Novel compositions and methods for identification, assessment, prevention, and therapy of ovarian cancer

Abstract

directed to the identification of markers that can be used to determine whether ovarian cancer is sensitive or resistant to a therapeutic agent. In particular, the present invention is directed to the use of certain combinations of markers, wherein the expression of the markers correlates with sensitivity or resistance to a therapeutic agent. Thus, by examining the expression of the individual markers of a marker set, also referred to as the expression profile of the marker set, it is possible to determine whether a therapeutic agent, or combination of agents, will be most likely to reduce the growth rate of the ovarian cancer.

Description

RELATED APPLICATIONS

[0001]The present application is a divisional of U.S. patent application Ser. No. 10/361,112, filed Feb. 7, 2003 (pending), which claims the benefit of U.S. Provisional Application Ser. No. 60/384,042, filed May 29, 2002 (abandoned), and US. Provisional Application Ser. No. 60/355,388, filed Feb. 8, 2002 (abandoned). The entire contents of each of the above-referenced patent applications are incorporated herein by this reference.

BACKGROUND OF THE INVENTION

[0002]The increased number of cancer cases reported in the United States, and, indeed, around the world, is a major concern. Currently there are only a handful of detection and treatment methods available for specific types of cancer, and these provide no absolute guarantee of success. In order to be most effective, these treatments require not only an early detection of the malignancy, but also a reliable assessment of the severity of the malignancy.

[0003]Ovarian cancer is responsible for significant morbidity and mortality in populations around the world. Ovarian cancer is classified, on the basis of clinical and pathological features, in three groups, namely epithelial ovarian cancer (EOC; >90% of ovarian cancer in Western countries), germ cell tumors (circa 2-3% of ovarian cancer), and stromal ovarian cancer (circa 5% of ovarian cancer; Ozols et al., 1997, Cancer Principles and Practice of Oncology, 5th ed., DeVita et al., Eds. pp. 1502). Relative to EOC, germ cell tumors and stromal ovarian cancers are more easily detected and treated at an early stage, translating into higher/better survival rates for patients afflicted with these two types of ovarian cancer.

[0004]There are numerous types of ovarian tumors, some of which are benign, and others of which are malignant. Treatment (including non-treatment) options and predictions of patient outcome depend on accurate classification of the ovarian cancer. Ovarian cancers are named according to the type of cells from which the cancer is derived and whether the ovarian cancer is benign or malignant. Recognized histological tumor types include, for example, serous, mucinous, endometrioid, and clear cell tumors. In addition, ovarian cancers are classified according to recognized grade and stage scales.

[0005]In grade I, the tumor tissue is well differentiated from normal ovarian tissue. In grade II, tumor tissue is moderately well differentiated. In grade III, the tumor tissue is poorly differentiated from normal tissue, and this grade correlates with a less favorable prognosis than grades I and II. Stage I is generally confined within the capsule surrounding one (stage IA) or both (stage IB) ovaries, although in some stage I (i.e. stage IC) cancers, malignant cells may be detected in ascites, in peritoneal rinse fluid, or on the surface of the ovaries. Stage II involves extension or metastasis of the tumor from one or both ovaries to other pelvic structures. In stage IIA, the tumor extends or has metastasized to the uterus, the fallopian tubes, or both. Stage IIB involves extension of the tumor to the pelvis. Stage IIC is stage IIA or IIB in which malignant cells may be detected in ascites, in peritoneal rinse fluid, or on the surface of the ovaries. In stage III, the tumor comprises at least one malignant extension to the small bowel or the omentum, has formed extrapelvic peritoneal implants of microscopic (stage IIIA) or macroscopic (<2 centimeter diameter, stage IIIB; >2 centimeter diameter, stage IIIC) size, or has metastasized to a retroperitoneal or inguinal lymph node (an alternate indicator of stage IIIC). In stage IV, distant (i.e. non-peritoneal) metastases of the tumor can be detected.

[0006]The durations of the various stages of ovarian cancer are not presently known, but are believed to be at least about a year each (Richart et al., 1969, Am. J. Obstet. Gynecol. 105:386). Prognosis declines with increasing stage designation. For example, 5-year survival rates for patients diagnosed with stage I, II, III, and IV ovarian cancer are 80%, 57%, 25%, and 8%, respectively.

[0007]Despite being the third most prevalent gynecological cancer, ovarian cancer is the leading cause of death among those afflicted with gynecological cancers. The disproportionate mortality of ovarian cancer is attributable to a substantial absence of symptoms among those afflicted with early-stage ovarian cancer and to difficulty diagnosing ovarian cancer at an early stage. Patients afflicted with ovarian cancer most often present with non-specific complaints, such as abnormal vaginal bleeding, gastrointestinal symptoms, urinary tract symptoms, lower abdominal pain, and generalized abdominal distension. These patients rarely present with paraneoplastic symptoms or with symptoms which clearly indicate their affliction. Presently, less than about 40% of patients afflicted with ovarian cancer present with stage I or stage II. Management of ovarian cancer would be significantly enhanced if the disease could be detected at an earlier stage, when treatments are much more generally efficacious.

[0008]Ovarian cancer may be diagnosed, in part, by collecting a routine medical history from a patient and by performing physical examination, x-ray examination, and chemical and hematological studies on the patient. Hematological tests which may be indicative of ovarian cancer in a patient include analyses of serum levels of proteins designated CA125 and DF3 and plasma levels of lysophosphatidic acid (LPA). Palpation of the ovaries and ultrasound techniques (particularly including endovaginal ultrasound and color Doppler flow ultrasound techniques) can aid detection of ovarian tumors and differentiation of ovarian cancer from benign ovarian cysts. However, a definitive diagnosis of ovarian cancer typically requires performing exploratory laparotomy of the patient.

[0009]Potential tests for the detection of ovarian cancer (e.g., screening, reflex or monitoring) may be characterized by a number of factors. The "sensitivity" of an assay refers to the probability that the test will yield a positive result in an individual afflicted with ovarian cancer. The "specificity" of an assay refers to the probability that the test will yield a negative result in an individual not afflicted with ovarian cancer. The "positive predictive value" (PPV) of an assay is the ratio of true positive results (i.e. positive assay results for patients afflicted with ovarian cancer) to all positive results (i.e. positive assay results for patients afflicted with ovarian cancer+positive assay results for patients not afflicted with ovarian cancer). It has been estimated that in order for an assay to be an appropriate population-wide screening tool for ovarian cancer the assay must have a PPV of at least about 10% (Rosenthal et al., 1998, Sem. Oncol. 25:315-325). It would thus be desirable for a screening assay for detecting ovarian cancer in patients to have a high sensitivity and a high PPV. Monitoring and reflex tests would also require appropriate specifications.

[0010]Owing to the cost, limited sensitivity, and limited specificity of known methods of detecting ovarian cancer, screening is not presently performed for the general population. In addition, the need to perform laparotomy in order to diagnose ovarian cancer in patients who screen positive for indications of ovarian cancer limits the desirability of population-wide screening, such that a PPV even greater than 10% would be desirable.

[0011]Prior use of serum CA 125 level as a diagnostic marker for ovarian cancer indicated that this method exhibited insufficient specificity for use as a general screening method. Use of a refined algorithm for interpreting CA125 levels in serial retrospective samples obtained from patients improved the specificity of the method without shifting detection of ovarian cancer to an earlier stage (Skakes, 1995, Cancer 76:2004). Screening for LPA to detect gynecological cancers including ovarian cancer exhibited a sensitivity of about 96% and a specificity of about 89%. However, CA125-based screening methods and LPA-based screening methods are hampered by the presence of CA125 and LPA, respectively, in the serum of patients afflicted with conditions other than ovarian cancer. For example, serum CA 125 levels are known to be associated with menstruation, pregnancy, gastrointestinal and hepatic conditions such as colitis and cirrhosis, pericarditis, renal disease, and various non-ovarian malignancies. Serum LPA is known, for example, to be affected by the presence of non-ovarian gynecological malignancies. A screening method having a greater specificity for ovarian cancer than the current screening methods for CA125 and LPA could provide a population-wide screening for early stage ovarian cancer.

[0012]Presently greater than about 60% of ovarian cancers diagnosed in patients are stage III or stage IV cancers. Treatment at these stages is largely limited to cytoreductive surgery (when feasible) and chemotherapy, both of which aim to slow the spread and development of metastasized tumor. Substantially all late stage ovarian cancer patients currently undergo combination chemotherapy as primary treatment, usually a combination of a platinum compound and a taxane. Median survival for responding patients is about one year. Combination chemotherapy involving agents such as doxorubicin, cyclophosphamide, cisplatin, hexamethylmelamine, paclitaxel, and methotrexate may improve survival rates in these groups, relative to single-agent therapies. Various recently-developed chemotherapeutic agents and treatment regimens have also demonstrated usefulness for treatment of advanced ovarian cancer. For example, use of the topoisomerase I inhibitor topectan, use of amifostine to minimize chemotherapeutic side effects, and use of intraperitoneal chemotherapy for patients having peritoneally implanted tumors have demonstrated at least limited utility. Presently, however, the 5-year survival rate for patients afflicted with stage III ovarian cancer is 25%, and the survival rate for patients afflicted with stage IV ovarian cancer is 8%.

[0013]It would therefore be beneficial to provide specific methods and reagents for the diagnosis, staging, prognosis, monitoring, and treatment of diseases associated with ovarian cancer, or to indicate a predisposition to such for preventative measures. The present invention is directed towards these needs.

SUMMARY OF THE INVENTION

[0014]The present invention is directed to the identification of markers that can be used to determine the sensitivity or resistance of ovarian cancer to a therapeutic agent. By examining the expression of one or more of the identified markers, whose expression correlates with sensitivity to a therapeutic agent or resistance to a therapeutic agent, in a sample of ovarian cancer cells, it is possible to determine whether a therapeutic agent or combination of agents will be most likely to reduce the growth rate of the ovarian cancer cells and can further be used in selecting appropriate treatment agents. In one embodiment, the invention is further directed to the identification of markers that can be used to determine the sensitivity or resistance of ovarian tumors to a therapeutic agent. By examining the expression of one or more of the identified markers, whose expression correlates with sensitivity to a therapeutic agent or resistance to a therapeutic agent, in a sample of ovarian tumor cells, it is possible to determine whether a therapeutic agent or combination of agents will be most likely to reduce the growth rate of the ovarian tumor cells and can further be used in selecting appropriate treatment agents. The markers of the present invention, whose expression correlates with sensitivity or with resistance to an agent, are identified in Table 1 as n1-n78 and further characterized in Table 16.

[0015]The invention further comprises the use of certain combinations of markers, wherein the expression of one or more markers, correlates with sensitivity or resistance to a therapeutic agent. Preferred combinations of markers referred to herein as "marker sets" are set forth in Tables 2-15. In addition, by examining the expression of the individual markers of the newly-identified marker sets (also referred to as the "expression profile" of the marker set), it is possible to determine whether a therapeutic agent or combination of agents will be most likely to reduce the growth rate of the ovarian cancer cells and can further be used in selecting appropriate treatment agents. Moreover, by examining the expression of individual markers and marker sets, it is also possible to determine whether a patient will most likely experience early or late recurrence of ovarian cancer growth. This information can be used in selecting an appropriate treatment.

[0016]Table 1 lists all of the markers of the invention (and comprises markers listed in Tables 2-16) which are designated with a marker identification number ("No."), the image Clone ID ("Image Clone ID"), the gene corresponding to the marker ("Gene Name"), the Accession Number ("Accession"), the GeneBank number ("GI number"), and the Reference Sequence Nucleic Accession Number ("RefSeq").

[0017]Tables 2-15 list marker sets, comprised of multiple individual markers, which are designated with a marker identification number within each marker set ("Number"), the marker identification numbers set forth in Table 1 ("Marker Number"), the Image clone identification number ("Image Clone Id"), the feature selection ("Feature Selection"), and the classification error rate of the model ("Classification Error Rate of the Model"). Table 2 is a preferred marker set.

[0018]Table 16 identifies the 78 individual markers of the present invention (n1-n78). The marker identification numbers are set forth in Table 16 ("No"), the Image clone identification number ("Image Clone Id"), and the Signal-to-noise ("SNR score"). Table 16 lists markers using SNR statistics applied to 18,539 genes of the 51 ovarian samples. In particular, the markers in Table 16 with negative SNR values are correlated with resistance to an agent (referred to herein as "resistance markers"), and the markers with positive SNR scores are correlated with sensitivity to an agent (referred to herein as "sensitivity markers").

[0019]By examining the expression of one or more of the identified markers or marker sets in ovarian cancer, it is possible to determine which therapeutic agent or combination of agents will be most likely to reduce the growth rate of the ovarian cancer. By examining the expression of one or more of the identified markers or marker sets in ovarian cancer, it is also possible to determine which therapeutic agent or combination of agents will be the least likely to reduce the growth rate of the ovarian cancer. By examining the expression of one or more of the identified markers or marker sets, it is therefore possible to eliminate ineffective or inappropriate therapeutic agents. Moreover, by examining the expression of one or more of the identified markers or marker sets in an ovarian cancer sample taken from a patient during the course of therapeutic treatment, it is possible to determine whether the therapeutic treatment is continuing to be effective or whether the ovarian cancer has become resistant (refractory) to the therapeutic treatment. It is also possible to identify new anti-cancer agents by examining the expression of one or more markers or marker sets when ovarian cancer cells are exposed to a potential anti-cancer agent. Thus, in one embodiment, the ovarian cancer cells used in the methods of the present invention are from an ovarian tumor sample. Importantly, these determinations can be made on a patient by patient basis or on an agent by agent (or combination of agents) basis. Thus, one can determine whether or not a particular therapeutic treatment is likely to benefit a particular patient or group/class of patients, or whether a particular treatment should be continued.

[0020]The invention also relates to various methods, reagents and kits for diagnosing, staging, prognosing, monitoring and treating cancers, particularly ovarian cancer. "Ovarian cancer" as used herein includes ovarian tumors, carcinomas, (e.g., carcinoma in situ, invasive carcinoma, metastatic carcinoma) and pre-malignant conditions. Thus, in one embodiment, the ovarian cancer cells used in the methods of the present invention are from an ovarian tumor sample.

[0021]In one embodiment, the invention provides a diagnostic method of assessing whether a patient has ovarian cancer or has higher than normal risk for developing ovarian cancer, comprising the steps of comparing the level of expression of a marker of the invention in a patient sample and the normal level of expression of the marker in a control, e.g., a sample from a patient without ovarian cancer. A significantly higher level of expression of the marker in the patient sample as compared to the normal level is an indication that the patient is afflicted with ovarian cancer or has higher than normal risk for developing ovarian cancer.

[0022]According to the invention, the markers are selected such that the positive predictive value of the methods of the invention is at least about 10%, preferably about 25%, more preferably about 50% and most preferably about 90%. Also preferred for use in the methods of the invention are markers that are differentially expressed, as compared to normal ovarian cells, by at least two-fold in at least about 20%, more preferably about 50%, and most preferably about 75% of any of the following conditions: stage I ovarian cancer patients, stage II ovarian cancer patients, stage III ovarian cancer patients, stage IV ovarian cancer patients, grade I ovarian cancer patients, grade II ovarian cancer patients, grade III ovarian cancer patients, epithelial ovarian cancer patients, stromal ovarian cancer patients, germ cell ovarian cancer patients, malignant ovarian cancer patients, benign ovarian cancer patients, serous neoplasm ovarian cancer patients, mucinous neoplasm ovarian cancer patients, endometrioid neoplasm ovarian cancer patients and/or clear cell neoplasm ovarian cancer patients.

[0023]The present invention further provides previously unknown or unrecognized targets for the development of anti-cancer agents, such as chemotherapeutic compounds. The markers and marker sets of the present invention can be used as targets in developing treatments (either single agent or multiple agent) for ovarian cancer, which displays resistance to agents and exhibits expression of one or more of the markers identified herein.

[0024]Other features and advantages of the invention will be apparent from the detailed description and from the claims. Although materials and methods similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred materials and methods are described below.

DETAILED DESCRIPTION OF THE INVENTION

[0025]The present invention is based, in part, on the identification of individual markers and marker sets that can be used to determine whether ovarian cancer is sensitive or resistant to a therapeutic agent. Based on these identifications, the present invention provides, without limitation: 1) methods for determining whether a therapeutic agent (or combination of agents) will or will not be effective in stopping or slowing ovarian cancer; 2) methods for determining the likelihood of recurrence and time of recurrence of ovarian cancer; 3) methods for monitoring the effectiveness of a therapeutic agent (or combination of agents) used for the treatment of ovarian cancer; 4) methods for identifying new therapeutic agents for the treatment of ovarian cancer; 5) methods for identifying combinations of therapeutic agents for use in treating ovarian cancer; 6) methods for identifying specific therapeutic agents and combinations of therapeutic agents that are effective for the treatment of ovarian cancer in specific patients; and 7) methods for identifying therapeutic agents and combinations of therapeutic agents that are effective for treating ovarian cancer that is likely to recur.

Definitions

[0026]Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The content of all GenBank and IMAGE Consortium database records cited throughout this application (including the Tables) are also hereby incorporated by reference. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0027]The articles "a" and "an" are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0028]A "marker" is a naturally-occurring polymer corresponding to at least one of the nucleic acids listed in Table 1. For example, markers include, without limitation, sense and anti-sense strands of genomic DNA (i.e. including any introns occurring therein), RNA generated by transcription of genomic DNA (i.e. prior to splicing), RNA generated by splicing of RNA transcribed from genomic DNA, and proteins generated by translation of spliced RNA (i.e. including proteins both before and after cleavage of normally cleaved regions such as transmembrane signal sequences). As used herein, "marker" may also include a cDNA made by reverse transcription of an RNA generated by transcription of genomic DNA (including spliced RNA).

[0029]A "marker set" is a group of markers. Preferred marker sets of the present invention are identified in Tables 2-15.

[0030]The term "probe" refers to any molecule which is capable of selectively binding to a specifically intended target molecule, for example a marker of the invention. Probes can be either synthesized by one skilled in the art, or derived from appropriate biological preparations. For purposes of detection of the target molecule, probes may be specifically designed to be labeled, as described herein. Examples of molecules that can be utilized as probes include, but are not limited to, RNA, DNA, proteins, antibodies, and organic monomers.

[0031]The "normal" level of expression of a marker is the level of expression of the marker in cells of a patient not afflicted with cancer. A normal level of expression of a marker may also refer to the level of expression of a "control sample", (e.g., sample from a healthy subjects not having the marker associated disease). A control sample may be comprised of a control database.

[0032]"Over-expression" and "under-expression" of a marker refer to expression of the marker of a patient at a greater or lesser level, respectively, than normal level of expression of the marker (e.g. at least two-fold greater or lesser level).

[0033]As used herein, the term "promoter/regulatory sequence" means a nucleic acid sequence which is required for expression of a gene product operably linked to the promoter/regulatory sequence. In some instances, this sequence may be the core promoter sequence and in other instances, this sequence may also include an enhancer sequence and other regulatory elements which are required for expression of the gene product. The promoter/regulatory sequence may, for example, be one which expresses the gene product in a tissue-specific manner.

[0034]A "constitutive" promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a living human cell under most or all physiological conditions of the cell.

[0035]An "inducible" promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a living human cell substantially only when an inducer which corresponds to the promoter is present in the cell.

[0036]A "tissue-specific" promoter is a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a living human cell substantially only if the cell is a cell of the tissue type corresponding to the promoter.

[0037]A "transcribed polynucleotide" is a polynucleotide (e.g. an RNA, a cDNA, or an analog of one of an RNA or cDNA) which is complementary to or homologous with all or a portion of a mature RNA made by transcription of a genomic DNA corresponding to a marker of the invention and normal post-transcriptional processing (e.g. splicing), if any, of the transcript.

[0038]"Complementary" refers to the broad concept of sequence complementarity between regions of two nucleic acid strands or between two regions of the same nucleic acid strand. It is known that an adenine residue of a first nucleic acid region is capable of forming specific hydrogen bonds ("base pairing") with a residue of a second nucleic acid region which is antiparallel to the first region if the residue is thymine or uracil. Similarly, it is known that a cytosine residue of a first nucleic acid strand is capable of base pairing with a residue of a second nucleic acid strand which is antiparallel to the first strand if the residue is guanine. A first region of a nucleic acid is complementary to a second region of the same or a different nucleic acid if, when the two regions are arranged in an antiparallel fashion, at least one nucleotide residue of the first region is capable of base pairing with a residue of the second region. Preferably, the first region comprises a first portion and the second region comprises a second portion, whereby, when the first and second portions are arranged in an antiparallel fashion, at least about 50%, and preferably at least about 75%, at least about 90%, or at least about 95% of the nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion. More preferably, all nucleotide residues of the first portion are capable of base pairing with nucleotide residues in the second portion.

[0039]"Homologous" as used herein, refers to nucleotide sequence similarity between two regions of the same nucleic acid strand or between regions of two different nucleic acid strands. When a nucleotide residue position in both regions is occupied by the same nucleotide residue, then the regions are homologous at that position. A first region is homologous to a second region if at least one nucleotide residue position of each region is occupied by the same residue. Homology between two regions is expressed in terms of the proportion of nucleotide residue positions of the two regions that are occupied by the same nucleotide residue. By way of example, a region having the nucleotide sequence 5'-ATTGCC-3' and a region having the nucleotide sequence 5'-TATGGC-3' share 50% homology. Preferably, the first region comprises a first portion and the second region comprises a second portion, whereby, at least about 50%, and preferably at least about 75%, at least about 90%, or at least about 95% of the nucleotide residue positions of each of the portions are occupied by the same nucleotide residue. More preferably, all nucleotide residue positions of each of the portions are occupied by the same nucleotide residue.

[0040]A marker is "fixed" to a substrate if it is covalently or non-covalently associated with the substrate such the substrate can be rinsed with a fluid (e.g. standard saline citrate, pH 7.4) without a substantial fraction of the marker dissociating from the substrate.

[0041]As used herein, a "naturally-occurring" nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g. encodes a natural protein).

[0042]Expression of a marker or marker set in a patient is "significantly" higher or lower than the normal level of expression of a marker or marker set if the level of expression of the marker or marker set is greater or less, respectively, than the normal level by an amount greater than the standard error of the assay employed to assess expression, and preferably at least twice, and more preferably three, four, five or ten times that amount. Alternately, expression of the marker or marker set in the patient can be considered "significantly" higher or lower than the normal level of expression if the level of expression is at least about two, and preferably at least about three, four, or five times, higher or lower, respectively, than the normal level of expression of the marker or marker set.

[0043]Cancer is "inhibited" if at least one symptom of the cancer is alleviated, terminated, slowed, or prevented. As used herein, cancer is also "inhibited" if recurrence or metastasis of the cancer is reduced, slowed, delayed, or prevented.

[0044]"Ovarian cancer" as used herein includes ovarian tumors, carcinomas, (e.g., carcinoma in situ, invasive carcinoma, metastatic carcinoma) and pre-malignant conditions. By "ovarian tumor" is meant both benign and malignant tumors, such as ovarian germ cell tumors, e.g. teratomas, dysgerminoma, endodermal sinus tumor and embryonal carcinoma, and ovarian stromal tumors, e.g. granulosa, theca, Sertoli, Leydig, and collagen-producing stromal cells. Ovarian cancers as used herein also includes art recognized histological tumor types, which include, for example, serous, mucinous, endometrioid, and clear cell tumors. The term ovarian cancer as used herein further includes art recognized grade and stage scales: grade I, II and III and stage I (including stage 1A, 1B and 1C), II (including stage IIA, IIB and IIC), III (including stage IIIA, IIIB and IIIC), and IV.

[0045]"Early recurrence" refers to recurrence of ovarian cancer in less than 21 months from removal of an original ovarian tumor.

[0046]"Late recurrence" refers to recurrence of ovarian cancer in greater than 21 months from removal of an original ovarian tumor.

[0047]Ovarian cancer, including an ovarian tumor, is "sensitive" to a therapeutic agent if its rate of growth is inhibited as a result of contact with the therapeutic agent, compared to its growth in the absence of contact with the therapeutic agent. The quality of being sensitive to a therapeutic agent is a variable one, with different ovarian cancers exhibiting different levels of "sensitivity" to a given therapeutic agent, under different conditions. In one embodiment of the invention, ovarian cancers may be predisposed to sensitivity to an agent if one or more of the corresponding sensitivity markers are expressed. In another embodiment of the invention, the predisposition of ovarian cancer to be sensitive to an agent is determined by the methods of the present invention, wherein expression of the individual markers of the marker sets identified in Tables 2-15, is evaluated.

[0048]Ovarian cancer, including an ovarian tumor and ovarian tumor cells, is "resistant" to a therapeutic agent if its rate of growth is not inhibited, or inhibited to a very low degree, as a result of contact with the therapeutic agent when compared to its growth in the absence of contact with the therapeutic agent. The quality of being resistant to a therapeutic agent is a highly variable one, with different ovarian cancers exhibiting different levels of "resistance" to a given therapeutic agent, under different conditions. In another embodiment of the invention, ovarian cancers may be predisposed to resistance to an agent if one or more of the corresponding resistance markers are expressed. In another embodiment of the invention, the predisposition of ovarian cancer to be resistant to an agent is determined by the methods of the present invention, wherein expression of the individual markers of the marker sets identified in Tables 2-15, is evaluated.

[0049]A kit is any manufacture (e.g. a package or container) comprising at least one reagent, e.g. a probe, for specifically detecting a marker or marker set of the invention. The manufacture may be promoted, distributed, or sold as a unit for performing the methods of the present invention. The reagents included in such a kit comprise probes/primers and/or antibodies for use in detecting sensitivity and resistance marker expression. In addition, the kits of the present invention may preferably contain instructions which describe a suitable detection assay. Such kits can be conveniently used, e.g., in clinical settings, to diagnose patients exhibiting symptoms of ovarian cancer, in particular patients exhibiting the possible presence of an ovarian tumor.

SPECIFIC EMBODIMENTS

I. Identification of Sensitivity and Resistance Markers

[0050]The present invention provides markers that are expressed in ovarian cancer that are sensitive to a given therapeutic agent and whose expression correlates with sensitivity to that therapeutic agent. The present invention also provides markers that are expressed in ovarian cancer that are resistant to a given therapeutic agent and whose expression correlates with resistance to that therapeutic agent. Accordingly, one or more of the markers can be used to identify ovarian cancer that can be successfully treated by that agent. In one embodiment, one or more of the markers of the present invention can be used to identify ovarian tumor cells that can be successfully treated by that agent. In addition, the markers of the present invention can be used to identify ovarian cancer that has become or is at risk of becoming refractory to treatment with the agent. The invention also features combinations of marker sets, referred to herein as "marker sets," that can predict patients that are likely to respond or not to respond to an agent.

[0051]Table 1 identifies markers whose expression correlates with sensitivity or resistance to a taxane compound and/or a platinum compound. In particular, Table 1 sets forth 78 markers identified in ovarian tumor samples as sensitive or resistant to the combination therapy of TAXOL and cisplatin. It is preferable to determine the expression of two or more of the identified sensitivity or resistance markers, more preferably, three or more of the identified sensitivity or resistance markers, most preferably, a set of the identified sensitivity and/or resistance markers, such as the sets identified in Tables 2-15. Thus, it is preferable to assess the expression of a set or panel of sensitivity and resistance markers, i.e., the expression profile of a marker set.

[0052]Table 16 identifies the 78 individual markers of the present invention whose expression correlates with sensitivity or resistance to a taxane compound and/or a platinum compound. Table 16 lists markers using SNR statistics applied to 18,539 genes of the 51 ovarian tumor samples. In particular, the markers in Table 16 with negative SNR values are correlated with resistance to an agent (referred to herein as "resistance markers"), and the markers with positive SNR scores are correlated with sensitivity to an agent (referred to herein as "sensitivity markers").

II. Determining Sensitivity or Resistance to an Agent

[0053]The expression level (including protein level) of the identified sensitivity and resistance markers may be used to: 1) determine if ovarian cancer can be treated by an agent or combination of agents; 2) determine if ovarian cancer is responding to treatment with an agent or combination of agents; 3) select an appropriate agent or combination of agents for treating ovarian cancer; 4) monitor the effectiveness of an ongoing treatment; 5) identify new treatments (either single agent or combination of agents); 6) differentiate early versus late recurrence of the ovarian cancer; and 7) select an appropriate agent or combination of agents in treating early and late recurrence of the ovarian cancer. In particular, the identified sensitivity and resistance markers may be utilized to determine appropriate therapy, to monitor clinical therapy and human trials of a drug being tested for efficacy, and to develop new agents and therapeutic combinations.

[0054]The present invention provides methods for determining whether an agent, e.g., a chemotherapeutic agent, can be used to reduce the growth rate of ovarian cancer comprising the steps of: [0055]a) obtaining a sample of ovarian cancer cells; [0056]b) evaluating the expression of the individual markers of a marker set; and [0057]c) identifying that an agent is or is not appropriate to reduce the growth rate of the ovarian cancer cells based on the evaluation.In a preferred embodiment, the marker set is selected from those set forth in Tables 2-15.

