttat gttctgagtt ttgaaatagt tttatgaaat 780 ttctttattt ttcattgcat agactgttaa tatgtatata atacaagact atatgaattg 840 gataatgagt atcagttttt tattcctgag atttagaact tgatctactc cctgagccag 900 ggttacatca tcttgtcatt ttagaagtaa ccactcttgt ctctctggcc gggcacggtg 960 gctcatgcct gtaatcccag cactttggga ggccgaggcg ggccgattgc ttgaggtcaa 1020 gtgttttgag accagcctgg ccaacatggc gaaaccccat ctactaaaaa tacaaaaatt 1080 agccaggcat ggtggtgggt gcctgtaatc ccaactacct aggaggctga ggcaggagaa 1140 tcgcttgaac ccggggggca gaggttgtag tgagctgagt ttgcgccact gcactctagc 1200 ctgggggaga aagtgaaact ccctctcaaa aaaaagaagg accactctca gtatctgatt 1260 tctgaagatg tacaaaaaaa tatagcttca tatatctaga atgagcactg agccataaaa 1320 ggttttcagc aagttgtaac ttattttggc ctaaaaatga ggtttttttg gtaaagaaaa 1380 aatatttgtt cttatgtatt gaagaagtgt acttttatat aatgattttt taaatgccca 1440 aaggactagt ttgaaagctt cttttaaaaa gaattcctct aatatgactt tatgtgagaa 1500 gggataatac atgatcaaat aaactcagtt ttttatggtt actgtaaaaa gactgtgtaa 1560 ggcagctcag caccatgctt ctcgtaaaag cagcttcaaa tatccactgg ggttatcttt 1620 tgacgacttg ccattatctg atgttacaca attcaatagc aagcaagttt gagacaatcg 1680 cagtttaaaa gcatgaacca tttaacaaaa agtggaataa ttaaagataa agcacttctt 1740 cccaaaggga attatcacct agtgaaaaat tatgcatttc atctactcag ttaccgactg 1800 caagtctctc ctcgctctag ctctcaagct ttgggtgaat attcctgtga aatatatctt 1860 caacttgaaa gttcatactc caatcaaaaa ctccttttac tgagtttgca gtactgtatt 1920 tgcactgttt gtattcctct gggcccttat tgctactttt gctttccttt gttacacaga 1980 ttttgtgttg cactttttct ccagaggggt gttgtagagc cttggttgta tgaataatac 2040 cagtggtagt gtccacggct ctaatgtaag cccatttggc atcactcctc tcctctctct 2100 tgagaggatt tcttgtgcac agagtatgaa gcagttgtgg agcgctgtgc ctttgtcaag 2160 ataccatctt gtttgatgac ttctttcttt gctgtttttt tcttcaaaat gttagtaagc 2220 tctgtcatgc ttctagcaaa ttgtaagact aattatttgt ttccacctca taacctgttg 2280 caataaatat tacttctcat acagtttaat attgttgttt gttggagaaa atgaaccata 2340 aaaattgatt tgctgttcag ttttcaatta ttcaagtata cccaattaaa gatgcagtta 2400 tgtttataaa ataagaagaa atagacttgt aaaatgctta tgtgagggtt attgaaggtt 2460 tccctgaaga ctgactggaa atggtggctg tttttttcta tttctgactc tgccatgaat 2520 tttttttttt tttttttaaa gacaatatct cactctgttg cctaggctgg agtgcagtgg 2580 tgcaaccaca gctcactgca ccttcaaatg ctggagctca ggcaatcctc ttacctccgc 2640 tttccaagca gctgggacca cagatgtatc ctccactcct cgctggccac catcctgctg 2700 cccaacagaa gaagctcttc tgtctccgat ttcctgaacg gtctaaggac caggaagaaa 2760 caggctcctg ccagcaccga cagcaacgaa aatgttccca cggagatcag gatgacttgc 2820 tgaagctcag tggaggctaa aaagaggaca cgaaagtgaa cagaatgatc ttcctacgca 2880 caacacaaac atcagttaat gttccatcca tgctgcttaa agagcattcc tgtcctagta 2940 aaatgggcaa gtccctctac cccccaccct cacctggtat gcttacatta atagctaaag 3000 tcaatcctgt aatgaaataa agcaagtggt agctgtctgg tagcctccac tactgcaaat 3060 ctcaagaaaa aaaaaaaaaa aaaa 3084 <210> SEQ ID NO 41 <211> LENGTH: 158 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: c21orf4 <400> SEQUENCE: 41 Met Ala Gly Phe Leu Asp Asn Phe Arg Trp Pro Glu Cys Glu Cys Ile 1 5 10 15 Asp Trp Ser Glu Arg Arg Asn Ala Val Ala Ser Val Val Ala Gly Ile 20 25 30 Leu Phe Phe Thr Gly Trp Trp Ile Met Ile Asp Ala Ala Val Val Tyr 35 40 45 Pro Lys Pro Glu Gln Leu Asn His Ala Phe His Thr Cys Gly Val Phe 50 55 60 Ser Thr Leu Ala Phe Phe Met Ile Asn Ala Val Ser Asn Ala Gln Val 65 70 75 80 Arg Gly Asp Ser Tyr Glu Ser Gly Cys Leu Gly Arg Thr Gly Ala Arg 85 90 95 Val Trp Leu Phe Ile Gly Phe Met Leu Met Phe Gly Ser Leu Ile Ala 100 105 110 Ser Met Trp Ile Leu Phe Gly Ala Tyr Val Thr Gln Asn Thr Asp Val 115 120 125 Tyr Pro Gly Leu Ala Val Phe Phe Gln Asn Ala Leu Ile Phe Phe Ser 130 135 140 Thr Leu Ile Tyr Lys Phe Gly Arg Thr Glu Glu Leu Trp Thr 145 150 155 <210> SEQ ID NO 42 <211> LENGTH: 2822 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Hs.145049 <400> SEQUENCE: 42 gtttctctga atagcagagg catcaaattt tggtggggaa tgagaggagt attaggggaa 60 agtttgaaaa tagctctcct ggagatggag ggcacacaga gtggtcctca ggctcacctt 120 gactgagttg attcacagtt atcctgcatc agaccattag atttctttag tgctatgatt 180 ataataggga tttttgaatc accaaaaaca gtttttagat gtttatgttc tttgttttac 240 tatcaatgtt gtgctggtta agggagagaa aagttcaaga agatcttaca tatttgaaag 300 gaaattggta ctcttgaagg ctatgcaaca tgagtctttg aacaagaatt ccttgctact 360 ttgattcatt catcaaatac tgagtgcctg tgtgccaggc acaggtgaac tctggggatt 420 caggggtaac taaaacagat tgcaaccctg cccttgtgaa gctttcagtc tagaagggag 480 acgtgaaaca aattttagct tcaaaagcaa catctatttt tgcctgttag catgcattta 540 ttttaaaagt catattagag ttacctggtt ccgcttcaga gcagactggg aaaatcaggc 600 ttacaatgga atcagatgct gtgggcctaa aacagctctt taaaaatcta tttttttagg 660 ccaggtgcgt tggctcacac ctgtaatccc agcactttgg gaggccaagg tgggtggata 720 tgaggtcagg aggtcgagac cagcctggtc aatatgatga aaccttacct ctactaaaaa 780 taaaaaatta gccgggcatg gtggcacatg cctgtagtcc cagctactcg ggaaactgag 840 gcagaagaat cgcttgaacc cgggaggcgg aggttgcagt gagccgggat cacgtcactg 900 tactccagcc tgggcaagag tgagacaccg tctcaaaaaa aaaaaaaatt tttttttaaa 960 tggaatcaga gaaaccaaca aaatatgtaa catgtataaa tgcctgagga gatcagttat 1020 tgagaaatcc atttacaatg ctggaggaga ggggatggcc aggaaagaag tgcaacaaat 1080 aaatggaaga tgaccctaaa aatgcaccag tgacagtcag tcaatccatc agaccacctc 1140 acatgcaggg tagaaacatg gagtgtgcgg cagcatcctc ctcacatccc tttgtgagca 1200 cggctgctcc ggaatactga ccatctgggc tagcacgact tagcagaggg ttctgcagga 1260 tgtgctattt taaagcagct gggtgcaact tgtgaaaacg ggaatctaga gcagaacatg 1320 taatcagcga tggctgggat tggtggacag gattgacagg agtatttgag gctctaccag 1380 gcctgtctac aggacagctt catcaaaggg acatttttta acctgttatt ttaaatgcca 1440 catatatgtt gtaatgctga agcatacagg tagaatttct ggatcgtaac tactagtgac 1500 ttctgaggtt tacagttaga aaatgttctc aaaggtttat cagttatgta ttgatgattg 1560 gtaatctaga ccctctggag gctgtagaat gtgaaaagat acagctgagc tgacaagttt 1620 tagggcacta tcttctggaa tgaaatcggc caagaaaatg gttcaagggc atgggggtta 1680 gagaatgttt cttttaccta aaaatgttaa gccaactatg gaagattggg gtcgtggggg 1740 catgaaatac aaaattatga taatttatac agaactaggt ttctttatgt tctgcaagaa 1800 ggtttttatt agctaatttg gggagggggg catgctgcag tatttttttt cctgggaaca 1860 tgcatttctg atgggaagtt attttgttta caagagttgg ttttacacac aaccctgaat 1920 gaatgtgtct atggcctaaa aatggtagac ctgtatttcc ttcccgaggc aggctgattc 1980 gtttcctgat tccttctgtc tgagattacc tgatgctgac cagacttatt tttcctttcc 2040 tgaatcttca cagctgagtt tatggcaccc atccaagacc ttcccatttg aatgactaga 2100 tttctattct atccccgatc atccttttga aatagttcta gtgataaact cagagaaatt 2160 caatatattg attgaatttt attttttcgc tttgtatcta caacagaaat tgatttgttc 2220 atttttattt caaatctctt catggcaagt tgggctaatg gactttgcac tcaagaaagg 2280