[0058]In another embodiment, the invention provides a method for determining whether an agent, e.g., a chemotherapeutic agent, can be used to reduce the growth rate of ovarian cancer comprising the steps of: [0059]a) obtaining a sample of ovarian cancer cells; [0060]b) determining the expression profile of a marker set; and [0061]c) identifying that an agent is or is not appropriate to reduce the growth rate of the ovarian cancer cells based on the expression profile.In a preferred embodiment, the marker set is selected from those set forth in Tables 2-15.

[0062]In another embodiment, the invention provides a method for determining whether an agent can be used to reduce the growth of ovarian cancer, comprising the steps of: [0063]a) obtaining a sample of ovarian cancer cells; [0064]b) exposing some of the ovarian cancer cells to one or more test agents; [0065]c) evaluating the expression of the individual markers of a marker set, both in ovarian cancer cells exposed to the agent and in ovarian cancer cells that have not been exposed to the agent; and [0066]d) identifying that an agent is or is not appropriate to treat the ovarian cancer based on the evaluation.

[0067]In a preferred embodiment, the marker set is selected from those set forth in Tables 2-15.

[0068]In another embodiment, the invention provides a method for determining whether an agent can be used to reduce the growth of ovarian cancer, comprising the steps of: [0069]a) obtaining a sample of ovarian cancer cells; [0070]b) exposing some of the ovarian cancer cells to one or more test agents; [0071]c) determining the expression profile of the marker set, both in ovarian cancer cells exposed to the agent and in ovarian cancer cells that have not been exposed to the agent; and [0072]d) identifying that an agent is appropriate to treat the ovarian cancer when the expression profile of the marker set demonstrates decreased resistance or increased sensitivity in the presence of the agent.

[0073]Alternatively, in step (d), an agent can be identified as not being appropriate to treat the ovarian cancer when the expression profile of the marker set demonstrates decreased sensitivity or increased resistance in the presence of the agent. In a preferred embodiment, the marker set is selected from those set forth in Tables 2-15.

[0074]In another embodiment, the invention provides a method for determining whether treatment with an anti-cancer agent should be continued in an ovarian cancer patient, comprising the steps of: [0075]a) obtaining two or more samples of ovarian cancer cells from a patient at different times during the course of anti-cancer agent treatment; [0076]b) evaluating the expression of the individual markers of a marker set, in the two or more samples; and [0077]c) continuing or discontinuing the treatment based on the evaluation.In a preferred embodiment, the marker set is selected from those set forth in Tables 2-15.

[0078]In another embodiment, the invention provides a method for determining whether treatment with an anti-cancer agent should be continued in an ovarian cancer patient, comprising the steps of: [0079]a) obtaining two or more samples of ovarian cancer cells from a patient at different times during the course of anti-cancer agent treatment; [0080]b) determining the expression profile a marker set, in the two or more samples; and [0081]c) continuing the treatment when the expression profile of the marker set does not demonstrate decreased sensitivity and/or does not demonstrate increased resistance during the course of treatment.

[0082]Alternatively, in step (c), the treatment is discontinued when the expression profile of the marker set demonstrates decreased sensitivity and/or increased resistance during the course of treatment. In a preferred embodiment, the marker set is selected from those set forth in Tables 2-15.

[0083]In a further embodiment, the invention provides a method for determining whether treatment with an anti-cancer agent should be continued in an ovarian cancer patient, comprising the steps of: [0084]a) obtaining two or more samples of ovarian cancer cells from a patient at different times during the course of anti-cancer agent treatment; [0085]b) determining the expression profile of a marker set, in the two or more samples; and [0086]c) continuing the treatment when the expression profile of the marker set demonstrates increased sensitivity and/or decreased resistance during the course of treatment.

[0087]Alternatively, in step (c), the treatment is discontinued when the expression profile of the marker set demonstrates decreased sensitivity and/or increased resistance during the course of treatment. In a preferred embodiment, the marker set is selected from those set forth in Tables 2-15.

[0088]The present invention further provides methods for determining whether an agent, e.g., a chemotherapeutic agent, can be used to reduce the growth rate of ovarian cancer comprising the steps of: [0089]a) obtaining a sample of ovarian cancer cells; [0090]b) determining whether the ovarian cancer cells express one or more markers identified in Table 16; and [0091]c) identifying that an agent is or is not appropriate to treat the ovarian cancer based on the expression of one or more markers identified in Table 16.

[0092]In another embodiment, the invention provides a method for determining whether an agent can be used to reduce the growth of ovarian cancer, comprising the steps of: [0093]a) obtaining a sample of ovarian cancer cells; [0094]b) determining whether the ovarian cancer cells express one or more markers identified in Table 16; and [0095]c) identifying that an agent is appropriate to treat the ovarian cancer when the expression of the sensitivity markers identified in Table 16 is increased and/or the expression of the resistance markers identified in Table 16 is decreased in the presence of the agent.

[0096]Alternatively, in step (c), an agent can be identified as not being appropriate to treat the ovarian cancer when the expression of the sensitivity markers identified in Table 16 is decreased and/or the expression of the resistance markers identified in Table 16 is increased in the presence of the agent.

[0097]In another embodiment, the invention provides a method for determining whether an agent can be used to reduce the growth of ovarian cancer, comprising the steps of: [0098]a) obtaining a sample of ovarian cancer cells; [0099]b) exposing some of the ovarian cancer cells to one or more test agents; [0100]c) determining the level of expression of one or more markers identified in Table 16 both in ovarian cancer cells exposed to the agent and in ovarian cancer cells that have not been exposed to the agent; and [0101]d) identifying that an agent is appropriate to treat the ovarian cancer when the expression of the sensitivity markers identified in Table 16 is increased and/or the expression of the resistance markers identified in Table 16 is decreased in the presence of the agent.

[0102]Alternatively, in step (d), an agent can be identified as not being appropriate to treat the ovarian cancer when the expression of the sensitivity markers identified in Table 16 is decreased and/or the expression of the resistance markers identified in Table 16 is increased in the presence of the agent.

[0103]In another embodiment, the invention provides a method for determining whether treatment with an anti-cancer agent should be continued in an ovarian cancer patient, comprising the steps of: [0104]a) obtaining two or more samples of ovarian cancer cells from a patient at different times during the course of anti-cancer agent treatment; [0105]b) determining the level of expression in the ovarian cancer cells of one or more genes which correspond to markers identified in Table 16 in the two or more samples; and [0106]c) continuing the treatment when the expression level of the sensitivity markers identified in Table 16 does not decrease and/or the expression level of the resistance markers identified in Table 16 does not increase during the course of treatment.

[0107]Alternatively, in step (c), the treatment is discontinued when the expression level of the sensitivity markers identified in Table 16 is decreased and/or the expression level of the resistance markers identified in Table 16 is increased, during the course of treatment.

[0108]The markers and marker sets of the present invention are predictive of chemotherapeutic agents, generally. In one embodiment of the invention, the agent used in methods of the invention is a taxane compound. In another embodiment, the agent is a platinum compound. In yet another embodiment, the agent is a combination of a taxane compound and a platinum compound e.g., TAXOL and cisplatin, respectively.

[0109]In another embodiment of the invention, the expression of markers identified in Tables 1-16 is detected by measuring mRNA which corresponds to the marker. In yet another embodiment of the invention, the expression of markers which correspond to markers or marker sets identified in Tables 1-16 is detected by measuring protein which corresponds to the marker.

[0110]In another embodiment, the invention provides a method of treating a patient with ovarian cancer by administering to the patient a compound which has been identified as being effective against ovarian cancer by the methods of the invention described herein.

[0111]As used herein, the term "agent" is defined broadly as anything that cancer cells, including tumor cells, may be exposed to in a therapeutic protocol. In the context of the present invention, such agents include, but are not limited to, chemotherapeutic agents, such as anti-metabolic agents, e.g., Ara AC, 5-FU and methotrexate, antimitotic agents, e.g., TAXOL, inblastine and vincristine, alkylating agents, e.g., melphanlan, BCNU and nitrogen mustard, Topoisomerase II inhibitors, e.g., VW-26, topotecan and Bleomycin, strand-breaking agents, e.g., doxorubicin and DHAD, cross-linking agents, e.g., cisplatin and CBDCA, radiation and ultraviolet light. In a preferred embodiment, the agent is a taxane compound (e.g., TAXOL) and/or a platinum compound (e.g., cisplatin).

[0112]Further to the above, the language "chemotherapeutic agent" is intended to include chemical reagents which inhibit the growth of proliferating cells or tissues wherein the growth of such cells or tissues is undesirable. Chemotherapeutic agents are well known in the art (see e.g., Gilman A. G., et al., The Pharmacological Basis of Therapeutics, 8th Ed., Sec 12:1202-1263 (1990)), and are typically used to treat neoplastic diseases. The chemotherapeutic agents generally employed in chemotherapy treatments are listed below in Table A.

TABLE-US-00001 TABLE A NONPROPRIETARY NAMES CLASS TYPE OF AGENT (OTHER NAMES) Alkylating Nitrogen Mustards Mechlorethamine (HN₂) Cyclophosphamide Ifosfamide Melphalan (L-sarcolysin) Chlorambucil Ethylenimines Hexamethylmelamine And Methylmelamines Thiotepa Alkyl Sulfonates Busulfan Alkylating Nitrosoureas Carmustine (BCNU) Lomustine (CCNU) Semustine (methyl-CCNU) Streptozocin (streptozotocin) Triazenes Decarbazine (DTIC; dimethyltriazenoimi- dazolecarboxamide) Alkylator cis-diamminedichloroplatinum II (CDDP) Antimetabolites Folic Acid Methotrexate Analogs (amethopterin) Pyrimidine Fluorouracil Analogs ('5-fluorouracil; 5-FU) Floxuridine (fluorode-oxyuridine; FUdR) Cytarabine (cytosine arabinoside) Purine Analogs Mercaptopuine and Related (6-mercaptopurine; Inhibitors 6-MP) Thioguanine (6-thioguanine; TG) Pentostatin (2'- deoxycoformycin) Natural Vinca Alkaloids Vinblastin (VLB) Products Vincristine Topoisomerase Etoposide Inhibitors Teniposide Camptothecin Topotecan 9-amino-campotothecin CPT-11 Antibiotics Dactinomycin (actinomycin D) Adriamycin Daunorubicin (daunomycin; rubindomycin) Doxorubicin Bleomycin Plicamycin (mithramycin) Mitomycin (mitomycin C) TAXOL Taxotere Enzymes L-Asparaginase Biological Interfon alfa Response interleukin 2 Modifiers Miscellaneous Platinum cis-diamminedichloroplatinum Agents Coordination II (CDDP) Complexes Carboplatin Anthracendione Mitoxantrone Substituted Urea Hydroxyurea Methyl Hydraxzine Procarbazine Derivative (N-methylhydrazine, (MIH) Adrenocortical Mitotane (o,p'-DDD) Suppressant Aminoglutethimide Hormones and Adrenocorticosteroids Prednisone Antagonists Progestins Hydroxyprogesterone caproate Medroxyprogesterone acetate Megestrol acetate Estrogens Diethylstilbestrol Ethinyl estradiol Antiestrogen Tamoxifen Androgens Testosterone propionate Fluoxymesterone Antiandrogen Flutamide Gonadotropin-releasing Leuprolide Hormone analog

[0113]The agents tested in the present methods can be a single agent or a combination of agents. For example, the present methods can be used to determine whether a single chemotherapeutic agent, such as methotrexate, can be used to treat a cancer or whether a combination of two or more agents can be used. Preferred combinations will include agents that have different mechanisms of action, e.g., the use of an anti-mitotic agent in combination with an alkylating agent.

[0114]As used herein, cancer cells, including tumor cells, refer to cells that divide at an abnormal (increased) rate. Cancer cells include, but are not limited to, carcinomas, such as squamous cell carcinoma, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, undifferentiated carcinoma, bronchogenic carcinoma, melanoma, renal cell carcinoma, hepatoma-liver cell carcinoma, bile duct carcinoma, cholangiocarcinoma, papillary carcinoma, transitional cell carcinoma, choriocarcinoma, semonoma, embryonal carcinoma, mammary carcinomas, gastrointestinal carcinoma, colonic carcinomas, bladder carcinoma, prostate carcinoma, and squamous cell carcinoma of the neck and head region; sarcomas, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synoviosarcoma and mesotheliosarcoma; leukemias and lymphomas such as granulocytic leukemia, monocytic leukemia, lymphocytic leukemia, malignant lymphoma, plasmocytoma, reticulum cell sarcoma, or Hodgkins disease; and tumors of the nervous system including glioma, meningoma, medulloblastoma, schwannoma or epidymoma.

[0115]The source of the cancer cells used in the present method will be based on how the method of the present invention is being used. For example, if the method is being used to determine whether a patient's cancer can be treated with an agent, or a combination of agents, then the preferred source of cancer cells will be cancer cells obtained from a cancer biopsy from the patient, e.g., a tumor biopsy. Alternatively, a cancer cell line similar to the type of cancer being treated can be assayed. For example if ovarian cancer is being treated, then an ovarian cancer cell line can be used. If the method is being used to monitor the effectiveness of a therapeutic protocol, then a tissue sample from the patient being treated is the preferred source. If the method is being used to identify new therapeutic agents or combinations, any cancer cells, e.g., cells of a cancer cell line, can be used.

[0116]A skilled artisan can readily select and obtain the appropriate cancer cells that are used in the present method. For cancer cell lines, sources such as The National Cancer Institute, for the NCI-60 cells, are preferred. For cancer cells obtained from a patient, standard biopsy methods, such as a needle biopsy, can be employed.

[0117]Ovarian tumor samples were used to obtain the markers of the present invention. It will thus be appreciated that cells from ovarian tumors are particularly useful in the methods of the present invention.

[0118]In the methods of the present invention, the level or amount of expression of one or more markers selected from the group consisting of the markers identified in Table 1 is determined. As used herein, the level or amount of expression refers to the absolute level of expression of an mRNA encoded by the marker or the absolute level of expression of the protein encoded by the marker (i.e., whether or not expression is or is not occurring in the cancer cells).

[0119]Generally, it is preferable to determine the expression of two or more of the identified sensitivity or resistance markers, more preferably, three or more of the identified sensitivity or resistance markers, most preferably, a set of the identified sensitivity and/or resistance markers, such as the marker sets identified in Tables 2-15. Thus, it is preferable to assess the expression of a panel of sensitivity and resistance markers.

[0120]As an alternative to making determinations based on the absolute expression level of selected markers, determinations may be based on the normalized expression levels. Expression levels are normalized by correcting the absolute expression level of a sensitivity or resistance marker by comparing its expression to the expression of a marker that is not a sensitivity or resistance marker, e.g., a housekeeping gene that is constitutively expressed. Suitable markers for normalization include housekeeping genes, such as the actin gene. This normalization allows one to compare the expression level in one sample, e.g., a tumor sample, to another sample, e.g., a non-tumor sample, or between samples from different sources.

[0121]Alternatively, the expression level can be provided as a relative expression level. To determine a relative expression level of a marker or marker set, the level of expression of the marker or marker set is determined for 10 or more samples, preferably 50 or more samples, prior to the determination of the expression level for the sample in question. The mean expression level of each of the markers or marker sets assayed in the larger number of samples is determined and this is used as a baseline expression level for the markers or marker sets in question. The expression level of the marker or marker set determined for the test sample (absolute level of expression) is then divided by the mean expression value obtained for that marker or marker set. This provides a relative expression level and aids in identifying extreme cases of sensitivity or resistance.

[0122]Preferably, the samples used will be from similar tumors or from non-cancerous cells of the same tissue origin as the tumor in question. The choice of the cell source is dependent on the use of the relative expression level data. For example, using tumors of similar types for obtaining a mean expression score allows for the identification of extreme cases of sensitivity or resistance. Using expression found in normal tissues as a mean expression score aids in validating whether the sensitivity/resistance marker or marker set assayed is tumor specific (versus normal cells). Such a later use is particularly important in identifying whether a sensitivity or resistance marker or marker set can serve as a target marker or marker set. In addition, as more data is accumulated, the mean expression value can be revised, providing improved relative expression values based on accumulated data.

III. Isolated Nucleic Acid Molecules

[0123]One aspect of the invention pertains to isolated nucleic acid molecules that correspond to a marker of the invention, including nucleic acids which encode a polypeptide corresponding to a marker of the invention or a portion of such a polypeptide. Isolated nucleic acids of the invention also include nucleic acid molecules sufficient for use as hybridization probes to identify nucleic acid molecules that correspond to a marker of the invention, including nucleic acids which encode a polypeptide corresponding to a marker of the invention, and fragments of such nucleic acid molecules, e.g., those suitable for use as PCR primers for the amplification or mutation of nucleic acid molecules. As used herein, the term "nucleic acid molecule" is intended to include DNA molecules (e.g., cDNA or genomic DNA) and RNA molecules (e.g., mRNA) and analogs of the DNA or RNA generated using nucleotide analogs. The nucleic acid molecule can be single-stranded or double-stranded, but preferably is double-stranded DNA.

[0124]An "isolated" nucleic acid molecule is one which is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid molecule. Preferably, an "isolated" nucleic acid molecule is free of sequences (preferably protein-encoding sequences) which naturally flank the nucleic acid (i.e., sequences located at the 5' and 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated nucleic acid molecule can contain less than about 5 kB, 4 kB, 3 kB, 2 kB, 1 kB, 0.5 kB or 0.1 kB of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell from which the nucleic acid is derived. Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized.

[0125]A nucleic acid molecule of the present invention, e.g., a nucleic acid encoding a protein corresponding to a marker listed in Tables 1-16, can be isolated using standard molecular biology techniques and the sequence information in the database records described herein. Using all or a portion of such nucleic acid sequences, nucleic acid molecules of the invention can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook et al., ed., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989).

[0126]A nucleic acid molecule of the invention can be amplified using cDNA, mRNA, or genomic DNA as a template and appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to all or a portion of a nucleic acid molecule of the invention can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.

[0127]In another preferred embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule which has a nucleotide sequence complementary to the nucleotide sequence of a nucleic acid corresponding to a marker of the invention or to the nucleotide sequence of a nucleic acid encoding a protein which corresponds to a marker of the invention. A nucleic acid molecule which is complementary to a given nucleotide sequence is one which is sufficiently complementary to the given nucleotide sequence that it can hybridize to the given nucleotide sequence thereby forming a stable duplex.

[0128]Moreover, a nucleic acid molecule of the invention can comprise only a portion of a nucleic acid sequence, wherein the full length nucleic acid sequence comprises a marker of the invention or which encodes a polypeptide corresponding to a marker of the invention. Such nucleic acids can be used, for example, as a probe or primer. The probe/primer typically is used as one or more substantially purified oligonucleotides. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 7, preferably about 15, more preferably about 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400 or more consecutive nucleotides of a nucleic acid of the invention.

[0129]Probes based on the sequence of a nucleic acid molecule of the invention can be used to detect transcripts or genomic sequences corresponding to one or more markers of the invention. The probe comprises a label group attached thereto, e.g., a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as part of a diagnostic test kit for identifying cells or tissues which mis-express the protein, such as by measuring levels of a nucleic acid molecule encoding the protein in a sample of cells from a subject, e.g., detecting mRNA levels or determining whether a gene encoding the protein has been mutated or deleted.

[0130]The invention further encompasses nucleic acid molecules that differ, due to degeneracy of the genetic code, from the nucleotide sequence of nucleic acids encoding a protein which corresponds to a marker of the invention, and thus encode the same protein.

[0131]In addition to the nucleotide sequences described in the database records described herein, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequence can exist within a population (e.g., the human population). Such genetic polymorphisms can exist among individuals within a population due to natural allelic variation. An allele is one of a group of genes which occur alternatively at a given genetic locus. In addition, it will be appreciated that DNA polymorphisms that affect RNA expression levels can also exist that may affect the overall expression level of that gene (e.g., by affecting regulation or degradation).

[0132]As used herein, the phrase "allelic variant" refers to a nucleotide sequence which occurs at a given locus or to a polypeptide encoded by the nucleotide sequence.

[0133]As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame encoding a polypeptide corresponding to a marker of the invention. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of a given gene. Alternative alleles can be identified by sequencing the gene of interest in a number of different individuals. This can be readily carried out by using hybridization probes to identify the same genetic locus in a variety of individuals. Any and all such nucleotide variations and resulting amino acid polymorphisms or variations that are the result of natural allelic variation and that do not alter the functional activity are intended to be within the scope of the invention.

[0134]In another embodiment, an isolated nucleic acid molecule of the invention is at least 7, 15, 20, 25, 30, 40, 60, 80, 100, 150, 200, 250, 300, 350, 400, 450, 550, 650, 700, 800, 900, 1000, 1200, 1400, 1600, 1800, 2000, 2200, 2400, 2600, 2800, 3000, 3500, 4000, 4500, or more nucleotides in length and hybridizes under stringent conditions to a nucleic acid corresponding to a marker of the invention or to a nucleic acid encoding a protein corresponding to a marker of the invention. As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences at least 75% (80%, 85%, preferably 95%) identical to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in sections 6.3.1-6.3.6 of Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989). A preferred, non-limiting example of stringent hybridization conditions for annealing two single-stranded DNA each of which is at least about 100 bases in length and/or for annealing a single-stranded DNA and a single-stranded RNA each of which is at least about 100 bases in length, are hybridization in 6× sodium chloride/sodium citrate (SSC) at about 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 50-65° C. Further preferred hybridization conditions are taught in Lockhart, et al., Nature Biotechnology, Volume 14, 1996 August: 1675-1680; Breslauer, et al., Proc. Natl. Acad. Sci. USA, Volume 83, 1986 June: 3746-3750; Van Ness, et al., Nucleic Acids Research, Volume 19, No. 19, 1991 September: 5143-5151; McGraw, et al., BioTechniques, Volume 8, No. 6 1990: 674-678; and Milner, et al., Nature Biotechnology, Volume 15, 1997 June: 537-541, all expressly incorporated by reference.

[0135]In addition to naturally-occurring allelic variants of a nucleic acid molecule of the invention that can exist in the population, the skilled artisan will further appreciate that sequence changes can be introduced by mutation thereby leading to changes in the amino acid sequence of the encoded protein, without altering the biological activity of the protein encoded thereby. For example, one can make nucleotide substitutions leading to amino acid substitutions at "non-essential" amino acid residues. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequence without altering the biological activity, whereas an "essential" amino acid residue is required for biological activity. For example, amino acid residues that are not conserved or only semi-conserved among homologs of various species may be non-essential for activity and thus would be likely targets for alteration. Alternatively, amino acid residues that are conserved among the homologs of various species (e.g., murine and human) may be essential for activity and thus would not be likely targets for alteration.

[0136]Accordingly, another aspect of the invention pertains to nucleic acid molecules encoding a polypeptide of the invention that contain changes in amino acid residues that are not essential for activity. Such polypeptides differ in amino acid sequence from the naturally-occurring proteins which correspond to the markers of the invention, yet retain biological activity. In one embodiment, such a protein has an amino acid sequence that is at least about 40% identical, 50%, 60%, 70%, 80%, 90%, 95%, or 98% identical to the amino acid sequence of one of the proteins which correspond to the markers of the invention.

[0137]An isolated nucleic acid molecule encoding a variant protein can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of nucleic acids of the invention, such that one or more amino acid residue substitutions, additions, or deletions are introduced into the encoded protein. Mutations can be introduced by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted non-essential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for biological activity to identify mutants that retain activity. Following mutagenesis, the encoded protein can be expressed recombinantly and the activity of the protein can be determined.

[0138]The present invention encompasses antisense nucleic acid molecules, i.e., molecules which are complementary to a sense nucleic acid of the invention, e.g., complementary to the coding strand of a double-stranded cDNA molecule corresponding to a marker of the invention or complementary to an mRNA sequence corresponding to a marker of the invention. Accordingly, an antisense nucleic acid of the invention can hydrogen bond to (i.e. anneal with) a sense nucleic acid of the invention. The antisense nucleic acid can be complementary to an entire coding strand, or to only a portion thereof, e.g., all or part of the protein coding region (or open reading frame). An antisense nucleic acid molecule can also be antisense to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding a polypeptide of the invention. The non-coding regions ("5' and 3' untranslated regions") are the 5' and 3' sequences which flank the coding region and are not translated into amino acids.

[0139]An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 or more nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used. Examples of modified nucleotides which can be used to generate the antisense nucleic acid include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been sub-cloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

[0140]The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a polypeptide corresponding to a selected marker of the invention to thereby inhibit expression of the marker, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule which binds to DNA duplexes, through specific interactions in the major groove of the double helix. Examples of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site or infusion of the antisense nucleic acid into an ovary-associated body fluid. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface, e.g., by linking the antisense nucleic acid molecules to peptides or antibodies which bind to cell surface receptors or antigens. The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient intracellular concentrations of the antisense molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

[0141]An antisense nucleic acid molecule of the invention can be an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual α-units, the strands run parallel to each other (Gaultier et al., 1987, Nucleic Acids Res. 15:6625-6641). The antisense nucleic acid molecule can also comprise a 2'-o-methylribonucleotide (Inoue et al., 1987, Nucleic Acids Res. 15:6131-6148) or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330).

[0142]The invention also encompasses ribozymes. Ribozymes are catalytic RNA molecules with ribonuclease activity which are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Haselhoff and Gerlach, 1988, Nature 334:585-591) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. A ribozyme having specificity for a nucleic acid molecule encoding a polypeptide corresponding to a marker of the invention can be designed based upon the nucleotide sequence of a cDNA corresponding to the marker. For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved (see Cech et al. U.S. Pat. No. 4,987,071; and Cech et al. U.S. Pat. No. 5,116,742). Alternatively, an mRNA encoding a polypeptide of the invention can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules (see, e.g., Bartel and Szostak, 1993, Science 261:1411-1418).

[0143]The invention also encompasses nucleic acid molecules which form triple helical structures. For example, expression of a polypeptide of the invention can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the polypeptide (e.g., the promoter and/or enhancer) to form triple helical structures that prevent transcription of the gene in target cells. See generally Helene (1991) Anticancer Drug Des. 6(6):569-84; Helene (1992) Ann. N.Y. Acad. Sci. 660:27-36; and Maher (1992) Bioassays 14(12):807-15.

[0144]In various embodiments, the nucleic acid molecules of the invention can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al., 1996, Bioorganic & Medicinal Chemistry 4(1): 5-23). As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup et al. (1996), supra; Perry-O'Keefe et al. (1996) Proc. Natl. Acad. Sci. USA 93:14670-675.

[0145]PNAs can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs can also be used, e.g., in the analysis of single base pair mutations in a gene by, e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S1 nucleases (Hyrup (1996), supra; or as probes or primers for DNA sequence and hybridization (Hyrup, 1996, supra; Perry-O'Keefe et al., 1996, Proc. Natl. Acad. Sci. USA 93:14670-675).

[0146]In another embodiment, PNAs can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras can be generated which can combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes, e.g., RNASE H and DNA polymerases, to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleobases, and orientation (Hyrup, 1996, supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup (1996), supra, and Finn et al. (1996) Nucleic Acids Res. 24(17):3357-63. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry and modified nucleoside analogs. Compounds such as 5'-(4-methoxytrityl)amino-5'-deoxy-thymidine phosphoramidite can be used as a link between the PNA and the 5' end of DNA (Mag et al., 1989, Nucleic Acids Res. 17:5973-88). PNA monomers are then coupled in a step-wise manner to produce a chimeric molecule with a 5' PNA segment and a 3' DNA segment (Finn et al., 1996, Nucleic Acids Res. 24(17):3357-63). Alternatively, chimeric molecules can be synthesized with a 5' DNA segment and a 3' PNA segment (Peterser et al., 1975, Bioorganic Med. Chem. Lett. 5:1119-11124).

[0147]In other embodiments, the oligonucleotide can include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger et al., 1989, Proc. Natl. Acad. Sci. USA 86:6553-6556; Lemaitre et al., 1987, Proc. Natl. Acad. Sci. USA 84:648-652; PCT Publication No. WO 88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization-triggered cleavage agents (see, e.g., Krol et al., 1988, Bio/Techniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988, Pharm. Res. 5:539-549). To this end, the oligonucleotide can be conjugated to another molecule, e.g., a peptide, hybridization triggered cross-linking agent, transport agent, hybridization-triggered cleavage agent, etc.

[0148]The invention also includes molecular beacon nucleic acids having at least one region which is complementary to a nucleic acid of the invention, such that the molecular beacon is useful for quantitating the presence of the nucleic acid of the invention in a sample. A "molecular beacon" nucleic acid is a nucleic acid comprising a pair of complementary regions and having a fluorophore and a fluorescent quencher associated therewith. The fluorophore and quencher are associated with different portions of the nucleic acid in such an orientation that when the complementary regions are annealed with one another, fluorescence of the fluorophore is quenched by the quencher. When the complementary regions of the nucleic acid are not annealed with one another, fluorescence of the fluorophore is quenched to a lesser degree. Molecular beacon nucleic acids are described, for example, in U.S. Pat. No. 5,876,930.