tttgtttacc agttttgtag ccatgtttgg caaatcttag caactagaaa ccccgtcctt 2340 tcttttcctt ctttatatgt tcttgcagtt actcttgtat tgcaagattt tctgacttta 2400 agctttgaga ctactgcatc ttaaaagaag aactaggctg actggcaaaa agtcttgcca 2460 gtggccctgt cactcccatg atgctttggt tttgagagtt gggaaaactc tgagaactta 2520 agggaaccaa actcaggaat cccaaaattg gtggcattgt gccattcgtt taggggctga 2580 acataggacc tgtctgaaac tgagtgagct agatgcattt gggtttgaat ttttgtcaca 2640 tactgaaatg taagtcagcc ctaaataatc aaaacacttt attttatttt tcttttttta 2700 aataggaact ttctgaagaa aaagtggtgt gtaaaacatt tgatatttaa gacaataaag 2760 tttttatcat aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaagaaaaa aaaaaaaaaa 2820 aa 2822 <210> SEQ ID NO 43 <211> LENGTH: 152 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Hs.145049 <400> SEQUENCE: 43 Met Val His Ser Pro Arg Ser Leu Val Ala Asn Pro Ser Gln Val Leu 1 5 10 15 Phe Phe Leu Ser Phe Leu Phe Phe Phe Phe Leu Arg Gln Ser Phe Ala 20 25 30 Leu Val Ala Gln Ala Gly Val Gln Trp Arg Asn Leu Gly Ser Leu Gln 35 40 45 Pro Pro Pro Pro Gly Phe Lys Gln Phe Ser Cys Leu Ser Leu Leu Ser 50 55 60 Ser Trp Asp Tyr Arg His Ala Pro Pro Cys Pro Ala Tyr Phe Val Phe 65 70 75 80 Leu Val Asp Met Gly Phe Pro His Val Gly Gln Thr Gly Leu Glu Leu 85 90 95 Leu Thr Ser Gly Asp Pro Pro Ala Ser Ala Ser Gln Ser Ala Gly Ile 100 105 110 Thr Gly Gly Ser His Arg Ala Gln Pro Thr Ser Ser Asn Pro Tyr Gly 115 120 125 Ile Val Phe Phe Phe Leu Pro Val Lys Thr Phe Ser Gly Met Ser Gln 130 135 140 Glu Ala Gly Asp Cys Arg Glu Thr 145 150 <210> SEQ ID NO 44 <211> LENGTH: 4597 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Hs.296031 <400> SEQUENCE: 44 aatggtacga ttgagagatg agtgctatgg agaaaaatcc agccagaaag ggagatgcag 60 aagatagcac cagatcttct caatgttgtt ttcatcatgg acaggtgcgt tccttagaag 120 atgaagtgtt agtgattcct gagtttttct caccttcacg tcgattgatc tgaatttgga 180 gagtctgttt tctgtgtctg gctctgcact caactttgta ggggaccctg tcgaggtccc 240 cacactgtgg cttcaggtag acagagcaga tgggagccca tttcagttca ttgtcttgct 300 gaccaatggg gaactgtggt caggtgagag gaggcagctt ttacaatcag acttcattga 360 atagtgtggg ctgctgtttc cttgtaacaa aaccccataa tgatggcagt ttccggatgt 420 gtctttttag gacttcagaa cttattattt gaatagaagt ttaaagcatc tggatgatga 480 tgctgtagct aaaacagctg cttgtcagaa gagaccctat ttaacacttc taaacttgtt 540 tcagaggtgg aggaaaggat aatctgggaa ggcctccctc tcaagtccac aggttggtat 600 cagctgtgtt catcccccaa aaggaaaata aaatgacaac aatattttgg tcacagaatt 660 cctgagaaac ctctgtttct atcttcatgt ctttaagata gggacatgaa ttccccatga 720 tctgggtgat agggttagag tggccaggac actgttactt tgtgtgtgac acaggtggct 780 cctcatgaca gttcctccat gccttagaac atgttgtctg tctggtcatc cctgggggta 840 gagctgagtg acccagcagt gggagattta acaactggag aagaagatgg gatgtgttta 900 attatcccca gaggtagggc caatttgtca ccctttaaat agacttattt gcatataaac 960 taaagcacct tagggcatca ttaccgaaag tgtctaagca aatgtctgat atagttacgt 1020 gcctgcatta aaagaaagca gcccccttat cttgccttaa tatccttaca gtgttttaat 1080 aagttcataa tgcatcctgt atgtgcattt tttggtataa aacaccgaaa ggtggagaat 1140 tgacttcagt tctctccatc ctttcccctt aagtgttggt ggcgctgcag gggcaacgtg 1200 cctcccattg gaagtggtga cttcctcttt gatagaggtt tgcctgtctc ttgaaaatga 1260 aaagaagcgg agattgatct ctggagtccc atggtccagt ttggactatt gggaatattt 1320 tttatgggat gttaaaaaca atattagaga cgtgagatag taaatttgtg gtaataccgg 1380 atccaggaag cttacagtga agagtatgaa cttaacctga aaagtatttc tctgttctat 1440 aaatctctca gtgacatttg gattaatcaa gcataattaa atgtagttag atttttgtca 1500 gattgtagtt caaaataata ttcatctatg gagagggtaa tatattatgt agaaatttta 1560 ttaagcactt tagttaagca aacactaagg agaacaaaat caacctcagg aaggttaatt 1620 actaaaaaaa tcacaaagta tagtagatta tgtaaatcat tttaattttg aataccatgg 1680 cttgagcttt aatttacata gagacgtatt ttggatttgt ttttcacatt atattttcta 1740 gtacaggatt gcaattgcat tcttgaaaag ttctactcat tttaggattc cattaagttt 1800 gcttaacttt tttcatgtta taatttccaa aagcaaagaa ttacaattgt attctagcta 1860 attattttaa tgtttcacta actttgtgtg tattgtaaga ccatattttt atttctatac 1920 aaatgatgat tttaagagaa gtatcaggag agagaatgta tatgaaagca tcgcgtccac 1980 gcctggcttt gcaataagtg ttcatttaaa agaaagacat ttacaaaggt aaaacataag 2040 agtttagact atagcgataa atctttttat tttagtaatt tctttaaagg gaaaagtaaa 2100 gagatcaaaa tgattttata tgtatttttt ttgtactcag agaattacat tttcactacc 2160 cccgcctgtc tcagggaata gcctttgata agaatcccat ggagatctct ggaactctat 2220 tacagtgtgt tcagatttgt tagttcatat gtaaatttca gagctagagc ttcaaaacta 2280 gagtattgta atctcaggaa cataagatta tccaagaagc ctgaaccttg ctcttttcat 2340 gataaatgac atccaaattt cctttgtcta ggagataagc atagatccct tttatcatgc 2400 ttctctgaga ttttcacaga acaaccctgc aatttgattt tgtttgataa ttttgctttt 2460 tggcttttca gtgaggactc tattttccat tggaactgac tcctttgggg ataataagct 2520 ttcacttaaa agaacattcc attagatagt tctaacttca atgaacctaa aagtggcttc 2580 ttaatttgaa taatctggat aacttttgca aatgggtcaa aacagcacaa gtatcaacaa 2640 tcacgtatgt actgagtaat atttgccctc cagttagcaa agtcaagaaa tgtctaactc 2700 tggcacacag cactggtttt aactactctt tagttcatct ttgccttcca aattggttga 2760 aaatggcaag cttagaatgg aatgcatatt aataacagaa ccacttaatg ttttaaaata 2820 ttcatacctt gagattcttt ttgagagaaa aaagaaatct taacatccaa ttctagttgt 2880 tttggctttt cacatatgct agacatgaaa aaggcagtta caaaagtgaa atccgattgg 2940 aagtcagtgg tgtccgccat tgagccgtgc taaatgtcgt gtcacaaaag gagtttgtga 3000 aaacaggatg agtagaaaat gttatactgt tgtttctatc gtggcaccgc tttcttataa 3060 attccatttg ctttttgtca tctgaactgt tacaaccatg ggaaacctca gtccatattt 3120 ttaaaagcac tatatactta caggaaaaac cgacttatgc cttcattgaa aaaatgttga 3180 agttaatatc ccaaatgttt aatgagcatg ttttagaata tttacagcta aagtctgtca 3240 ctttagggat ttgacaaaac ttgagactgc ctgccaccga agagggacca ggcagaatct 3300 tctcagcctt gtaaccagcg ttaaaaaaat ataaggggct tgatgagatc ctagatctgc 3360 tccttttctc ctaggtgcct gggtaactcc tggggaaagc atcatattaa gtccttttca 3420 agcaaggtgt gtgattttga ccaatgaatt gagctgatat gtgattttga ccaatgaatt 3480 gtgcatctat ttaaaaatta ccaagtgtat cttgactctt gagtggacag tcaaggcaaa 3540 gtttacttag gaaatgtaaa gtatggagtg ttttaaaaaa ttcaaattga gtttattcac 3600 tgttggagga attgaattct attgcctccc tcatttcaat tatgttcatt gttacaattg 3660 tgctgctctg ttctcattgt gatgcttagt tctcgtgtag aactgagtgc tacattgtga 3720 ttagaaactg gagttgtgct tgagtcagtc ctggaaaaca ggacccattt ttaagaagaa 3780 cggaacatac cactttggca ttctggctga ccctaatttc tgcagagttc cttggtgtta 3840 aaatcatttg aggtcatagt tgctgcttat ggtttatata cacaccatct gctgctctaa 3900 gttcacatcc tctcaaaagc atgcaagtgc ttgaaattta aatatttccc agatctaaaa 3960 caacttgtga ctacctaaga aatgcttgaa ccaaataaga aacagcactg tggaataaaa 4020 tataccattg tgaacatatc tgatgctgca atgaaatgta aagttcctta ctttgctgat 4080 ttttcatcat aactccttga ctcataaaag cggtgtctaa actgggaaca gctgctaata 4140 gggtaaaagt attatacatc aaataaaagt tcattacaat atttgtactc ataagtcaaa 4200 atctgacctg gttcgctttg tgcctctgtc agcctactta cagtgataaa tgtacacaca 4260 agtccagtgt tgccaaggag ctttgtttat agaaagaagc ttggtcccct cagttctatg 4320 ctgttgtgtg gcctggttgg tacatgccgt catgatgaag gatgactttg gtttgagata 4380 atttgtcact ccacattcca tggagaaaag tgtttcattt tgatgttgga aaaacatgac 4440 cagagaagca tgtgactcag ataatgttcc ccggaagttg cagagcaatc tgtggtgtct 4500 gtcatagccc aactagtcct ggagcacatg gacaattctg taccccaata atcagaacaa 4560 taaaatggta gttgtgattc aaaaaaaaaa aaaaaaa 4597 <210> SEQ ID NO 45 <211> LENGTH: 5084 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: KIT <400> SEQUENCE: 45 gatcccatcg cagctaccgc gatgagaggc gctcgcggcg cctgggattt tctctgcgtt 60 ctgctcctac tgcttcgcgt ccagacaggc tcttctcaac catctgtgag tccaggggaa 120 ccgtctccac catccatcca tccaggaaaa tcagacttaa tagtccgcgt gggcgacgag 180 attaggctgt tatgcactga tccgggcttt gtcaaatgga cttttgagat cctggatgaa 240 acgaatgaga ataagcagaa tgaatggatc acggaaaagg cagaagccac caacaccggc 300 aaatacacgt gcaccaacaa acacggctta agcaattcca tttatgtgtt tgttagagat 360 cctgccaagc ttttccttgt tgaccgctcc ttgtatggga aagaagacaa cgacacgctg 420 gtccgctgtc ctctcacaga cccagaagtg accaattatt ccctcaaggg gtgccagggg 480 aagcctcttc ccaaggactt gaggtttatt cctgacccca aggcgggcat catgatcaaa 540

agtgtgaaac gcgcctacca tcggctctgt ctgcattgtt ctgtggacca ggagggcaag 600 tcagtgctgt cggaaaaatt catcctgaaa gtgaggccag ccttcaaagc tgtgcctgtt 660 gtgtctgtgt ccaaagcaag ctatcttctt agggaagggg aagaattcac agtgacgtgc 720 acaataaaag atgtgtctag ttctgtgtac tcaacgtgga aaagagaaaa cagtcagact 780 aaactacagg agaaatataa tagctggcat cacggtgact tcaattatga acgtcaggca 840 acgttgacta tcagttcagc gagagttaat gattctggag tgttcatgtg ttatgccaat 900 aatacttttg gatcagcaaa tgtcacaaca accttggaag tagtagataa aggattcatt 960 aatatcttcc ccatgataaa cactacagta tttgtaaacg atggagaaaa tgtagatttg 1020 attgttgaat atgaagcatt ccccaaacct gaacaccagc agtggatcta tatgaacaga 1080 accttcactg ataaatggga agattatccc aagtctgaga atgaaagtaa tatcagatac 1140 gtaagtgaac ttcatctaac gagattaaaa ggcaccgaag gaggcactta cacattccta 1200 gtgtccaatt ctgacgtcaa tgctgccata gcatttaatg tttatgtgaa tacaaaacca 1260 gaaatcctga cttacgacag gctcgtgaat ggcatgctcc aatgtgtggc agcaggattc 1320 ccagagccca caatagattg gtatttttgt ccaggaactg agcagagatg ctctgcttct 1380 gtactgccag tggatgtgca gacactaaac tcatctgggc caccgtttgg aaagctagtg 1440 gttcagagtt ctatagattc tagtgcattc aagcacaatg gcacggttga atgtaaggct 1500 tacaacgatg tgggcaagac ttctgcctat tttaactttg catttaaagg taacaacaaa 1560 gagcaaatcc atccccacac cctgttcact cctttgctga ttggtttcgt aatcgtagct 1620 ggcatgatgt gcattattgt gatgattctg acctacaaat atttacagaa acccatgtat 1680 gaagtacagt ggaaggttgt tgaggagata aatggaaaca attatgttta catagaccca 1740 acacaacttc cttatgatca caaatgggag tttcccagaa acaggctgag ttttgggaaa 1800 accctgggtg ctggagcttt cgggaaggtt gttgaggcaa ctgcttatgg cttaattaag 1860 tcagatgcgg ccatgactgt cgctgtaaag atgctcaagc cgagtgccca tttgacagaa 1920 cgggaagccc tcatgtctga actcaaagtc ctgagttacc ttggtaatca catgaatatt 1980 gtgaatctac ttggagcctg caccattgga gggcccaccc tggtcattac agaatattgt 2040 tgctatggtg atcttttgaa ttttttgaga agaaaacgtg attcatttat ttgttcaaag 2100 caggaagatc atgcagaagc tgcactttat aagaatcttc tgcattcaaa ggagtcttcc 2160 tgcagcgata gtactaatga gtacatggac atgaaacctg gagtttctta tgttgtccca 2220 accaaggccg acaaaaggag atctgtgaga ataggctcat acatagaaag agatgtgact 2280 cccgccatca tggaggatga cgagttggcc ctagacttag aagacttgct gagcttttct 2340 taccaggtgg caaagggcat ggctttcctc gcctccaaga attgtattca cagagacttg 2400 gcagccagaa atatcctcct tactcatggt cggatcacaa agatttgtga ttttggtcta 2460 gccagagaca tcaagaatga ttctaattat gtggttaaag gaaacgctcg actacctgtg 2520 aagtggatgg cacctgaaag cattttcaac tgtgtataca cgtttgaaag tgacgtctgg 2580 tcctatggga tttttctttg ggagctgttc tctttaggaa gcagccccta tcctggaatg 2640 ccggtcgatt ctaagttcta caagatgatc aaggaaggct tccggatgct cagccctgaa 2700 cacgcacctg ctgaaatgta tgacataatg aagacttgct gggatgcaga tcccctaaaa 2760 agaccaacat tcaagcaaat tgttcagcta attgagaagc agatttcaga gagcaccaat 2820 catatttact ccaacttagc aaactgcagc cccaaccgac agaagcccgt ggtagaccat 2880 tctgtgcgga tcaattctgt cggcagcacc gcttcctcct cccagcctct gcttgtgcac 2940 gacgatgtct gagcagaatc agtgtttggg tcacccctcc aggaatgatc tcttcttttg 3000 gcttccatga tggttatttt cttttctttc aacttgcatc caactccagg atagtgggca 3060 ccccactgca atcctgtctt tctgagcaca ctttagtggc cgatgatttt tgtcatcagc 3120 caccatccta ttgcaaaggt tccaactgta tatattccca atagcaacgt agcttctacc 3180 atgaacagaa aacattctga tttggaaaaa gagagggagg tatggactgg gggccagagt 3240 cctttccaag gcttctccaa ttctgcccaa aaatatggtt gatagtttac ctgaataaat 3300 ggtagtaatc acagttggcc ttcagaacca tccatagtag tatgatgata caagattaga 3360 agctgaaaac ctaagtcctt tatgtggaaa acagaacatc attagaacaa aggacagagt 3420 atgaacacct gggcttaaga aatctagtat ttcatgctgg gaatgagaca taggccatga 3480 aaaaaatgat ccccaagtgt gaacaaaaga tgctcttctg tggaccactg catgagcttt 3540 tatactaccg acctggtttt taaatagagt ttgctattag agcattgaat tggagagaag 3600 gcctccctag ccagcacttg tatatacgca tctataaatt gtccgtgttc atacatttga 3660 ggggaaaaca ccataaggtt tcgtttctgt atacaaccct ggcattatgt ccactgtgta 3720 tagaagtaga ttaagagcca tataagtttg aaggaaacag ttaataccat tttttaagga 3780 aacaatataa ccacaaagca cagtttgaac aaaatctcct cttttagctg atgaacttat 3840 tctgtagatt ctgtggaaca agcctatcag cttcagaatg gcattgtact caatggattt 3900 gatgctgttt gacaaagtta ctgattcact gcatggctcc cacaggagtg ggaaaacact 3960 gccatcttag tttggattct tatgtagcag gaaataaagt ataggtttag cctccttcgc 4020 aggcatgtcc tggacaccgg gccagtatct atatatgtgt atgtacgttt gtatgtgtgt 4080 agacaaatat ttggaggggt atttttgccc tgagtccaag agggtccttt agtacctgaa 4140 aagtaacttg gctttcatta ttagtactgc tcttgtttct tttcacatag ctgtctagag 4200 tagcttacca gaagcttcca tagtggtgca gaggaagtgg aaggcatcag tccctatgta 4260 tttgcagttc acctgcactt aaggcactct gttatttaga ctcatcttac tgtacctgtt 4320 ccttagacct tccataatgc tactgtctca ctgaaacatt taaattttac cctttagact 4380 gtagcctgga tattattctt gtagtttacc tctttaaaaa caaaacaaaa caaaacaaaa 4440 aactcccctt cctcactgcc caatataaaa ggcaaatgtg tacatggcag agtttgtgtg 4500 ttgtcttgaa agattcaggt atgttgcctt tatggtttcc cccttctaca tttcttagac 4560 tacatttaga gaactgtggc cgttatctgg aagtaaccat ttgcactgga gttctatgct 4620 ctcgcacctt tccaaagtta acagattttg gggttgtgtt gtcacccaag agattgttgt 4680 ttgccatact ttgtctgaaa aattcctttg tgtttctatt gacttcaatg atagtaagaa 4740 aagtggttgt tagttataga tgtctaggta cttcaggggc acttcattga gagttttgtc 4800 ttgccatact ttgtctgaaa aattcctttg tgtttctatt gacttcaatg atagtaagaa 4860 aagtggttgt tagttataga tgtctaggta cttcaggggc acttcattga gagttttgtc 4920 aatgtctttt gaatattccc aagcccatga gtccttgaaa atatttttta tatatacagt 4980 aactttatgt gtaaatacat aagcggcgta agtttaaagg atgttggtgt tccacgtgtt 5040 ttattcctgt atgttgtcca attgttgaca gttctgaaga attc 5084 <210> SEQ ID NO 46 <211> LENGTH: 976 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: KIT <400> SEQUENCE: 46 Met Arg Gly Ala Arg Gly Ala Trp Asp Phe Leu Cys Val Leu Leu Leu 1 5 10 15 Leu Leu Arg Val Gln Thr Gly Ser Ser Gln Pro Ser Val Ser Pro Gly 20 25 30 Glu Pro Ser Pro Pro Ser Ile His Pro Gly Lys Ser Asp Leu Ile Val 35 40 45 Arg Val Gly Asp Glu Ile Arg Leu Leu Cys Thr Asp Pro Gly Phe Val 50 55 60 Lys Trp Thr Phe Glu Ile Leu Asp Glu Thr Asn Glu Asn Lys Gln Asn 65 70 75 80 Glu Trp Ile Thr Glu Lys Ala Glu Ala Thr Asn Thr Gly Lys Tyr Thr 85 90 95 Cys Thr Asn Lys His Gly Leu Ser Asn Ser Ile Tyr Val Phe Val Arg 100 105 110 Asp Pro Ala Lys Leu Phe Leu Val Asp Arg Ser Leu Tyr Gly Lys Glu 115 120 125 Asp Asn Asp Thr Leu Val Arg Cys Pro Leu Thr Asp Pro Glu Val Thr 130 135 140 Asn Tyr Ser Leu Lys Gly Cys Gln Gly Lys Pro Leu Pro Lys Asp Leu 145 150 155 160 Arg Phe Ile Pro Asp Pro Lys Ala Gly Ile Met Ile Lys Ser Val Lys 165 170 175 Arg Ala Tyr His Arg Leu Cys Leu His Cys Ser Val Asp Gln Glu Gly 180 185 190 Lys Ser Val Leu Ser Glu Lys Phe Ile Leu Lys Val Arg Pro Ala Phe 195 200 205 Lys Ala Val Pro Val Val Ser Val Ser Lys Ala Ser Tyr Leu Leu Arg 210 215 220 Glu Gly Glu Glu Phe Thr Val Thr Cys Thr Ile Lys Asp Val Ser Ser 225 230 235 240 Ser Val Tyr Ser Thr Trp Lys Arg Glu Asn Ser Gln Thr Lys Leu Gln 245 250 255 Glu Lys Tyr Asn Ser Trp His His Gly Asp Phe Asn Tyr Glu Arg Gln 260 265 270 Ala Thr Leu Thr Ile Ser Ser Ala Arg Val Asn Asp Ser Gly Val Phe 275 280 285 Met Cys Tyr Ala Asn Asn Thr Phe Gly Ser Ala Asn Val Thr Thr Thr 290 295 300 Leu Glu Val Val Asp Lys Gly Phe Ile Asn Ile Phe Pro Met Ile Asn 305 310 315 320 Thr Thr Val Phe Val Asn Asp Gly Glu Asn Val Asp Leu Ile Val Glu 325 330 335 Tyr Glu Ala Phe Pro Lys Pro Glu His Gln Gln Trp Ile Tyr Met Asn 340 345 350 Arg Thr Phe Thr Asp Lys Trp Glu Asp Tyr Pro Lys Ser Glu Asn Glu 355 360 365 Ser Asn Ile Arg Tyr Val Ser Glu Leu His Leu Thr Arg Leu Lys Gly 370 375 380 Thr Glu Gly Gly Thr Tyr Thr Phe Leu Val Ser Asn Ser Asp Val Asn 385 390 395 400 Ala Ala Ile Ala Phe Asn Val Tyr Val Asn Thr Lys Pro Glu Ile Leu 405 410 415 Thr Tyr Asp Arg Leu Val Asn Gly Met Leu Gln Cys Val Ala Ala Gly 420 425 430 Phe Pro Glu Pro Thr Ile Asp Trp Tyr Phe Cys Pro Gly Thr Glu Gln 435 440 445 Arg Cys Ser Ala Ser Val Leu Pro Val Asp Val Gln Thr Leu Asn Ser 450 455 460 Ser Gly Pro Pro Phe Gly Lys Leu Val Val Gln Ser Ser Ile Asp Ser