IV. Isolated Proteins and Antibodies

[0149]One aspect of the invention pertains to isolated proteins which correspond to individual markers of the invention, and biologically active portions thereof, as well as polypeptide fragments suitable for use as immunogens to raise antibodies directed against a polypeptide corresponding to a marker of the invention. In one embodiment, the native polypeptide corresponding to a marker can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, polypeptides corresponding to a marker of the invention are produced by recombinant DNA techniques. Alternative to recombinant expression, a polypeptide corresponding to a marker of the invention can be synthesized chemically using standard peptide synthesis techniques.

[0150]An "isolated" or "purified" protein or biologically active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the protein is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of protein in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, protein that is substantially free of cellular material includes preparations of protein having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as a "contaminating protein"). When the protein or biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation. When the protein is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly such preparations of the protein have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the polypeptide of interest.

[0151]Biologically active portions of a polypeptide corresponding to a marker of the invention include polypeptides comprising amino acid sequences sufficiently identical to or derived from the amino acid sequence of the protein corresponding to the marker, which include fewer amino acids than the full length protein, and exhibit at least one activity of the corresponding full-length protein. Typically, biologically active portions comprise a domain or motif with at least one activity of the corresponding protein. A biologically active portion of a protein of the invention can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acids in length. Moreover, other biologically active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of the native form of a polypeptide of the invention.

[0152]Preferred polypeptides have the amino acid sequence listed in the one of the GenBank and NUC database records described herein. Other useful proteins are substantially identical (e.g., at least about 40%, preferably 50%, 60%, 70%, 80%, 90%, 95%, or 99%) to one of these sequences and retain the functional activity of the protein of the corresponding naturally-occurring protein yet differ in amino acid sequence due to natural allelic variation or mutagenesis.

[0153]To determine the percent identity of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity=# of identical positions/total # of positions (e.g., overlapping positions)×100). In one embodiment the two sequences are the same length.

[0154]The determination of percent identity between two sequences can be accomplished using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul, et al. (1990) J. Mol. Biol. 215:403-410. BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecules of the invention. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to a protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402. Alternatively, PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules. When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov. Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, (1988) CABIOS 4:11-17. Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Yet another useful algorithm for identifying regions of local sequence similarity and alignment is the FASTA algorithm as described in Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85:2444-2448. When using the FASTA algorithm for comparing nucleotide or amino acid sequences, a PAM120 weight residue table can, for example, be used with a k-tuple value of 2.

[0155]The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, only exact matches are counted.

[0156]The invention also provides chimeric or fusion proteins corresponding to a marker of the invention. As used herein, a "chimeric protein" or "fusion protein" comprises all or part (preferably a biologically active part) of a polypeptide corresponding to a marker of the invention operably linked to a heterologous polypeptide (i.e., a polypeptide other than the polypeptide corresponding to the marker). Within the fusion protein, the term "operably linked" is intended to indicate that the polypeptide of the invention and the heterologous polypeptide are fused in-frame to each other. The heterologous polypeptide can be fused to the amino-terminus or the carboxyl-terminus of the polypeptide of the invention.

[0157]One useful fusion protein is a GST fusion protein in which a polypeptide corresponding to a marker of the invention is fused to the carboxyl terminus of GST sequences. Such fusion proteins can facilitate the purification of a recombinant polypeptide of the invention.

[0158]In another embodiment, the fusion protein contains a heterologous signal sequence at its amino terminus. For example, the native signal sequence of a polypeptide corresponding to a marker of the invention can be removed and replaced with a signal sequence from another protein. For example, the gp67 secretory sequence of the baculovirus envelope protein can be used as a heterologous signal sequence (Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, NY, 1992). Other examples of eukaryotic heterologous signal sequences include the secretory sequences of melittin and human placental alkaline phosphatase (Stratagene; La Jolla, Calif.). In yet another example, useful prokaryotic heterologous signal sequences include the phoA secretory signal (Sambrook et al., supra) and the protein A secretory signal (Pharmacia Biotech; Piscataway, N.J.).

[0159]In yet another embodiment, the fusion protein is an immunoglobulin fusion protein in which all or part of a polypeptide corresponding to a marker of the invention is fused to sequences derived from a member of the immunoglobulin protein family. The immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a ligand (soluble or membrane-bound) and a protein on the surface of a cell (receptor), to thereby suppress signal transduction in vivo. The immunoglobulin fusion protein can be used to affect the bioavailability of a cognate ligand of a polypeptide of the invention. Inhibition of ligand/receptor interaction can be useful therapeutically, both for treating proliferative and differentiative disorders and for modulating (e.g. promoting or inhibiting) cell survival. Moreover, the immunoglobulin fusion proteins of the invention can be used as immunogens to produce antibodies directed against a polypeptide of the invention in a subject, to purify ligands and in screening assays to identify molecules which inhibit the interaction of receptors with ligands.

[0160]Chimeric and fusion proteins of the invention can be produced by standard recombinant DNA techniques. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers which give rise to complementary overhangs between two consecutive gene fragments which can subsequently be annealed and re-amplified to generate a chimeric gene sequence (see, e.g., Ausubel et al., supra). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A nucleic acid encoding a polypeptide of the invention can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the polypeptide of the invention.

[0161]A signal sequence can be used to facilitate secretion and isolation of the secreted protein or other proteins of interest. Signal sequences are typically characterized by a core of hydrophobic amino acids which are generally cleaved from the mature protein during secretion in one or more cleavage events. Such signal peptides contain processing sites that allow cleavage of the signal sequence from the mature proteins as they pass through the secretory pathway. Thus, the invention pertains to the described polypeptides having a signal sequence, as well as to polypeptides from which the signal sequence has been proteolytically cleaved (i.e., the cleavage products). In one embodiment, a nucleic acid sequence encoding a signal sequence can be operably linked in an expression vector to a protein of interest, such as a protein which is ordinarily not secreted or is otherwise difficult to isolate. The signal sequence directs secretion of the protein, such as from a eukaryotic host into which the expression vector is transformed, and the signal sequence is subsequently or concurrently cleaved. The protein can then be readily purified from the extracellular medium by art recognized methods. Alternatively, the signal sequence can be linked to the protein of interest using a sequence which facilitates purification, such as with a GST domain.

[0162]The present invention also pertains to variants of the polypeptides corresponding to individual markers of the invention. Such variants have an altered amino acid sequence which can function as either agonists (mimetics) or as antagonists. Variants can be generated by mutagenesis, e.g., discrete point mutation or truncation. An agonist can retain substantially the same, or a subset, of the biological activities of the naturally occurring form of the protein. An antagonist of a protein can inhibit one or more of the activities of the naturally occurring form of the protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the protein of interest. Thus, specific biological effects can be elicited by treatment with a variant of limited function. Treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein can have fewer side effects in a subject relative to treatment with the naturally occurring form of the protein.

[0163]Variants of a protein of the invention which function as either agonists (mimetics) or as antagonists can be identified by screening combinatorial libraries of mutants, e.g., truncation mutants, of the protein of the invention for agonist or antagonist activity. In one embodiment, a variegated library of variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential protein sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g., for phage display). There are a variety of methods which can be used to produce libraries of potential variants of the polypeptides of the invention from a degenerate oligonucleotide sequence. Methods for synthesizing degenerate oligonucleotides are known in the art (see, e.g., Narang, 1983, Tetrahedron 39:3; Itakura et al., 1984, Annu. Rev. Biochem. 53:323; Itakura et al., 1984, Science 198:1056; Ike et al., 1983 Nucleic Acid Res. 11:477).

[0164]In addition, libraries of fragments of the coding sequence of a polypeptide corresponding to a marker of the invention can be used to generate a variegated population of polypeptides for screening and subsequent selection of variants. For example, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of the coding sequence of interest with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double stranded DNA which can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with S1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, an expression library can be derived which encodes amino terminal and internal fragments of various sizes of the protein of interest.

[0165]Several techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. The most widely used techniques, which are amenable to high through-put analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a technique which enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify variants of a protein of the invention (Arkin and Yourvan, 1992, Proc. Natl. Acad. Sci. USA 89:7811-7815; Delgrave et al., 1993, Protein Engineering 6(3):327-331).

[0166]An isolated polypeptide corresponding to a marker of the invention, or a fragment thereof, can be used as an immunogen to generate antibodies using standard techniques for polyclonal and monoclonal antibody preparation. The full-length polypeptide or protein can be used or, alternatively, the invention provides antigenic peptide fragments for use as immunogens. The antigenic peptide of a protein of the invention comprises at least 8 (preferably 10, 15, 20, or 30 or more) amino acid residues of the amino acid sequence of one of the polypeptides of the invention, and encompasses an epitope of the protein such that an antibody raised against the peptide forms a specific immune complex with a marker of the invention to which the protein corresponds. Preferred epitopes encompassed by the antigenic peptide are regions that are located on the surface of the protein, e.g., hydrophilic regions. Hydrophobicity sequence analysis, hydrophilicity sequence analysis, or similar analyses can be used to identify hydrophilic regions.

[0167]An immunogen typically is used to prepare antibodies by immunizing a suitable (i.e. immunocompetent) subject such as a rabbit, goat, mouse, or other mammal or vertebrate. An appropriate immunogenic preparation can contain, for example, recombinantly-expressed or chemically-synthesized polypeptide. The preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or a similar immunostimulatory agent.

[0168]Accordingly, another aspect of the invention pertains to antibodies directed against a polypeptide of the invention. The terms "antibody" and "antibody substance" as used interchangeably herein refer to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site which specifically binds an antigen, such as a polypeptide of the invention, e.g., an epitope of a polypeptide of the invention. A molecule which specifically binds to a given polypeptide of the invention is a molecule which binds the polypeptide, but does not substantially bind other molecules in a sample, e.g., a biological sample, which naturally contains the polypeptide. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab')₂ fragments which can be generated by treating the antibody with an enzyme such as pepsin. The invention provides polyclonal and monoclonal antibodies. The term "monoclonal antibody" or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope.

[0169]Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a polypeptide of the invention as an immunogen. Preferred polyclonal antibody compositions are ones that have been selected for antibodies directed against a polypeptide or polypeptides of the invention. Particularly preferred polyclonal antibody preparations are ones that contain only antibodies directed against a polypeptide or polypeptides of the invention. Particularly preferred immunogen compositions are those that contain no other human proteins such as, for example, immunogen compositions made using a non-human host cell for recombinant expression of a polypeptide of the invention. In such a manner, the only human epitope or epitopes recognized by the resulting antibody compositions raised against this immunogen will be present as part of a polypeptide or polypeptides of the invention.

[0170]The antibody titer in the immunized subject can be monitored over time by standard techniques, such as with an enzyme linked immunosorbent assay (ELISA) using immobilized polypeptide. If desired, the antibody molecules can be harvested or isolated from the subject (e.g., from the blood or serum of the subject) and further purified by well-known techniques, such as protein A chromatography to obtain the IgG fraction. Alternatively, antibodies specific for a protein or polypeptide of the invention can be selected or (e.g., partially purified) or purified by, e.g., affinity chromatography. For example, a recombinantly expressed and purified (or partially purified) protein of the invention is produced as described herein, and covalently or non-covalently coupled to a solid support such as, for example, a chromatography column. The column can then be used to affinity purify antibodies specific for the proteins of the invention from a sample containing antibodies directed against a large number of different epitopes, thereby generating a substantially purified antibody composition, i.e., one that is substantially free of contaminating antibodies. By a substantially purified antibody composition is meant, in this context, that the antibody sample contains at most only 30% (by dry weight) of contaminating antibodies directed against epitopes other than those of the desired protein or polypeptide of the invention, and preferably at most 20%, yet more preferably at most 10%, and most preferably at most 5% (by dry weight) of the sample is contaminating antibodies. A purified antibody composition means that at least 99% of the antibodies in the composition are directed against the desired protein or polypeptide of the invention.

[0171]At an appropriate time after immunization, e.g., when the specific antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler and Milstein (1975) Nature 256:495-497, the human B cell hybridoma technique (see Kozbor et al., 1983, Immunol. Today 4:72), the EBV-hybridoma technique (see Cole et al., pp. 77-96 In Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., 1985) or trioma techniques. The technology for producing hybridomas is well known (see generally Current Protocols in Immunology, Coligan et al. ed., John Wiley & Sons, New York, 1994). Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the hybridoma culture supernatants for antibodies that bind the polypeptide of interest, e.g., using a standard ELISA assay.

[0172]Alternative to preparing monoclonal antibody-secreting hybridomas, a monoclonal antibody directed against a polypeptide of the invention can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the polypeptide of interest. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurfZAP Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, U.S. Pat. No. 5,223,409; PCT Publication No. WO 92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO 92/20791; PCT Publication No. WO 92/15679; PCT Publication No. WO 93/01288; PCT Publication No. WO 92/01047; PCT Publication No. WO 92/09690; PCT Publication No. WO 90/02809; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum. Antibod. Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffiths et al. (1993) EMBO J. 12:725-734.

[0173]Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are within the scope of the invention. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region. (See, e.g., Cabilly et al., U.S. Pat. No. 4,816,567; and Boss et al., U.S. Pat. No. 4,816,397, which are incorporated herein by reference in their entirety.) Humanized antibodies are antibody molecules from non-human species having one or more complementarily determining regions (CDRs) from the non-human species and a framework region from a human immunoglobulin molecule. (See, e.g., Queen, U.S. Pat. No. 5,585,089, which is incorporated herein by reference in its entirety.) Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in PCT Publication No. WO 87/02671; European Patent Application 184,187; European Patent Application 171,496; European Patent Application 173,494; PCT Publication No. WO 86/01533; U.S. Pat. No. 4,816,567; European Patent Application 125,023; Better et al. (1988) Science 240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al. (1987) J. Immunol. 139:3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al. (1987) Cancer Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; and Shaw et al. (1988) J. Natl. Cancer Inst. 80:1553-1559); Morrison (1985) Science 229:1202-1207; Oi et al. (1986) Bio/Techniques 4:214; U.S. Pat. No. 5,225,539; Jones et al. (1986) Nature 321:552-525; Verhoeyan et al. (1988) Science 239:1534; and Beidler et al. (1988) J. Immunol. 141:4053-4060.

[0174]Antibodies of the invention may be used as therapeutic agents in treating cancers. In a preferred embodiment, completely human antibodies of the invention are used for therapeutic treatment of human cancer patients, particularly those having ovarian cancer. Such antibodies can be produced, for example, using transgenic mice which are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. The transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide corresponding to a marker of the invention. Monoclonal antibodies directed against the antigen can be obtained using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation. Thus, using such a technique, it is possible to produce therapeutically useful IgG, IgA and IgE antibodies. For an overview of this technology for producing human antibodies, see Lonberg and Huszar (1995) Int. Rev. Immunol. 13:65-93). For a detailed discussion of this technology for producing human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., U.S. Pat. No. 5,625,126; U.S. Pat. No. 5,633,425; U.S. Pat. No. 5,569,825; U.S. Pat. No. 5,661,016; and U.S. Pat. No. 5,545,806. In addition, companies such as Abgenix, Inc. (Freemont, Calif.), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.

[0175]Completely human antibodies which recognize a selected epitope can be generated using a technique referred to as "guided selection." In this approach a selected non-human monoclonal antibody, e.g., a murine antibody, is used to guide the selection of a completely human antibody recognizing the same epitope (Jespers et al., 1994, Bio/technology 12:899-903).

[0176]An antibody directed against a polypeptide corresponding to a marker of the invention (e.g., a monoclonal antibody) can be used to isolate the polypeptide by standard techniques, such as affinity chromatography or immunoprecipitation. Moreover, such an antibody can be used to detect the marker (e.g., in a cellular lysate or cell supernatant) in order to evaluate the level and pattern of expression of the marker. The antibodies can also be used diagnostically to monitor protein levels in tissues or body fluids (e.g. in an ovary-associated body fluid) as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹31I, ³⁵S or ³H.

[0177]Further, an antibody (or fragment thereof) can be conjugated to a therapeutic moiety such as a cytotoxin, a therapeutic agent or a radioactive metal ion. A cytotoxin or cytotoxic agent includes any agent that is detrimental to cells. Examples include taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, and puromycin and analogs or homologs thereof. Therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine and vinblastine).

[0178]The conjugates of the invention can be used for modifying a given biological response, the drug moiety is not to be construed as limited to classical chemical therapeutic agents. For example, the drug moiety may be a protein or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such as tumor necrosis factor, α-interferon, β-interferon, nerve growth factor, platelet derived growth factor, tissue plasminogen activator; or, biological response modifiers such as, for example, lymphokines, interleukin-1 ("IL-1"), interleukin-2 ("IL-2"), interleukin-6 ("IL-6"), granulocyte macrophase colony stimulating factor ("GM-CSF"), granulocyte colony stimulating factor ("G-CSF"), or other growth factors.

[0179]Techniques for conjugating such therapeutic moiety to antibodies are well known, see, e.g., Amon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy", in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., "Antibodies For Drug Delivery", in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review", in Monoclonal Antibodies '84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); "Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy", in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., "The Preparation And Cytotoxic Properties Of Antibody-Toxin Conjugates", Immunol. Rev., 62:119-58 (1982).

[0180]Alternatively, an antibody can be conjugated to a second antibody to form an antibody heteroconjugate as described by Segal in U.S. Pat. No. 4,676,980.

[0181]Accordingly, in one aspect, the invention provides substantially purified antibodies or fragments thereof, and non-human antibodies or fragments thereof, which antibodies or fragments specifically bind to a polypeptide comprising an amino acid sequence selected from the group consisting of the amino acid sequences of the present invention, an amino acid sequence encoded by the cDNA of the present invention, a fragment of at least 15 amino acid residues of an amino acid sequence of the present invention, an amino acid sequence which is at least 95% identical to the amino acid sequence of the present invention (wherein the percent identity is determined using the ALIGN program of the GCG software package with a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4) and an amino acid sequence which is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule consisting of the nucleic acid molecules of the present invention, or a complement thereof, under conditions of hybridization of 6×SSC at 45° C. and washing in 0.2×SSC, 0.1% SDS at 65° C. In various embodiments, the substantially purified antibodies of the invention, or fragments thereof, can be human, non-human, chimeric and/or humanized antibodies.

[0182]In another aspect, the invention provides non-human antibodies or fragments thereof, which antibodies or fragments specifically bind to a polypeptide comprising an amino acid sequence selected from the group consisting of: the amino acid sequence of the present invention, an amino acid sequence encoded by the cDNA of the present invention, a fragment of at least 15 amino acid residues of the amino acid sequence of the present invention, an amino acid sequence which is at least 95% identical to the amino acid sequence of the present invention (wherein the percent identity is determined using the ALIGN program of the GCG software package with a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4) and an amino acid sequence which is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule consisting of the nucleic acid molecules of the present invention, or a complement thereof, under conditions of hybridization of 6×SSC at 45° C. and washing in 0.2×SSC, 0.1% SDS at 65° C. Such non-human antibodies can be goat, mouse, sheep, horse, chicken, rabbit, or rat antibodies. Alternatively, the non-human antibodies of the invention can be chimeric and/or humanized antibodies. In addition, the non-human antibodies of the invention can be polyclonal antibodies or monoclonal antibodies.

[0183]In still a further aspect, the invention provides monoclonal antibodies or fragments thereof, which antibodies or fragments specifically bind to a polypeptide comprising an amino acid sequence selected from the group consisting of the amino acid sequences of the present invention, an amino acid sequence encoded by the cDNA of the present invention, a fragment of at least 15 amino acid residues of an amino acid sequence of the present invention, an amino acid sequence which is at least 95% identical to an amino acid sequence of the present invention (wherein the percent identity is determined using the ALIGN program of the GCG software package with a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4) and an amino acid sequence which is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule consisting of the nucleic acid molecules of the present invention, or a complement thereof, under conditions of hybridization of 6×SSC at 45° C. and washing in 0.2×SSC, 0.1% SDS at 65° C. The monoclonal antibodies can be human, humanized, chimeric and/or non-human antibodies.

[0184]The substantially purified antibodies or fragments thereof may specifically bind to a signal peptide, a secreted sequence, an extracellular domain, a transmembrane or a cytoplasmic domain or cytoplasmic membrane of a polypeptide of the invention. In a particularly preferred embodiment, the substantially purified antibodies or fragments thereof, the non-human antibodies or fragments thereof, and/or the monoclonal antibodies or fragments thereof, of the invention specifically bind to a secreted sequence or an extracellular domain of the amino acid sequences of the present invention.

[0185]Any of the antibodies of the invention can be conjugated to a therapeutic moiety or to a detectable substance. Non-limiting examples of detectable substances that can be conjugated to the antibodies of the invention are an enzyme, a prosthetic group, a fluorescent material, a luminescent material, a bioluminescent material, and a radioactive material.

[0186]The invention also provides a kit containing an antibody of the invention conjugated to a detectable substance, and instructions for use. Still another aspect of the invention is a pharmaceutical composition comprising an antibody of the invention and a pharmaceutically acceptable carrier. In preferred embodiments, the pharmaceutical composition contains an antibody of the invention, a therapeutic moiety, and a pharmaceutically acceptable carrier.

[0187]Still another aspect of the invention is a method of making an antibody that specifically recognizes a polypeptide of the present invention, the method comprising immunizing a mammal with a polypeptide. The polypeptide used as an immungen comprises an amino acid sequence selected from the group consisting of the amino acid sequence of the present invention, an amino acid sequence encoded by the cDNA of the nucleic acid molecules of the present invention, a fragment of at least 15 amino acid residues of the amino acid sequence of the present invention, an amino acid sequence which is at least 95% identical to the amino acid sequence of the present invention (wherein the percent identity is determined using the ALIGN program of the GCG software package with a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4) and an amino acid sequence which is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule consisting of the nucleic acid molecules of the present invention, or a complement thereof, under conditions of hybridization of 6×SSC at 45° C. and washing in 0.2×SSC, 0.1% SDS at 65° C.

[0188]After immunization, a sample is collected from the mammal that contains an antibody that specifically recognizes the polypeptide. Preferably, the polypeptide is recombinantly produced using a non-human host cell. Optionally, the antibodies can be further purified from the sample using techniques well known to those of skill in the art. The method can further comprise producing a monoclonal antibody-producing cell from the cells of the mammal. Optionally, antibodies are collected from the antibody-producing cell.

V. Recombinant Expression Vectors and Host Cells

[0189]Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a polypeptide corresponding to a marker of the invention (or a portion of such a polypeptide). As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid", which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors, namely expression vectors, are capable of directing the expression of genes to which they are operably linked. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids (vectors). However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

[0190]The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell. This means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operably linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, "operably linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, Methods in Enzymology: Gene Expression Technology vol. 185, Academic Press, San Diego, Calif. (1991). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in many types of host cell and those which direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, and the like. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein.

[0191]The recombinant expression vectors of the invention can be designed for expression of a polypeptide corresponding to a marker of the invention in prokaryotic (e.g., E. coli) or eukaryotic cells (e.g., insect cells {using baculovirus expression vectors}, yeast cells or mammalian cells). Suitable host cells are discussed further in Goeddel, supra. Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0192]Expression of proteins in prokaryotes is most often carried out in E. coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: 1) to increase expression of recombinant protein; 2) to increase the solubility of the recombinant protein; and 3) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988, Gene 67:31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.

[0193]Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., 1988, Gene 69:301-315) and pET 11d (Studier et al., p. 60-89, In Gene Expression Technology: Methods in Enzymology vol. 185, Academic Press, San Diego, Calif., 1991). Target gene expression from the pTrc vector relies on host RNA polymerase transcription from a hybrid trp-lac fusion promoter. Target gene expression from the pET 11d vector relies on transcription from a T7 gn10-lac fusion promoter mediated by a co-expressed viral RNA polymerase (T7 gn1). This viral polymerase is supplied by host strains BL21(DE3) or HMS174(DE3) from a resident prophage harboring a T7 gn1 gene under the transcriptional control of the lacUV 5 promoter.

[0194]One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein (Gottesman, p. 119-128, In Gene Expression Technology: Methods in Enzymology vol. 185, Academic Press, San Diego, Calif., 1990. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (Wada et al., 1992, Nucleic Acids Res. 20:2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.

[0195]In another embodiment, the expression vector is a yeast expression vector. Examples of vectors for expression in yeast S. cerevisiae include pYepSec1 (Baldari et al., 1987, EMBO J. 6:229-234), pMFa (Kurjan and Herskowitz, 1982, Cell 30:933-943), pJRY88 (Schultz et al., 1987, Gene 54:113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and pPicZ (Invitrogen Corp, San Diego, Calif.).

[0196]Alternatively, the expression vector is a baculovirus expression vector. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., 1983, Mol. Cell Biol. 3:2156-2165) and the pVL series (Lucklow and Summers, 1989, Virology 170:31-39).

[0197]In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987, Nature 329:840) and pMT2PC (Kaufman et al., 1987, EMBO J. 6:187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, Adenovirus 2, cytomegalovirus and Simian Virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see chapters 16 and 17 of Sambrook et al., supra.

[0198]In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert et al., 1987, Genes Dev. 1:268-277), lymphoid-specific promoters (Calame and Eaton, 1988, Adv. Immunol. 43:235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989, EMBO J. 8:729-733) and immunoglobulins (Banerji et al., 1983, Cell 33:729-740; Queen and Baltimore, 1983, Cell 33:741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989, Proc. Natl. Acad. Sci. USA 86:5473-5477), pancreas-specific promoters (Edlund et al., 1985, Science 230:912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, for example the murine hox promoters (Kessel and Gruss, 1990, Science 249:374-379) and the α-fetoprotein promoter (Camper and Tilghman, 1989, Genes Dev. 3:537-546).

[0199]The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operably linked to a regulatory sequence in a manner which allows for expression (by transcription of the DNA molecule) of an RNA molecule which is antisense to the mRNA encoding a polypeptide of the invention. Regulatory sequences operably linked to a nucleic acid cloned in the antisense orientation can be chosen which direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen which direct constitutive, tissue-specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid, or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see Weintraub et al., 1986, Trends in Genetics, Vol. 1(1).

[0200]Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms "host cell" and "recombinant host cell" are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

[0201]A host cell can be any prokaryotic (e.g., E. coli) or eukaryotic cell (e.g., insect cells, yeast or mammalian cells).

[0202]Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (supra), and other laboratory manuals.

[0203]For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Preferred selectable markers include those which confer resistance to drugs, such as G418, hygromycin and methotrexate. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker will survive, while the other cells die).

[0204]A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce a polypeptide corresponding to a marker of the invention. Accordingly, the invention further provides methods for producing a polypeptide corresponding to a marker of the invention using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding a polypeptide of the invention has been introduced) in a suitable medium such that the marker is produced. In another embodiment, the method further comprises isolating the marker polypeptide from the medium or the host cell.

[0205]The host cells of the invention can also be used to produce nonhuman transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which a sequences encoding a polypeptide corresponding to a marker of the invention have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous sequences encoding a marker protein of the invention have been introduced into their genome or homologous recombinant animals in which endogenous gene(s) encoding a polypeptide corresponding to a marker of the invention sequences have been altered. Such animals are useful for studying the function and/or activity of the polypeptide corresponding to the marker and for identifying and/or evaluating modulators of polypeptide activity. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, an "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

[0206]A transgenic animal of the invention can be created by introducing a nucleic acid encoding a polypeptide corresponding to a marker of the invention into the male pronuclei of a fertilized oocyte, e.g., by microinjection, retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of the polypeptide of the invention to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, U.S. Pat. No. 4,873,191 and in Hogan, Manipulating the Mouse Embryo, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of mRNA encoding the transgene in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying the transgene can further be bred to other transgenic animals carrying other transgenes.

[0207]To create an homologous recombinant animal, a vector is prepared which contains at least a portion of a gene encoding a polypeptide corresponding to a marker of the invention into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the gene. In a preferred embodiment, the vector is designed such that, upon homologous recombination, the endogenous gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a "knock out" vector). Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous protein). In the homologous recombination vector, the altered portion of the gene is flanked at its 5' and 3' ends by additional nucleic acid of the gene to allow for homologous recombination to occur between the exogenous gene carried by the vector and an endogenous gene in an embryonic stem cell. The additional flanking nucleic acid sequences are of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5' and 3' ends) are included in the vector (see, e.g., Thomas and Capecchi, 1987, Cell 51:503 for a description of homologous recombination vectors). The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced gene has homologously recombined with the endogenous gene are selected (see, e.g., Li et al., 1992, Cell 69:915). The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras (see, e.g., Bradley, Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, Robertson, Ed., IRL, Oxford, 1987, pp. 113-152). A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley (1991) Current Opinion in Bio/Technology 2:823-829 and in PCT Publication NOS. WO 90/11354, WO 91/01140, WO 92/0968, and WO 93/04169.

[0208]In another embodiment, transgenic non-human animals can be produced which contain selected systems which allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, see, e.g., Lakso et al. (1992) Proc. Natl. Acad. Sci. USA 89:6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae (O'Gorman et al., 1991, Science 251:1351-1355). If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

[0209]Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut et al. (1997) Nature 385:810-813 and PCT Publication NOS. WO 97/07668 and WO 97/07669.