465 470 475 480 Ser Ala Phe Lys His Asn Gly Thr Val Glu Cys Lys Ala Tyr Asn Asp 485 490 495 Val Gly Lys Thr Ser Ala Tyr Phe Asn Phe Ala Phe Lys Gly Asn Asn 500 505 510 Lys Glu Gln Ile His Pro His Thr Leu Phe Thr Pro Leu Leu Ile Gly 515 520 525 Phe Val Ile Val Ala Gly Met Met Cys Ile Ile Val Met Ile Leu Thr 530 535 540 Tyr Lys Tyr Leu Gln Lys Pro Met Tyr Glu Val Gln Trp Lys Val Val 545 550 555 560 Glu Glu Ile Asn Gly Asn Asn Tyr Val Tyr Ile Asp Pro Thr Gln Leu 565 570 575 Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly 580 585 590 Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys Val Val Glu Ala Thr Ala 595 600 605 Tyr Gly Leu Ile Lys Ser Asp Ala Ala Met Thr Val Ala Val Lys Met 610 615 620 Leu Lys Pro Ser Ala His Leu Thr Glu Arg Glu Ala Leu Met Ser Glu 625 630 635 640 Leu Lys Val Leu Ser Tyr Leu Gly Asn His Met Asn Ile Val Asn Leu 645 650 655 Leu Gly Ala Cys Thr Ile Gly Gly Pro Thr Leu Val Ile Thr Glu Tyr 660 665 670 Cys Cys Tyr Gly Asp Leu Leu Asn Phe Leu Arg Arg Lys Arg Asp Ser 675 680 685 Phe Ile Cys Ser Lys Gln Glu Asp His Ala Glu Ala Ala Leu Tyr Lys 690 695 700 Asn Leu Leu His Ser Lys Glu Ser Ser Cys Ser Asp Ser Thr Asn Glu 705 710 715 720 Tyr Met Asp Met Lys Pro Gly Val Ser Tyr Val Val Pro Thr Lys Ala 725 730 735 Asp Lys Arg Arg Ser Val Arg Ile Gly Ser Tyr Ile Glu Arg Asp Val 740 745 750 Thr Pro Ala Ile Met Glu Asp Asp Glu Leu Ala Leu Asp Leu Glu Asp 755 760 765 Leu Leu Ser Phe Ser Tyr Gln Val Ala Lys Gly Met Ala Phe Leu Ala 770 775 780 Ser Lys Asn Cys Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Leu 785 790 795 800 Thr His Gly Arg Ile Thr Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp 805 810 815 Ile Lys Asn Asp Ser Asn Tyr Val Val Lys Gly Asn Ala Arg Leu Pro 820 825 830 Val Lys Trp Met Ala Pro Glu Ser Ile Phe Asn Cys Val Tyr Thr Phe 835 840 845 Glu Ser Asp Val Trp Ser Tyr Gly Ile Phe Leu Trp Glu Leu Phe Ser 850 855 860 Leu Gly Ser Ser Pro Tyr Pro Gly Met Pro Val Asp Ser Lys Phe Tyr 865 870 875 880 Lys Met Ile Lys Glu Gly Phe Arg Met Leu Ser Pro Glu His Ala Pro 885 890 895 Ala Glu Met Tyr Asp Ile Met Lys Thr Cys Trp Asp Ala Asp Pro Leu 900 905 910 Lys Arg Pro Thr Phe Lys Gln Ile Val Gln Leu Ile Glu Lys Gln Ile 915 920 925 Ser Glu Ser Thr Asn His Ile Tyr Ser Asn Leu Ala Asn Cys Ser Pro 930 935 940 Asn Arg Gln Lys Pro Val Val Asp His Ser Val Arg Ile Asn Ser Val 945 950 955 960 Gly Ser Thr Ala Ser Ser Ser Gln Pro Leu Leu Val His Asp Asp Val 965 970 975 <210> SEQ ID NO 47 <211> LENGTH: 489 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LSM7 <400> SEQUENCE: 47 cgcgacaaga tggcggataa ggagaagaag aaaaaggaga gcatcttgga cttgtccaag 60 tacatcgaca agacgatccg ggtaaagttc cagggaggcc gcgaagccag tggaatcctg 120 aagggcttcg acccactcct caaccttgtg ctggacggca ccattgagta catgcgagac 180 cctgacgacc agtacaagct cacggaggac acccggcagc tgggcctcgt ggtgtgccgg 240 ggcacgtccg tggtgctaat ctgcccgcag gacggcatgg aggccatccc caaccccttc 300 atccagcagc aggacgccta gcctggccgg gggcgcgggg ggtgcagggc aggcccgagc 360 agctcggttt cccgcggact tggctgctgc tcccaccgca gtaccgcctc ctggaacgga 420 agcatttctc ctttttgtat aggttgaatt tttgttttct taataaaatt gcaaacctca 480 aaaaaaaaa 489 <210> SEQ ID NO 48 <211> LENGTH: 103 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: LSM7 <400> SEQUENCE: 48 Met Ala Asp Lys Glu Lys Lys Lys Lys Glu Ser Ile Leu Asp Leu Ser 1 5 10 15 Lys Tyr Ile Asp Lys Thr Ile Arg Val Lys Phe Gln Gly Gly Arg Glu 20 25 30 Ala Ser Gly Ile Leu Lys Gly Phe Asp Pro Leu Leu Asn Leu Val Leu 35 40 45 Asp Gly Thr Ile Glu Tyr Met Arg Asp Pro Asp Asp Gln Tyr Lys Leu 50 55 60 Thr Glu Asp Thr Arg Gln Leu Gly Leu Val Val Cys Arg Gly Thr Ser 65 70 75 80 Val Val Leu Ile Cys Pro Gln Asp Gly Met Glu Ala Ile Pro Asn Pro 85 90 95 Phe Ile Gln Gln Gln Asp Ala 100 <210> SEQ ID NO 49 <211> LENGTH: 1694 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: SYNGR2 <400> SEQUENCE: 49 ggcggcggca gcggcggcga cggcgacatg gagagcgggg cctacggcgc ggccaaggcg 60 ggcggctcct tcgacctgcg gcgcttcctg acgcagccgc aggtggtggc gcgcgccgtg 120 tgcttggtct tcgccttgat cgtgttctcc tgcatctatg gtgagggcta cagcaatgcc 180 cacgagtcta agcagatgta ctgcgtgttc aaccgcaacg aggatgcctg ccgctatggc 240 agtgccatcg gggtgctggc cttcctggcc tcggccttct tcttggtggt cgacgcgtat 300 ttcccccaga tcagcaacgc cactgaccgc aagtacctgg tcattggtga cctgctcttc 360 tcagctctct ggaccttcct gtggtttgtt ggtttctgct tcctcaccaa ccagtgggca 420 gtcaccaacc cgaaggacgt gctggtgggg gccgactctg tgagggcagc catcaccttc 480 agcttctttt ccatcttctc ctggggtgtg ctggcctccc tggcctacca gcgctacaag 540 gctggcgtgg acgacttcat ccagaattac gttgacccca ctccggaccc caacactgcc 600 tacgcctcct acccaggtgc atctgtggac aactaccaac agccaccctt cacccagaac 660 gcggagacca ccgagggcta ccagccgccc cctgtgtact gagcggcggt tagcgtggga 720 agggggacag agagggccct cccctctgcc ctggactttc ccatgagcct cctggaactg 780 ccagcccctc tctttcacct gttccatcct gtgcagctga cacacagcta aggagcctca 840 tagcctggcg ggggctggca gagccacacc ccaagtgcct gtgcccagag ggcttcagtc 900 agccgctcac tcctccaggg cacttttagg aaagggtttt tagctagtgt ttttcctcgc 960 ttttaatgac ctcagccccg cctgcagtgg ctagaagcca gcaggtgccc atgtgctact 1020 gacaagtgcc tcagcttccc cccggcccgg gtcaggccgt gggagccgct attatctgcg 1080 ttctctgcca aagactcgtg ggggccatca cacctgccct gtgcagcgga gccggaccag 1140 gctcttgtgt cctcactcag gtttgcttcc cctgtgccca ctgctgtatg atctgggggc 1200 caccaccctg tgccggtggc ctctgggctg cctcccgtgg tgtgagggcg gggctggtgc 1260 tcatggcact tcctccttgc tcccacccct ggcagcaggg aagggctttg cctgacaaca 1320 cccagcttta tgtaaatatt ctgcagttgt tacttaggaa gcctggggag ggcaggggtg 1380 ccccatggct cccagactct gtctgtgccg agtgtattat aaaatcgtgg gggagatgcc 1440 cggcctggga tgctgtttgg agacggaata aatgttttct cattcagtct ccagtcattg 1500 gttgagccac agcctagggg ttggaggaag actccactct gggtacaccc ttaggggctg 1560 gctttatgga acttgtagtt tgaacaaggc agtggcaatc cgccccctcc agcctgcctg 1620 gctggccccc ttccctctgt ctggggtcgc attccgcaca agcctttcat caacatctta 1680 aaatagtaac tgtg 1694 <210> SEQ ID NO 50 <211> LENGTH: 224 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: SYNGR2 <400> SEQUENCE: 50 Met Glu Ser Gly Ala Tyr Gly Ala Ala Lys Ala Gly Gly Ser Phe Asp 1 5 10 15 Leu Arg Arg Phe Leu Thr Gln Pro Gln Val Val Ala Arg Ala Val Cys 20 25 30 Leu Val Phe Ala Leu Ile Val Phe Ser Cys Ile Tyr Gly Glu Gly Tyr 35 40 45 Ser Asn Ala His Glu Ser Lys Gln Met Tyr Cys Val Phe Asn Arg Asn 50 55 60 Glu Asp Ala Cys Arg Tyr Gly Ser Ala Ile Gly Val Leu Ala Phe Leu 65 70 75 80 Ala Ser Ala Phe Phe Leu Val Val Asp Ala Tyr Phe Pro Gln Ile Ser 85 90 95 Asn Ala Thr Asp Arg Lys Tyr Leu Val Ile Gly Asp Leu Leu Phe Ser 100 105 110