VI. Pharmaceutical Compositions

[0210]The nucleic acid molecules, polypeptides, and antibodies (also referred to herein as "active compounds") corresponding to a marker of the invention can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein the language "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0211]The invention includes methods for preparing pharmaceutical compositions for modulating the expression or activity of a polypeptide or nucleic acid corresponding to a marker of the invention. Such methods comprise formulating a pharmaceutically acceptable carrier with an agent which modulates expression or activity of a polypeptide or nucleic acid corresponding to a marker of the invention. Such compositions can further include additional active agents. Thus, the invention further includes methods for preparing a pharmaceutical composition by formulating a pharmaceutically acceptable carrier with an agent which modulates expression or activity of a polypeptide or nucleic acid corresponding to a marker of the invention and one or more additional active compounds.

[0212]The invention also provides methods (also referred to herein as "screening assays") for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, peptoids, small molecules or other drugs) which (a) bind to the marker, or (b) have a modulatory (e.g., stimulatory or inhibitory) effect on the activity of the marker or, more specifically, (c) have a modulatory effect on the interactions of the marker with one or more of its natural substrates (e.g., peptide, protein, hormone, co-factor, or nucleic acid), or (d) have a modulatory effect on the expression of the marker. Such assays typically comprise a reaction between the marker and one or more assay components. The other components may be either the test compound itself, or a combination of test compound and a natural binding partner of the marker.

[0213]The test compounds of the present invention may be obtained from any available source, including systematic libraries of natural and/or synthetic compounds. Test compounds may also be obtained by any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; peptoid libraries (libraries of molecules having the functionalities of peptides, but with a novel, non-peptide backbone which are resistant to enzymatic degradation but which nevertheless remain bioactive; see, e.g., Zuckermann et al., 1994, J. Med. Chem. 37:2678-85); spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the `one-bead one-compound` library method; and synthetic library methods using affinity chromatography selection. The biological library and peptoid library approaches are limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, 1997, Anticancer Drug Des. 12:145).

[0214]Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA 91:11422; Zuckermann et al. (1994). J. Med. Chem. 37:2678; Cho et al. (1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061; and in Gallop et al. (1994) J. Med. Chem. 37:1233.

[0215]Libraries of compounds may be presented in solution (e.g., Houghten, 1992, Biotechniques 13:412-421), or on beads (Lam, 1991, Nature 354:82-84), chips (Fodor, 1993, Nature 364:555-556), bacteria and/or spores, (Ladner, U.S. Pat. No. 5,223,409), plasmids (Cull et al, 1992, Proc Natl Acad Sci USA 89:1865-1869) or on phage (Scott and Smith, 1990, Science 249:386-390; Devlin, 1990, Science 249:404-406; Cwirla et al, 1990, Proc. Natl. Acad. Sci. 87:6378-6382; Felici, 1991, J. Mol. Biol. 222:301-310; Ladner, supra.).

[0216]In one embodiment, the invention provides assays for screening candidate or test compounds which are substrates of a marker or biologically active portion thereof. In another embodiment, the invention provides assays for screening candidate or test compounds which bind to a marker or biologically active portion thereof. Determining the ability of the test compound to directly bind to a marker can be accomplished, for example, by coupling the compound with a radioisotope or enzymatic label such that binding of the compound to the marker can be determined by detecting the labeled marker compound in a complex. For example, compounds (e.g., marker substrates) can be labeled with ¹²⁵I, ³⁵S, ¹⁴C, or ³H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, assay components can be enzymatically labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product.

[0217]In another embodiment, the invention provides assays for screening candidate or test compounds which modulate the activity of a marker or a biologically active portion thereof. In all likelihood, the marker can, in vivo, interact with one or more molecules, such as but not limited to, peptides, proteins, hormones, cofactors and nucleic acids. For the purposes of this discussion, such cellular and extracellular molecules are referred to herein as "binding partners" or marker "substrate".

[0218]One necessary embodiment of the invention in order to facilitate such screening is the use of the marker to identify its natural in vivo binding partners. There are many ways to accomplish this which are known to one skilled in the art. One example is the use of the marker protein as "bait protein" in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al, 1993, Cell 72:223-232; Madura et al, 1993, J. Biol. Chem. 268:12046-12054; Bartel et al, 1993, Biotechniques 14:920-924; Iwabuchi et al, 1993 Oncogene 8:1693-1696; Brent WO94/10300) in order to identify other proteins which bind to or interact with the marker (binding partners) and, therefore, are possibly involved in the natural function of the marker. Such marker binding partners are also likely to be involved in the propagation of signals by the marker or downstream elements of a marker-mediated signaling pathway. Alternatively, such marker binding partners may also be found to be inhibitors of the marker.

[0219]The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that encodes a marker protein fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein ("prey" or "sample") is fused to a gene that codes for the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact, in vivo, forming a marker-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) which is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be readily detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene which encodes the protein which interacts with the marker protein.

[0220]In a further embodiment, assays may be devised through the use of the invention for the purpose of identifying compounds which modulate (e.g., affect either positively or negatively) interactions between a marker and its substrates and/or binding partners. Such compounds can include, but are not limited to, molecules such as antibodies, peptides, hormones, oligonucleotides, nucleic acids, and analogs thereof. Such compounds may also be obtained from any available source, including systematic libraries of natural and/or synthetic compounds. The preferred assay components for use in this embodiment is an ovarian cancer marker identified herein, the known binding partner and/or substrate of same, and the test compound. Test compounds can be supplied from any source.

[0221]The basic principle of the assay systems used to identify compounds that interfere with the interaction between the marker and its binding partner involves preparing a reaction mixture containing the marker and its binding partner under conditions and for a time sufficient to allow the two products to interact and bind, thus forming a complex. In order to test an agent for inhibitory activity, the reaction mixture is prepared in the presence and absence of the test compound. The test compound can be initially included in the reaction mixture, or can be added at a time subsequent to the addition of the marker and its binding partner. Control reaction mixtures are incubated without the test compound or with a placebo. The formation of any complexes between the marker and its binding partner is then detected. The formation of a complex in the control reaction, but less or no such formation in the reaction mixture containing the test compound, indicates that the compound interferes with the interaction of the marker and its binding partner. Conversely, the formation of more complex in the presence of compound than in the control reaction indicates that the compound may enhance interaction of the marker and its binding partner.

[0222]The assay for compounds that interfere with the interaction of the marker with its binding partner may be conducted in a heterogeneous or homogeneous format. Heterogeneous assays involve anchoring either the marker or its binding partner onto a solid phase and detecting complexes anchored to the solid phase at the end of the reaction. In homogeneous assays, the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the compounds being tested. For example, test compounds that interfere with the interaction between the markers and the binding partners (e.g., by competition) can be identified by conducting the reaction in the presence of the test substance, i.e., by adding the test substance to the reaction mixture prior to or simultaneously with the marker and its interactive binding partner. Alternatively, test compounds that disrupt preformed complexes, e.g., compounds with higher binding constants that displace one of the components from the complex, can be tested by adding the test compound to the reaction mixture after complexes have been formed. The various formats are briefly described below.

[0223]In a heterogeneous assay system, either the marker or its binding partner is anchored onto a solid surface or matrix, while the other corresponding non-anchored component may be labeled, either directly or indirectly. In practice, microtitre plates are often utilized for this approach. The anchored species can be immobilized by a number of methods, either non-covalent or covalent, that are typically well known to one who practices the art. Non-covalent attachment can often be accomplished simply by coating the solid surface with a solution of the marker or its binding partner and drying. Alternatively, an immobilized antibody specific for the assay component to be anchored can be used for this purpose. Such surfaces can often be prepared in advance and stored.

[0224]In related embodiments, a fusion protein can be provided which adds a domain that allows one or both of the assay components to be anchored to a matrix. For example, glutathione-S-transferase/marker fusion proteins or glutathione-S-transferase/binding partner can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtiter plates, which are then combined with the test compound or the test compound and either the non-adsorbed marker or its binding partner, and the mixture incubated under conditions conducive to complex formation (e.g., physiological conditions). Following incubation, the beads or microtiter plate wells are washed to remove any unbound assay components, the immobilized complex assessed either directly or indirectly, for example, as described above. Alternatively, the complexes can be dissociated from the matrix, and the level of marker binding or activity determined using standard techniques.

[0225]Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either a marker or a marker binding partner can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated marker protein or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). In certain embodiments, the protein-immobilized surfaces can be prepared in advance and stored.

[0226]In order to conduct the assay, the corresponding partner of the immobilized assay component is exposed to the coated surface with or without the test compound. After the reaction is complete, unreacted assay components are removed (e.g., by washing) and any complexes formed will remain immobilized on the solid surface. The detection of complexes anchored on the solid surface can be accomplished in a number of ways. Where the non-immobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the non-immobilized component is not pre-labeled, an indirect label can be used to detect complexes anchored on the surface; e.g., using a labeled antibody specific for the initially non-immobilized species (the antibody, in turn, can be directly labeled or indirectly labeled with, e.g., a labeled anti-Ig antibody). Depending upon the order of addition of reaction components, test compounds which modulate (inhibit or enhance) complex formation or which disrupt preformed complexes can be detected.

[0227]In an alternate embodiment of the invention, a homogeneous assay may be used. This is typically a reaction, analogous to those mentioned above, which is conducted in a liquid phase in the presence or absence of the test compound. The formed complexes are then separated from unreacted components, and the amount of complex formed is determined. As mentioned for heterogeneous assay systems, the order of addition of reactants to the liquid phase can yield information about which test compounds modulate (inhibit or enhance) complex formation and which disrupt preformed complexes.

[0228]In such a homogeneous assay, the reaction products may be separated from unreacted assay components by any of a number of standard techniques, including but not limited to: differential centrifugation, chromatography, electrophoresis and immunoprecipitation. In differential centrifugation, complexes of molecules may be separated from uncomplexed molecules through a series of centrifugal steps, due to the different sedimentation equilibria of complexes based on their different sizes and densities (see, for example, Rivas, G., and Minton, A. P., Trends Biochem Sci 1993 August; 18(8):284-7). Standard chromatographic techniques may also be utilized to separate complexed molecules from uncomplexed ones. For example, gel filtration chromatography separates molecules based on size, and through the utilization of an appropriate gel filtration resin in a column format, for example, the relatively larger complex may be separated from the relatively smaller uncomplexed components. Similarly, the relatively different charge properties of the complex as compared to the uncomplexed molecules may be exploited to differentially separate the complex from the remaining individual reactants, for example through the use of ion-exchange chromatography resins. Such resins and chromatographic techniques are well known to one skilled in the art (see, e.g., Heegaard, 1998, J Mol. Recognit. 11: 141-148; Hage and Tweed, 1997, J. Chromatogr. B. Biomed. Sci. Appl., 699:499-525). Gel electrophoresis may also be employed to separate complexed molecules from unbound species (see, e.g., Ausubel et al (eds.), In: Current Protocols in Molecular Biology, J. Wiley & Sons, New York. 1999). In this technique, protein or nucleic acid complexes are separated based on size or charge, for example. In order to maintain the binding interaction during the electrophoretic process, nondenaturing gels in the absence of reducing agent are typically preferred, but conditions appropriate to the particular interactants will be well known to one skilled in the art. Immunoprecipitation is another common technique utilized for the isolation of a protein-protein complex from solution (see, e.g., Ausubel et al (eds.), In: Current Protocols in Molecular Biology, J. Wiley & Sons, New York. 1999). In this technique, all proteins binding to an antibody specific to one of the binding molecules are precipitated from solution by conjugating the antibody to a polymer bead that may be readily collected by centrifugation. The bound assay components are released from the beads (through a specific proteolysis event or other technique well known in the art which will not disturb the protein-protein interaction in the complex), and a second immunoprecipitation step is performed, this time utilizing antibodies specific for the correspondingly different interacting assay component. In this manner, only formed complexes should remain attached to the beads. Variations in complex formation in both the presence and the absence of a test compound can be compared, thus offering information about the ability of the compound to modulate interactions between the marker and its binding partner.

[0229]Also within the scope of the present invention are methods for direct detection of interactions between the marker and its natural binding partner and/or a test compound in a homogeneous or heterogeneous assay system without further sample manipulation. For example, the technique of fluorescence energy transfer may be utilized (see, e.g., Lakowicz et al, U.S. Pat. No. 5,631,169; Stavrianopoulos et al, U.S. Pat. No. 4,868,103). Generally, this technique involves the addition of a fluorophore label on a first `donor` molecule (e.g., marker or test compound) such that its emitted fluorescent energy will be absorbed by a fluorescent label on a second, `acceptor` molecule (e.g., marker or test compound), which in turn is able to fluoresce due to the absorbed energy. Alternately, the `donor` protein molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels are chosen that emit different wavelengths of light, such that the `acceptor` molecule label may be differentiated from that of the `donor`. Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, spatial relationships between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the `acceptor` molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g., using a fluorimeter). A test substance which either enhances or hinders participation of one of the species in the preformed complex will result in the generation of a signal variant to that of background. In this way, test substances that modulate interactions between a marker and its binding partner can be identified in controlled assays.

[0230]In another embodiment, modulators of marker expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of mRNA or protein, corresponding to a marker in the cell, is determined. The level of expression of mRNA or protein in the presence of the candidate compound is compared to the level of expression of mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of marker expression based on this comparison. For example, when expression of marker mRNA or protein is greater (statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of marker mRNA or protein expression. Conversely, when expression of marker mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of marker mRNA or protein expression. The level of marker mRNA or protein expression in the cells can be determined by methods described herein for detecting marker mRNA or protein.

[0231]In another aspect, the invention pertains to a combination of two or more of the assays described herein. For example, a modulating agent can be identified using a cell-based or a cell free assay, and the ability of the agent to modulate the activity of a marker protein can be further confirmed in vivo, e.g., in a whole animal model for cellular transformation and/or tumorigenesis.

[0232]This invention further pertains to novel agents identified by the above-described screening assays. Accordingly, it is within the scope of this invention to further use an agent identified as described herein in an appropriate animal model. For example, an agent identified as described herein (e.g., an marker modulating agent, an antisense marker nucleic acid molecule, an marker-specific antibody, or an marker-binding partner) can be used in an animal model to determine the efficacy, toxicity, or side effects of treatment with such an agent. Alternatively, an agent identified as described herein can be used in an animal model to determine the mechanism of action of such an agent. Furthermore, this invention pertains to uses of novel agents identified by the above-described screening assays for treatments as described herein.

[0233]It is understood that appropriate doses of small molecule agents and protein or polypeptide agents depends upon a number of factors within the knowledge of the ordinarily skilled physician, veterinarian, or researcher. The dose(s) of these agents will vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable, and the effect which the practitioner desires the agent to have upon the nucleic acid or polypeptide of the invention. Exemplary doses of a small molecule include milligram or microgram amounts per kilogram of subject or sample weight (e.g. about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram). Exemplary doses of a protein or polypeptide include gram, milligram or microgram amounts per kilogram of subject or sample weight (e.g. about 1 microgram per kilogram to about 5 grams per kilogram, about 100 micrograms per kilogram to about 500 milligrams per kilogram, or about 1 milligram per kilogram to about 50 milligrams per kilogram). It is furthermore understood that appropriate doses of one of these agents depend upon the potency of the agent with respect to the expression or activity to be modulated. Such appropriate doses can be determined using the assays described herein. When one or more of these agents is to be administered to an animal (e.g. a human) in order to modulate expression or activity of a polypeptide or nucleic acid of the invention, a physician, veterinarian, or researcher can, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. In addition, it is understood that the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific agent employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

[0234]A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamine-tetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.

[0235]Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL (BASF; Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0236]Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a polypeptide or antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium, and then incorporating the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0237]Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.

[0238]Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches, and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0239]For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0240]Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0241]The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0242]In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes having monoclonal antibodies incorporated therein or thereon) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0243]It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0244]For antibodies, the preferred dosage is 0.1 mg/kg to 100 mg/kg of body weight (generally 10 mg/kg to 20 mg/kg). If the antibody is to act in the brain, a dosage of 50 mg/kg to 100 mg/kg is usually appropriate. Generally, partially human antibodies and fully human antibodies have a longer half-life within the human body than other antibodies. Accordingly, lower dosages and less frequent administration is often possible. Modifications such as lipidation can be used to stabilize antibodies and to enhance uptake and tissue penetration (e.g., into the ovarian epithelium). A method for lipidation of antibodies is described by Cruikshank et al. (1997) J. Acquired Immune Deficiency Syndromes and Human Retrovirology 14:193.

[0245]The nucleic acid molecules corresponding to a marker of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (U.S. Pat. No. 5,328,470), or by stereotactic injection (see, e.g., Chen et al., 1994, Proc. Natl. Acad. Sci. USA 91:3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g. retroviral vectors, the pharmaceutical preparation can include one or more cells which produce the gene delivery system.

[0246]The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

VII. Monitoring the Effectiveness of an Anti-Cancer Agent

[0247]As discussed above, the identified sensitivity and resistance markers can also be used as markers to assess whether the ovarian cancer has become refractory to an ongoing treatment (e.g., a chemotherapeutic treatment). When the ovarian cancer is no longer responding to a treatment the expression profile of the ovarian cancer cells will change: the level of expression of one or more of the sensitivity markers will be reduced and/or the level of expression of one or more of the resistance markers will increase.

[0248]In such a use, the invention provides methods for determining whether an anti-cancer treatment should be continued in a cancer patient, comprising the steps of: [0249]a) obtaining two or more samples of ovarian cancer cells from a patient undergoing anti-cancer therapy; [0250]b) determining the expression of the individual markers of a marker set, wherein the marker set is selected from those set forth in Tables 2-15 in the sample exposed to the agent and in a sample of ovarian cancer cells that is not exposed to the agent; and [0251]c) discontinuing or altering treatment when the expression profile of the marker sets identified in Tables 2-15 demonstrates increased resistance or decreased sensitivity to the agent being used.

[0252]As used herein, a patient refers to any subject undergoing treatment for ovarian cancer. In one embodiment, the subject will be a human patient undergoing chemotherapy treatment. This embodiment of the present invention relies on comparing two or more samples obtained from a patient undergoing anti-cancer treatment. In general, it is preferable to obtain a first sample from the patient prior to beginning therapy and one or more samples during treatment. In such a use, a baseline of expression prior to therapy is determined and then changes in the baseline state of expression is monitored during the course of therapy. Alternatively, two or more successive samples obtained during treatment can be used without the need of a pre-treatment baseline sample. In such a use, the first sample obtained from the subject is used as a baseline for determining whether the expression of a particular marker or marker set is increasing or decreasing.

[0253]In general, when monitoring the effectiveness of a therapeutic treatment, two or more samples from the patient are examined. Preferably, three or more successively obtained samples are used, including at least one pretreatment sample.

VIII. Detection Assays

[0254]An exemplary method for detecting the presence or absence of a polypeptide or nucleic acid corresponding to a marker of the invention in a biological sample involves obtaining a biological sample (e.g. an ovarian tumor sample) from a test subject and contacting the biological sample with a compound or an agent capable of detecting the polypeptide or nucleic acid (e.g., mRNA, genomic DNA, or cDNA). The detection methods of the invention can thus be used to detect mRNA, protein, cDNA, or genomic DNA, for example, in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of a polypeptide corresponding to a marker of the invention include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence. In vitro techniques for detection of genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of a polypeptide corresponding to a marker of the invention include introducing into a subject a labeled antibody directed against the polypeptide. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0255]A general principle of such diagnostic and prognostic assays involves preparing a sample or reaction mixture that may contain a marker, and a probe, under appropriate conditions and for a time sufficient to allow the marker and probe to interact and bind, thus forming a complex that can be removed and/or detected in the reaction mixture. These assays can be conducted in a variety of ways.

[0256]For example, one method to conduct such an assay would involve anchoring the marker or probe onto a solid phase support, also referred to as a substrate, and detecting target marker/probe complexes anchored on the solid phase at the end of the reaction. In one embodiment of such a method, a sample from a subject, which is to be assayed for presence and/or concentration of marker, can be anchored onto a carrier or solid phase support. In another embodiment, the reverse situation is possible, in which the probe can be anchored to a solid phase and a sample from a subject can be allowed to react as an unanchored component of the assay.

[0257]There are many established methods for anchoring assay components to a solid phase. These include, without limitation, marker or probe molecules which are immobilized through conjugation of biotin and streptavidin. Such biotinylated assay components can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). In certain embodiments, the surfaces with immobilized assay components can be prepared in advance and stored.

[0258]Other suitable carriers or solid phase supports for such assays include any material capable of binding the class of molecule to which the marker or probe belongs. Well-known supports or carriers include, but are not limited to, glass, polystyrene, nylon, polypropylene, nylon, polyethylene, dextran, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.

[0259]In order to conduct assays with the above mentioned approaches, the non-immobilized component is added to the solid phase upon which the second component is anchored. After the reaction is complete, uncomplexed components may be removed (e.g., by washing) under conditions such that any complexes formed will remain immobilized upon the solid phase. The detection of marker/probe complexes anchored to the solid phase can be accomplished in a number of methods outlined herein.

[0260]In a preferred embodiment, the probe, when it is the unanchored assay component, can be labeled for the purpose of detection and readout of the assay, either directly or indirectly, with detectable labels discussed herein and which are well-known to one skilled in the art.

[0261]It is also possible to directly detect marker/probe complex formation without further manipulation or labeling of either component (marker or probe), for example by utilizing the technique of fluorescence energy transfer (see, for example, Lakowicz et al., U.S. Pat. No. 5,631,169; Stavrianopoulos, et al., U.S. Pat. No. 4,868,103). A fluorophore label on the first, `donor` molecule is selected such that, upon excitation with incident light of appropriate wavelength, its emitted fluorescent energy will be absorbed by a fluorescent label on a second `acceptor` molecule, which in turn is able to fluoresce due to the absorbed energy. Alternately, the `donor` protein molecule may simply utilize the natural fluorescent energy of tryptophan residues. Labels are chosen that emit different wavelengths of light, such that the `acceptor` molecule label may be differentiated from that of the `donor`. Since the efficiency of energy transfer between the labels is related to the distance separating the molecules, spatial relationships between the molecules can be assessed. In a situation in which binding occurs between the molecules, the fluorescent emission of the `acceptor` molecule label in the assay should be maximal. An FET binding event can be conveniently measured through standard fluorometric detection means well known in the art (e.g., using a fluorimeter).

[0262]In another embodiment, determination of the ability of a probe to recognize a marker can be accomplished without labeling either assay component (probe or marker) by utilizing a technology such as real-time Biomolecular Interaction Analysis (BIA) (see, e.g., Sjolander, S, and Urbaniczky, C., 1991, Anal. Chem. 63:2338-2345 and Szabo et al., 1995, Curr. Opin. Struct. Biol. 5:699-705). As used herein, "BIA" or "surface plasmon resonance" is a technology for studying biospecific interactions in real time, without labeling any of the interactants (e.g., BIAcore). Changes in the mass at the binding surface (indicative of a binding event) result in alterations of the refractive index of light near the surface (the optical phenomenon of surface plasmon resonance (SPR)), resulting in a detectable signal which can be used as an indication of real-time reactions between biological molecules.

[0263]Alternatively, in another embodiment, analogous diagnostic and prognostic assays can be conducted with marker and probe as solutes in a liquid phase. In such an assay, the complexed marker and probe are separated from uncomplexed components by any of a number of standard techniques, including but not limited to: differential centrifugation, chromatography, electrophoresis and immunoprecipitation. In differential centrifugation, marker/probe complexes may be separated from uncomplexed assay components through a series of centrifugal steps, due to the different sedimentation equilibria of complexes based on their different sizes and densities (see, for example, Rivas, G., and Minton, A. P., 1993, Trends Biochem Sci. 18(8):284-7). Standard chromatographic techniques may also be utilized to separate complexed molecules from uncomplexed ones. For example, gel filtration chromatography separates molecules based on size, and through the utilization of an appropriate gel filtration resin in a column format, for example, the relatively larger complex may be separated from the relatively smaller uncomplexed components. Similarly, the relatively different charge properties of the marker/probe complex as compared to the uncomplexed components may be exploited to differentiate the complex from uncomplexed components, for example through the utilization of ion-exchange chromatography resins. Such resins and chromatographic techniques are well known to one skilled in the art (see, e.g., Heegaard, N. H., 1998, J. Mol. Recognit. Winter 11(1-6):141-8; Hage, D. S., and Tweed, S. A. J Chromatogr B Biomed Sci Appl 1997 Oct. 10; 699(1-2):499-525). Gel electrophoresis may also be employed to separate complexed assay components from unbound components (see, e.g., Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, New York, 1987-1999). In this technique, protein or nucleic acid complexes are separated based on size or charge, for example. In order to maintain the binding interaction during the electrophoretic process, non-denaturing gel matrix materials and conditions in the absence of reducing agent are typically preferred. Appropriate conditions to the particular assay and components thereof will be well known to one skilled in the art.

[0264]In a particular embodiment, the level of mRNA corresponding to the marker can be determined both by in situ and by in vitro formats in a biological sample using methods known in the art. The term "biological sample" is intended to include tissues, cells, biological fluids and isolates thereof, isolated from a subject, as well as tissues, cells and fluids present within a subject. Many expression detection methods use isolated RNA. For in vitro methods, any RNA isolation technique that does not select against the isolation of mRNA can be utilized for the purification of RNA from ovarian cells (see, e.g., Ausubel et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, New York 1987-1999). Additionally, large numbers of tissue samples can readily be processed using techniques well known to those of skill in the art, such as, for example, the single-step RNA isolation process of Chomczynski (1989, U.S. Pat. No. 4,843,155).

[0265]The isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses and probe arrays. One preferred diagnostic method for the detection of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to the mRNA encoded by the gene being detected. The nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least 7, 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to a mRNA or genomic DNA encoding a marker of the present invention. Other suitable probes for use in the diagnostic assays of the invention are described herein. Hybridization of an mRNA with the probe indicates that the marker in question is being expressed.

[0266]In one format, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative format, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in an Affymetrix gene chip array. A skilled artisan can readily adapt known mRNA detection methods for use in detecting the level of mRNA encoded by the markers of the present invention.

[0267]An alternative method for determining the level of mRNA corresponding to a marker of the present invention in a sample involves the process of nucleic acid amplification, e.g., by rtPCR (the experimental embodiment set forth in Mullis, 1987, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany, 1991, Proc. Natl. Acad. Sci. USA, 88:189-193), self sustained sequence replication (Guatelli et al., 1990, Proc. Natl. Acad. Sci. USA 87:1874-1878), transcriptional amplification system (Kwoh et al., 1989, Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-Beta Replicase (Lizardi et al., 1988, Bio/Technology 6:1197), rolling circle replication (Lizardi et al., U.S. Pat. No. 5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. As used herein, amplification primers are defined as being a pair of nucleic acid molecules that can anneal to 5' or 3' regions of a gene (plus and minus strands, respectively, or vice-versa) and contain a short region in between. In general, amplification primers are from about 10 to 30 nucleotides in length and flank a region from about 50 to 200 nucleotides in length. Under appropriate conditions and with appropriate reagents, such primers permit the amplification of a nucleic acid molecule comprising the nucleotide sequence flanked by the primers.

[0268]For in situ methods, mRNA does not need to be isolated from the ovarian cells prior to detection. In such methods, a cell or tissue sample is prepared/processed using known histological methods. The sample is then immobilized on a support, typically a glass slide, and then contacted with a probe that can hybridize to mRNA that encodes the marker.

[0269]As an alternative to making determinations based on the absolute expression level of the marker, determinations may be based on the normalized expression level of the marker. Expression levels are normalized by correcting the absolute expression level of a marker by comparing its expression to the expression of a gene that is not a marker, e.g., a housekeeping gene that is constitutively expressed. Suitable genes for normalization include housekeeping genes such as the actin gene, or epithelial cell-specific genes. This normalization allows the comparison of the expression level in one sample, e.g., a patient sample, to another sample, e.g., a non-ovarian cancer sample, or between samples from different sources.

[0270]Alternatively, the expression level can be provided as a relative expression level. To determine a relative expression level of a marker, the level of expression of the marker is determined for 10 or more samples of normal versus cancer cell isolates, preferably 50 or more samples, prior to the determination of the expression level for the sample in question. The mean expression level of each of the markers and marker sets assayed in the larger number of samples is determined and this is used as a baseline expression level for the marker. The expression level of the marker determined for the test sample (absolute level of expression) is then divided by the mean expression value obtained for that marker. This provides a relative expression level.

[0271]In another embodiment of the present invention, a polypeptide corresponding to a marker is detected. A preferred agent for detecting a polypeptide of the invention is an antibody capable of binding to a polypeptide corresponding to a marker of the invention, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab')₂) can be used. The term "labeled", with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin.

[0272]A variety of formats can be employed to determine whether a sample contains a protein that binds to a given antibody. Examples of such formats include, but are not limited to, enzyme immunoassay (EIA), radioimmunoassay (RIA), Western blot analysis and enzyme linked immunoabsorbant assay (ELISA). A skilled artisan can readily adapt known protein/antibody detection methods for use in determining whether ovarian cells express a marker of the present invention.

[0273]In one format, antibodies, or antibody fragments, can be used in methods such as Western blots or immunofluorescence techniques to detect the expressed proteins. In such uses, it is generally preferable to immobilize either the antibody or proteins on a solid support. Suitable solid phase supports or carriers include any support capable of binding an antigen or an antibody. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite.

[0274]One skilled in the art will know many other suitable carriers for binding antibody or antigen, and will be able to adapt such support for use with the present invention. For example, protein isolated from ovarian cells can be run on a polyacrylamide gel electrophoresis and immobilized onto a solid phase support such as nitrocellulose. The support can then be washed with suitable buffers followed by treatment with the detectably labeled antibody. The solid phase support can then be washed with the buffer a second time to remove unbound antibody. The amount of bound label on the solid support can then be detected by conventional means.

[0275]The invention also encompasses kits for detecting the presence of a polypeptide or nucleic acid corresponding to a marker of the invention in a biological sample (e.g. an ovary-associated body fluid such as a urine sample). Such kits can be used to determine if a subject is suffering from or is at increased risk of developing ovarian cancer. For example, the kit can comprise a labeled compound or agent capable of detecting a polypeptide or an mRNA encoding a polypeptide corresponding to a marker of the invention in a biological sample and means for determining the amount of the polypeptide or mRNA in the sample (e.g., an antibody which binds the polypeptide or an oligonucleotide probe which binds to DNA or mRNA encoding the polypeptide). Kits can also include instructions for interpreting the results obtained using the kit.

[0276]For antibody-based kits, the kit can comprise, for example: (1) a first antibody (e.g., attached to a solid support) which binds to a polypeptide corresponding to a marker of the invention; and, optionally, (2) a second, different antibody which binds to either the polypeptide or the first antibody and is conjugated to a detectable label.

[0277]For oligonucleotide-based kits, the kit can comprise, for example: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a polypeptide corresponding to a marker of the invention or (2) a pair of primers useful for amplifying a nucleic acid molecule corresponding to a marker of the invention. The kit can also comprise, e.g., a buffering agent, a preservative, or a protein stabilizing agent. The kit can further comprise components necessary for detecting the detectable label (e.g., an enzyme or a substrate). The kit can also contain a control sample or a series of control samples which can be assayed and compared to the test sample. Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit.

IX. Electronic Apparatus Readable Media and Arrays

[0278]Electronic apparatus readable media comprising a marker of the present invention is also provided. As used herein, "electronic apparatus readable media" refers to any suitable medium for storing, holding or containing data or information that can be read and accessed directly by an electronic apparatus. Such media can include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage medium, and magnetic tape; optical storage media such as compact disc; electronic storage media such as RAM, ROM, EPROM, EEPROM and the like; general hard disks and hybrids of these categories such as magnetic/optical storage media. The medium is adapted or configured for having recorded thereon a marker of the present invention.

[0279]As used herein, the term "electronic apparatus" is intended to include any suitable computing or processing apparatus or other device configured or adapted for storing data or information. Examples of electronic apparatus suitable for use with the present invention include stand-alone computing apparatus; networks, including a local area network (LAN), a wide area network (WAN) Internet, Intranet, and Extranet; electronic appliances such as a personal digital assistants (PDAs), cellular phone, pager and the like; and local and distributed processing systems.

[0280]As used herein, "recorded" refers to a process for storing or encoding information on the electronic apparatus readable medium. Those skilled in the art can readily adopt any of the presently known methods for recording information on known media to generate manufactures comprising the markers of the present invention.

[0281]A variety of software programs and formats can be used to store the marker information of the present invention on the electronic apparatus readable medium. For example, the nucleic acid sequence corresponding to the markers or marker sets can be represented in a word processing text file, formatted in commercially-available software such as WordPerfect and MicroSoft Word, or represented in the form of an ASCII file, stored in a database application, such as DB2, Sybase, Oracle, or the like, as well as in other forms. Any number of dataprocessor structuring formats (e.g., text file or database) may be employed in order to obtain or create a medium having recorded thereon the markers and marker sets of the present invention.

[0282]By providing the markers and marker sets of the invention in readable form, one can routinely access the marker sequence information for a variety of purposes. For example, one skilled in the art can use the nucleotide or amino acid sequences of the present invention in readable form to compare a target sequence or target structural motif with the sequence information stored within the data storage means. Search means are used to identify fragments or regions of the sequences of the invention which match a particular target sequence or target motif.

[0283]The invention also includes an array comprising a marker or marker set of the present invention. The array can be used to assay expression of one or more markers or marker sets in the array. In one embodiment, the array can be used to assay marker or marker set expression in a tissue to ascertain tissue specificity of markers in the array. In this manner, up to about 36,000 markers can be simultaneously assayed for expression. This allows a profile to be developed showing a battery of markers specifically expressed in one or more tissues.

[0284]In addition to such qualitative determination, the invention allows the quantitation of marker expression. Thus, not only tissue specificity, but also the level of expression of a battery of markers in the tissue is ascertainable. Thus, markers can be grouped on the basis of their tissue expression per se and level of expression in that tissue. This is useful, for example, in ascertaining the relationship of marker expression between or among tissues. Thus, one tissue can be perturbed and the effect on marker expression in a second tissue can be determined. In this context, the effect of one cell type on another cell type in response to a biological stimulus can be determined. Such a determination is useful, for example, to know the effect of cell-cell interaction at the level of marker expression. If an agent is administered therapeutically to treat one cell type but has an undesirable effect on another cell type, the invention provides an assay to determine the molecular basis of the undesirable effect and thus provides the opportunity to co-administer a counteracting agent or otherwise treat the undesired effect. Similarly, even within a single cell type, undesirable biological effects can be determined at the molecular level. Thus, the effects of an agent on expression of other than the target marker can be ascertained and counteracted.

[0285]In another embodiment, the array can be used to monitor the time course of expression of one or more markers in the array.

[0286]The array is also useful for ascertaining the effect of the expression of a marker on the expression of other markers in the same cell or in different cells. This provides, for example, for a selection of alternate molecular targets for therapeutic intervention if the ultimate or downstream target cannot be regulated.

[0287]The array is also useful for ascertaining differential expression patterns of one or more markers in normal and abnormal cells. This provides a battery of markers that could serve as a molecular target for diagnosis or therapeutic intervention.

SPECIFIC EXAMPLES

A. Therapeutic Agents

[0288]The markers of the present invention are shown to be sensitive or resistant to TAXOL. TAXOL is a chemical compound within a family of taxane compounds which are art-recognized as being a family of related compounds. The language "taxane compound" is intended to include TAXOL, compounds which are structurally similar to TAXOL and/or analogs of TAXOL. The language "taxane compound" can also include "mimics". "Mimics" is intended to include compounds which may not be structurally similar to TAXOL but mimic the therapeutic activity of TAXOL or structurally similar taxane compounds in vivo. The taxane compounds of this invention are those compounds which are useful for inhibiting ovarian cancer growth, including ovarian tumor growth in subjects (patients). The term taxane compound also is intended to include pharmaceutically acceptable salts of the compounds. Taxane compounds have previously been described in U.S. Pat. Nos. 5,641,803, 5,665,671, 5,380,751, 5,728,687, 5,415,869, 5,407,683, 5,399,363, 5,424,073, 5,157,049, 5,773,464, 5,821,263, 5,840,929, 4,814,470, 5,438,072, 5,403,858, 4,960,790, 5,433,364, 4,942,184, 5,362,831, 5,705,503, and 5,278,324, all of which are expressly incorporated by reference.

[0289]The structure of TAXOL, shown below, offers many groups capable of being synthetically functionalized to alter the physical or pharmaceutical properties of TAXOL.

##STR00001##

[0290]For example, a well known semi-synthetic analog of TAXOL, named Taxotere (docetaxel), has also been found to have good anti-tumor activity in animal models. Taxotere has t-butoxy amide at the 3' position and a hydroxyl group at the C10 position (U.S. Pat. No. 5,840,929).

[0291]Other examples of TAXOL derivatives include those mentioned in U.S. Pat. No. 5,840,929 which are directed to derivatives of TAXOL having the formula:

##STR00002##

[0292]wherein R¹ is hydroxy, --OC(O)R^x, or --OC(O)OR^x; R² is hydrogen, hydroxy, --OC(O)R^x, or --OC(O)OR^x; R²' is hydrogen, hydroxy, or fluoro; R⁶' is hydrogen or hydroxy or R²' and R⁶' can together form an oxirane ring; R³ is hydrogen, C_1-6 alkyloxy, hydroxy, --OC(O)R^x, --OC(O)OR^x, --OCONR⁷R¹¹; R⁸ is methyl or R⁸ and R² together can form a cyclopropane ring; R⁶ is hydrogen or R⁶ and R² can together form a bond; R⁹ is hydroxy or --OC(O)R^x; R⁷ and R¹¹ are independently C_1-6 alkyl, hydrogen, aryl, or substituted aryl; R⁴ and R⁵ are independently C_1-6 alkyl, C_2-6 alkenyl, C_2-6 alkynyl, or -Z-R¹⁰; Z is a direct bond, C_1-6 alkyl, or C_2-6 alkenyl; R¹⁰ is aryl, substituted aryl, C_3-6 cycloalkyl, C_2-6 alkenyl, C_1-6 alkyl, all can be optionally substituted with one to six same or different halogen atoms or hydroxy; R^x is a radical of the formula:

##STR00003##

wherein D is a bond or C_1-6 alkyl; and R^a, R^b and R^c are independently hydrogen, amino, C_1-6 alkyl or C_1-6 alkoxy.Further examples of R^x include methyl, hydroxymethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, chloromethyl, 2,2,2-trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, 2-propenyl, phenyl, benzyl, bromophenyl, 4-aminophenyl, 4-methylaminophenyl, 4-methylphenyl, 4-methoxyphenyl and the like. Examples of R⁴ and R⁵ include 2-propenyl, isobutenyl, 3-furanyl (3-furyl), 3-thienyl, phenyl, naphthyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, ethenyl, 2-propenyl, 2-propynyl, benzyl, phenethyl, phenylethenyl, 3,4-dimethoxyphenyl, 2-furanyl (2-furyl), 2-thienyl, 2-(2-furanyl)ethenyl, 2-methylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl and the like.

[0293]TAXOL derivatives can be readily made by following the well established paclitaxel chemistry. For example, C2, C6, C7, C10, and/or C8 position can be derivatized by essentially following the published procedure, into a compound in which R³, R¹, R², R²', R⁹, R⁶' and R⁶ have the meanings defined earlier. Subsequently, C4-acetyloxy group can be converted to the methoxy group by a sequence of steps. For example, for converting C2-benzoyloxy to other groups see, S. H. Chen et al, Bioorganic and Medicinal Chemistry Letters, Vol. 4, No. 3, pp 479-482 (1994); for modifying C10-acetyloxy see, J. Kant et al, Tetrahedron Letters, Vol. 35, No. 31, pp 5543-5546 (1994) and U.S. Pat. No. 5,294,637 issued Mar. 15, 1994; for making C10 and/or C7 unsubstituted (deoxy) derivatives see, European Patent Application 590 267A2 published Apr. 6, 1994 and PCT application WO 93/06093 published Apr. 1, 1993; for making 7β,8β-methano, 6,7-α,α-dihydroxy and 6,7-olefinic groups see, R. A. Johnson, Tetrahedron Letters, Vol. 35, No 43, pp 7893-7896 (1994), U.S. Pat. No. 5,254,580, issued Oct. 19, 1993, and European Patent Application 600 517A1 published Jun. 8, 1994; for making C7/C6 oxirane see, U.S. Pat. No. 5,395,850 issued Mar. 7, 1995; for making C7-epi-fluoro see, G. Roth et al, Tetrahedron Letters, Vol 36, pp 1609-1612 (1993); for forming C7 esters and carbonates see, U.S. Pat. No. 5,272,171 issued Dec. 21, 1993 and S. H. Chen et al., Tetrahedron, 49, No. 14, pp 2805-2828 (1993).

[0294]In U.S. Pat. No. 5,773,464, TAXOL derivatives containing epoxides at the C₁₀ position are disclosed as antitumor agents. Other C-10 taxane analogs have also appeared in the literature. Taxanes with alkyl substituents at C-10 have been reported in a published PCT patent application WO 9533740. The synthesis of C-10 epi hydroxy or acyloxy compounds is disclosed in PCT application WO 96/03394. Additional C-10 analogs have been reported in Tetrahedron Letters 1995, 36(12), 1985-1988; J. Org. Chem. 1994, 59, 4015-4018 and references therein; K. V. Rao et. al. Journal of Medicinal Chemistry 1995, 38 (17), 3411-3414; J. Kant et. al. Tetrahedron Lett. 1994, 35(31), 5543-5546; WO 9533736; WO 93/02067; U.S. Pat. No. 5,248,796; WO 9415929; and WO 94/15599.

[0295]Other relevant TAXOL derivatives include the sulfenamide taxane derivatives described in U.S. Pat. No. 5,821,263. These compounds are characterized by the C3' nitrogen bearing one or two sulfur substituents. These compounds have been useful in the treatment of cancers such as ovarian, breast, lung, gastric, colon, head, neck, melanoma, and leukemia.

[0296]U.S. Pat. No. 4,814,470 discusses TAXOL derivatives with hydroxyl or acetyl group at the C10 position and hydroxy or t-butylcarbonyl at C2' and C3' positions.

[0297]U.S. Pat. No. 5,438,072 discusses TAXOL derivatives with hydroxyl or acetate groups at the C10 position and a C2' substitutent of either t-butylcarbonyl or benzoylamino.

[0298]U.S. Pat. No. 4,960,790 discusses derivatives of TAXOL which have, at the C2' and/or C7 position a hydrogen, or the residue of an amino acid selected from the group consisting of alanine, leucine, isoleucine, saline, phenylalanine, proline, lysine, and arginine, or a group of the formula:

##STR00004##

[0299]wherein n is an integer of 1 to 3 and R² and R³ are each hydrogen on an alkyl radical having one to three carbon atoms or wherein R² and R³ together with the nitrogen atom to which they are attached form a saturated heterocyclic ring having four to five carbon atoms, with the proviso that at least one of the substituents are not hydrogen.

[0300]Other similar water soluble TAXOL derivatives are discussed in U.S. Pat. No. 4,942,184, U.S. Pat. No. 5,433,364, and in U.S. Pat. No. 5,278,324.

[0301]Many TAXOL derivatives may also include protecting groups such as, for example, hydroxy protecting groups. "Hydroxy protecting groups" include, but are not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, dialkylsilylethers, such as dimethylsilyl ether, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates such as methyl, ethyl, 2,2,2-trichloroethyl, allyl, benzyl, and p-nitrophenyl. Additional examples of hydroxy protecting groups may be found in standard reference works such as Greene and Wuts, Protective Groups in Organic Synthesis, 2d Ed., 1991, John Wiley & Sons, and McOmie; and Protective Groups in Organic Chemistry, 1975, Plenum Press. Methods for introducing and removing protecting groups are also found in such textbooks.

[0302]The markers and marker sets of the present invention are also shown to be sensitive to cis-Diamminedichloroplatinum (II), otherwise known as cisplatin. Cisplatin is a chemical compound within a family of platinum coordination complexes which are art-recognized as being a family of related compounds. Cisplatin was the first platinum compound shown to have anti-malignant properties. The language "platinum compounds" is intended to include cisplatin, compounds which are structurally similar to cisplatin, as well as analogs and derivatives of cisplatin. The language "platinum compounds" can also include "mimics." "Mimics" is intended to include compounds which may not be structurally similar to cisplatin but mimic the therapeutic activity of cisplatin or structurally related compounds in vivo.

[0303]The platinum compounds of this invention are those compounds which are useful for inhibiting ovarian cancer growth in subjects (patients). More than 1000 platinum-containing compounds have been synthesized and tested for therapeutic properties. One of these, carboplatin, has been approved for treatment of ovarian cancer. Both cisplatin and carboplatin are amenable to intravenous delivery. However, compounds of the invention can be formulated for therapeutic delivery by any number of strategies. The term platinum compounds also is intended to include pharmaceutically acceptable salts and related compounds. Platinum compounds have previously been described in U.S. Pat. Nos. 6,001,817, 5,945,122, 5,942,389, 5,922,689, 5,902,610, 5,866,617, 5,849,790, 5,824,346, 5,616,613, and 5,578,571, all of which are expressly incorporated by reference.

[0304]Cisplatin and related compounds are thought to enter cells through diffusion, whereupon the molecule likely undergoes metabolic processing to yield the active metabolite of the drug, which then reacts with nucleic acids and proteins. Cisplatin has biochemical properties similar to that of bifunctional alkylating agents, producing interstrand, intrastrand, and monofunctional adduct cross-linking with DNA.

B. Sensitivity Assays and Identification of Therapeutic and Drug Screening Targets

[0305]A sample of cancerous cells with unknown sensitivity to a given therapeutic agent is obtained from a patient. An expression level is measured in the sample for a marker corresponding to one of the markers identified in Table 1. In a preferred embodiment, the expression level for a set of markers (e.g., the marker sets of Tables 2-15) is determined (also referred to herein as the "expression profile"). An evaluation of the expression level is then made employing the methods described herein. Based on the outcome of this evaluation, it is possible to determine which therapeutic agent, or combination of agents, to use as the appropriate treatment.

[0306]A therapeutic agent may be identified as appropriate to treat the ovarian cancer when the outcome of the evaluation demonstrates decreased resistance or increased sensitivity in the presence of the agent. The invention further comprises identifying that a therapeutic agent may be identified as not being appropriate to treat the ovarian cancer when the outcome of the evaluation demonstrates increased resistance or decreased sensitivity in the presence of the agent.

[0307]By examining the expression of one or more of the identified markers or marker sets in a sample of ovarian cancer cells taken from a patient during the course of therapeutic treatment, it is also possible to determine whether the therapeutic agent is continuing to work or whether the ovarian cancer has become resistant (refractory) to the treatment protocol. For example, an ovarian cancer patient receiving a treatment of TAXOL would have ovarian cancer cells removed and monitored for the expression of a marker or marker set. If the expression profile of one or more marker sets identified in Tables 2-15 demonstrates decreased resistance or increased sensitivity in the presence of the agent, the treatment with TAXOL would continue. However, if the expression profile of one or more marker sets identified in Tables 2-15 demonstrates increased resistance or decreased sensitivity in the presence of the agent, then the ovarian cancer may have become resistant to TAXOL and another chemotherapy protocol should be initiated to treat the patient.

[0308]Importantly, these determinations can be made on a patient by patient basis or on an agent by agent (or combinations of agents). Thus, one can determine whether or not a particular therapeutic treatment is likely to benefit a particular patient or group/class of patients, or whether a particular treatment should be continued.

[0309]The identified markers and marker sets further provide previously unknown or unrecognized targets for the development of anti-cancer agents, such as chemotherapeutic compounds, and can be used as targets in developing single agent treatment as well as combinations of agents for the treatment of ovarian cancer.

C. Identification of Sensitivity and Resistant Markers

[0310]Tumors from 79 ovarian cancer patients were used in this study. In particular, RNA was isolated from ovarian tumors using a Qiagen RNeasy kit according to the manufacturers directions. Probes for transcriptional profiling were generated by reverse transcribing the RNA into cDNA with Superscript II Reverse transcriptase, done in the presence of 33P-dCTP. Transcriptional profiling was then performed using the radio labeled cDNA probe by hybridizing the probe to nylon filter arrays on which were spotted >36,000 target cDNAs. Hybridization of the specific cDNA probes to the target cDNAs was done for 18 hours at 65° C. in the presence of Cot1 and Salmon sperm DNA to block non-specific binding. The filters were then washed once with 4% SDS-- low stringency wash buffer and twice with 1% SDS-- high stringency wash buffer. After drying the filters they were placed on a Fuji phosphoimager screen for 48 hours. The image was then read on a Fuji phosphoimager, the intensity of the cDNA probe bound to target cDNA digitized using Grid Guru and AIMZOO software packages.

[0311]The response of the 79 ovarian cancer patients was determined by analyzing clinical oncologist reports. 21 month outcome was used to define those patients that had no evidence of disease (NED) for the 21 months following disease identification. NED was determined by either a second-look surgery or by increasing levels of the serum marker, CA125 (see, supra).

[0312]Candidate markers that are likely to predict the outcome of ovarian cancer patients to a combined TAXOL/cisplatin therapy were selected by using a combination of predictive algorithms. Statistical algorithms were then used to identify the markers of the present invention.

D. Data Analysis

[0313]A data set was comprised of 51 discovery samples, classified as sensitive (N_S=25) or resistant (N_R=26), based on the time to recurrence of cancer or a tumor growth off of 21 months, and 28 validation samples (N_S=7, N_R=21). For each sample, 30,512 transcripts (image clones) were profiled on 5 nylon arrays.

Initial Clone Filtering. For duplicate hybridizations, expression values for all markers on an array were normalized to a median value of I and then averaged. Three filtering steps were applied to the initial 30,512 clones. First, the frequency filter was applied to the clones, wherein none of the 51 samples had an intensity value of greater than one. Second, the clones with annotation suggested the presence of Alu repeats. Third, clones that were not printed on the array were removed from analysis. This process resulted in an analytic set of 18,539 clones.Model Selection. Determining which combination of clone(s) and clinical phenotypes best classify samples into sensitive and resistant groups are referred to as a "model." This section describes the process of how the models of the present invention were identified.

[0314]1. Multiple Random Sampling Method

[0315]A 70% training fraction was obtained from the 51 discovery samples using block randomized sampling with blocking on outcome and several covariates of interest including debulking status, histology, and stage of tumor for the 18,539 clones.

[0316]Using this training fraction, signal-to-noise ratio ("SNR") values [absolute(μ_S-μ_R)/(σ_S+σ_R), where μ and σ represent the mean and standard deviation of expression for each class S (sensitive) and R (resistant)] were calculated for each clone. Feature selection and classification were carried out using the top 500 SNR clones which resulted in a best model for this training fraction. The random sampling method was repeated 100 times resulting in, possibly, 100 different best models.

[0317]2. Feature Selection

[0318]Feature selection is the process of grouping a combination of individual markers into a marker set. The feature selection process involves determining the best combination of individual markers, that form a marker set, in order to classify patients into sensitive and resistant groups. Four different feature selection methods were considered for determining the best classifier for each of the 100 patient fractions: 1) Stepwise linear discriminant analysis; 2) Signal-to-noise; 3) Fisher score; and 4) Support Vector Feature selection. In preferred embodiments, Support Vector Feature selection was used as the feature selection method.

[0319]3. Classifiers

[0320]Various algorithms are currently available that can be used to classify patient samples into prior defined groups using the models discovered through the feature selection process described above. Therefore, the combination of markers selected through the feature selection process may be used in one of the following classifying algorithms in order to derive a prediction equation as to whether the patient sample is sensitive or resistant. The classifiers used in the present invention were: 1) K-nearest neighbors ("KNN"); 2) Linear Discriminant Analysis ("LDA"); 3) Weighted Voting Scheme ("WTV"); and 4) Support Vector Machines ("SVM"). In preferred embodiments, Support Vector Feature selection was used as the classifier.

[0321]Each classifier can have several user selected parameters. The classifier KNN was performed by averaging the 5 closest gene neighbors using Euclidean distance to define closeness. A Standard linear discriminant analysis was performed using proportional priors and estimating a quadratic discriminant function. A weighted voting scheme was implemented as described by Golub et al., "Molecular Classification of Cancer: Class discovery and class prediction by marker expression monitoring." Science, 286:531-537 (1999), the contents of which are incorporated herein by reference. A support vector machine was also used for classification using a 2^nd order polynomial kernal function. A detailed description of the support vector machine classifier may be found in the following references, Hastie et al., "The Elements of Statistical Learning Data Mining, Inference and Prediction." Springer-Verlag, New York, (2001) and Ramaswamy et al., "Multiclass cancer diagnosis using tumor marker expression signatures." PNAS (USA) 98(26):15149-15154 (2001), the contents of which are incorporated herein by reference.

[0322]4. Classification Error

[0323]To determine the ability of a model to predict sensitivity or resistance in an independent group of tumors, all of the models were refit using 51 discovery samples. Classification error rates and the proportion of incorrect predictions were estimated for each model using the 28 validation samples. The best models were defined as those with the fewest classification errors.

Model Performance. To determine if the most highly predictive models could be obtained by chance alone, a permutation test was performed. The labels were permuted on the 51 discovery samples 10 times and performed the entire marker selection procedure resulting in 1,000 random models. The overall error rate for the 1,000 permuted models was 50%, compared to 44% for the observed labels using the SVM models. The best two models generated from the training data lay outside the 99% confidence interval for the best model from the permuted data, suggesting that it is unlikely that those models could be identified by chance alone.

[0324]It will be appreciated that additional marker sets may thus be obtained by employing the methods described herein for identifying models.

E. Specific Application of Class Prediction

[0325]1. Linear Discriminant Analysis

[0326]The Support Vector Machines feature selection and classification were used to select the individual markers of Table 2. The following algorithms were then used to determine the classification error rate and class prediction, i.e., to determine the group, either sensitive or resistant, to which a sample may be classified. Classification error rates and the proportion of incorrect predictions were estimated for each marker set using 28 validation samples. The following example details the process that was used on each of the 28 validation samples.

[0327]The criterion used for predicting the specific group to which a patient is classified, is given by the following formula:

c = 1 2 ( x _ R - x _ S ) S - 1 ' ( x _ R + x _ S ) ##EQU00001##

where X_R, X_S are the vector of means for the markers in the marker set for each group (resistant and sensitive, respectively) and S is the pooled covariance matrix of predictors.

[0328]Using the 51 discovery samples, the following coefficients were obtained from estimating the linear discriminant analysis model for each of the 14 markers of Table 2:

β=[β₁=-3.70, β₂=0.90, β₃=-0.71 β₄=-0.25, β₅=0.49, β₆=-0.84, β₇=0.31, β₈=0.76, β₉=-0.52, β₁₀=0.40, β₁₁=4.04 β₁₂=0.43 β₁₃=-0.25 β₁₄=-0.14],

wherein β₁-β₁₄ represents parameter estimates for markers 1-14 of Table 2, respectively.

[0329]By assessing the following patient validation sample, the following expression values were attained:

Z=[z₁=1.57, z₂=1.93, z₃=0.96, z₄=3.32, z₅=0.70, z₆=3.68, z₇=5.10, z₈=5.48, z₉=1.34, z₁₀=2.33, z₁₁=1.91, z₁₂=4.29, z₁₃=5.33, z₁₄=2.97],

wherein z₁-z₁₄ represent the expression of the markers 1-14 of Table 2 in the patient validation sample.

[0330]By using the equation, βz'≧c, it is possible to predict whether a patient is resistant or sensitive. The value for c from the model using the patient samples is -4.33. Therefore,

i = 1 14 β i z i = - 3.21 ##EQU00002##

The resulting expression profile of the patient validation sample shown above is -3.21, which is greater than c=-4.33. Therefore, the patient sample at issue is predicted to be resistant based on the expression profile.

[0331]It will be appreciated that similar methods may be employed utilizing the marker sets of the present invention.

[0332]2. Weighted Voting

[0333]For weighted voting, the criterion was developed from a weighted voting scheme using the following:

V j = ( x _ R - x _ S ) S S + S R [ z j - ( x _ R + x _ S 2 ) j ] ##EQU00003##

where z_j represents the expression value for the j^th marker for in the LDA example above and S represents the standard deviation for the class indicated by the subscript. The first term in the equation is signal-to-noise ratio while the second term is called the decision boundary. A positive value of V_j is a vote for being a resistant sample, while a negative value is a vote for being sensitive value. The majority vote provides the class prediction.

[0334]For the above patient, 9/14 votes were for resistant therefore by WTV, this patient would be predicted to be resistant. A summary of the calculations are provided in the following table.

TABLE-US-00002 Decision SNR Boundry V_j Vote -0.67 0.86 -0.32 S 0.53 1.03 0.48 R -0.41 1.17 -0.48 S -0.52 1.71 -0.10 S 0.45 1.22 1.39 R 0.28 1.33 1.14 R 0.37 1.35 0.60 R 0.49 0.63 0.16 R -0.47 1.79 0.10 R 0.34 1.40 0.66 R 0.24 0.76 -0.01 S 0.37 1.18 0.92 R 0.30 1.47 1.10 R -0.36 2.23 -1.17 S

[0335]It will be appreciated that similar methods may be employed utilizing the marker sets of the present invention.

[0336]3. K-Nearest Neighbors

[0337]For the K nearest neighbors, prediction of how "close" the sample to be predicted is to its K nearest neighbors. K=5 was selected for the analyses and Euclidean distance as the measure of "distance" given by

d i = j = 1 14 ( x ij - z j ) 2 ##EQU00004##

and i is the i^th sample in the training set. Thus for prediction, one needs the expression values for all training samples for the 14 markers. These are provided below after log transformation along with identifiers for the samples contained in the training set, class designation, and d_i for each training sample using log transformed values of Z from above.