Ala Leu Trp Thr Phe Leu Trp Phe Val Gly Phe Cys Phe Leu Thr Asn 115 120 125 Gln Trp Ala Val Thr Asn Pro Lys Asp Val Leu Val Gly Ala Asp Ser 130 135 140 Val Arg Ala Ala Ile Thr Phe Ser Phe Phe Ser Ile Phe Ser Trp Gly 145 150 155 160 Val Leu Ala Ser Leu Ala Tyr Gln Arg Tyr Lys Ala Gly Val Asp Asp 165 170 175 Phe Ile Gln Asn Tyr Val Asp Pro Thr Pro Asp Pro Asn Thr Ala Tyr 180 185 190 Ala Ser Tyr Pro Gly Ala Ser Val Asp Asn Tyr Gln Gln Pro Pro Phe 195 200 205 Thr Gln Asn Ala Glu Thr Thr Glu Gly Tyr Gln Pro Pro Pro Val Tyr 210 215 220 <210> SEQ ID NO 51 <211> LENGTH: 2272 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: c11orf8 <400> SEQUENCE: 51 aatgcacagc ggtattgatg agtagatcct tggattcaga ggttggctga aacgcaccat 60 gcctgcttcc atcttttgct ctgtaaagtt gtgaattgct catgcctata gggaggaagg 120 atggcacatg ggattccttc tcaaggcaaa gttaccataa cggtggatga gtacagctca 180 aaccccaccc aggcattcac gcactacaac atcaaccaga gcagattcca gcctccacat 240 gtacatatgg tcgaccccat cccatatgac actccaaaac cagcgggcca cacgcggttt 300 gtctgcatct cagacacaca ctccagaaca gatggtatcc agatgcctta tggggacatc 360 cttctccaca caggcgattt caccgagctg ggactgccct cagaggttaa gaagtttaat 420 gactggttag gaaacctgcc atatgaatat aaaatagtga ttgctgggaa tcatgaactg 480 acatttgata aggaattcat ggcagacctt gttaaacagg actactaccg tttcccctct 540 gtgtccaaat tgaaaccaga ggactttgac aatgttcagt ccctcctgac aaacagtatt 600 tacttacaag attcggaggt aacagtgaag ggattcagga tatacggtgc accttggacc 660 ccgtggttta atggatgggg ctttaaccta cccagaggtc agtctctgct ggacaagtgg 720 aacctcatcc ctgagggcat tgacatactc atgacacatg gacctcctct aggttttcga 780 gactgggttc caaaggagct tcaaagagtg ggctgtgtgg agctgttaaa cacggttcag 840 aggcgagtcc ggcccaagct ccatgtgttt ggtggaatcc atgaaggtta tggcatcatg 900 accgacggtt acacaacgta catcaatgcc tcgacgtgta cagtcagctt tcaaccgacc 960 aaccctccaa ttatatttga ccttccaaac ccacagggtt cctgaagctc taaatgccct 1020 attggaatgt gagggaaggt ctataaactg ccatttttct aattataaac ttacattctc 1080 ttacttattt acaaaccctg tgagttcttt ttgtaaattg ttggaacaca aatgatgcta 1140 gaggttgtgc ttcttatttt attttatttt aaatggggca tccatttgaa atcagaggaa 1200 cattgtgaat ttgtaaaatg acttctgttt tctcaaaggc catgccattg taaattgtta 1260 gtgttcgcca aaggacagcc aagctttctt ttaaaaagtg ataaaagtct tattttaata 1320 tgctttaagc tgaaagaaaa aaaaataaga aacaggcagt gttttaaaaa ccaacacaga 1380 tttgcacaac tgtttaagag tattgtttga aatattttaa ttttcaatgt tttgttgttg 1440 ttgttttctt ggtaatgctt cttttttgca gatgtggtcc caatttatag caatcttctc 1500 aacagaagta ggcatggaaa agacttcttt tcatactctc actataaaga aagctgcatt 1560 gagaagaaaa tggctgtcat ttaaaggatg gtttaactag tgagattcct attgtggtta 1620 tacaaggtct cattgtttgt ttgtttcttt taaattattt cagctttaaa aatacagaaa 1680 tggaatctgt caagagcagg tatttcatac ggttaaaaaa atgaacatgc agactccttt 1740 tcaatatggg tttatatata taagtatttt ttgtgtatta tgactacgtt aggagtttaa 1800 tattgtcaag gacagtacaa ctgcaaaggg atgctgtata gcagcacatc agaagtcgga 1860 aggaactgac acattctctc agagctcaag gtcttaaaga gcttgagtta aatctaggta 1920 cagttacagg catgtataga cttaaatgga tgcaatggaa gctaactaaa ataaggctta 1980 gttgtccttt ctatttaaat accccaagtt gtcttcttac ttcctctccc ctctcccatt 2040 ttgcactgtg tgtcgatgca atcttcgcta gcacaaaata ttgtcgctaa tagtcatttc 2100 tgttttccca ttgtaaatgc tgttgagctt tattctattt tatgttactt tgttaatgaa 2160 atttaggaaa gcagttgttt ctttaaattt attgtgatat tctatatcta gcggccttta 2220 tatgcaaata aaattgcaag atttttaaaa aaaaaaaaaa aaaaaaaaaa aa 2272 <210> SEQ ID NO 52 <211> LENGTH: 294 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: c11orf8 <400> SEQUENCE: 52 Met Ala His Gly Ile Pro Ser Gln Gly Lys Val Thr Ile Thr Val Asp 1 5 10 15 Glu Tyr Ser Ser Asn Pro Thr Gln Ala Phe Thr His Tyr Asn Ile Asn 20 25 30 Gln Ser Arg Phe Gln Pro Pro His Val His Met Val Asp Pro Ile Pro 35 40 45 Tyr Asp Thr Pro Lys Pro Ala Gly His Thr Arg Phe Val Cys Ile Ser 50 55 60 Asp Thr His Ser Arg Thr Asp Gly Ile Gln Met Pro Tyr Gly Asp Ile 65 70 75 80 Leu Leu His Thr Gly Asp Phe Thr Glu Leu Gly Leu Pro Ser Glu Val 85 90 95 Lys Lys Phe Asn Asp Trp Leu Gly Asn Leu Pro Tyr Glu Tyr Lys Ile 100 105 110 Val Ile Ala Gly Asn His Glu Leu Thr Phe Asp Lys Glu Phe Met Ala 115 120 125 Asp Leu Val Lys Gln Asp Tyr Tyr Arg Phe Pro Ser Val Ser Lys Leu 130 135 140 Lys Pro Glu Asp Phe Asp Asn Val Gln Ser Leu Leu Thr Asn Ser Ile 145 150 155 160 Tyr Leu Gln Asp Ser Glu Val Thr Val Lys Gly Phe Arg Ile Tyr Gly 165 170 175 Ala Pro Trp Thr Pro Trp Phe Asn Gly Trp Gly Phe Asn Leu Pro Arg 180 185 190 Gly Gln Ser Leu Leu Asp Lys Trp Asn Leu Ile Pro Glu Gly Ile Asp 195 200 205 Ile Leu Met Thr His Gly Pro Pro Leu Gly Phe Arg Asp Trp Val Pro 210 215 220 Lys Glu Leu Gln Arg Val Gly Cys Val Glu Leu Leu Asn Thr Val Gln 225 230 235 240 Arg Arg Val Arg Pro Lys Leu His Val Phe Gly Gly Ile His Glu Gly 245 250 255 Tyr Gly Ile Met Thr Asp Gly Tyr Thr Thr Tyr Ile Asn Ala Ser Thr 260 265 270 Cys Thr Val Ser Phe Gln Pro Thr Asn Pro Pro Ile Ile Phe Asp Leu 275 280 285 Pro Asn Pro Gln Gly Ser 290 <210> SEQ ID NO 53 <211> LENGTH: 4828 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: CDH1 <400> SEQUENCE: 53 agtggcgtcg gaactgcaaa gcacctgtga gcttgcggaa gtcagttcag actccagccc 60 gctccagccc ggcccgaccc gaccgcaccc ggcgcctgcc ctcgctcggc gtccccggcc 120 agccatgggc ccttggagcc gcagcctctc ggcgctgctg ctgctgctgc aggtctcctc 180 ttggctctgc caggagccgg agccctgcca ccctggcttt gacgccgaga gctacacgtt 240 cacggtgccc cggcgccacc tggagagagg ccgcgtcctg ggcagagtga attttgaaga 300 ttgcaccggt cgacaaagga cagcctattt ttccctcgac acccgattca aagtgggcac 360 agatggtgtg attacagtca aaaggcctct acggtttcat aacccacaga tccatttctt 420 ggtctacgcc tgggactcca cctacagaaa gttttccacc aaagtcacgc tgaatacagt 480 ggggcaccac caccgccccc cgccccatca ggcctccgtt tctggaatcc aagcagaatt 540 gctcacattt cccaactcct ctcctggcct cagaagacag aagagagact gggttattcc 600 tcccatcagc tgcccagaaa atgaaaaagg cccatttcct aaaaacctgg ttcagatcaa 660 atccaacaaa gacaaagaag gcaaggtttt ctacagcatc actggccaag gagctgacac 720 accccctgtt ggtgtcttta ttattgaaag agaaacagga tggctgaagg tgacagagcc 780 tctggataga gaacgcattg ccacatacac tctcttctct cacgctgtgt catccaacgg 840 gaatgcagtt gaggatccaa tggagatttt gatcacggta accgatcaga atgacaacaa 900 gcccgaattc acccaggagg tctttaaggg gtctgtcatg gaaggtgctc ttccaggaac 960 ctctgtgatg gaggtcacag ccacagacgc ggacgatgat gtgaacacct acaatgccgc 1020 catcgcttac accatcctca gccaagatcc tgagctccct gacaaaaata tgttcaccat 1080 taacaggaac acaggagtca tcagtgtggt caccactggg ctggaccgag agagtttccc 1140 tacgtatacc ctggtggttc aagctgctga ccttcaaggt gaggggttaa gcacaacagc 1200 aacagctgtg atcacagtca ctgacaccaa cgataatcct ccgatcttca atcccaccac 1260 gtacaagggt caggtgcctg agaacgaggc taacgtcgta atcaccacac tgaaagtgac 1320 tgatgctgat gcccccaata ccccagcgtg ggaggctgta tacaccatat tgaatgatga 1380 tggtggacaa tttgtcgtca ccacaaatcc agtgaacaac gatggcattt tgaaaacagc 1440 aaagggcttg gattttgagg ccaagcagca gtacattcta cacgtagcag tgacgaatgt 1500 ggtacctttt gaggtctctc tcaccacctc cacagccacc gtcaccgtgg atgtgctgga 1560 tgtgaatgaa gcccccatct ttgtgcctcc tgaaaagaga gtggaagtgt ccgaggactt 1620 tggcgtgggc caggaaatca catcctacac tgcccaggag ccagacacat ttatggaaca 1680 gaaaataaca tatcggattt ggagagacac tgccaactgg ctggagatta atccggacac 1740 tggtgccatt tccactcggg ctgagctgga cagggaggat tttgagcacg tgaagaacag 1800 cacgtacaca gccctaatca tagctacaga caatggttct ccagttgcta ctggaacagg 1860 gacacttctg ctgatcctgt ctgatgtgaa tgacaacgcc cccataccag aacctcgaac 1920 tatattcttc tgtgagagga atccaaagcc tcaggtcata aacatcattg atgcagacct 1980

tcctcccaat acatctccct tcacagcaga actaacacac ggggcgagtg ccaactggac 2040 cattcagtac aacgacccaa cccaagaatc tatcattttg aagccaaaga tggccttaga 2100 ggtgggtgac tacaaaatca atctcaagct catggataac cagaataaag accaagtgac 2160 caccttagag gtcagcgtgt gtgactgtga aggggccgcc ggcgtctgta ggaaggcaca 2220 gcctgtcgaa gcaggattgc aaattcctgc cattctgggg attcttggag gaattcttgc 2280 tttgctaatt ctgattctgc tgctcttgct gtttcttcgg aggagagcgg tggtcaaaga 2340 gcccttactg cccccagagg atgacacccg ggacaacgtt tattactatg atgaagaagg 2400 aggcggagaa gaggaccagg actttgactt gagccagctg cacaggggcc tggacgctcg 2460 gcctgaagtg actcgtaacg acgttgcacc aaccctcatg agtgtccccc ggtatcttcc 2520 ccgccctgcc aatcccgatg aaattggaaa ttttattgat gaaaatctga aagcggctga 2580 tactgacccc acagccccgc cttatgattc tctgctcgtg tttgactatg aaggaagcgg 2640 ttccgaagct gctagtctga gctccctgaa ctcctcagag tcagacaaag accaggacta 2700 tgactacttg aacgaatggg gcaatcgctt caagaagctg gctgacatgt acggaggcgg 2760 cgaggacgac taggggactc gagagaggcg ggccccagac ccatgtgctg ggaaatgcag 2820 aaatcacgtt gctggtggtt tttcagctcc cttcccttga gatgagtttc tggggaaaaa 2880 aaagagactg gttagtgatg cagttagtat agctttatac tctctccact ttatagctct 2940 aataagtttg tgttagaaaa gtttcgactt atttcttaaa gctttttttt ttttcccatc 3000 actctttaca tggtggtgat gtccaaaaga tacccaaatt ttaatattcc agaagaacaa 3060 ctttagcatc agaaggttca cccagcacct tgcagatttt cttaaggaat tttgtctcac 3120 ttttaaaaag aaggggagaa gtcagctact ctagttctgt tgttttgtgt atataatttt 3180 ttaaaaaaaa tttgtgtgct tctgctcatt actacactgg tgtgtccctc tgcctttttt 3240 ttttttttta agacagggtc tcattctatc ggccaggctg gagtgcagtg gtgcaatcac 3300 agctcactgc agccttgtcc tcccaggctc aagctatcct tgcacctcag cctcccaagt 3360 agctgggacc acaggcatgc accactacgc atgactaatt ttttaaatat ttgagacggg 3420 gtctccctgt gttacccagg ctggtctcaa actcctgggc tcaagtgatc ctcccatctt 3480 ggcctcccag agtattggga ttacagacat gagccactgc acctgcccag ctccccaact 3540 ccctgccatt ttttaagaga cagtttcgct ccatcgccca ggcctgggat gcagtgatgt 3600 gatcatagct cactgtaacc tcaaactctg gggctcaagc agttctccca ccagcctcct 3660 ttttattttt ttgtacagat ggggtcttgc tatgttgccc aagctggtct taaactcctg 3720 gcctcaagca atccttctgc cttggccccc caaagtgctg ggattgtggg catgagctgc 3780 tgtgcccagc ctccatgttt taatatcaac tctcactcct gaattcagtt gctttgccca 3840 agataggagt tctctgatgc agaaattatt gggctctttt agggtaagaa gtttgtgtct 3900 ttgtctggcc acatcttgac taggtattgt ctactctgaa gacctttaat ggcttccctc 3960 tttcatctcc tgagtatgta acttgcaatg ggcagctatc cagtgacttg ttctgagtaa 4020 gtgtgttcat taatgtttat ttagctctga agcaagagtg atatactcca ggacttagaa 4080 tagtgcctaa agtgctgcag ccaaagacag agcggaacta tgaaaagtgg gcttggagat 4140 ggcaggagag cttgtcattg agcctggcaa tttagcaaac tgatgctgag gatgattgag 4200 gtgggtctac ctcatctctg aaaattctgg aaggaatgga ggagtctcaa catgtgtttc 4260 tgacacaaga tccgtggttt gtactcaaag cccagaatcc ccaagtgcct gcttttgatg 4320 atgtctacag aaaatgctgg ctgagctgaa cacatttgcc caattccagg tgtgcacaga 4380 aaaccgagaa tattcaaaat tccaaatttt ttcttaggag caagaagaaa atgtggccct 4440 aaagggggtt agttgagggg tagggggtag tgaggatctt gatttggatc tctttttatt 4500 taaatgtgaa tttcaacttt tgacaatcaa agaaaagact tttgttgaaa tagctttact 4560 gtttctcaag tgttttggag aaaaaaatca accctgcaat cactttttgg aattgtcttg 4620 atttttcggc agttcaagct atatcgaata tagttctgtg tagagaatgt cactgtagtt 4680 ttgagtgtat acatgtgtgg gtgctgataa ttgtgtattt tctttggggg tggaaaagga 4740 aaacaattca agctgagaaa agtattctca aagatgcatt tttataaatt ttattaaaca 4800 attttgttaa accataaaaa aaaaaaaa 4828 <210> SEQ ID NO 54 <211> LENGTH: 882 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: CDH1 <400> SEQUENCE: 54 Met Gly Pro Trp Ser Arg Ser Leu Ser Ala Leu Leu Leu Leu Leu Gln 1 5 10 15 Val Ser Ser Trp Leu Cys Gln Glu Pro Glu Pro Cys His Pro Gly Phe 20 25 30 Asp Ala Glu Ser Tyr Thr Phe Thr Val Pro Arg Arg His Leu Glu Arg 35 40 45 Gly Arg Val Leu Gly Arg Val Asn Phe Glu Asp Cys Thr Gly Arg Gln 50 55 60 Arg Thr Ala Tyr Phe Ser Leu Asp Thr Arg Phe Lys Val Gly Thr Asp 65 70 75 80 Gly Val Ile Thr Val Lys Arg Pro Leu Arg Phe His Asn Pro Gln Ile 85 90 95 His Phe Leu Val Tyr Ala Trp Asp Ser Thr Tyr Arg Lys Phe Ser Thr 100 105 110 Lys Val Thr Leu Asn Thr Val Gly His His His Arg Pro Pro Pro His 115 120 125 Gln Ala Ser Val Ser Gly Ile Gln Ala Glu Leu Leu Thr Phe Pro Asn 130 135 140 Ser Ser Pro Gly Leu Arg Arg Gln Lys Arg Asp Trp Val Ile Pro Pro 145 150 155 160 Ile Ser Cys Pro Glu Asn Glu Lys Gly Pro Phe Pro Lys Asn Leu Val 165 170 175 Gln Ile Lys Ser Asn Lys Asp Lys Glu Gly Lys Val Phe Tyr Ser Ile 180 185 190 Thr Gly Gln Gly Ala Asp Thr Pro Pro Val Gly Val Phe Ile Ile Glu 195 200 205 Arg Glu Thr Gly Trp Leu Lys Val Thr Glu Pro Leu Asp Arg Glu Arg 210 215 220 Ile Ala Thr Tyr Thr Leu Phe Ser His Ala Val Ser Ser Asn Gly Asn 225 230 235 240 Ala Val Glu Asp Pro Met Glu Ile Leu Ile Thr Val Thr Asp Gln Asn 245 250 255 Asp Asn Lys Pro Glu Phe Thr Gln Glu Val Phe Lys Gly Ser Val Met 260 265 270 Glu Gly Ala Leu Pro Gly Thr Ser Val Met Glu Val Thr Ala Thr Asp 275 280 285 Ala Asp Asp Asp Val Asn Thr Tyr Asn Ala Ala Ile Ala Tyr Thr Ile 290 295 300 Leu Ser Gln Asp Pro Glu Leu Pro Asp Lys Asn Met Phe Thr Ile Asn 305 310 315 320 Arg Asn Thr Gly Val Ile Ser Val Val Thr Thr Gly Leu Asp Arg Glu 325 330 335 Ser Phe Pro Thr Tyr Thr Leu Val Val Gln Ala Ala Asp Leu Gln Gly 340 345 350 Glu Gly Leu Ser Thr Thr Ala Thr Ala Val Ile Thr Val Thr Asp Thr 355 360 365 Asn Asp Asn Pro Pro Ile Phe Asn Pro Thr Thr Tyr Lys Gly Gln Val 370 375 380 Pro Glu Asn Glu Ala Asn Val Val Ile Thr Thr Leu Lys Val Thr Asp 385 390 395 400 Ala Asp Ala Pro Asn Thr Pro Ala Trp Glu Ala Val Tyr Thr Ile Leu 405 410 415 Asn Asp Asp Gly Gly Gln Phe Val Val Thr Thr Asn Pro Val Asn Asn 420 425 430 Asp Gly Ile Leu Lys Thr Ala Lys Gly Leu Asp Phe Glu Ala Lys Gln 435 440 445 Gln Tyr Ile Leu His Val Ala Val Thr Asn Val Val Pro Phe Glu Val 450 455 460 Ser Leu Thr Thr Ser Thr Ala Thr Val Thr Val Asp Val Leu Asp Val 465 470 475 480 Asn Glu Ala Pro Ile Phe Val Pro Pro Glu Lys Arg Val Glu Val Ser 485 490 495 Glu Asp Phe Gly Val Gly Gln Glu Ile Thr Ser Tyr Thr Ala Gln Glu 500 505 510 Pro Asp Thr Phe Met Glu Gln Lys Ile Thr Tyr Arg Ile Trp Arg Asp 515 520 525 Thr Ala Asn Trp Leu Glu Ile Asn Pro Asp Thr Gly Ala Ile Ser Thr 530 535 540 Arg Ala Glu Leu Asp Arg Glu Asp Phe Glu His Val Lys Asn Ser Thr 545 550 555 560 Tyr Thr Ala Leu Ile Ile Ala Thr Asp Asn Gly Ser Pro Val Ala Thr 565 570 575 Gly Thr Gly Thr Leu Leu Leu Ile Leu Ser Asp Val Asn Asp Asn Ala 580 585 590 Pro Ile Pro Glu Pro Arg Thr Ile Phe Phe Cys Glu Arg Asn Pro Lys 595 600 605 Pro Gln Val Ile Asn Ile Ile Asp Ala Asp Leu Pro Pro Asn Thr Ser 610 615 620 Pro Phe Thr Ala Glu Leu Thr His Gly Ala Ser Ala Asn Trp Thr Ile 625 630 635 640 Gln Tyr Asn Asp Pro Thr Gln Glu Ser Ile Ile Leu Lys Pro Lys Met 645 650 655 Ala Leu Glu Val Gly Asp Tyr Lys Ile Asn Leu Lys Leu Met Asp Asn 660 665 670 Gln Asn Lys Asp Gln Val Thr Thr Leu Glu Val Ser Val Cys Asp Cys 675 680 685 Glu Gly Ala Ala Gly Val Cys Arg Lys Ala Gln Pro Val Glu Ala Gly 690 695 700 Leu Gln Ile Pro Ala Ile Leu Gly Ile Leu Gly Gly Ile Leu Ala Leu 705 710 715 720 Leu Ile Leu Ile Leu Leu Leu Leu Leu Phe Leu Arg Arg Arg Ala Val 725 730 735 Val Lys Glu Pro Leu Leu Pro Pro Glu Asp Asp Thr Arg Asp Asn Val 740 745 750 Tyr Tyr Tyr Asp Glu Glu Gly Gly Gly Glu Glu Asp Gln Asp Phe Asp 755 760 765 Leu Ser Gln Leu His Arg Gly Leu Asp Ala Arg Pro Glu Val Thr Arg