TABLE-US-00003 Sample ID x_i1 x_i2 x_i3 x_i4 x_i5 x_i6 x_i7 x_i8 x_i9 x_i10 x_i11 x_i12 x_i13 x_i14 d_i Class 1 1.89 0.93 0.41 0.88 0.70 1.15 1.57 2.31 1.29 0.86 2.36 1.10 1.88 1.67 2.03 S 2 1.61 1.24 0.81 1.80 0.83 1.10 1.94 2.80 1.07 0.75 1.72 1.64 2.02 1.11 1.60 S 3 1.68 1.36 0.54 1.28 0.99 1.29 1.66 2.17 0.58 0.96 1.72 1.34 1.09 1.76 1.56 R 4 1.80 0.88 0.69 1.95 0.94 1.34 1.50 1.90 0.89 1.38 1.34 1.26 1.60 1.66 1.31 R 5 1.65 0.96 0.67 1.25 0.93 1.35 1.25 2.30 0.83 1.02 1.70 1.35 1.50 2.48 1.76 R 6 2.06 1.03 0.72 1.39 0.73 1.00 1.36 1.88 0.88 1.40 1.84 1.20 1.51 1.13 1.67 S 7 1.90 0.42 0.60 1.26 0.75 1.26 1.30 2.54 0.76 1.39 3.09 1.02 0.96 1.38 2.75 S 8 1.55 1.17 0.70 2.08 0.70 1.35 1.99 2.24 0.80 0.71 0.91 1.27 1.48 1.46 1.25 R 9 1.96 0.64 0.54 1.09 0.82 0.84 1.21 3.02 1.01 1.45 2.37 0.96 0.67 0.98 2.73 S 10 1.80 1.08 0.51 1.70 0.76 1.20 1.73 1.86 0.75 1.17 1.37 1.03 1.27 1.30 1.35 R 11 1.69 0.86 0.73 1.79 0.78 0.95 1.51 1.95 0.96 0.92 0.83 0.89 2.19 1.67 1.48 S 12 1.72 1.43 0.54 1.61 0.72 1.41 1.20 2.29 0.65 0.92 0.60 1.28 1.99 1.66 1.40 R 13 1.53 0.64 0.67 1.44 1.12 1.28 1.54 2.13 1.09 0.82 1.52 1.19 1.31 1.77 1.47 S 14 1.98 0.59 0.53 1.46 0.77 0.91 1.42 2.54 1.01 1.04 2.44 1.24 0.76 1.24 2.39 S 15 1.63 2.18 0.89 1.40 0.37 1.04 1.85 2.21 0.63 0.90 1.59 1.11 1.52 1.33 1.72 R 16 1.64 1.45 0.40 0.97 0.70 1.19 1.90 1.92 0.66 1.45 1.10 1.18 1.25 1.66 1.37 R 17 2.38 0.99 0.73 1.30 0.51 1.16 1.41 2.67 1.01 1.27 0.67 1.01 1.18 0.70 2.14 S 18 1.86 0.66 0.57 0.91 0.77 0.91 1.50 2.50 1.08 1.22 1.67 1.42 1.23 0.69 1.90 S 19 2.09 0.82 0.56 1.31 0.50 1.19 1.32 2.11 0.94 0.68 0.85 1.42 0.81 1.36 1.81 S 20 1.96 0.92 0.24 1.26 0.77 0.96 1.39 1.96 0.97 1.13 2.96 0.73 1.02 1.12 2.67 S 21 1.28 1.33 1.22 2.04 0.72 1.58 2.22 2.10 0.77 0.81 1.40 1.81 1.61 2.17 1.43 R 22 1.64 0.94 0.47 1.27 0.79 0.78 1.24 2.48 0.81 1.31 1.51 1.73 0.79 0.92 1.87 R 23 2.26 0.68 0.65 1.95 0.89 1.18 1.38 1.81 0.94 2.15 3.29 1.17 1.11 1.68 3.05 S 24 1.93 0.67 0.50 0.71 0.67 0.67 1.21 2.51 0.92 1.86 1.90 0.77 1.09 1.03 2.43 S 25 1.69 1.07 0.54 1.33 0.68 1.09 1.44 2.35 0.66 1.21 1.93 1.07 1.27 1.09 1.65 S 26 1.38 0.72 0.38 1.24 0.66 1.03 1.19 2.55 0.95 1.35 2.91 1.18 1.27 1.28 2.37 S 27 2.37 0.96 0.56 1.53 0.75 0.90 1.52 2.28 0.98 0.75 2.37 0.80 0.66 1.16 2.63 S 28 1.67 0.99 0.47 1.44 0.67 1.15 1.51 2.21 0.93 0.84 1.61 1.61 1.58 1.28 1.21 R 29 2.14 0.73 0.44 1.26 0.73 1.11 1.11 2.93 1.00 1.72 2.82 0.91 1.20 0.85 2.85 S 30 1.58 0.58 0.60 1.68 0.90 1.39 1.63 2.18 0.72 1.00 1.93 1.22 1.68 1.03 1.46 R 31 1.81 1.17 0.48 1.35 0.74 1.11 0.96 2.60 1.13 1.90 2.28 1.13 0.69 0.99 2.47 S 32 1.57 0.92 1.15 1.21 0.95 0.98 1.07 2.19 0.84 1.13 1.74 1.11 1.54 1.58 1.65 R 33 1.98 1.16 0.93 1.94 1.00 2.12 1.11 2.21 0.82 0.92 0.54 0.98 1.54 1.33 1.86 R 34 1.73 1.31 0.56 1.19 0.72 1.21 1.28 2.10 0.72 1.83 1.32 1.28 1.08 1.27 1.57 R 35 1.81 1.07 0.48 0.77 0.62 1.36 1.25 1.71 0.87 1.60 1.05 1.71 1.23 1.01 1.52 S 36 1.63 0.65 0.73 1.69 0.82 1.20 1.19 1.72 0.86 1.02 1.72 1.16 1.16 1.51 1.59 R 37 1.53 1.18 0.57 1.53 0.94 1.39 1.35 1.73 0.88 1.02 1.28 0.93 1.60 1.13 1.24 R 38 2.23 1.36 0.93 0.97 0.83 1.25 1.55 1.88 1.02 0.73 0.99 1.64 1.48 1.17 1.65 R 39 1.73 1.62 0.84 1.88 0.69 1.39 2.02 2.41 0.83 1.03 0.76 1.70 1.73 1.01 1.33 R 40 1.99 1.15 0.51 1.22 0.71 0.87 1.41 2.15 1.14 1.33 1.88 0.83 1.28 1.60 1.93 S 41 1.42 1.43 0.58 1.16 0.78 1.38 1.76 2.27 0.80 1.28 1.27 1.24 2.18 1.13 1.05 S 42 1.95 0.97 0.50 0.70 0.49 1.03 1.25 1.99 0.87 1.71 1.34 1.08 1.19 1.04 1.86 S 43 1.82 1.05 0.42 1.51 0.55 1.37 1.17 2.18 1.03 1.59 1.68 1.08 1.26 1.42 1.62 S 44 1.69 1.12 0.59 1.12 1.00 1.05 1.08 1.84 0.75 1.13 1.36 1.46 0.95 1.76 1.66 R 45 1.51 1.53 0.77 1.42 1.03 0.83 2.10 1.85 0.68 1.08 1.77 1.67 1.25 1.57 1.52 R 46 1.54 1.42 1.09 1.87 0.87 1.59 1.24 2.01 0.86 0.54 1.02 1.34 2.11 1.87 1.47 R 47 1.61 1.45 0.72 1.68 0.94 1.10 2.00 2.23 0.50 1.19 2.02 1.47 1.81 1.09 1.52 R 48 1.99 0.67 0.40 0.99 0.21 1.02 1.34 2.48 0.90 1.03 1.70 1.21 0.70 1.06 2.14 R 49 1.71 0.90 0.84 1.54 0.85 1.34 2.00 2.53 0.72 0.87 1.82 1.19 1.67 1.89 1.58 R 50 1.76 0.76 0.48 1.08 0.86 1.52 1.46 2.27 0.68 1.30 3.67 0.94 0.81 1.24 3.13 S 51 1.82 0.46 0.36 1.63 0.63 1.01 1.51 2.56 0.72 1.25 1.73 1.17 0.84 1.52 1.97 S

Since K=5, the 5 nearest neighbors are considered, that is the 5 smallest values of d_i with class prediction based on a majority vote. For this example, 4/5 of the closest neighbors were resistant, therefore this sample is predicted to be resistant.

[0338]It will be appreciated that similar methods may be employed utilizing the marker sets of the present invention.

[0339]4. Support Vector Machine

[0340]A support vector machine using a second order polynomial kernel has the form

d ( Z ) = i = 1 S α i ( 1 + j = 1 14 z j x ij ) 2 C + b ##EQU00005##

where z_j (log transformed) and x_ij are the same as in above examples, C is a scaling constant set to 200, b is a penalty term (=-4.4675), and α_i is the i^th support vector estimated from the training data. They are listed below.

TABLE-US-00004 Sample ID α_i 1 0 2 70.0164 3 0 4 -0.282 5 0 6 32.281 7 0 8 0 9 0 10 -23.3735 11 3.3081 12 -12.8285 13 0 14 0 15 0 16 0 17 0 18 0 19 100 20 0 21 0 22 -42.1717 23 0 24 0 25 100 26 0 27 0 28 -90.7953 29 0 30 -83.4233 31 0 32 -0.7843 33 0 34 -100 35 100 36 0 37 0 38 -42.3951 39 -11.9709 40 0 41 37.9963 42 0 43 0 44 0 45 0 46 0 47 0 48 -100 49 -33.8659 50 15.3422 51 82.9463

Values of d(Z) represent the distance the sample Z is from the decision boundary (often referred to as the margin). Values less than the margin (0.04 for these data) are predicted to be resistant while larger values are sensitive. For this example, d(z) is equal to -3.19 and is therefore predicted to be resistant.

[0341]It will be appreciated that similar methods may be employed utilizing the marker sets of the present invention.

F. Summary of the Data Provided in the Tables

[0342]The following terms are used throughout the Tables:

[0343]"No." or "Number" corresponds to an identification number for the markers.

[0344]"Image Clone Id" corresponds to the cDNA clone number from the IMAGE Consortium. All referenced IMAGE clone sequences are expressly incorporated herein by reference.

[0345]"Accession" corresponds to the GenBank accession number assigned to the particular sequence. All referenced GenBank sequences are expressly incorporated herein by reference.

[0346]"Gene name" corresponds to the name the gene is commonly known by.

[0347]"GI number" corresponds to the GenBank number.

[0348]"RefSeq" corresponds to the Reference Sequence Nucleic Accession Number.

[0349]"Marker Number" corresponds the marker identification numbers set forth in Table 1.

[0350]"Feature Selection" corresponds to the process of determining which individual markers may be used in combination to group or classify a sample, for example, as sensitive or resistant. Four different feature selection methods were utilized for determining the best classifier: 1) Stepwise linear discriminant analysis ("LDA"); 2) Signal-to-noise ("SNR"); 3) Fisher score ("FISHER"); and 4) Support Vector Feature Selection ("SVM").

[0351]"Classification Error Rate of the Model" corresponds to the classification algorithm which uses the model established in the feature selection process to make predictions as to the group, for example, either sensitive or resistant, to which each validation sample may be classified. The error rate is simply the proportion of occurrences in which the algorithm predicted a sample incorrectly, e.g., 1 error in 10 predictions would be a Classification Error Rate of 10% for the model.

[0352]Table 1 lists all of the markers of the invention (and comprises the markers listed in Tables 2-16), which are designated with a marker identification number ("No."), the Image Clone ID ("Image Clone ID"), the gene corresponding to the marker ("Gene Name"), the Accession Number ("Accession"), the GeneBank number ("GI number"), and the Reference Sequence Nucleic Accession Number ("RefSeq").

TABLE-US-00005 TABLE 1 Image Clone No Id Gene name Accession GI number RefSeq n1 31866 splicing factor 3a, R43015 820077 NM_006802 subunit 3 R17811 771421 n2 43936 unnamed H05777 869329 n3 51970 NAG14 protein H23117 891812 NM_022143 n4 52724 hypothetical protein H29399 900309 NM_017721 FLJ20241 H29307 900217 n5 77577 FOS-like antigen 2 T58873 660710 NM_005253 T58932 660769 n6 110812 unnamed T83174 711462 T90647 719160 n7 124575 zinc finger protein 200 R01941 751677 NM_003454 R01991 751727 n8 133872 hypothetical protein R28239 784374 NM_021942 FLJ12716 R27982 784117 n9 149895 unnamed H00660 863593 H00752 863685 n10 182818 pre-mRNA processing H45335 921387 NM_015629 factor 31 homolog H45266 921318 n11 187147 ras association R83224 928101 (RalGDS/AF-6) domain R83223 928100 n12 244055 CCR4-NOT N34048 1154448 NM_014516 transcription complex n13 277403 Homo sapiens mRNA N47672 1188838 cDNA DKFZp586D0918 N57522 1201412 n14 283301 KIAA0914 gene N51424 1192590 NM_014883 product n15 284497 Homo sapiens mRNA N52362 1193528 cDNA DKFZp586E1624 N75133 1237711 n16 289652 none N59881 1203771 N77022 1239600 n17 306921 eukaryotic translation W24209 1301121 NM_004280 elongation factor 1 N91962 1264271 n18 308412 unnamed N93790 1266099 W31338 1312329 n19 342082 Homo sapiens cDNA W60310 1367069 FLJ30816 W60401 1367160 n20 342181 B-cell CLL/lymphoma 2 W61100 1367877 NM_000633NM_000657 W63749 1371329 n21 343174 Homo sapiens cDNA W67536 1376407 FLJ31204 n22 380245 protein kinase C AA047803 1527482 NM_006255 n23 416049 unnamed W85947 1398375 W85843 1398292 n24 428296 unnamed AA004944 1447731 n25 449126 unnamed AA777493 2836972 n26 451706 polymerase (DNA AA707650 2717568 NM_016937 directed), alpha n27 454798 unnamed AA677295 2657817 n28 491184 unnamed AA137072 1698289 AA137144 1698379 n29 509887 non-POU-domain- AA056465 1548805 NM_007363 containing, octamer- binding AA054701 1545625 n30 513200 60S ribosomal protein AA063398 1557267 NM_016304 L30 isolog n31 565235 spermine synthase AA136125 1697335 NM_00459 AA136221 1697431 n32 611532 troponin 1 AA181334 1764986 NM_003282 AA182927 1766096 n33 681910 unnamed AA256174 1891713 AA256233 1891772 n34 682088 unnamed AA256824 1890970 AA256482 1892020 n35 703838 chromosome 8 open AA279100 1920583 NM_004337 reading frame 1 AA278836 1920357 n36 740620 tropomyosin 2 AA479560 2205446 NM_003289 AA477400 2206034 n37 740672 polymerase (RNA) II AA479589 2205475 NM_002696 (DNA directed) polypeptide G AA477428 2206062 n38 745158 Homo sapiens mRNA; AA626716 2539103 cDNA DKFZp434A1635 n39 753587 butyrophilin, subfamily 3 AA478585 2207219 NM_006994 AA479322 2207878 n40 767388 unnamed AA418593 2080394 AA418655 2080474 n41 781109 KIAA1488 protein AA430052 2113226 n42 789369 inhibitor of DNA binding 4 AA464856 2189740 NM_001546 AA453341 2167010 n43 795847 COP9 subunit 5 AA461527 2185391 NM_006837 AA460599 2185719 n44 809828 E2F transcription factor 5 AA464403 2189287 NM_001951 AA455521 2178297 n45 810027 mitochondrial ribosomal AA464995 2189879 NM_030811 protein S26 AA455275 2178051 n46 810237 hypothetical protein AA464708 2189592 NM_032333 MGC4248 n47 810305 Homo sapiens cDNA AA463961 2188845 FLJ30463 AA464098 2188982 n48 810671 hypothetical protein AA464121 2189005 NM_032219 FLJ22269 AA463986 2188870 n49 814595 protein kinase C AA480969 2210521 NM_012408 binding protein 1 AA480906 2210458 n50 815563 DKFZp434J1813 AA456833 2179553 protein n51 825083 mitogen-activated AA489245 2218847 NM_015133 protein kinase 8 AA504316 2240476 n52 837904 ribosomal protein L15 AA434360 2139274 NM_002948 AA434088 2139002 n53 884867 eukaryotic translation AA669443 2630942 NM_001969 initiation factor 5 n54 897656 FERM, RhoGEF AA496796 2230117 NM_005766 (ARHGEF) and pleckstrin domain protein 1 n55 897722 HMBA-inducible AA598983 2432023 NM_006460 n56 1031717 unnamed AA609584 2458012 n57 1240298 low density lipoprotein AA788645 2848765 NM_002335 receptor-related protein 5 n58 1536925 3-phosphoinositide AA973277 3148457 NM_002613 dependent protein kinase-1 n59 1558940 Homo sapiens cDNA AA917744 3057634 FLJ20046 fis n60 1650934 Homo sapiens cDNA AI022993 3238234 FLJ11472 fis n61 1901754 Homo sapiens cDNA AI302412 3961758 FLJ10500 fis n62 1908973 cocaine- and AI300511 3959857 NM_004291 amphetamine-regulated transcript n63 1916700 kallikrein 1, AI347629 4084835 NM_002257 renal/pancreas/salivary n64 269663 unnamed N24785 1138935 n65 278137 none N63520 1211349 n66 289499 unnamed N63996 1211825 n67 384634 none AA708997 2718915 n68 399440 semaphorin sem2 AA732915 2754274 NM_020163 n69 743211 AA400125 2053927 n70 745190 unnamed AA626846 2539233 n71 753794 small inducible cytokine AA406115 2064231 NM_006419 B subfamily AA410383 2069486 n72 1293184 Homo sapiens AA682767 2669450 unknown mRNA n73 1534173 frequenin AA918755 3058645 NM_014286 n74 1583344 Homo sapiens mRNA; AA983933 3162458 cDNA DKFZp434D115 n75 275060 none R85700 944106 n76 381036 unnamed AA054643 1545567 n77 504630 S164 protein AA150143 1721364 AA152212 1721413 n78 897950 ATPase AA598814 2432486 NM_001677

[0353]Tables 2-15 list marker sets, comprised of multiple individual markers, which are designated with a marker identification number within each marker set ("Number"), the marker identification numbers set forth in Table 1 ("Marker Number"), the Image clone identification number ("Image Clone Id"), the feature selection ("Feature Selection"), and the classification error rate of the model ("Classification Error Rate of the Model").

TABLE-US-00006 TABLE 2 Marker Feature Classification error Number number Image clone Id selection rate of the model 1 n35 703838 SVM SVM - 0.14286 2 n4 52724 SVM 3 n39 753587 SVM 4 n42 789369 SVM 5 n48 810671 SVM 6 n54 897656 SVM 7 n55 897722 SVM 8 n7 124575 SVM 9 n1 31866 SVM 10 n10 182818 SVM 11 n19 342082 SVM 12 n22 380245 SVM 13 n28 491184 SVM 14 n30 513200 SVM

TABLE-US-00007 TABLE 3 Classification Marker Image Feature error rate of Number number clone Id selection the model 1 n33 681910 SVM KNN = 0.21429 2 n3 51970 SVM 3 n40 767388 SVM 4 n43 795847 SVM 5 n46 810237 SVM 6 n49 814595 SVM 7 n1 31866 SVM 8 n13 277403 SVM 9 n65 278137 SVM 10 n18 308412 SVM 11 n20 342181 SVM 12 n25 449126 SVM

TABLE-US-00008 TABLE 4 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n34 682088 SNR SVM = 0.21429 2 n44 809828 SNR 3 n49 814595 SNR 4 n56 1031717 SNR 5 n59 1558940 SNR 6 n62 1908973 SNR 7 n63 1916700 SNR 8 n12 244055 SNR 9 n21 343174 SNR 10 n2 43936 SNR 11 n27 454798 SNR 12 n32 611532 SNR

TABLE-US-00009 TABLE 5 Marker Feature Classification error Number number Image clone Id selection rate of the model 1 n36 740620 FISHER WTV = SVM = 0.21429 2 n37 740672 FISHER 3 n38 745158 FISHER 4 n39 753587 FISHER 5 n45 810027 FISHER 6 n58 1536925 FISHER 7 n61 1901754 FISHER 8 n17 306921 FISHER 9 n26 451706 FISHER 10 n27 454798 FISHER 11 n32 611532 FISHER

TABLE-US-00010 TABLE 6 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n3 51970 SNR SVM = 0.21429 2 n4 52724 SNR 3 n42 789369 SNR 4 n47 810305 SNR 5 n48 810671 SNR 6 n54 897656 SNR 7 n10 182818 SNR 8 n11 187147 SNR 9 n64 269663 SNR 10 n18 308412 SNR 11 n24 428296 SNR 12 n28 491184 SNR 13 n29 509887 SNR

TABLE-US-00011 TABLE 7 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n35 703838 SVM SVM = 0.21429 2 n4 52724 SVM 3 n39 753587 SVM 4 n42 789369 SVM 5 n48 810671 SVM 6 n54 897656 SVM 7 n55 897722 SVM 8 n7 124575 SVM 9 n1 31866 SVM 10 n10 182818 SVM 11 n19 342082 SVM 12 n28 491184 SVM 13 n30 513200 SVM

TABLE-US-00012 TABLE 8 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n37 740620 SVM WTV = 0.21429 2 n39 753587 SVM 3 n42 789369 SVM 4 n52 837904 SVM 5 n53 884867 SVM 6 n60 1650934 SVM 7 n8 133872 SVM 8 n1 31866 SVM 9 n14 283301 SVM 10 n15 284497 SVM 11 n67 384634 SVM 12 n29 509887 SVM

TABLE-US-00013 TABLE 9 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n34 682088 SNR WTV = 0.21429 2 n38 745158 SNR 3 n41 781109 SNR 4 n49 814595 SNR 5 n5 77577 SNR 6 n56 1031717 SNR 7 n57 1240298 SNR 8 n9 149895 SNR 9 n16 289652 SNR 10 n2 43936 SNR 11 n27 454798 SNR 12 n32 611532 SNR

TABLE-US-00014 TABLE 10 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n33 681910 SVM KNN = 0.21429 2 n38 745158 SVM 3 n4 52724 SVM 4 n39 753587 SVM 5 n50 815563 SVM 6 n51 825083 SVM 7 n54 897656 SVM 8 n6 110812 SVM 9 n8 133872 SVM 10 n15 284497 SVM 11 n23 416049 SVM 12 n26 451706 SVM 13 n31 565235 SVM 14 n32 611532 SVM

TABLE-US-00015 TABLE 11 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n3 51970 SNR SVM = 0.21429 2 n4 52724 SNR 3 n42 789369 SNR 4 n47 810305 SNR 5 n48 810671 SNR 6 n54 897656 SNR 7 n10 182818 SNR 8 n11 187147 SNR 9 n64 269663 SNR 10 n66 289499 SNR 11 n18 308412 SNR 12 n24 428296 SNR 13 n28 491184 SNR 14 n29 509887 SNR

TABLE-US-00016 TABLE 12 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n33 681910 SVM KNN = 0.21429 2 n38 745158 SVM 3 n4 52724 SVM 4 n39 753587 SVM 5 n50 815563 SVM 6 n51 825083 SVM 7 n54 897656 SVM 8 n6 110812 SVM 9 n8 133872 SVM 10 n15 284497 SVM 11 n23 416049 SVM 12 n26 451706 SVM 13 n31 565235 SVM 14 n32 611532 SVM

TABLE-US-00017 TABLE 13 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n38 745158 FISHER KNN = 0.14286 2 n4 52724 FISHER 3 n71 753794 FISHER 4 n49 814595 FISHER 5 n58 1536925 FISHER 6 n74 1583344 FISHER 7 n62 1908973 FISHER 8 n12 244055 FISHER 9 n75 275060 FISHER 10 n65 278137 FISHER 11 n68 399440 FISHER 12 n32 611532 FISHER

TABLE-US-00018 TABLE 14 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n35 703838 SNR KNN = 0.14286 2 n69 743211 SNR 3 n38 745158 SNR 4 n70 745190 SNR 5 n78 897950 SNR 6 n72 1293184 SNR 7 n73 1534173 SNR 8 n9 149895 SNR 9 n65 278137 SNR 10 n76 381036 SNR 11 n27 454798 SNR 12 n77 504630 SNR

TABLE-US-00019 TABLE 15 Marker Feature Classification error rate Number number Image clone Id selection of the model 1 n35 703838 FISHER WTV = 0.14286 2 n69 743211 FISHER 3 n70 745190 FISHER 4 n71 753794 FISHER 5 n72 1293184 FISHER 6 n73 1534173 FISHER 7 n62 1908973 FISHER 8 n9 149895 FISHER 9 n13 277403 FISHER 10 n65 278137 FISHER 11 n76 381036 FISHER 12 n27 454789 FISHER

[0354]Table 16 identifies the 78 individual markers of the present invention (n1-n78). The marker identification numbers are set forth in Table 16 ("No"), the Image clone identification number ("Image Clone Id"), and the Signal-to-noise ("SNR score"). Table 16 lists markers using SNR statistics applied to 18,539 genes of the 51 ovarian tumor samples. In particular, the markers in Table 16 with negative SNR values are correlated with resistance to an agent (referred to herein as "resistance markers"), and the markers with positive SNR scores are correlated with sensitivity to an agent (referred to herein as "sensitivity markers").

TABLE-US-00020 TABLE 16 No Image Clone Id SNR score n1 31866 0.520 n2 43936 -0.331 n3 51970 -0.495 n4 52724 -0.454 n5 77577 -0.463 n6 110812 -0.411 n7 124575 -0.486 n8 133872 -0.371 n9 149895 -0.414 n10 182818 -0.349 n11 187147 0.443 n12 244055 -0.453 n13 277403 -0.537 n14 283301 0.364 n15 284497 -0.474 n16 289652 0.329 n17 306921 0.300 n18 308412 -0.347 n19 342082 -0.253 n20 342181 0.345 n21 343174 0.323 n22 380245 -0.387 n23 416049 0.404 n24 428296 -0.365 n25 449126 -0.376 n26 451706 0.581 n27 454798 -0.604 n28 491184 -0.302 n29 509887 0.456 n30 513200 0.370 n31 565235 0.382 n32 611532 0.572 n33 681910 -0.489 n34 682088 0.453 n35 703838 0.565 n36 740620 0.367 n37 740672 0.374 n38 745158 0.573 n39 753587 0.396 n40 767388 -0.473 n41 781109 -0.366 n42 789369 0.489 n43 795847 0.355 n44 809828 0.414 n45 810027 0.474 n46 810237 0.426 n47 810305 -0.432 n48 810671 -0.464 n49 814595 -0.386 n50 815563 0.341 n51 825083 -0.402 n52 837904 0.169 n53 884867 0.301 n54 897656 -0.301 n55 897722 -0.430 n56 1031717 0.506 n57 1240298 0.432 n58 1536925 -0.575 n59 1558940 0.365 n60 1650934 -0.379 n61 1901754 -0.390 n62 1908973 0.149 n63 1916700 -0.482 n64 269663 0.385 n65 278137 0.520 n66 289499 0.348 n67 384634 -0.521 n68 399440 -0.457 n69 743211 -0.398 n70 745190 0.470 n71 753794 0.475 n72 1293184 0.447 n73 1534173 -0.394 n74 1583344 0.475 n75 275060 -0.290 n76 381036 -0.317 n77 504630 -0.286 n78 897950 0.306

OTHER EMBODIMENTS

[0355]The present invention is not to be limited in scope by the specific embodiments described that are intended as single illustrations of individual aspects of the invention and functionally equivalent methods and components are within the scope of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

[0356]All references cited herein, including journal articles, patents, and databases are expressly incorporated by reference.

Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 159 <210> SEQ ID NO 1 <211> LENGTH: 459 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 tttttttttt taatgagaca gggtctcact atgttaccta ggctagtctc aagcaaccct 60 cctgcctcag cctcccaagt agctgggact acaggcacaa gccactgcac ccagctccaa 120 ctcctttctt tatgcaaata caaaaggcaa accttggtgc gacacttagt ccttagtagc 180 aaccctgggc tcatcctcct agtctttccc tagtatttgc atcaatggct aactaagctg 240 atggcagacc tcatcctggg gtaatactca ttcagggaag cagcaacaaa ggagggtggg 300 gaaagaggtc aggtcagatt tacctaacat gatatgtagg cataataggt gcccattaaa 360 tctcagctac tagtaaagtt ggtgaggaag aggtatggag gcattaagac ctgaagcatt 420 gagttggtcc ttaacctggg ttttagaaca aggtttggt 459 <210> SEQ ID NO 2 <211> LENGTH: 487 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 383, 397, 408, 459, 467, 476 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 2 agaaatggga gaatgggacc tttcctggat ggccgaaaga gacaagcagt gccctgaccc 60 atgctggagc ccatcttgac ctctctgcat tctcctcctg ggaggagttg gcttctctgg 120 gtttggacag attgaaatct gctctcttag ctttaggctt gaaatgtggc gggaccctag 180 aagagcgagc ccagagacta ttcagtacca aaggaaagtc cctggagtca cttgatacct 240 ctttgtttgc caaaaatccc aagtcaaagg gcaccaagcg agacactgaa aggaacaaag 300 acattgcttt tctagaagcc cagatctatg gaatatgtag gagattcttc gggggaacag 360 cgacattctt cactcatgga aantgttaca gcgcaanaag gccagggnca gggagaagga 420 gcgaggaagg aaggagggag gaaggggcag ttccagttna ggagttnagg atttanggtt 480 gaaggag 487 <210> SEQ ID NO 3 <211> LENGTH: 2733 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 3 aagggaagat ggagacaata ctggagcagc agcggcgcta tcatgaggag aaggaacggc 60 tcatggacgt catggctaaa gagatgctca ccaagaagtc cacgctccgg gaccagatca 120 attctgatca ccgcactcgg gccatgcaag ataggtatat ggaggtcagt gggaacctga 180 gggatttgta tgatgataag gatggattac gaaaggagga gctcaatgcc atttcaggac 240 ccaatgagtt tgctgaattc tataatagac tcaagcaaat aaaggaattc caccggaagc 300 acccaaatga gatctgtgtg ccaatgtcag tggaatttga ggaactcctg aaggctcgag 360 agaatccaag tgaagaggca caaaacttgg tggagttcac agatgaggag ggatatggtc 420 gttatctcga tctccatgac tgttacctca agtacattaa cctgaaggca tctgagaagc 480 tggattatat cacatacctg tccatctttg accaattatt tgacattcct aaagaaagga 540 agaatgcaga gtataagaga tacctagaga tgctgcttga gtaccttcag gattacacag 600 atagagtgaa gcctctccaa gatcagaatg aactttttgg gaagattcag gctgagtttg 660 agaagaaatg ggagaatggg acctttcctg gatggccgaa agagacaagc agtgccctga 720 cccatgctgg agcccatctt gacctctctg cattctcctc ctgggaggag ttggcttctc 780 tgggtttgga cagattgaaa tctgctctct tagctttagg cttgaaatgt ggcgggaccc 840 tagaagagcg agcccagaga ctattcagta ccaaaggaaa gtccctggag tcacttgata 900 cctctttgtt tgccaaaaat cccaagtcaa agggcaccaa gcgagacact gaaaggaaca 960 aagacattgc ttttctagaa gcccagatct atgaatatgt agagattctc ggggaacagc 1020 gacatctcac tcatgaaaat gtacagcgca agcaagccag gacaggagaa gagcgagaag 1080 aagaggaaga agagcagatc agtgagagtg agagtgaaga tgaagagaac gagatcattt 1140 acaaccccaa aaacctgcca cttggctggg atggcaaacc tattccctac tggctgtata 1200 agcttcatgg cctaaatatc aactacaact gtgagatttg tggaaactac acctaccgag 1260 ggcccaaagc cttccagcga cactttgctg aatggcgtca tgctcatggc atgaggtgtt 1320 tgggcatccc aaatactgct cactttgcta atgtgacaca gattgaagat gctgtctcct 1380 tgtgggccaa actgaaattg cagaaggctt cagaacgatg gcagcctgac actgaggaag 1440 aatatgaaga ctcaagtggg aatgttgtga ataagaagac atacgaggat ctgaaaagac 1500 aaggactgct ctagtgttga gggatgtagc tcagcttttg ggctagccca ggcttcccta 1560 agatctgctt tttctatttc tcccaaccaa atcctcttaa agaccctttg ctatgtagtc 1620 tcatggtcta gcatgcatct tgtagaaaca aggcatgctg gcagattgca gggttgagat 1680 gtgttttatc tgttttatat tttaaaagat tctgccagaa aataaaacca gaccttgttc 1740 taaagcccag ggttatggac caactcagtg cttcaggtct taatgcctcc atacctcttc 1800 ctcaccaact ttactagtag ctgagattta atgggcacct attatgctac atatcatgtt 1860 aggtaaatct gacctgacct ctttccccac cctcctttgt tgctgcttcc ctgaatgagt 1920 attaccccag gatgaggtct gccatcagct tagttagcca ttgatgcaaa tactagggaa 1980 agactaggag gatgagccag ggttgctact aaggactaag tgtcgcacca aggtttgcct 2040 tttgtatttg cataaagaaa ggagttggag ctgggtgcag tggcttgtgc ctgtagtccc 2100 agctacttgg gaggctgagg caggagggtt gcttgagact agcctaggta acatagtgag 2160 accctgtctc attaaaaaaa aaaaaaaaag gcatggtggc acgcactgta gtcccagcta 2220 ctcaggagac tgaggctaga agatcctttg aacctaggag tttgagacca gcctgggcga 2280 tatagtgagg ccccatctca aaaaaaaaaa aaagcggggg gggggagttg ggctgtgttg 2340 gaatgggcct gcagcccaac aaacaaggga actaggaccg acagtgactt caccagcttg 2400 ctaggtcaga atgagagact ggtgggtctg tctacctgtt tcttctacaa gatccctatt 2460 tgactgtaaa agtagctaat actcacatgt tctccaatcc caggtagcca tggtagagtt 2520 gggtagagtt gagcagccgc cccaggatcc aaatgtggtg tctgaaatgg aaagaactaa 2580 ggcaaccagg aaggcactga tctgccttat aagcacagtc atctgaaagt caggcctgct 2640 gcaggacagg atcccccaga gaccccattt gcctctcaac actcagacct tcaactgttt 2700 tttaataaat ctacttttta aaaaaaaaaa ata 2733 <210> SEQ ID NO 4 <211> LENGTH: 441 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 200, 248, 362, 393, 429 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 4 tttttttttt tttttttatt tatttaaagt tttatttgct agctaataaa taccactgaa 60 actatgcact tttaaacaaa gtataattgt acatgagtgg gggcagagtg gaatgcaaca 120 tagtaattca tttcacatct tgcataccat taaggtgcct tccagtttgc ctgtaattgc 180 atgaaatgag tatctgagcn taacttcttt taccacaaag gccactaaca ctgtagaggg 240 tgccaggnaa aggtccctga ttcccggggc ttaattaacg aaactggaaa ggcaaaatca 300 aacttcaata caaatggaat gtacagatcc atcactttct tacttcattc taggattcta 360 angtcagggc tctcaaaccc ttgggtttat ggncttacct atgtgctgag gacatctttt 420 tttcatacna gtccttttgg a 441 <210> SEQ ID NO 5 <211> LENGTH: 483 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 424, 442, 458, 481 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 5 tttttttttt tgttttgact ttttgtcttt aaattttaat ataatctgtt ttttttaacc 60 agcccataga cttaatatat aagcatatac aagaaaaagt ctctccccac tctgtacaaa 120 agttgctgtc tttgtgtgca ttctattgca ttttataagt ttttgggggg aggggagtca 180 tatttgagtt tcctgtacct tgtccttggt atgggtctga attatataag gttcagagat 240 agtggtgact gtggggtgca gagagttccc cagggctgtt ttctgtccag tgggccccat 300 gtgctggttt gtaggtgttg tagttaatat gggtcatgaa ttgtggggca gcactactgc 360 ccccttcacc tgatacaccg gacgggagct gctgttgctg ctgcggatgt tggctgctgg 420 ggangtcttc gtccacccgg gnttatctca acagtccngg cggctgtgac tgtaactccg 480 ngc 483 <210> SEQ ID NO 6 <211> LENGTH: 2306 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 cggggacacc acgccagtgc tttcctgcct tccttccgag atggaaagag gagctcctag 60 ctcacttaag ccggggtagg gctggttctc ctttccgagc caaaatccca ggcgatggtg 120 aattatgaac gtgccacacc atgaagctct tgtggcaggt aactgtgcac caccacacct 180 ggaatgccat cctgctcccg ttcgtctacc tcacggcgca agtgtggatt ctgtgtgcag 240 ccatcgctgc tgccgcctca gccgggcccc agaactgccc ctccgtctgc tcgtgcagta 300 accagttcag caaggtggtg tgcacgcgcc ggggcctctc cgaggtcccg cagggtattc 360 cctcgaacac ccggtacctc aacctcatgg agaacaacat ccagatgatc caggccgaca 420 ccttccgcca cctccaccac ctggaggtcc tgcagttggg caggaactcc atccggcaga 480 ttgaggtggg ggccttcaac ggcctggcca gcctcaacac cctggagctg ttcgacaact 540 ggctgacagt catccctagc ggggcctttg aatacctgtc caagctgcgg gagctctggc 600 ttcgcaacaa ccccatcgaa agcatcccct cttacgcctt caaccgggtg ccctccctca 660 tgcgcctgga cttgggggag ctcaagaagc tggagtatat ctctgaggga gcttttgagg 720 ggctgttcaa cctcaagtat ctgaacttgg gcatgtgcaa cattaaagac atgcccaatc 780 tcacccccct ggtggggctg gaggagctgg agatgtcagg gaaccacttc cctgagatca 840 ggcctggctc cttccatggc ctgagctccc tcaagaagct ctgggtcatg aactcacagg 900 tcagcctgat tgagcggaat gcttttgacg ggctggcttc acttgtggaa ctcaacttgg 960 cccacaataa cctctcttct ttgccccatg acctctttac cccgctgagg tacctggtgg 1020 agttgcatct acaccacaac ccttggaact gtgattgtga cattctgtgg ctagcctggt 1080 ggcttcgaga gtatataccc accaattcca cctgctgtgg ccgctgtcat gctcccatgc 1140 acatgcgagg ccgctacctc gtggaggtgg accaggcctc cttccagtgc tctgccccct 1200 tcatcatgga cgcacctcga gacctcaaca tttctgaggg tcggatggca gaacttaagt 1260 gtcggactcc ccctatgtcc tccgtgaagt ggttgctgcc caatgggaca gtgctcagcc 1320 acgcctcccg ccacccaagg atctctgtcc tcaacgacgg caccttgaac ttttcccacg 1380 tgctgctttc agacactggg gtgtacacat gcatggtgac caatgttgca ggcaactcca 1440 acgcctcggc ctacctcaat gtgagcacgg ctgagcttaa cacctccaac tacagcttct 1500 tcaccacagt aacagtggag accacggaga tctcgcctga ggacacaacg cgaaagtaca 1560 agcctgttcc taccacgtcc actggttacc agccggcata taccacctct accacggtgc 1620 tcattcagac tacccgtgtg cccaagcagg tggcagtacc cgcgacagac accactgaca 1680 agatgcagac cagcctggat gaagtcatga agaccaccaa gatcatcatt ggctgctttg 1740 tggcagtgac tctgctagct gccgccatgt tgattgtctt ctataaactt cgtaagcggc 1800 accagcagcg gagtacagtc acagccgccc ggactgttga gataatccag gtggacgaag 1860 acatcccagc agcaacatcc gcagcagcaa cagcagctcc gtccggtgta tcaggtgagg 1920 gggcagtagt gctgcccaca attcatgacc atattaacta caacacctac aaaccagcac 1980 atggggccca ctggacagaa aacagcctgg ggaactctct gcaccccaca gtcaccacta 2040 tctctgaacc ttatataatt cagacccata ccaaggacaa ggtacaggaa actcaaatat 2100 gactcccctc ccccaaaaaa cttataaaat gcaatagaat gcacacaaag acagcaactt 2160 ttgtacagag tggggagaga ctttttcttg tatatgctta tatattaagt ctatgggctg 2220 gttaaaaaaa acagattata ttaaaattta aagacaaaaa gtcaaaacaa aaaaaaaaaa 2280 aaaaaaaaat tccgagatgt caggga 2306 <210> SEQ ID NO 7 <211> LENGTH: 438 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 206, 334, 366, 408, 425, 431 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 7 tctccccacg cccaccgccc gctttgagca aaggaccttc agcgtcatca agatcttccc 60 tgacctcagc agcaacgaca tgctcctctt catcgtgaag ggcatcaact tgcccacacc 120 cccaggactg tcccctggcg atctggatgt ctttgttcgg tttgacttcc cctatcccaa 180 cgtggaagaa gctcagaaag acaagnccag tgtgatcaag aacacagact cccctgagtt 240 caaggagcag ttcaaactct gcatcaaccg cagccaccgt ggcttccgaa gggccatcca 300 gaccaagggc atcaagttcg aagtggtttc acangggggg ggctgttcaa gatttaccgg 360 gtgttngggg acagcccagt tgaagttggg ttgcattggg agatagcntt tgaagttccg 420 ggagntcttt naggttct 438 <210> SEQ ID NO 8 <211> LENGTH: 108 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 15, 17, 42, 93 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 8 tttttttttt gagtntngcc ctggctattt tattccatgt gnctggccct ggggacccag 60 ctgggccagg tcgacgcccc tggggagaca gtntggctcg gccagcct 108 <210> SEQ ID NO 9 <211> LENGTH: 2126 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 agctcaaagg caaaggtccc ttgccgatgg aggccattga gaagatggcc agcctgtgca 60 tgagagaccc ggatgaggat gaggaggagg ggacggatga ggacgacttg gaggctgatg 120 atgacctgct ggcggagcta aatgaggtcc ttggagagga gcagaaggct tcagagaccc 180 cacctcctgt ggcccagccg aagcctgagg cccctcatcc ggggctggag accaccttgc 240 aggagaggct ggcgctctat cagacagcaa ttgaaagcgc cagacaagct ggagacagcg 300 ccaagatgcg gcgctacgat cgggggctta aaacactgga aaacctgctc gcctccatcc 360 gtaagggcaa tgccattgac gaagcggaca tcccgccgcc agtggccata ggaaaaggcc 420 cggcgtccac tcaaaccaat tcacccagct gggcaacatc actgaaacca ccaagtttga 480 aaagttggcg gaggactgta agcggagcat ggacattctg aagcaagcct tcgtccgggg 540 tctccccacg cccaccgccc gctttgagca aaggaccttc agcgtcatca agatcttccc 600 tgacctcagc agcaacgaca tgctcctctt catcgtgaag ggcatcaact tgcccacacc 660 cccaggactg tcccctggcg atctggatgt ctttgttcgg tttgacttcc cctatcccaa 720 cgtggaagaa gctcagaaag acaagaccag tgtgatcaag aacgcagact cccctgagtt 780 caaggagcag ttcaaactct gcatcaaccg cagccaccct ggccctctgg cccagttgca 840 gagccgccag cgcgactaca agctggctgc cctccacgcc aagcagcagg gagataccac 900 tgctgccgct agacacttcc gcgtggctaa gagctttgat gctgtcttgg aggccctgag 960 ccggggtgag cccgtggacc tctcctgcct gccccctcca cccgaccagc tgcccccaga 1020 cccaccgtca ccaccgtcgc agcctccgac ccccgctacg gcgccctcca caacagaggt 1080 gcccccaccc ccgaggaccc tgctggaggc gctggagcag cggatggagc ggtaccaggt 1140 ggccgcagcc caggccaaga gcaaggggga ccagcggaaa gctcgaatgc acgagcgcat 1200 cgtcaagcaa taccaagatg ccatccgagc ccacaaggct ggccgagccg tggatgtcgc 1260 tgaattgccc gtgcccccag gcttcccccc aatccagggc ctggaggcca ccaagcccac 1320 ccagcagagt ctggtgggtg tcctggagac tgccatgaag ctggccaacc aggatgaagg 1380 cccagaggat gaagaggatg aggtgcctaa gaagcagaac agccctgtgg cccccacagc 1440 ccagcccaaa gccccaccct caagaactcc ccagtcggga tcagccccaa cagccaaagc 1500 gccccccaaa gccacatcca ccagagccca gcagcagctg gccttcctag agggccgcaa 1560 gaagcagctc ctgcaggccg cactgcgagc caagcagaaa aacgacgtgg agggtgccaa 1620 gatgcacctg cgccaagcca agggactgga gcctatgctg gaggcctcgc gcaatgggct 1680 gcctgtggac atcaccaagg tgccgcctgc ccctgtcaac aaggacgact ttgccctggt 1740 ccagcggcct ggcccgggtc tgtctcagga ggccgcccgg cgctatggtg aactcaccaa 1800 gctcatacgg cagcagcacg agatgtgcct gaaccactca aaccaattca cccagctggg 1860 caacatcact gaaaccatcc tggctaacat ggtgaaaccc tgtttctact aaaatacaaa 1920 aaaattagcc aggcatggtg gcgggcgcct gtagtcccag ctactcggga ggctgaggca 1980 ggagaatggc gtaagtaaac ccaggaggcg gagcttgcag tgagcccaga ttgcaccact 2040 gcactccagc ctggacaaca gagcgagact ctatctcaaa aaaaaaaaaa aaaaaaaaaa 2100 aaaaaaaaaa aaaaaaaaaa aaaaaa 2126 <210> SEQ ID NO 10 <211> LENGTH: 326 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 170, 268, 279, 284, 303, 308, 320 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 10 gatgaaatgt catggcaaat ttgataaaaa ccaagaggga gtgaaactga cgctggggga 60 gggaagggtc aagtcgaggg aaggtgaaac caaaaggcac tgagcatgcg tggtggggca 120 gggaaggaca ccatcactcc agagacagta tggtaacaaa gggacaggan tggtccaggc 180 cagcttcagg ctcttcagaa gccagagaga tgtccaagtc taccaaaccc gagttctcca 240 aggcttttca agaaatgggg tttgcttnca agatgaatna gggnggaggt cccatggctt 300 ctnagggntc caccccagtn ttccca 326 <210> SEQ ID NO 11 <211> LENGTH: 360 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 257, 274, 312, 340 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 11 ctcggtgggc gctgtagtgg tgaaacagga gcccctggaa gaggacagcc cctcgtcctc 60 gtcggcgggg ctggacaagg cccagcgctc tgtcatcaag cccatcagca ttgctggggg 120 cttctacggt gaggagcccc tgcacacccc catcgtggtg acctccacac ctgctgtcac 180 tccgggcacc tcgaacctcg tcttcaccta tcctagcgtc ctgggagcag gagtcacccg 240 catcttccct ccgaatnctt gcttccaagg gttnaccgca gaagcagtta gcagcggggg 300 accaattcat tnagattcct ttgaaattcc cccatttttn ttgggttttt taaacccagt 360 <210> SEQ ID NO 12 <211> LENGTH: 1007 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 atcatgtacc aggattatcc cgggaacttt gacacctcgt cccggggcag cagcggctct 60 cctgcgcacg ccgagtccta ctccagcggc ggcggcggcc agcagaaatt ccgggtagat 120 atgcctggct caggcagtgc attcatcccc accatcaacg ccatcacgac cagccaggac 180 ctgcagtgga tggtgcagcc cacagtgatc acctccatgt ccaacccata ccctcgctcg 240 cacccctaca gccccctgcc gggcctggcc tctgtccctg gacacatggc cctcccaaga 300 cctggcgtga tcaagaccat tggcaccacc gtgggccgca ggaggagaga tgagcagctg 360 tctcctgaag aggaggagaa gcgtcgcatc cggcgggaga ggaacaagct ggctgcagcc 420 aagtgccgga accgacgccg ggagctgaca gagaagctgc aggcggagac agaggagctg 480 gaggaggaga agtcaggcct gcagaaggag attgctgagc tgcagaagga gaaggagaag 540 ctggagttca tgttggtggc tcacggccca gtgtgcaaga ttagccccga ggagcgccga 600 tcgcccccag cccctgggct gcagcccatg cgcagtgggg gtggctcggt gggcgctgta 660 gtggtgaaac aggagcccct ggaagaggac agcccctcgt cctcgtcggc ggggctggac 720 aaggcccagc gctctgtcat caagcccatc agcattgctg ggggcttcta cggtgaggag 780 cccctgcaca cccccatcgt ggtgacctcc acacctgctg tcactccggg cacctcgaac 840 ctcgtcttca cctatcctag cgtcctggag caggagtcac ccgcatctcc ctccgaatcc 900 tgctccaagg ctcaccgcag aagcagtagc agcggggacc aatcatcaga ctccttgaac 960 tcccccactc tgctggctct gtaacccagt gcacctccct ccggagc 1007 <210> SEQ ID NO 13 <211> LENGTH: 373 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 140, 367 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 13 tgatcatagc tcactgcagc ctcagcctcc tgagctcaag taatcctacc acttcagcct 60 cctgagtagc tcggactacg tctggacctc atttatttat ttattttgta gagatagggt 120 cttgtcacgt tgtccagggn tggtcttgaa ctcctgggcc tcaagcaatc ttcccacctc 180 agcctcccaa agtgctgaga ctacaggtgt gagccatgat tgccagtcca cgtcttagtt 240 tttaatctcc cctgcatggc tgaggggcag aggccagcca gggagcatct gaggagaccc 300 aaattttgca tcccaccatg ggccagttag tagttgtgtg acctttggtg atgggcatca 360 cttttgntga ggc 373 <210> SEQ ID NO 14 <211> LENGTH: 457 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 372, 437 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 14 gtcgccgagg ctgaagtgca gaggtacgac catagctcag ttcagaagcc tcgacctccc 60 atgcttaagt tatcctcctg cctcagcctc ccaagtaact gggattatga gattacaggt 120 gcaccaccac acccagctaa tttcttaact ttttgtagag acaagggtct cacactgtgt 180 tgcccgggct ggtctcaaac tcgtggcctc cagtgatact tccacctcaa cctcgcaaag 240 tgctgggatt ttaagtgtga gccaccgcac ctgggccaaa tctttactct gttaagcaac 300 tgcagccagg ggacttttgg ttactgcagc ataacccaac ctgttctgcc caattctggg 360 tacatgagag antgcaagga agaaaaaaag gagggaggca ggagaaagga gggaggagat 420 gagagttgct gggtctntcg gaggcctgct gtgacca 457 <210> SEQ ID NO 15 <211> LENGTH: 222 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 21, 157, 168, 176, 199, 205, 215 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 15 ttttttttct ttgtagatgg ngtcatttta ccaaaagtta acagaactaa accaagaaac 60 tattgaaaat taacaacagt gagatgacta tacaaatata taattaaaaa taactttccc 120 atgtaaaagc aataatcaac tataaaaata taatggnaaa aactacanta acaaanttgt 180 gtaaaacaag tgaagaaant taggnaaatt tttcncaggg gt 222 <210> SEQ ID NO 16 <211> LENGTH: 402 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 273, 290 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 16 ttgaaaggaa ttgtttactt tggaatatag gaaaacagtt gaatgtcaga ctctcatttg 60 tatgtgatct aaatttgcaa tcaatttcaa taatatttac aatttgtgat aaaactgact 120 tttacagatt ccttttcaca acataattta ggtgtctact gttcttattg tattttgttc 180 tgctgttgat ctctccagca gccgtctcat gcttctccct tgctaaaaga agtttggatt 240 actcaggcag ggccatccca gccccaccca ctnagaaaag ctcttcagan tcttgtcccc 300 tctgttgagc cccagatctc catgtgctac ggagggaaac ccccaagacc ccagagaggg 360 aaggggtcaa ccctggggag ggccagggga aaaagtttgg ct 402 <210> SEQ ID NO 17 <211> LENGTH: 2098 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 gcggcgcgaa cgaatagtcg ccggcgacct gtgagggcac tcggaagggc gaggggaggg 60 ctcgaccgct cgcgcctagt ttttctatct ctcccggagc ctgagtctct gagccgtccc 120 cagcaaacgc tcaggggctg cagaggcccc gagagcttgg ctctctggca gatttcctct 180 agtaagaggt ggctctggag gccccgcgaa acgagtgtgg tgtgtggttg caaggcatga 240 tggctgcaaa agtggttcct atgcccccaa agccaaagca gtcctttata ctgagagttc 300 cgccagactc caagctgggc caagacctac ttcgagatgc cactaacggg cccaagacca 360 tccaccagct agtgctggag cacttcctca ccttcttgcc caagccaagc ctggtccagc 420 ccagtcagaa agtcaaggag accttggtta ttatgaaaga tgtgagctca agccttcaga 480 acagagtgca tcctcgtccc ttggtgaagc ttctgcccaa aggagtccaa aaggaacaag 540 agacagtgtc tctgtatttg aaagctaacc ctgaggagct ggtggtcttt gaggatttga 600 atgtatttca ctgccaggaa gaatgtgtga gcttggatcc tactcaacaa ctcacgtcag 660 agaaggaaga tgacagcagt gtcggggaaa tgatgttact ggcagtcaat ggcagtaatc 720 ctgaaggtga agatcctgag agggaacctg tagaaaatga agattataga gaaaagtctt 780 cagatgatga tgaaatggat tcttccttgg tctctcagca gcctcccgat aaccaggaaa 840 aggaacgact aaatacatcc attccacaaa aaaggaaaat gagaaatctg ttagttacca 900 ttgagaatga tactcctcta gaggaactct caaaatatgt agacatcagt attattgccc 960 ttactcgaaa tcggaggaca aggagatggt acacttgtcc actgtgtggg aaacagttta 1020 atgaaagttc ttacctcatt tcccaccaga ggacccacac tggagaaaaa ccctatgact 1080 gtaatcactg tgggaaaagc ttcaatcata aaacaaacct caataaacat gagcgaattc 1140 atacaggaga gaaaccttat tcctgttctc agtgtggaaa aaacttccgt cagaattctc 1200 atcggagtcg tcatgaagga atccatataa gggagaagat atttaagtgt ccagaatgtg 1260 ggaaaacctt cccaaagaat gaggagtttg tgcttcatct gcagagtcat gaggctgaga 1320 gaccatatgg ttgcaaaaaa tgtgggagaa gatttggtcg gctgtcaaac tgtacccggc 1380 atgagaaaac ccactcagcc tgtaagaccc gaaagcagaa gtaatactgg gaaccctttc 1440 tgggtctgat ggtgctgcct caacctgaga gctttcataa gtagttctga attcccaagc 1500 tgcctaaaaa ggtataaatg tgtaaaaatc tcattattgc caaaattgga taaatgccca 1560 tcttagctaa aacctcaaat tgctagaaaa ttcacaggga agaaaacatt tcaagggcta 1620 tacctcagca tctaggcttt ttggactaag gagctttcct ttttgaagtt atatgataat 1680 gtacaggtca cagatcccct ttcccaacac tttgaagatg aatctggagt ctgcttactt 1740 ggaaggcaaa gagtgacttg tgtctattga aagtatatcc gttttccccc cacatgggga 1800 ttcatacttg agaaatagtg caaagatgct tatctggaac tgtgttctgg tgaaagaacc 1860 aaattactgg cttgttagcc aacagcttct gatagcaatt catataaccc tctaagaata 1920 cctgtttaag tcttgagtgt tgaaaggaat tgtttacttt ggaatatagg aaaacagttg 1980 aatgtcagac tctcatttgt atgtgatcta aatttgcaat caatttcaat aatatttaca 2040 atttgtgata aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 2098 <210> SEQ ID NO 18 <211> LENGTH: 383 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 282, 328, 341, 371 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 18 gttacagaga tgttgggcag agtatgcagg tgtttcattg tgaactctag ctttgatcat 60 ggtaaaaagt taaccttttc tattttttaa tggatgttat accaactatt cagaggaact 120 catacttcaa aaatattagg aaaatctgtc ttatagtttc tctaataaat atctgaaatc 180 tcagtacgac atgaaagaat gtcagaccat tgttattgtt gaaagtcatt tgatgatggg 240 taaattctat ggaaaagtaa gtgatttgca tgtataatat cngggaaaat ttaggcatcc 300 ccagtgtgac tggggccaag gaggagcngg tgcacccgtg ncccgtggcc ctaaggtccc 360 gattcccccc ngtgtcccct ttt 383 <210> SEQ ID NO 19 <211> LENGTH: 311 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 8, 39, 101, 120, 175, 231, 289, 295, 306 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 19 tttttttntt tacttgaaag agaacatgtt tatttacanc actatttcct ttttacaatg 60 cctccacctt ttgaataata aaattttcca gggaatcagg ncattttaaa ttattaaggn 120 attttaacaa atacaatttt caccctatga tttttattta catgagtttt caagngtttt 180 