770 775 780 Asn Asp Val Ala Pro Thr Leu Met Ser Val Pro Arg Tyr Leu Pro Arg 785 790 795 800 Pro Ala Asn Pro Asp Glu Ile Gly Asn Phe Ile Asp Glu Asn Leu Lys 805 810 815 Ala Ala Asp Thr Asp Pro Thr Ala Pro Pro Tyr Asp Ser Leu Leu Val 820 825 830 Phe Asp Tyr Glu Gly Ser Gly Ser Glu Ala Ala Ser Leu Ser Ser Leu 835 840 845 Asn Ser Ser Glu Ser Asp Lys Asp Gln Asp Tyr Asp Tyr Leu Asn Glu 850 855 860 Trp Gly Asn Arg Phe Lys Lys Leu Ala Asp Met Tyr Gly Gly Gly Glu 865 870 875 880 Asp Asp <210> SEQ ID NO 55 <211> LENGTH: 5858 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: FAM13A1 <400> SEQUENCE: 55 ccttccagcc atgtgggttc agcggaaaga gaagcaaaac cactcttcct aaaatgttag 60 aagctgctct tcgcttacct tggggccttt gcattgggag ctgtttttca catcaaagaa 120 tatgtgctga atggaatttt agtattttgc tgtcgtttta atattttcgt ctggtcttcc 180 tcagttcttc cagacgcttt ctgagagaat gggggcagga gctctagcca tctgtcaaag 240 taaagcagcg gttcggctga aagaagacat gaaaaagata gtggcagtgc cattaaatga 300 acagaaggat tttacctatc agaagttatt tggagtcagt ctccaagaac ttgaacggca 360 ggggctcacc gagaatggca ttccagcagt agtgtggaat atagtggaat atttgacgca 420 gcatggactt acccaagaag gtctttttag ggtgaatggt aacgtgaagg tggtggaaca 480 acttcgactg aagttcgaga gtggagtgcc cgtggagctc gggaaggacg gtgatgtctg 540 ctcagcagcc agtctgttga agctgtttct gagggagctg cctgacagtc tgatcacctc 600 agcgttgcag cctcgattca ttcaactctt tcaggatggc agaaatgatg ttcaggagag 660 tagcttaaga gacttaataa aagagctgcc agacacccac tactgcctcc tcaagtacct 720 ttgccagttc ttgacaaaag tagccaagca tcatgtgcag aatcgcatga atgttcacaa 780 tctcgccact gtatttgggc caaattgctt tcatgtgcca cctgggcttg aaggcatgaa 840 ggaacaggac ctgtgcaaca agataatggc taaaattcta gaaaattaca ataccctgtt 900 tgaagtagag tatacagaaa atgatcatct gagatgtgaa aacctggcta ggcttatcat 960 agtaaaagag gtctattata agaactccct gcccatcctt ttaacaagag gcttagaaag 1020 agacatgcca aaaccacctc caaaaaccaa gatcccaaaa tccaggagtg agggatctat 1080 tcaggcccac agagtactgc aaccagagct atctgatggc attcctcagc tcagcttgcg 1140 gctaagttat agaaaagcct gcttggaaga catgaattca gcagagggtg ctattagtgc 1200 caagttggta cccagttcac aggaagatga aagacctctg tcacctttct atttgagtgc 1260 tcatgtaccc caagtcagca atgtgtctgc aaccggagaa ctcttagaaa gaaccatccg 1320 atcagctgta gaacaacatc tttttgatgt taataactct ggaggtcaaa gttcagagga 1380 ctcagaatct ggaacactat cagcatcttc tgccacatct gccagacagc gccgccgcca 1440 gtccaaggag caggatgaag ttcgacatgg gagagacaag ggacttatca acaaagaaaa 1500 tactccttct gggttcaacc accttgatga ttgtattttg aatactcagg aagtcgaaaa 1560 ggtacacaaa aatacttttg gttgtgctgg agaaaggagc aagcctaaac gtcagaaatc 1620 cagtactaaa ctttctgagc ttcatgacaa tcaggacggt cttgtgaata tggaaagtct 1680 caattccaca cgatctcatg agagaactgg acctgatgat tttgaatgga tgtctgatga 1740 aaggaaagga aatgaaaaag atggtggaca cactcagcat tttgagagcc ccacaatgaa 1800 gatccaggag catcccagcc tatctgacac caaacagcag agaaatcaag atgccggtga 1860 ccaggaggag agctttgtct ccgaagtgcc ccagtcggac ctgactgcat tgtgtgatga 1920 aaagaactgg gaagagccta tccctgcttt ctcctcctgg cagcgggaga acagtgactc 1980 tgatgaagcc cacctctcgc cgcaggctgg gcgcctgatc cgtcagctgc tggacgaaga 2040 cagcgacccc atgctctctc ctcggttcta cgcttatggg cagagcaggc aatacctgga 2100 tgacacagaa gtgcctcctt ccccaccaaa ctcccattct ttcatgaggc ggcgaagctc 2160 ctctctgggg tcctatgatg atgagcaaga ggacctgaca cctgcccagc tcacacgaag 2220 gattcagagc cttaaaaaga agatccggaa gtttgaagat agattcgaag aagagaagaa 2280 gtacagacct tcccacagtg acaaagcagc caatccggag gttctgaaat ggacaaatga 2340 ccttgccaaa ttccggagac aacttaaaga atcaaaacta aagatatctg aagaggacct 2400 aactcccagg atgcggcagc gaagcaacac actccccaag agttttggtt cccaacttga 2460 gaaagaagat gagaagaagc aagagctggt ggataaagca ataaagccca gtgttgaagc 2520 cacattggaa tctattcaga ggaagctcca ggagaagcga gcggaaagca gccgccctga 2580 ggacattaag gatatgacca aagaccagat tgctaatgag aaagtggctc tgcagaaagc 2640 tctgttatat tatgaaagca ttcatggacg gccggtaaca aagaacgaac ggcaggtgat 2700 gaagccacta tacgacaggt accggctggt caaacagatc ctctcccgag ctaacaccat 2760 acccatcatt ggttccccct ccagcaagcg gagaagccct ttgctgcagc caattatcga 2820 gggcgaaact gcttccttct tcaaggagat aaaggaagaa gaggaggggt cagaagacga 2880 tagcaatgtg aagccagact tcatggtcac tctgaaaacc gatttcagtg cacgatgctt 2940 tctggaccaa ttcgaagatg acgctgatgg atttatttcc ccaatggatg ataaaatacc 3000 atcaaaatgc agccaggaca cagggctttc aaatctccat gctgcctcaa tacctgaact 3060 cctggaacac ctccaggaaa tgagagaaga aaagaaaagg attcgaaaga aacttcggga 3120 ttttgaagac aactttttca gacagaatgg aagaaatgtc cagaaggaag accgcactcc 3180 tatggctgaa gaatacagtg aatataagca cataaaggcg aaactgaggc tcctggaggt 3240 gctcatcagc aagagagaca ctgattccaa gtccatgtga ggggcatggc caagcacagg 3300 gggctggcag ctgcggtgag agtttactgt ccccagagaa agtgcagctc tggaaggcag 3360 ccttggggct ggccctgcaa agcatgcagc ccttctgcct ctagaccatt tggcatcggc 3420 tcctgtttcc attgcctgcc ttagaaactg gctggaagaa gacaatgtga cctgacttag 3480 gcattttgta attggaaagt caagactgca gtatgtgcac atgcgcacgc gcatgcacgc 3540 acacacacac acagtagtgg agctttccta acactagcag agattaatca ctacattaga 3600 caacactcat ctacagagaa tatacactgt tcttccctgg ataactgaga aacaagagac 3660 cattctctgt ctaactgtga taaaaacaag ctcaggactt tattctatag agcaaacttg 3720 ctgtggaggg ccatgctctc cttggaccca gttaactgca aacgtgcatt ggagccctat 3780 ttgctgccgc tgccattcta gtgacctttc cacagagctg cgccttcctc acgtgtgtga 3840 aaggttttcc ccttcagccc tcaggtagat ggaagctgca tctgcccacg atggcagtgc 3900 agtcatcatc ttcaggatgt ttcttcagga cttcctcagc tgacaaggaa ttttggtccc 3960 tgcctaggac cgggtcatct gcagaggaca gagagatggt aagcagctgt atgaatgctg 4020 attttaaaac caggtcatgg gagaagagcc tggagattct ttcctgaaca ctgactgcac 4080 ttaccagtct gattttatcg tcaaacacca agccaggcta gcatgctcat ggcaatctgt 4140 ttggggctgt tttgttgtgg cactagccaa acataaaggg gcttaagtca gcctgcatac 4200 agaggatcgg ggagagaagg ggcctgtgtt ctcagcctcc tgagtactta ccagagttta 4260 atttttttaa aaaaaatctg cactaaaatc cccaaactga caggtaaatg tagccctcag 4320 agctcagccc aaggcagaat ctaaatcaca ctattttcga gatcatgtat aaaaagaaaa 4380 aaaagaagtc atgctgtgtg gccaattata atttttttca aagactttgt cacaaaactg 4440 tctatattag acattttgga gggaccagga aatgtaagac accaaatcct ccatctcttc 4500 agtgtgcctg atgtcacctc atgatttgct gttacttttt taactcctgc gccaaggaca 4560 gtgggttctg tgtccacctt tgtgctttgc gaggccgagc ccaggcatct gctcgcctgc 4620 cacggctgac cagagaaggt gcttcaggag ctctgcctta gacgacgtgt tacagtatga 4680 acacacagca gaggcaccct cgtatgtttt gaaagttgcc ttctgaaagg gcacagtttt 4740 aaggaaaaga aaaagaatgt aaaactatac tgacccgttt tcagttttaa agggtcgtga 4800 gaaactggct ggtccaatgg gatttacagc aacattttcc attgctgaag tgaggtagca 4860 gctctcttct gtcagctgaa tgttaaggat ggggaaaaag aatgccttta agtttgctct 4920 taatcgtatg gaagcttgag ctatgtgttg gaagtgccct ggttttaatc catacacaaa 4980 gacggtacat aatcctacag gtttaaatgt acataaaaat atagtttgga attctttgct 5040 ctactgttta cattgcagat tgctataatt tcaaggagtg agattataaa taaaatgatg 5100 cactttagga tgtttcctat ttttgaaatc tgaacatgaa tcattcacat gaccaaaaat 5160 tgtgtttttt taaaaataca tgtctagtct gtcctttaat agctctctta aataagctat 5220 gatattaatc agatcattac cagttagctt ttaaagcaca tttgtttaag actatgtttt 5280 tggaaaaata cgctacagaa ttttttttta agctacaaat aaatgagatg ctactaattg 5340 ttttggaatc tgttgtttct gccaaaggta aattaactaa agatttattc aggaatcccc 5400 atttgaattt gtatgattca ataaaagaaa acaccaagta agttatataa aataaattgt 5460 gtatgagatg ttgtgttttc ctttgtaatt tccactaact aactaactaa cttatattct 5520 tcatggaatg gagcccagaa gaaatgagag gaagcccttt tcacactaga tcttatttga 5580 agaaatgttt gttagtcagt cagtcagtgg tttctggctc tgccgaggga gatgtgttcc 5640 ccagcaacca tttctgcagc ccagaatctc aaggcactag aggcggtgtc ttaattaatt 5700 ggcttcacaa agacaaaatg ctctggactg ggatttttcc tttgctgtgt tgggaatatg 5760 tgtttattaa ttagcacatg ccaacaaaat aaatgtcaag agttatttca taagtgtaag 5820 taaacttaag aattaaagag tgcagactta taattttc 5858 <210> SEQ ID NO 56 <211> LENGTH: 1023 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: FAM13A1 <400> SEQUENCE: 56 Met Gly Ala Gly Ala Leu Ala Ile Cys Gln Ser Lys Ala Ala Val Arg 1 5 10 15 Leu Lys Glu Asp Met Lys Lys Ile Val Ala Val Pro Leu Asn Glu Gln 20 25 30 Lys Asp Phe Thr Tyr Gln Lys Leu Phe Gly Val Ser Leu Gln Glu Leu 35 40 45 Glu Arg Gln Gly Leu Thr Glu Asn Gly Ile Pro Ala Val Val Trp Asn 50 55 60 Ile Val Glu Tyr Leu Thr Gln His Gly Leu Thr Gln Glu Gly Leu Phe

65 70 75 80 Arg Val Asn Gly Asn Val Lys Val Val Glu Gln Leu Arg Leu Lys Phe 85 90 95 Glu Ser Gly Val Pro Val Glu Leu Gly Lys Asp Gly Asp Val Cys Ser 100 105 110 Ala Ala Ser Leu Leu Lys Leu Phe Leu Arg Glu Leu Pro Asp Ser Leu 115 120 125 Ile Thr Ser Ala Leu Gln Pro Arg Phe Ile Gln Leu Phe Gln Asp Gly 130 135 140 Arg Asn Asp Val Gln Glu Ser Ser Leu Arg Asp Leu Ile Lys Glu Leu 145 150 155 160 Pro Asp Thr His Tyr Cys Leu Leu Lys Tyr Leu Cys Gln Phe Leu Thr 165 170 175 Lys Val Ala Lys His His Val Gln Asn Arg Met Asn Val His Asn Leu 180 185 190 Ala Thr Val Phe Gly Pro Asn Cys Phe His Val Pro Pro Gly Leu Glu 195 200 205 Gly Met Lys Glu Gln Asp Leu Cys Asn Lys Ile Met Ala Lys Ile Leu 210 215 220 Glu Asn Tyr Asn Thr Leu Phe Glu Val Glu Tyr Thr Glu Asn Asp His 225 230 235 240 Leu Arg Cys Glu Asn Leu Ala Arg Leu Ile Ile Val Lys Glu Val Tyr 245 250 255 Tyr Lys Asn Ser Leu Pro Ile Leu Leu Thr Arg Gly Leu Glu Arg Asp 260 265 270 Met Pro Lys Pro Pro Pro Lys Thr Lys Ile Pro Lys Ser Arg Ser Glu 275 280 285 Gly Ser Ile Gln Ala His Arg Val Leu Gln Pro Glu Leu Ser Asp Gly 290 295 300 Ile Pro Gln Leu Ser Leu Arg Leu Ser Tyr Arg Lys Ala Cys Leu Glu 305 310 315 320 Asp Met Asn Ser Ala Glu Gly Ala Ile Ser Ala Lys Leu Val Pro Ser 325 330 335 Ser Gln Glu Asp Glu Arg Pro Leu Ser Pro Phe Tyr Leu Ser Ala His 340 345 350 Val Pro Gln Val Ser Asn Val Ser Ala Thr Gly Glu Leu Leu Glu Arg 355 360 365 Thr Ile Arg Ser Ala Val Glu Gln His Leu Phe Asp Val Asn Asn Ser 370 375 380 Gly Gly Gln Ser Ser Glu Asp Ser Glu Ser Gly Thr Leu Ser Ala Ser 385 390 395 400 Ser Ala Thr Ser Ala Arg Gln Arg Arg Arg Gln Ser Lys Glu Gln Asp 405 410 415 Glu Val Arg His Gly Arg Asp Lys Gly Leu Ile Asn Lys Glu Asn Thr 420 425 430 Pro Ser Gly Phe Asn His Leu Asp Asp Cys Ile Leu Asn Thr Gln Glu 435 440 445 Val Glu Lys Val His Lys Asn Thr Phe Gly Cys Ala Gly Glu Arg Ser 450 455 460 Lys Pro Lys Arg Gln Lys Ser Ser Thr Lys Leu Ser Glu Leu His Asp 465 470 475 480 Asn Gln Asp Gly Leu Val Asn Met Glu Ser Leu Asn Ser Thr Arg Ser 485 490 495 His Glu Arg Thr Gly Pro Asp Asp Phe Glu Trp Met Ser Asp Glu Arg 500 505 510 Lys Gly Asn Glu Lys Asp Gly Gly His Thr Gln His Phe Glu Ser Pro 515 520 525 Thr Met Lys Ile Gln Glu His Pro Ser Leu Ser Asp Thr Lys Gln Gln 530 535 540 Arg Asn Gln Asp Ala Gly Asp Gln Glu Glu Ser Phe Val Ser Glu Val 545 550 555 560 Pro Gln Ser Asp Leu Thr Ala Leu Cys Asp Glu Lys Asn Trp Glu Glu 565 570 575 Pro Ile Pro Ala Phe Ser Ser Trp Gln Arg Glu Asn Ser Asp Ser Asp 580 585 590 Glu Ala His Leu Ser Pro Gln Ala Gly Arg Leu Ile Arg Gln Leu Leu 595 600 605 Asp Glu Asp Ser Asp Pro Met Leu Ser Pro Arg Phe Tyr Ala Tyr Gly 610 615 620 Gln Ser Arg Gln Tyr Leu Asp Asp Thr Glu Val Pro Pro Ser Pro Pro 625 630 635 640 Asn Ser His Ser Phe Met Arg Arg Arg Ser Ser Ser Leu Gly Ser Tyr 645 650 655 Asp Asp Glu Gln Glu Asp Leu Thr Pro Ala Gln Leu Thr Arg Arg Ile 660 665 670 Gln Ser Leu Lys Lys Lys Ile Arg Lys Phe Glu Asp Arg Phe Glu Glu 675 680 685 Glu Lys Lys Tyr Arg Pro Ser His Ser Asp Lys Ala Ala Asn Pro Glu 690 695 700 Val Leu Lys Trp Thr Asn Asp Leu Ala Lys Phe Arg Arg Gln Leu Lys 705 710 715 720 Glu Ser Lys Leu Lys Ile Ser Glu Glu Asp Leu Thr Pro Arg Met Arg 725 730 735 Gln Arg Ser Asn Thr Leu Pro Lys Ser Phe Gly Ser Gln Leu Glu Lys 740 745 750 Glu Asp Glu Lys Lys Gln Glu Leu Val Asp Lys Ala Ile Lys Pro Ser 755 760 765 Val Glu Ala Thr Leu Glu Ser Ile Gln Arg Lys Leu Gln Glu Lys Arg 770 775 780 Ala Glu Ser Ser Arg Pro Glu Asp Ile Lys Asp Met Thr Lys Asp Gln 785 790 795 800 Ile Ala Asn Glu Lys Val Ala Leu Gln Lys Ala Leu Leu Tyr Tyr Glu 805 810 815 Ser Ile His Gly Arg Pro Val Thr Lys Asn Glu Arg Gln Val Met Lys 820 825 830 Pro Leu Tyr Asp Arg Tyr Arg Leu Val Lys Gln Ile Leu Ser Arg Ala 835 840 845 Asn Thr Ile Pro Ile Ile Gly Ser Pro Ser Ser Lys Arg Arg Ser Pro 850 855 860 Leu Leu Gln Pro Ile Ile Glu Gly Glu Thr Ala Ser Phe Phe Lys Glu 865 870 875 880 Ile Lys Glu Glu Glu Glu Gly Ser Glu Asp Asp Ser Asn Val Lys Pro 885 890 895 Asp Phe Met Val Thr Leu Lys Thr Asp Phe Ser Ala Arg Cys Phe Leu 900 905 910 Asp Gln Phe Glu Asp Asp Ala Asp Gly Phe Ile Ser Pro Met Asp Asp 915 920 925 Lys Ile Pro Ser Lys Cys Ser Gln Asp Thr Gly Leu Ser Asn Leu His 930 935 940 Ala Ala Ser Ile Pro Glu Leu Leu Glu His Leu Gln Glu Met Arg Glu 945 950 955 960 Glu Lys Lys Arg Ile Arg Lys Lys Leu Arg Asp Phe Glu Asp Asn Phe 965 970 975 Phe Arg Gln Asn Gly Arg Asn Val Gln Lys Glu Asp Arg Thr Pro Met 980 985 990 Ala Glu Glu Tyr Ser Glu Tyr Lys His Ile Lys Ala Lys Leu Arg Leu 995 1000 1005 Leu Glu Val Leu Ile Ser Lys Arg Asp Thr Asp Ser Lys Ser Met 1010 1015 1020 <210> SEQ ID NO 57 <211> LENGTH: 3683 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: IMPACT <400> SEQUENCE: 57 cctggcaggc ggcggctgca gggcaggtcc aggggccaca tggctgaggg ggacgcaggg 60 agcgaccaga ggcagaatga ggaaattgaa gcaatggcag ccatttatgg cgaggagtgg 120 tgtgtcattg atgactgtgc caaaatattt tgtattagaa ttagcgacga tatagatgac 180 cccaaatgga cactttgctt gcaggtgatg ctgccgaatg aatacccagg tacagctcca 240 cctatctacc agttgaatgc tccttggctt aaagggcaag aacgtgcgga tttatcaaat 300 agccttgagg aaatatatat tcagaatatc ggtgaaagta ttctttacct gtgggtggag 360 aaaataagag atgttcttat acaaaaatct cagatgacag aaccaggccc agatgtaaag 420 aagaaaactg aagaggaaga tgttgaatgt gaagatgatc tcattttagc atgtcagccg 480 gaaagttcgg ttaaagcatt ggattttgat atcagtgaaa ctcggacaga agtagaagta 540 gaagaattac ctccgattga tcatggcatt cctattacag accgaagaag tacttttcag 600 gcacacttgg ctccagtggt ttgtcccaaa caggtgaaaa tggttctttc caaattgtat 660 gagaataaga aaatagctag tgccacccac aacatctatg cctacagaat atattgtgag 720 gataaacaga ccttcttaca ggattgtgag gatgatgggg aaacagcagc tggtgggcgt 780 cttcttcatc tcatggagat tttgaatgtg aagaatgtca tggtggtagt atcacgctgg 840 tatggaggga ttctgctagg accagatcgc tttaaacata tcaacaactg tgccagaaac 900 atactagtgg aaaagaacta cacaaattca cctgaggagt catctaaggc tttgggaaag 960 aacaaaaaag taagaaaaga caagaagagg aatgaacatt aatacctgaa actataggaa 1020 aggttaattt gcctataatt atatatacat tccatagtca tcaaggaata tattgtgcag 1080 agagagtatc cttgactgct taagtcagcc agttcagcat ggataccaac attagctttt 1140 cttcttggtt atatcatctg ccaaaaatag agaacttatg atctattcat gtgtgtttca 1200 ggcttatttg ggagaactaa tttgaactta atcaccactt catctaattt tagcaaggta 1260 acagttgccc agggcagtac ctgaattaac tgtccatttc agtacatgtc aagtgccttt 1320 gttaggtgga gaagaaatgt ctctagagga atataaatac ctgatttctt gtcatcgaga 1380 ttcttgtact gttaaatgaa tattgccttt tactgctctt tatggcttat tggaatagga 1440 gctcatttaa gattgatctt ggagagtttc ttcttgtgat tttagttcat aagtatgtca 1500 cctttcattt tatagtgttc atcattgagt aatggattaa gtgaaaatcc aggagtatcc 1560 atctgcagtt atgtgctgag gtgataattc atccaacata tttgttagca taaatattat 1620 gcttcagttt ctgttgcaaa ttggtgattg tgaaattaca gaaagtgatt ttctagtctg 1680 ctttttttgt ttaattcttg taatgtaagc aataaatatg gagtgtcagt agtctccttc 1740 caccccagaa atgtgttggt gtaacattct cgtttctttt aacaacctgg aagtaccttt 1800 cttgtgatct tcactgagga attagaacta tgatagaagt taggctgtgg caaatgggac 1860

attcgtagag tgggatagag gtggcagaat gaacctggtg tagggcagga gtatgttgtg 1920 tagttacatc aatttgatgc atgctttcca tctgcactcc agacggcttt ctcagttcca 1980 agattttgca gagagaagga gcaaaccttt tcattggaaa aacagaaaca accctccccc 2040 ccattttttc ccctctattc atcaaacctt tatgtatctt tcatcttcca gttacctcta 2100 ggcatttaga tagtgaaatt tacctttgag atataacaat aagtgattaa ctgttcactt 2160 tcagatgtaa tggcaaacaa ttgttaaaag ttattaactg atcacagatt tgcctggact 2220 tcccttccca gggagggaac agaagttagg aggcaacttt gggatggtgc tagagcatgg 2280 aaagcacaga gaattggaca aacaggtctt tttctctttt ctctgatgtt ttacctttaa 2340 aagatccaac atccttaccg ttggtatttt tagtaaggtt atagtaaata gctttacacc 2400 aggatggatt ctgaaatata aattctaaat tatatttgtt ataactatat tttatgttgt 2460 atgttatcag gagccatcag agaatgacct ttttgtgttt ggaacacttg gttccatgaa 2520 aagtatgctt tgtgttttaa ctgttaaaat aatttaaaaa ttaattattt tacataatta 2580 aagaagttaa aaactattaa cattaaataa tttcacaatt tcaacatgtc aaacctatga 2640 agggagatag gaaacaatga gaaacttact tttgctcctt tatacagaat tattaactat 2700 attttactaa ctaaaaaact ctagtattct ttacctaaag tcaattggct ggtaagaggg 2760 agagatgcaa aattctccag ctctgaactt ggagctactt cacactctac tcttaatgga 2820 aacttgaact aatgatagat agtatttttt tcctctattt aaaatttttg tcttgattag 2880 gagatttttc agttctccat ataataattt tctacaatca gatctatgct gtggcatatt 2940 ttgctttatt taaaaatttt tttttagaga tgagttcttg ctctgtcacc taggctggag 3000 tgcagtggca tgatcatggc tcactgcagc cttgaccttc cagcctgcca agtagctggg 3060 attacagaca ggcatgtgct attacacctg gctaattttt aaagtttttt ttgtaaagat 3120 agggtctttc tatgttgccc aggctcgtct tgagctcctg gcctcaatcg atcttcctgc 3180 caaggttttg gaattacagg tgtgagccac catgcctggc ctgctttgac atattttata 3240 gtgtgttaat tacaaatagt cttcatatgc cagaatataa gagcaagtgt tatctacttt 3300 ttagatggga attgcagaag ctgcatcaaa agtatgcttt gaggtatata tagtgaaaca 3360 gagcctttct gaagagaatt atatcaaact aattacaacc aagaaataat agtatgaagc 3420 ggatgctgtt tggaggacag gaaaatttat cgggaaaatt acataatccc tctgattcca 3480 ctatccagag atagccatta ttattaatat ttggtatgta catccttata ttattttttt 3540 tttatgcatg attttgtata tatggttatt tttctttcca taaaaatggt attaaactgt 3600 atatactgtt ttgtagccta catatttcat atagaagtat attgttaaca ttttccatgt 3660 caataaatat tctatggctt tct 3683 <210> SEQ ID NO 58 <211> LENGTH: 320 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: IMPACT <400> SEQUENCE: 58 Met Ala Glu Gly Asp Ala Gly Ser Asp Gln Arg Gln Asn Glu Glu Ile 1 5 10 15 Glu Ala Met Ala Ala Ile Tyr Gly Glu Glu Trp Cys Val Ile Asp Asp 20 25 30 Cys Ala Lys Ile Phe Cys Ile Arg Ile Ser Asp Asp Ile Asp Asp Pro 35 40 45 Lys Trp Thr Leu Cys Leu Gln Val Met Leu Pro Asn Glu Tyr Pro Gly 50 55 60 Thr Ala Pro Pro Ile Tyr Gln Leu Asn Ala Pro Trp Leu Lys Gly Gln 65 70 75 80 Glu Arg Ala Asp Leu Ser Asn Ser Leu Glu Glu Ile Tyr Ile Gln Asn 85 90 95 Ile Gly Glu Ser Ile Leu Tyr Leu Trp Val Glu Lys Ile Arg Asp Val 100 105 110 Leu Ile Gln Lys Ser Gln Met Thr Glu Pro Gly Pro Asp Val Lys Lys 115 120 125 Lys Thr Glu Glu Glu Asp Val Glu Cys Glu Asp Asp Leu Ile Leu Ala 130 135 140 Cys Gln Pro Glu Ser Ser Val Lys Ala Leu Asp Phe Asp Ile Ser Glu 145 150 155 160 Thr Arg Thr Glu Val Glu Val Glu Glu Leu Pro Pro Ile Asp His Gly 165 170 175 Ile Pro Ile Thr Asp Arg Arg Ser Thr Phe Gln Ala His Leu Ala Pro 180 185 190 Val Val Cys Pro Lys Gln Val Lys Met Val Leu Ser Lys Leu Tyr Glu 195 200 205 Asn Lys Lys Ile Ala Ser Ala Thr His Asn Ile Tyr Ala Tyr Arg Ile 210 215 220 Tyr Cys Glu Asp Lys Gln Thr Phe Leu Gln Asp Cys Glu Asp Asp Gly 225 230 235 240 Glu Thr Ala Ala Gly Gly Arg Leu Leu His Leu Met Glu Ile Leu Asn 245 250 255 Val Lys Asn Val Met Val Val Val Ser Arg Trp Tyr Gly Gly Ile Leu 260 265 270 Leu Gly Pro Asp Arg Phe Lys His Ile Asn Asn Cys Ala Arg Asn Ile 275 280 285 Leu Val Glu Lys Asn Tyr Thr Asn Ser Pro Glu Glu Ser Ser Lys Ala 290 295 300 Leu Gly Lys Asn Lys Lys Val Arg Lys Asp Lys Lys Arg Asn Glu His 305 310 315 320 <210> SEQ ID NO 59 <211> LENGTH: 6737 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: KIAA1128 <400> SEQUENCE: 59 gctgtggatc ttacaaagcc ttatcagaac caacagctat ccattagagt gcctctacgg 60 tcaagtatgc taacaagaaa ttcccggcag ccagaagtac tcaatgggaa tgaacatttg 120 gggtatggat ttaataggcc ttatgctgct ggtggaaaga agttggcttt accaaatggc 180 ccaggtgtaa cttctacttt aggttataga atggttcatc cctctctact gaaatctagc 240 cgatctccat tttctgggac tatgacagtt gatggaaata aaaattcacc tgctgacaca 300 tgtgtagagg aagatgctac agttttggct aaggacagag ctgctaataa ggaccaagaa 360 ctgattgaaa atgaaagtta tagaacaaaa aacaaccaga ccatgaaaca tgatgctaaa 420 atgagatacc tgagtgatga tgtggatgac atttccttgt cgtctttgtc atcttctgat 480 aagaatgatt taagtgaaga ctttagtgat gattttatag atatagaaga ctccaacaga 540 actagaataa ctccagagga aatgtctctc aaagaagaga aacatgaaaa tgggccacca 600 caggatatgt ttgattcccc caaggaaaat gaaaaagcct tcagtaaaac tgatgaatgg 660 atagatataa gtgtctctga caggagtgaa tgtacaaaac atacttctgg gaataatttg 720 gtttcaccag atacagacta cagagctggt tcttcgtttg aactctctcc atctgatagc 780 tctgatggaa catacatgtg ggatgaagaa ggcttggaac ccattggaaa tgtccatcca 840 gttgggagct atgagtcctc tgaaatgaac agcatagata ttttgaataa tcttgaatca 900 tgtgaccttg aggatgatga tcttatgctt gatgtggatc tgcctgagga tgcacctctt 960 gaaaatgtgg agtgtgacaa tatgaaccgc tttgaccgac cagacagaaa tgttcggcag 1020 cctcaggaag gtttttggaa aaggccaccc cagaggtgga gtggacagga gcattaccac 1080 ctcagccacc ctgaccacta tcatcaccat ggaaaaagtg acttgagcag aggctctccc 1140 tatagagaat ctcctttggg tcattttgaa agctatggag ggatgccctt tttccaggct 1200 cagaagatgt ttgttgatgt accagaaaat acagtgatac tggatgagat gacccttcgg 1260 cacatggttc aggattgcac tgctgtaaaa actcagttac tcaaactgaa acgtctcctg 1320 catcagcatg atggaagtgg ttcattgcat gatattcaac tgtcattgcc atccagtcca 1380 gaaccagaag atggtgataa agtatataag aatgaagatt tattaaatga aataaaacaa 1440 cttaaagacg aaataaagaa aaaagatgaa aagatccaac tattagaact tcagcttgca 1500 actcagcata tctgccacca aaaatgtaaa gaggaaaaat gcacttatgc tgataaatat 1560 acccaaacac cctggagacg aattcctggt gggtattctg ctccctcctt ctctccttgg 1620 cagggctcct tccaggggat cccacggact gttccaccgc accgcagaca gacctcaagt 1680 actacagcct tccagcagcc ttcccagacc cacagatcac acccagggaa aactaataaa 1740 gccacaacgt atcgaggccc gcagtgaatg ctcaatccaa gacatgcatc agggcggtgc 1800 acatccggaa gaaagcttta cacacgtctt gcaccaagaa agcaactatg gtttggaaga 1860 gcagcctttt tcatcaggcc cacaattaac aatggatgtg gctaagagta caccttctga 1920 agcaaactta aacattactg taaatgctca agagccttat catttggcaa acaatcaaat 1980 tagtgacatg cagtttatac ccacttctct tcagacacct cccgagtcaa gtacagtaga 2040 ccaggctaag agagttggaa gaaatcagtc tccgccagtg ggttatatgt ctcagcccaa 2100 gtccttgcag cttttaaagc catccatatt gagttctttg gtaccgcctc cagtttctga 2160 atcatctcca agtaggactc ccacttgtaa aaagtcacca ataatcacaa catgtaattc 2220 agcaaaactt cagccaacat ctagtcaaac aaatcttgca aataatcaga atctgaaagc 2280 atctaagctc cgccccccct caggctcttt caaacaaaaa caaacaaaca gcccccaact 2340 agagcctcaa agcttccagg ccaagacaag catcccaagg ccactaacac aacgaaaaga 2400 aatcatgcag aatccaaatg gcaatttgca ttctggggat tgtttggcct ctaatcgata 2460 ttctcgtctt cctaaaccaa agatacatta agtacatagc catcacctgc caatttgttt 2520 cttaaaaaca atctcttctg taatagcttt atgtgcagct tgcagcttgc tactgtggtg 2580 gaggttccat tgaaagcctg caaatcttaa attaaaatgt ggaagcttct actagtttgg 2640 ctccttcatt ttatatcctg gttgaagtac atgccatttg agcataatta tctcaggtaa 2700 acacgaaagt ttgcttaccc atttcagagg cctgccaaag gcccaaatca tgttatccat 2760 ccctctccag gtcagaaaat tcataatatt ttactgagca ggcaagaagt gtgctttgct 2820 ggtttagtcc tattaaggtc tgtatttatt gtggttgtca gaacctcacc ccttttcact 2880 tgtctctcct gtgaatatgg ctactatttt aactaaagat atggtgataa tggaagatgg 2940 tagtctgtaa gcagagttct ggccagtgtt ttgtatattt aaaaggtcta tgcaaaagct 3000 ttgtgatgaa taaaggagat taggctttta atggaaagtc tatgtaagtt ttatttttcc 3060 ttgccagggt cagtcagcta atgttactgt tgattcattt cccaaattcc ccagactgaa 3120 aatgtttctt attacatata aatcagttat atattccttt acatcttgtt ttacaaacac 3180 atgtgcatgc acacacacac atacacacac ataccattta tgtttgtatt tgttactggg 3240 taaattttgg agcgcttgag atacaccttg aaacctgtac ctaaagatgt attcatttgt 3300

aacatatgtt ggtgctagag ttttgctggt aattcaggtt tgaaccctta ggcttgtgga 3360 tccatgatag ccattttaag gttccacagc attatgtctt taattgtaat atttatattt 3420 attgattttc tgctaatatc tgaagactga aataatgaac ttgaaacatt tgcacaaaac 3480 tttgatgggg tataaatata ccatatatag ggattgtaaa ctattttcta tagcaaaaca 3540 agttaaaata ttttgagaaa aataacaaat ttaaataaga ctatcttgag aaagctggag 3600 ttcataatat tctccccctc ccccatctcc agtctcctag gtttcccttt tctgtgtttt 3660 ttgttttttt ctgtttgttt tttgagacag agtcttgctc cattgcccag gctggattac 3720 agtggcgcaa tctcggctca ctgcaacttc tgcctcccgg gttcaagcga ttctcctgcc 3780 tcagcctcct gagtagctgg gactacaggc atgtgccacc atgcctggct aatttttttg 3840 tatttttagt agagatgagg tttcaccttg ttggtcaggc tggtctcgaa ctcctgacct 3900 caagtgatcc acccacctcg tctatggtgt atttttgaaa gacaattttt taaaggtaga 3960 tttgggaaaa aaatagaatt gaagatggga aattttgttt tattaaaaag gtgctagaag 4020 atgtttcaaa gacaatattc ttattttaat acgctgtaga aggtaggtgt ggaacctcca 4080 tgctaccatg tgcacaaacc taattatgct ttgggtcact tgtcagttca gtaaatctgc 4140 cttcctcttc tcccaaatca tgtcatcttt aggttgttca cctgcagctg ctttaaatga 4200 attagtatct ttcagataga taaccttaca aggagaatgt ttgttttgag cagctgacca 4260 aaaatatatc aaacaggatt atggccaaaa agtcactcaa atttctagag attcctttaa 4320 aagatgtatg ttgatgaaat tgccccttta taagaaaaac aacagcaagt cttttagtag 4380 aaatttgaaa gaagtgtttg ctaccatttt gacccattat tcccttacct atcagatgaa 4440 tttgccattc actggataga aaccattctt ggatttggta agaggtgagc aagacaaatc 4500 ttgtaccata ctcttatgta ccagcacttc tgatggagaa gcagtgaagt tcagaacgtt 4560 cttcacatag tccagatact gttagagtca ggcaaatcag caaagcactt tgttatggag 4620 atgacccatg atggctgcag ttgtaagtgg gcatacatgt tctatcattt tgaaggagaa 4680 agaaaaccgt tctcacatgt cgcaaatatg tgaatcatac tatattcccc taaagtaaaa 4740 ccagtgactt agtggttttt ggtttattta gaagttggtt tagaccctta tgaaacatta 4800 tttacgagtt ggccttatcc ttaagggaaa agttctaaat ttttaaattt atttttaatt 4860 ccctagtctg agggaaatgt ctttattgtc cattacataa aaatgttgac tccagtaatt 4920 tatttttctc tattttttcc tccatgtatt tactccattt ttctctattt tttccttccc 4980 tgatggattt gcagaaatgt taaccaatta gctcaacttt tctctacctt tgttgagtct 5040 taatctttta gaagataggc ttaccgtata tttatgaagc ataatatatt aaaagaaaac 5100 aaatctagga tgcttgcatg acataaagta tttgcctgca gttttcatta aaaactgcaa 5160 gaatatcatg cttgtctgct tcttagtaaa tgttaagtct gaaatggaag tgaggatgta 5220 actctactga ataatcaaag atcatcttag atttggcttg atctgtgttt attgcttcta 5280 ttaatgtaaa tcaactctgt gccaaatcct cctccacaaa ccatttattg tcttagttct 5340 agtggtatca atgaagatag ttacagtata tgaattctaa gtcctgagga agaaatttta 5400 tggggtttgt taagtttcac attcgtgaaa gaggaaatta gtagagtatt cagactttga 5460 tatttggctg ttaatgggat gcatatcaaa tttttaaaag aaggcttggc ctaaggagtt 5520 tattggtaca ggtgcagatg attttaaggc attaaaggat tatagagtta tgtcatttag 5580 actgtttcta ataactgaga ccatctaaca tttttctttt ggagtctcat ttttatttgt 5640 gcaatatttt caggcatata ggctactgtt cattgtattt atatatatat tagaatttac 5700 taagtacttt aacaagtaaa aatctgaata tgaaagaaaa tatcagattt gcactttaaa 5760 tgagcttaat tgcttgaagt tgtgcctgaa atatcgaatt gcctcctatt gggtgtggct 5820 ttgttgaaat aaatttgtaa ttgttgctgt ttgaagatat cagtacagct gttcacagaa 5880 atatattccc agcatgtcac ttttccatta aagcactaag ttttctttga atgttccatt 5940 gttccgataa gtattttact tttttctcag tacatcagag agagcgtgat ccccctacag 6000 ctgtcacttc caaatgttcc tgtagcataa atggtgttac agacactgag gtgcactctt 6060 ggtttctgag cagagttgtc atactggttt cctggtctct agggcactgg ggatgtactt 6120 tgaaatcacc gaacaggctt gcaattaaga tcaataaggc tgcagcacca tttcaattta 6180 ctttccatct tacccagtag tttttgtgtt tttaaattcg tttgggtggt tatgtttgca 6240 tgcttaagca cacatttgaa aattaattat agctgtacta cccgatgttt ttccttgggg 6300 atgatggcct tgttcctttt taaattctga tgcttgaatt ctattttcta gtgatttttc 6360 acatctccct ttaagttttt gctgcagcaa tttgagagag tacttttgat taaatgattc 6420 tgatggtggg caccaatcta caactatgtc attaactgaa gatacatgtt ttaatcttgt 6480 tgggaataag cttacccact ttctccttgg taaagcgttt acttaacaaa ataatacccg 6540 agaatgtaag gtctctaagt cattactaac aaagagcaaa aataatatct gcagtattgt 6600 ttttcccatt gattttaagt cagtttagag tacaaactgt atattagaat ttgcctgtaa 6660 aatgaattct aaaaagcaga tgtaaagtct ctcctgaaaa tgttggcata gtaaataaaa 6720 ataaagttca taattat 6737 <210> SEQ ID NO 60 <211> LENGTH: 588 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: KIAA1128 <400> SEQUENCE: 60 Ala Val Asp Leu Thr Lys Pro Tyr Gln Asn Gln Gln Leu Ser Ile Arg 1 5 10 15 Val Pro Leu Arg Ser Ser Met Leu Thr Arg Asn Ser Arg Gln Pro Glu 20 25 30 Val Leu Asn Gly Asn Glu His Leu Gly Tyr Gly Phe Asn Arg Pro Tyr 35 40 45 Ala Ala Gly Gly Lys Lys Leu Ala Leu Pro Asn Gly Pro Gly Val Thr 50 55 60 Ser Thr Leu Gly Tyr Arg Met Val His Pro Ser Leu Leu Lys Ser Ser 65 70 75 80 Arg Ser Pro Phe Ser Gly Thr Met Thr Val Asp Gly Asn Lys Asn Ser 85 90 95 Pro Ala Asp Thr Cys Val Glu Glu Asp Ala Thr Val Leu Ala Lys Asp 100 105 110 Arg Ala Ala Asn Lys Asp Gln Glu Leu Ile Glu Asn Glu Ser Tyr Arg 115 120 125 Thr Lys Asn Asn Gln Thr Met Lys His Asp Ala Lys Met Arg Tyr Leu 130 135 140 Ser Asp Asp Val Asp Asp Ile Ser Leu Ser Ser Leu Ser Ser Ser Asp 145 150 155 160 Lys Asn Asp Leu Ser Glu Asp Phe Ser Asp Asp Phe Ile Asp Ile Glu 165 170 175 Asp Ser Asn Arg Thr Arg Ile Thr Pro Glu Glu Met Ser Leu Lys Glu 180 185 190 Glu Lys His Glu Asn Gly Pro Pro Gln Asp Met Phe Asp Ser Pro Lys 195 200 205 Glu Asn Glu Lys Ala Phe Ser Lys Thr Asp Glu Trp Ile Asp Ile Ser 210 215 220 Val Ser Asp Arg Ser Glu Cys Thr Lys His Thr Ser Gly Asn Asn Leu 225 230 235 240 Val Ser Pro Asp Thr Asp Tyr Arg Ala Gly Ser Ser Phe Glu Leu Ser 245 250 255 Pro Ser Asp Ser Ser Asp Gly Thr Tyr Met Trp Asp Glu Glu Gly Leu 260 265 270 Glu Pro Ile Gly Asn Val His Pro Val Gly Ser Tyr Glu Ser Ser Glu 275 280 285 Met Asn Ser Ile Asp Ile Leu Asn Asn Leu Glu Ser Cys Asp Leu Glu 290 295 300 Asp Asp Asp Leu Met Leu Asp Val Asp Leu Pro Glu Asp Ala Pro Leu 305 310 315 320 Glu Asn Val Glu Cys Asp Asn Met Asn Arg Phe Asp Arg Pro Asp Arg 325 330 335 Asn Val Arg Gln Pro Gln Glu Gly Phe Trp Lys Arg Pro Pro Gln Arg 340 345 350 Trp Ser Gly Gln Glu His Tyr His Leu Ser His Pro Asp His Tyr His 355 360 365 His His Gly Lys Ser Asp Leu Ser Arg Gly Ser Pro Tyr Arg Glu Ser 370 375 380 Pro Leu Gly His Phe Glu Ser Tyr Gly Gly Met Pro Phe Phe Gln Ala 385 390 395 400 Gln Lys Met Phe Val Asp Val Pro Glu Asn Thr Val Ile Leu Asp Glu 405 410 415 Met Thr Leu Arg His Met Val Gln Asp Cys Thr Ala Val Lys Thr Gln 420 425 430 Leu Leu Lys Leu Lys Arg Leu Leu His Gln His Asp Gly Ser Gly Ser 435 440 445 Leu His Asp Ile Gln Leu Ser Leu Pro Ser Ser Pro Glu Pro Glu Asp 450 455 460 Gly Asp Lys Val Tyr Lys Asn Glu Asp Leu Leu Asn Glu Ile Lys Gln 465 470 475 480 Leu Lys Asp Glu Ile Lys Lys Lys Asp Glu Lys Ile Gln Leu Leu Glu 485 490 495 Leu Gln Leu Ala Thr Gln His Ile Cys His Gln Lys Cys Lys Glu Glu 500 505 510 Lys Cys Thr Tyr Ala Asp Lys Tyr Thr Gln Thr Pro Trp Arg Arg Ile 515 520 525 Pro Gly Gly Tyr Ser Ala Pro Ser Phe Ser Pro Trp Gln Gly Ser Phe 530 535 540 Gln Gly Ile Pro Arg Thr Val Pro Pro His Arg Arg Gln Thr Ser Ser 545 550 555 560 Thr Thr Ala Phe Gln Gln Pro Ser Gln Thr His Arg Ser His Pro Gly 565 570 575 Lys Thr Asn Lys Ala Thr Thr Tyr Arg Gly Pro Gln 580 585

Claims

1. A method of identifying the stage of a thyroid tumor in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of differentially expressed thyroid (DET) gene C21 or f4, Hs.145049, Hs.296031, KIT, LSM7, and SYNGR2 in a test cell population obtained from the thyroid tumor in the subject, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET gene C21 or f4, Hs.145049, Hs.296031, KIT, LSM7, and SYNGR2; b) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET gene C21 or f4, Hs.145049, Hs.296031, KIT, LSM7, and SYNGR2, in the test cell population and reference cell population, thereby identifying the stage of the thyroid tumor in the subject.

2. The method of claim 1, wherein a difference in the expression of the nucleic acid(s) in the test cell population as compared to the reference cell population indicates that the test cell population has a different stage than the cells from the reference cell population.

3. The method of claim 1, wherein a similar expression pattern of the nucleic acid(s) in the test cell population as compared to the reference cell population indicates that the test cell population has the same thyroid tumor stage as the cells from the reference cell population.

4. The method of claim 1, wherein the reference cell population is a plurality of cells or a database.

5. The method of claim 1, wherein the subject is a human.

6. The method of claim 1, wherein the tumor or thyroid lesion is selected from the group consisting of: papillary thyroid carcinoma, follicular variant of papillary thyroid carcinoma, follicular carcinoma, Hurthle cell tumor, anaplastic thyroid cancer, medullary thyroid cancer, thyroid lymphoma, poorly differentiated thyroid cancer and thyroid angiosarcoma.

7. The method of claim 1, wherein expression of the nucleic acid(s) is measured by microarray.

8. The method of claim 1, wherein expression of the nucleic acid(s) is measured by probing the nucleic acid(s).

9. The method of claim 1, wherein expression of the nucleic acids(s) is measured by amplifying the nucleic acid(s).

10. The method of claim 1, wherein the expression of the nucleic acid(s) is measured by amplifying the nucleic acid(s) and detecting the amplified nucleic acid with a fluorescent probe.

11. The method of claim 10, wherein C21 or f4 nucleic acid is amplified utilizing forward primer GCAATCCTCTTACCTCCGCTTT (SEQ ID NO: 7) and reverse primer GGAATCGGAGACAGAAGAGAGCTT (SEQ ID NO: 8) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence CTGGGACCACAGATGTATCCTCCACTCC (SEQ ID NO: 9) linked to a fluorescent label.

12. The method of claim 10, wherein Hs.145049 nucleic acid is amplified utilizing forward primer GGCTGACTGGCAAAAAGTCTTG (SEQ ID NO: 1) and reverse primer TTGGTTCCCTTAAGTTCTCAGAGTTT (SEQ ID NO: 2) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence TGGCCCTGTCACTCCCATGATGC (SEQ ID NO: 3) linked to a fluorescent label.

13. The method of claim 10, wherein Hs.296031 nucleic acid is amplified utilizing forward primer TGCCAAGGAGCTTTGTTTATAGAA (SEQ ID NO: 19) and reverse primer ATGACGGCATGTACCAACCA (SEQ ID NO: 20) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence TTGGTCCCCTCAGTTCTATGCTGTTGTGT (SEQ ID NO: 21) linked to a fluorescent label.

14. The method of claim 10, wherein KIT nucleic acid is amplified utilizing forward primer GCACCTGCTGAAATGTATGACATAAT (SEQ ID NO: 22) and reverse primer TTTGCTAAGTTGGAGTAAATATGATTGG (SEQ ID NO: 23) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence ATTGTTCAGCTAATTGAGAAGCAGATTTCAGAGAGC (SEQ ID NO: 24) linked to a fluorescent label.

15. The method of claim 10, wherein LSM7 nucleic acid is amplified utilizing forward primer GACGATCCGGGTAAAGTTCCA (SEQ ID NO: 34) and reverse primer AGGTTGAGGAGTGGGTCGAA (SEQ ID NO: 35) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence AGGCCGCGAAGCCAGTGGAATC (SEQ ID NO: 36) linked to a fluorescent label.

16. The method of claim 10, wherein SYNGR2 nucleic acid is amplified utilizing forward primer GCTGGTGCTCATGGCACTT (SEQ ID NO: 31) and reverse primer CCCTCCCCAGGCTTCCTAA (SEQ ID NO: 32) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence AAGGGCTTTGCCTGACAACACCCA (SEQ ID NO: 33) linked to a fluorescent label.

17. The method of claim 1, wherein expression of the nucleic acid(s) is measured by detecting the protein expression product of the nucleic acid(s).

18. A method of identifying the stage of a thyroid tumor in a subject comprising: a) measuring the expression of one or more nucleic acid sequences selected from the group consisting of differentially expressed thyroid (DET) gene C21 or f4, Hs.145049, Hs.296031, KIT, SYNGR2, C11 or f8, CDH1, FAM13A1, IMPACT, and KIAA1128 in a test cell population obtained from the thyroid tumor in the subject, wherein at least one cell in said test cell population is capable of expressing one or more nucleic acid sequences selected from the group consisting of DET gene C21 or f4, Hs.145049, Hs.296031, KIT, SYNGR2, C11 or f8, CDH1, FAM13A1, IMPACT, and KIAA1128; b) comparing the expression of the nucleic acid sequence(s) to the expression of the nucleic acid sequence(s) in a reference cell population comprising at least one cell for which a thyroid tumor stage is known; and c) identifying a difference, if present, in expression levels of one or more nucleic acid sequences selected from the group consisting of DET gene C21 or f4, Hs.145049, Hs.296031, KIT, SYNGR2, C11 or f8, CDH1, FAM13A1, IMPACT, and KIAA1128, in the test cell population and reference cell population, thereby identifying the stage of the thyroid tumor in the subject.

19. The method of claim 18, wherein a difference in the expression of the nucleic acid(s) in the test cell population as compared to the reference cell population indicates that the test cell population has a different stage than the cells from the reference cell population.

20. The method of claim 18, wherein a similar expression pattern of the nucleic acid(s) in the test cell population as compared to the reference cell population indicates that the test cell population has the same thyroid carcinoma stage as the cells from the reference cell population.

21. The method of claim 18, wherein the reference cell population is a plurality of cells or a database.

22. The method of claim 18, wherein the subject is a human.

23. The method of claim 18, wherein the thyroid tumor is selected from the group consisting of: papillary thyroid carcinoma, follicular variant of papillary thyroid carcinoma, follicular carcinoma, Hurthle cell tumor, anaplastic thyroid cancer, medullary thyroid cancer, thyroid lymphoma, poorly differentiated thyroid cancer and thyroid angiosarcoma.

24. The method of claim 18, wherein expression of the nucleic acid(s) is measured by microarray.

25. The method of claim 18, wherein expression of the nucleic acid(s) is measured by probing the nucleic acid(s).

26. The method of claim 18, wherein expression of the nucleic acids(s) is measured by amplifying the nucleic acid(s).

27. The method of claim 18, wherein the expression of the nucleic acid(s) is measured by amplifying the nucleic acid(s) and detecting the amplified nucleic acid with a fluorescent probe.

28. The method of claim 27, wherein C21 or f4 nucleic acid is amplified utilizing forward primer GCAATCCTCTTACCTCCGCTTT (SEQ ID NO: 7) and reverse primer GGAATCGGAGACAGAAGAGAGCTT (SEQ ID NO: 8) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence CTGGGACCACAGATGTATCCTCCACTCC (SEQ ID NO: 9) linked to a fluorescent label.

29. The method of claim 27, wherein Hs.145049 nucleic acid is amplified utilizing forward primer GGCTGACTGGCAAAAAGTCTTG (SEQ ID NO: 1) and reverse primer TTGGTTCCCTTAAGTTCTCAGAGTTT (SEQ ID NO: 2) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence TGGCCCTGTCACTCCCATGATGC (SEQ ID NO: 3) linked to a fluorescent label.

30. The method of claim 27, wherein Hs.296031 nucleic acid can be amplified utilizing forward primer TGCCAAGGAGCTTTGTTTATAGAA (SEQ ID NO: 19) and reverse primer ATGACGGCATGTACCAACCA (SEQ ID NO: 20) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence TTGGTCCCCTCAGTTCTATGCTGTTGTGT (SEQ ID NO: 21) linked to a fluorescent label.

31. The method of claim 27, wherein KIT nucleic acid is amplified utilizing forward primer GCACCTGCTGAAATGTATGACATAAT (SEQ ID NO: 22) and reverse primer TTTGCTAAGTTGGAGTAAATATGATTGG (SEQ ID NO: 23) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence ATTGTTCAGCTAATTGAGAAGCAGATTTCAGAGAGC (SEQ ID NO: 24) linked to a fluorescent label.

32. The method of claim 27, wherein SYNGR2 nucleic acid is amplified utilizing forward primer GCTGGTGCTCATGGCACTT (SEQ ID NO: 31) and reverse primer CCCTCCCCAGGCTTCCTAA (SEQ ID NO: 32) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence AAGGGCTTTGCCTGACAACACCCA (SEQ ID NO: 33) linked to a fluorescent label.

33. The method of claim 27, wherein C11 or f8 nucleic acid is amplified utilizing forward primer CCGGCCCAAGCTCCAT (SEQ ID NO: 13) and reverse primer TTGTGTAACCGTCGGTCATGA (SEQ ID NO: 14) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence TGTTTGGTGGAATCCATGAAGGTTATGGC (SEQ ID NO: 15) linked to a fluorescent label.

34. The method of claim 27, wherein CDH1 nucleic acid is amplified utilizing forward primer TGAGTGTCCCCCGGTATCTTC (SEQ ID NO: 28) and reverse primer CAGCCGCTTTCAGATTTTCAT (SEQ ID NO: 29) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence CCTGCCAATCCCGATGAAATTGGAAAT (SEQ ID NO: 30) linked to a fluorescent label.

35. The method of claim 27, wherein IMPACT nucleic acid is amplified utilizing forward primer ATGGCAGTGCAGTCATCATCTT (SEQ ID NO: 10) and reverse primer GCATTCATACAGCTGCTTACCATCT (SEQ ID NO: 11) and the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence TTTGGTCCCTGCCTAGGACCGGG (SEQ ID NO: 12) linked to a fluorescent label.

36. The method of claim 27, wherein FAM13A1 nucleic acid is amplified utilizing forward primer TGAAGAATGTCATGGTGGTAGTATCA (SEQ ID NO: 25) and reverse primer ATGACTCCTCAGGTGAATTTGTGTAG (SEQ ID NO: 26) and wherein the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence CTGGTATGGAGGGATTCTGCTAGGACCAG (SEQ ID NO: 27) linked to a fluorescent label.

37. The method of claim 27, wherein KIAA1128 nucleic acid is amplified utilizing forward primer GAGAGCGTGATCCCCCTACA (SEQ ID NO: 16) and reverse primer ACCAAGAGTGCACCTCAGTGTCT (SEQ ID NO: 17) and the amplified nucleic acid is detected with a probe comprising the nucleic acid sequence TCACTTCCAAATGTTCCTGTAGCATAAATGGTG (SEQ ID NO: 18) linked to a fluorescent label.

38. The method of claim 18, wherein expression of the nucleic acid(s) is measured by detecting the protein expression product of the nucleic acid(s).