aaataggttc ttttggaaac tgcacaatat aaccaggagg gcctgactcg naccctggca 240 tcttttccaa aaactttcag tctgggggaa ttatggttta taatcaaanc cttgncactt 300 gggggncttt t 311 <210> SEQ ID NO 20 <211> LENGTH: 1951 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 aaaaatttaa ctcagaagac tcacgtgact cttcatggaa cagaactgtg tgatgaatcc 60 tacccggctt tactcactga cattcctgtt ggagacttac atccagggga acagctggaa 120 aaaatgttgt atgttcgctg tggaacagtg ggttccagaa tgtttcttgt atatgtttct 180 tacctgataa atacaaccat tgaagaaaaa gaaattgttt gcaagtgtca caaggatgaa 240 actgtaacaa ttgaaacagt ctttccattt gatgttgcgg ttaaatttgt ttctaccaag 300 tttgagcacc tggaaagggt ttatgctgac atcccctttc tgttgatgac ggacctctta 360 agtgcctcac cctgggccct cactattgtt tccagtgagc tccagcttgc tccatccatg 420 accacagtgg accagctcga gtctcaagtg gacaatgtta tcttacagac tggagagagt 480 gctagtgaat gcttttgtct tcaatgccca tctcttggaa atattgaagg tggagtagca 540 accgggcatt atattatctc ttggaaaagg acctcagcaa tggagaatat ccccatcatc 600 acaactgtca tcactctgcc gcacgtgatt gtggagagta tccctctcca tgtgaatgca 660 gatctgccgt catttgggcg tgtcagagag tcgttacctg tcaagtatca cctacagaat 720 aagaccgact tagttcaaga tgtagaaatt tctgtggagc ccagtgatgc cttcatgttc 780 tcaggtctca aacagattcg attacgtatc ctccctggca cggagcagga aatgctatat 840 aatttctatc ctctgatggc tggataccag cagctgccat ctctcaacat caacttgctt 900 agatttccta acttcacaaa tcagctgctc aggcgtttta tacctaccag tatttttgtc 960 aagccacagg gtcgactcat ggatgatacc tctattgctg ctgcatgatg ttcaagaccg 1020 gcccttggct gttgttacag agatgttggg cagagctatg caggtgtttc attgtgaact 1080 ctagctttga tcatggtaaa aagctaacct tttctatttt ttaatggatg ttataccaac 1140 tattcagagg aactcatact tcaaaaatat taggaaaatc tgtcttatag tttctctaat 1200 aaatatctga aatctcagta cgacatgaaa gaatgtcaga ccattgttat tgttgaaagt 1260 catttgatga atggtaaatt ctatgaaaag taagtgattt gcatgtataa tatcaggaaa 1320 attaagcatc ccaagtgtga ctggacaaag agagcagatg caccagtgcc tgtgccataa 1380 agttccgaat cccccatgtg tctctttcag agctggccag accggaaata aatcattctc 1440 ataaattcag tgtgtactca gaacacatac acaacaacat agtgagttgt atgactgata 1500 cggaaaactt ccagaaagtt ttaatcaaag cagtttaatt aaggtatcaa aaatatcttt 1560 gcttactatc aagaagtgtc aaataggttc agcttgctgc caaaatatgg atcatttatg 1620 aagcaggttc atattttaga ggtgttaata aaatcctcat cggaaaagat ccaaagtgca 1680 aggatttgat tataaacata atttcctaga ctgaaagttt ttggaaaaga tgcagggtct 1740 gagtcaggcc ttctggttat attgtgcagt ttcaaaagaa ctatttaaaa ctcttgaaaa 1800 ctcatgtaaa taaaaatcat agggtgaaaa ttgtatttgt taaaatacct taataattta 1860 aaatgacctg atttcctgga aaattttatt attcaaaagg tggaggcatt gtaaaaagga 1920 aatagtgatg taaataaaca tgttctcttt c 1951 <210> SEQ ID NO 21 <211> LENGTH: 245 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 132, 149, 174, 241 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 21 attaagtata tataatatta cagggtaata tttacaaagt tatgtttttt tttaaataaa 60 aaagtacctt ggcaaagatt gcagatattc aaagctttaa acagtgataa attgatttaa 120 tacatataaa anaaaaaacc tttaacggna acacagctgt aaaacaactt tggncttcaa 180 atcactggca aaaaaatggg ctactgacaa atgggcacac ctttaattgc tatgcaaaaa 240 ngctc 245 <210> SEQ ID NO 22 <211> LENGTH: 424 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 345, 395 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 22 tttactcctc catctcagta ataaaaatta agctgtaatc aaccttctag gtttctcttg 60 tcttaaaatg ggtattcaaa aatggggatc tgtggtgtat gtatggaaac acatactcct 120 taatttacct gttgttggaa actggagaaa tgattgtcgg gcaaccgttt attttttatt 180 gtattttatt tggttgaggg atttttttat aaacagtttt acttgtgtca tattttaaaa 240 ttactaactg ccatcacctg ctggggtcct ttgttaggtc attttcagtg actaataggg 300 gataatccag ggtaactttg gaagaggatg agcagtgagt gaccngggca gtttttctgg 360 cctttaggct tttggacagt ttcttaattt aaggntccat tgaaggaccc agcttttctc 420 atta 424 <210> SEQ ID NO 23 <211> LENGTH: 311 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 105, 303 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 23 ttttcttgac aatgtccttt taattgtact cttttcaaaa aatctccttt ctcagttaaa 60 aaagacaagg catgatgaag acctgctcta gcccatactg ggggntgatc tcggtcctgg 120 gggaggccag gccggactct tccaaggcct cctccctggg cagtcccagc aatggggcca 180 gtggcagggc aggttctccc tgccagaacc cgatcctagc ccttcagaag gactggacct 240 ctgtgtccct tcagtgggaa gccaccttgg gacacacgca gtcattcagg tgggacataa 300 ggncactttt t 311 <210> SEQ ID NO 24 <211> LENGTH: 450 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 196, 338, 355, 363, 406, 415, 434, 439 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 24 tgatccggaa gcaggccaac cgtatgagct tcggagagat cgaggaggac gcctaccagg 60 aggacctggg attcagcctg ggccacctgg gcaagtcggg cagtgggcgt gtgcggcaga 120 cacaggtaaa cgaggccacc aaggccagga tctccaagac gctgcaggta tgggccagac 180 ccaggtgggg ctgggngacc gagggacaca aggtgggggg agcccagatc gcagcctccc 240 tgtcctcccc acagcggacc ctgcagaagc agagcttcgt atatggcggg aagtccacca 300 tccgcgaccg ctccttcggg gcacggcctt ccagcgtngg cctttcaccc cattncaggg 360 gcntgggaga tttttgaaac ccacagggcg gcagagaaga aggttnggtt taggncaacc 420 agaatttttt tttncagant ggtttaattt 450 <210> SEQ ID NO 25 <211> LENGTH: 1834 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25 agaaacagtg gtgcgcggag aggagaggcc tcgggatgtc tctggcagat gagctcttag 60 ctgatctcga agaggcagca gaagaggagg aaggaggaag ctatggggag gaagaagagg 120 agccagcgat cgaggatgtg caggaggaga cacagctgga tctttccggg gattcagtca 180 agaccatcgc caagctatgg gatagtaaga tgtttgctga gattatgatg aagattgagg 240 agtatatcag caagcaagcc aaagcttcag aagtgatggg accagtggag gccgcgcctg 300 aataccgcgt catcgtggat gccaacaacc tgaccgtgga gatcgaaaac gagctgaaca 360 tcatccataa gttcatccgg gataagtact caaagagatt ccctgaactg gagtccttgg 420 tccccaatgc actggattac atccgcacgg tcaaggagct gggcaacagc ctggacaagt 480 gcaagaacaa tgagaacctg cagcagatcc tcaccaatgc caccatcatg gtcgtcagcg 540 tcaccgcctc caccacccag gggcagcagc tgtcggagga ggagctggag cggctggagg 600 aggcctgcga catggcgctg gagctgaacg cctccaagca ccgcatctac gagtatgtgg 660 agtcccggat gtccttcatc gcacccaacc tgtccatcat tatcggggca tccacggccg 720 ccaagatcat gggtgtggcc ggcggcctga ccaacctctc caaggtgccc gcctgcaaca 780 tcatgctgct cggggcccag cgcaagacgc tgtcgggctt ctcgtctacc tcagtgctgc 840 cccacaccgg ctacatctac cacagtgaca tcgtgcagtc cctgccaccg gatctgcggc 900 ggaaagcggc ccggctggtg gccgccaagt gcacactggc agcccgtgtg gacagtttcc 960 acgagagcac agaagggaag gtgggctacg aactgaagga tgagatcgag cgcaaattcg 1020 acaagtggca ggagccgccg cctgtgaagc aggtgaagcc gctgcctgcg cccctggatg 1080 gacagcggaa gaagcgaggc ggccgcaggt accgcaagat gaaggagcgg ctggggctga 1140 cggagatccg gaagcaggcc aaccgtatga gcttcggaga gatcgaggag gacgcctacc 1200 aggaggacct gggattcagc ctgggccacc tgggcaagtc gggcagtggg cgtgtgcggc 1260 agacacaggt aaacgaggcc accaaggcca ggatctccaa gacgctgcag cggaccctgc 1320 agaagcagag cgtcgtatat ggcgggaagt ccaccatccg cgaccgctcc tcgggcacgg 1380 cctccagcgt ggccttcacc ccactccagg gcctggagat tgtgaaccca caggcggcag 1440 agaagaaggt ggctgaggcc aaccagaagt atttctccag catggctgag ttcctcaagg 1500 tcaagggcga gaagagtggc cttatgtcca cctgaatgac tgcgtgtgtc caaggtggct 1560 tcccactgaa gggacacaga ggtccagtcc ttctgaaggg ctaggatcgg gttctggcag 1620 ggagaacctg ccctgccact ggccccattg ctgggactgc ccagggagga ggccttggaa 1680 gagtccggcc tggcttcccc caggaccgag atcaccgccc agtatgggct agagcaggtc 1740 ttcatcatgc cttgtctttt ttaactgaga aaggagattt tttgaaaaga gtacaattaa 1800 aaggacattg tcaagaaaaa aaaaaaaaaa aaaa 1834 <210> SEQ ID NO 26 <211> LENGTH: 251 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 3, 30, 36, 116, 122, 143, 239 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 26 aangttaaaa tcacatgcat aattatagan tatttnaaag ttacaaaaat attttaaaac 60 caatcctgac agtttacctg caactgctat aaaaatttct atgaaatata taaaancatg 120 anggctcttt gtaaaaaaaa aanggaaaaa gaaaggaagg aaggcaggga tgaagccatc 180 cacaggagtg agaatcacct gacgcactgc atcgcaagca tctgctgttg aattcaaang 240 aacttgtatc t 251 <210> SEQ ID NO 27 <211> LENGTH: 472 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 24, 25, 365, 392, 405, 420, 426, 433, 445, 458, 467 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 27 ggagaaccac caaccggacc atcnnctctg tggacgactt ccagaattac ctccgagttg 60 catttcagga ggtcaacagt ggttgcacag gaaagaccct ccttgtgaga ccttacatca 120 ccactgagga tgtgtgtcag atctgcgctg agaagttcaa ggtgggggac cctgaggagt 180 acagcctctt tctcttcgtt gacgagacat ggcagcagct ggcagaggac acttaccctc 240 aaaaaatcaa ggcggactgc cacagccgac cacagcccca catcttccac tttgtctaca 300 aacgcatcaa ggaacgatcc ttatgggcat cattttccag gaacggggaa ggaggacctc 360 accanctcct aggaaggaca gggcgggatt tnccagttgg ttgcntccaa agggggagtn 420 gggagncttt gcntttcccg ttttnaacat gtttgagntt gaaaagnagt tc 472 <210> SEQ ID NO 28 <211> LENGTH: 416 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 105, 119, 123, 188, 215, 216, 217, 223, 224, 416 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 28 ttcatataaa actatttatt cataaatatt ttccaaaatg aaaataggtt taccaaaaaa 60 tgtccctcac tggggagggg aggagggggc agccctcgcc cccgngcccc cagggtggna 120 tcnagaggaa aacctcccgg ccccctccct gcttcctggg agagggggat gccccgtcgg 180 cttggggnct ccctccagtc ttccagggca gggcnnnacc tgnncagggg gatcagcatg 240 agggggaagg gggtgggtag agggaggggc cggtgtcact ggaggtcccg gtcctccagg 300 tagcggtact caaaggtgaa gccttccttc ttccgctggc cccacttctc gtagtcaaag 360 tagatgtagg tgccctggcc gggggagaag gcggtcagtg agtggacgag gaggtn 416 <210> SEQ ID NO 29 <211> LENGTH: 4133 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 29 aaattctccc tgggggtaag gtaccagccc tgtcctttat gggcttcttg ttctaaagca 60 tatccgtccc atatggttgc tgctagtcac atgtggtgat tagtaactag ttaaaaatga 120 aaaattcagt tcctccatta cacttgccac atttcagatg ttcagtggcc aacagatatg 180 cgcaaataga gtgtttccag cattgcaaag ttctgttgga tagcactgtt tgccagatgt 240 tcccttcttt gtgggtgagg actcttttgg tgtgacttcc ctctgtattg aggctcttgt 300 tcctcagtat ggggctgttt ctgtctttac agtaagtgac tactccaggg ttccctgccc 360 tgcacacgta gagtgggagc ggcccgtgga tcccagggaa ctgtgctttt cattgtaggc 420 cccctccctg gaggggaaga gggcaatctc cgctggtatc tcagaagtct tcttctgagg 480 cataagcctc tcttcccagg gctcccctgg tctcgctgtc aggccctaag gtatgtcttc 540 ccttggacta aagctccttg gaactccctt ttgacctcag tcttctctgg gttccaggta 600 acttccttta aaataaagac gctcctctct tgaagttttg ggttcctgcc ctgatggtct 660 atgtctccct gactctaaat taccaatcca cttgctatgg gattcctcca tgagtgcaga 720 ttggctccct cacagctgcg gtacctttgc accctcttat cttagtaaga tttctgtctt 780 ctcccaggtc tctcttgggt actgccttct gcccccaaat ctctaagcct tcttggtatt 840 agcttctttg ggttaggagt gttatttcct tttggtttaa ggatcctgct ctggaataaa 900 tgtcttggtg gtttgagtcc cttctacttg gcattcagcc ctgtctgcat gagcgggttc 960 agctcttcac agctttcggc atctctgctc gccgtcgttt tcccccaccc ccaatctttc 1020 ttctcctacc tacagcttac acacacacac acacacacac acacacacac acgcccttct 1080 ctgtgagctg ccagtttcat ttgtctcctg acttgtctga gggatgacct ctcctagcca 1140 cctctgccca gcccctctga gtaggaagtg tgatttccag ggctaatgcc tccatcccag 1200 tcatcagctg tgtgcagcat gactgtcctg ctctgaaaaa cctttttgag tgtattctgg 1260 gggaaggtac tccatgctct aggaattttc cacttcctga gtcagaggca cacaaaaaag 1320 tatgtaactt ttcttgtttc aacaaactta tggggtcccc tgttggccag acactatgct 1380 gggcagtcaa gcgagcatca ggagaactgg ggctggtctc ttgtcagata gcaaatgctt 1440 cttctcttta ccagtcccac ctacctcact atgctgacta ggtccatgtc tctgggtttt 1500 taccagccag ggaatacgtg ttaattcctc tccaatctct cctagcagcg tccgtctcca 1560 agagagtatg aagagagtgc gtctgtaggg cagggaagat ggcggacaag cgcaaactcc 1620 aaggtgagat tgatcgctgc ctcaagaagg tgtccgaggg cgtggagcag tttgaagata 1680 tttggcagaa gctccacaat gcagccaacg cgaaccagaa agaaaagtat gaggctgacc 1740 taaagaagga gattaagaag ctacaacggc tgagggacca aatcaagaca tgggtagcgt 1800 ccaacgagat caaggacaag aggcagctta tagacaaccg caagctcatt gagacgcaaa 1860 tggaacggtt caaagttgtg gaacgagaga ccaaaaccaa agcttacagc aaagagggcc 1920 tgggcctggc ccagaaggta gatcctgccc agaaggagaa ggaagaggtt ggccagtggc 1980 tcacgaatac catcgacacg ctcaacatgc aggtggacca gtttgagagt gaagtggagt 2040 cactgtcagt gcagacacgc aagaagaagg gcgacaagga taagcaggac cggattgagg 2100 gcttgaagcg gcacatcgag aagcaccgct accacgtgcg catgctagag accatcctgc 2160 gcatgctgga caatgactcc atcctcgttg acgccatccg caagatcaag gacgacgttg 2220 agtactatgt tgactcatcc caggaccccg acttcgagga gaacgagttt ctctacgatg 2280 acctggacct cgaggacatt ccacaggcgc tggtcgccac ctcccccccc agccacagcc 2340 acatggagga tgagatcttc aaccagtcca gcagcacgcc cacctcaacc acctccagct 2400 ctcccatccc gcccagccca gccaactgta ccacggaaaa ctctgaagat gataagaaga 2460 ggggacgttc cacagacagt gaagtcagcc agtctccagc caaaaacggc tccaagcctg 2520 tccacagcaa ccagcaccct cagtccccag ctgtgccgcc cacctacccc tccggccccc 2580 cgcctgctgc ctctgccttg agcaccactc ctggcaacaa tggggtcccc gcccccgcag 2640 cacccccaag tgccctgggc cccaaggcca gtccagctcc cagccacaac tcgggcaccc 2700 ctgctcccta tgcccaggct gtggccccac cagctcccag tgggcccagc acgacccagc 2760 cccggccccc cagcgtccag cctagcggag gcggaggcgg cggcagcgga ggcggaggga 2820 gcagcagcag tagtaacagc agtgccggtg gaggggctgg caagcagaat ggcgccacca 2880 gttacagctc agttgtggca gacagcccgg cagaggtggc tttgagcagc agtgggggca 2940 acaatgccag cagccaggcc ttgggccccc cttccggccc ccacaaccca cctcccagca 3000 cctcgaagga acccagtgcg gcagccccaa cgggggctgg gggcgtggcc ccaggctcag 3060 ggaacaactc agggggaccc agcctcctgg tgccactgcc tgtgaatcct cccagctccc 3120 caacgcccag cttcagtgat gccaaggcag ccggtgccct gctcaatggg cctccacagt 3180 tcagcaccgc cccagaaatc aaggcccctg agcctctgag ctccttgaag tccatggcgg 3240 aacgggcagc catcagctct ggcattgagg accctgtgcc aacgctgcac ctgaccgagc 3300 gagacatcat cctgagcagt acatcagcac ctccggcctc agcccagccg cccctgcagc 3360 tgtcagaggt gaacataccg ctgtcgctgg gtgtctgtcc actgggccct gtgcccctca 3420 ccaaggagca gctctatcag caggccatgg aagaggccgc ctggcaccac atgcctcacc 3480 cctctgactc tgagcgtatt cggcagtacc tcccccggaa cccctgtccg acgcccccct 3540 accaccacca gatgccaccc ccacactcgg acactgtgga attctaccag cgcctgtcga 3600 ccgagacact cttcttcatc ttctactatc tggagggcac taaggcacag tatctggcag 3660 ccaaggccct aaagaagcag tcatggcgat tccacaccaa gtacatgatg tggttccaga 3720 ggcacgagga gcccaagacc atcactgacg agtttgagca gggcacctac atctactttg 3780 actacgagaa gtggggccag cggaagaagg aaggcttcac ctttgagtac cgctacctgg 3840 aggaccggga cctccagtga caccggcccc tccctctacc cacccccttc ccccgcatgc 3900 tgatccccct gcccaggtga gggccctgcc ctggaagact ggagggaggc cccaagccac 3960 ggggcatccc cctctcccag gaagcaggga gggggccggg aggttttcct ctcagcccca 4020 ccctgggggc ccgggggcga gggctgcccc ctcctcccct ccccagtgag ggacattttt 4080 tggtaaacct attttcattt tggaaaatat ttatgaataa atagttttat atg 4133 <210> SEQ ID NO 30 <211> LENGTH: 145 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 28, 29, 31, 117, 130 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 30 tatgagaaat gcccagaaag gctttgcnnc ntccatccgt ctgtggaggc tgcctgcctc 60 cggggtggga tgggtggttt ctcctccaat tcagacccaa gaggtagccc ccgaggnaat 120 gtacctggtn ggaagcagct caagt 145 <210> SEQ ID NO 31 <211> LENGTH: 444 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 13, 98, 359, 379, 431 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 31 attagactag ganatataat ttatttcata aaaattaatt ttgttacaat aggaatgcta 60 aaggttattt ataggttgca gtttacagaa taaacagngg tgggattggg ggccatccct 120 ggggccctgc acccccctct cccgggcata taaccatgtc cacagacctg gcaggggtcc 180 agccctttgc cccaccaaga gctccctgca ccaaagctcc tggtcacctc ccctaaggga 240 cccggctcag ctgcctagga gctggggaat agggaccaga gtgccctgga agggtccagg 300 aaattgagaa ggatcccctg caccctcaag gagaacccct accccttgag ctcttgganc 360 cgggggcact tgttgagang aaggccagaa gggagaggca ccttagaaag atacatttga 420 cttgaaccct ntgggcttca ggga 444 <210> SEQ ID NO 32 <211> LENGTH: 513 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 41 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 32 acatgatctc gaaaatagtg tgatttagat tctgccttgg ntgagctctg agggctacat 60 ttacctgtca gtttggggat tttagtgcag atttttttta aaaaaattaa actctggtaa 120 gtactcagga ggctgagaac acaggcccct tctctccccg atcctctgta tgcaggctga 180 cttaagcccc tttatgtttg gctagtgcca caacaaaaca gccccaaaca gattgccata 240 agcatgctag cctggcttgg tgtttgacga taaaatcaga ctggtaagtg cagtcagtgt 300 tcaggaaaga atctccaggc tcttctccca tgacctggtt ttaaaatcag cattcataca 360 gctgctttac catctctctg tcctctgcag atgacccggt cctaggcagg ggaccaaaat 420 tccttggtca gctgaggaag tcctgaagaa acatcctgaa gatgatgact gcactggcca 480 tcgtggggca gatgcagctt ccatctacct gat 513 <210> SEQ ID NO 33 <211> LENGTH: 4491 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33 aaatgtagag aagcagccga taaaatagca ttgcctgaag aagtttggag gctgagagca 60 gcagtagact ggccaactgc agagcaagtt gtttctccag ccgtgcggtg cagcctcatg 120 cccccaaccc agcttagcca ctgtaagaag acgttcactg tacagacgac caaacttgcc 180 gtggaagaga cagttgtgag attcccttgc aaatttacat acgagaatgg cttgtgaaat 240 catgcctctg caaagttcac aggaagatga aagacctctg tcacctttct atttgagtgc 300 tcatgtaccc caagtcagca atgtgtctgc aaccggagaa ctcttagaaa gaaccatccg 360 atcagctgta gaacaacatc tttttgatgt taataactct ggaggtcaaa gttcagagga 420 ctcagaatct ggaacactat cagcatcttc tgccacatct gccagacagc gccgccgcca 480 gtccaaggag caggatgaag ttcgacatgg gagagacaag ggacttatca acaaagaaaa 540 tactccttct gggttcaacc accttgatga ttgtattttg aatactcagg aagtcgaaaa 600 ggtacacaaa aatacttttg gttgtgctgg agaaaggagc aagcctaaac gtcagaaatc 660 cagtactaaa ctttctgagc ttcatgacaa tcaggacggt cttgtgaata tggaaagtct 720 caattccaca cgatctcatg agagaactgg acctgatgat tttgaatgga tgtctgatga 780 aaggaaagga aatgaaaaag atggtggaca cactcagcat tttgagagcc ccacaatgaa 840 gatccaggag catcccagcc tatctgacac caaacagcag agaaatcaag atgccggtga 900 ccaggaggag agctttgtct ccgaagtgcc ccagtcggac ctgactgcat tgtgtgatga 960 aaagaactgg gaagagccta tccctgcttt ctcctcctgg cagcgggaga acagtgactc 1020 tgatgaagcc cacctctcgc cgcaggctgg gcgcctgatc cgtcagctgc tggacgaaga 1080 cagcgacccc atgctctctc ctcggttcta cgcttatggg cagagcaggc aatacctgga 1140 tgacacagaa gtgcctcctt ccccaccaaa ctcccattct ttcatgaggc ggcgaagctc 1200 ctctctgggg tcctatgatg atgagcaaga ggacctgaca cctgcccagc tcacacgaag 1260 gattcagagc cttaaaaaga agatccggaa gtttgaagat agattcgaag aagagaagaa 1320 gtacagacct tcccacagtg acaaagcagc caatccggag gttctgaaat ggacaaatga 1380 ccttgccaaa ttccggagac aacttaaaga atcaaaacta aagatatctg aagaggacct 1440 aactcccagg atgcggcagc gaagcaacac actccccaag agttttggtt cccaacttga 1500 gaaagaagat gagaagaagc aagagctggt ggataaagca ataaagccca gtgttgaagc 1560 cacattggaa tctattcaga ggaagctcca ggagaagcga gcggaaagca gccgccctga 1620 ggacattaag gatatgacca aagaccagat tgctaatgag aaagtggctc tgcagaaagc 1680 tctgttatat tatgaaagca ttcatggacg gccggtaaca aagaacgaac ggcaggtgat 1740 gaagccacta tacgacaggt accggctggt caaacagatc ctctcccgag ctaacaccat 1800 acccatcatt ggttccccct ccagcaagcg gagaagccct ttgctgcagc caattatcga 1860 gggcgaaact gcttccttct tcaaggagat aaaggaagaa gaggaggggt cagaagacga 1920 tagcaatgtg aagccagact tcatggtcac tctgaaaacc gatttcagtg cacgatgctt 1980 tctggaccaa ttcgaagatg acgctgatgg atttatttcc ccaatggatg ataaaatacc 2040 atcaaaatgc agccaggaca cagggctttc aaatctccat gctgcctcaa tacctgaact 2100 cctggaacac ctccaggaaa tgagagaaga aaagaaaagg attcgaaaga aacttcggga 2160 ttttgaagac aactttttca gacagaatgg aagaaatgtc cagaaggaag accgcactcc 2220 tatggctgaa gaatacagtg aatataagca cataaaggcg aaactgaggc tcctggaggt 2280 gctcatcagc aagagagaca ctgattccaa gtccatgtga ggggcatggc caagcacagg 2340 gggctggcag ctgcggtgag agtttactgt ccccagagaa agtgcagctc tggaaggcag 2400 ccttggggct ggccctgcaa agcatgcagc ccttctgcct ctagaccatt tggcatcggc 2460 tcctgtttcc attgcctgcc ttagaaactg gctggaagaa gacaatgtga cctgacttag 2520 gcattttgta attggaaagt caagactgca gtatgtgcac atgcgcacgc gcatgcacgc 2580 acacacacac acagtagtgg agctttccta acactagcag agattaatca ctacattaga 2640 caacactcat ctacagagaa tatacactgt tcttccctgg ataactgaga aacaagagac 2700 cattctctgt ctaactgtga taaaaacaag ctcaggactt tattctatag agcaaacttg 2760 ctgtggaggg ccatgctctc cttggaccca gttaactgca aacgtgcatt ggagccctat 2820 ttgctgccgc tgccattcta gtgacctttc cacagagctg cgccttcctc acgtgtgtga 2880 aaggttttcc ccttcagccc tcaggtagat ggaagctgca tctgcccacg atggcagtgc 2940 agtcatcatc ttcaggatgt ttcttcagga cttcctcagc tgacaaggaa ttttggtccc 3000 tgcctaggac cgggtcatct gcagaggaca gagagatggt aagcagctgt atgaatgctg 3060 attttaaaac caggtcatgg gagaagagcc tggagattct ttcctgaaca ctgactgcac 3120 ttaccagtct gattttatcg tcaaacacca agccaggcta gcatgctcat ggcaatctgt 3180 ttggggctgt tttgttgtgg cactagccaa acataaaggg gcttaagtca gcctgcatac 3240 agaggatcgg ggagagaagg ggcctgtgtt ctcagcctcc tgagtactta ccagagttta 3300 atttttttaa aaaaaatctg cactaaaatc cccaaactga caggtaaatg tagccctcag 3360 agctcagccc aaggcagaat ctaaatcaca ctattttcga gatcatgtat aaaaagaaaa 3420 aaaagaagtc atgctgtgtg gccaattata atttttttca aagactttgt cacaaaactg 3480 tctatattag acattttgga gggaccagga aatgtaagac accaaatcct ccatctcttc 3540 agtgtgcctg atgtcacctc atgatttgct gttacttttt taactcctgc gccaaggaca 3600 gtgggttctg tgtccacctt tgtgctttgc gaggccgagc ccaggcatct gctcgcctgc 3660 cacggctgac cagagaaggt gcttcaggag ctctgcctta gacgacgtgt tacagtatga 3720 acacacagca gaggcaccct cgtatgtttt gaaagttgcc ttctgaaagg gcacagtttt 3780 aaggaaaaga aaaagaatgt aaaactatac tgacccgttt tcagttttaa agggtcgtga 3840 gaaactggct ggtccaatgg gatttacagc aacattttcc attgctgaag tgaggtagca 3900 gctctcttct gtcagctgaa tgttaaggat ggggaaaaag aatgccttta agtttgctct 3960 taatcgtatg gaagcttgag ctatgtgttg gaagtgccct ggttaatcca tacacaaaga 4020 cggtacataa tcctacaggt ttaaatgtac ataaaaatat agtttggaat tctttgctct 4080 actgtttaca ttgcagattg ctataatttc aaggagtgag attataaata aaatgatgca 4140 ctttaggatg tttcctattt ttgaaatctg aacatgaatc attcacatga ccaaaaattg 4200 tgttttttta aaaatacatg tctagtctgt cctttaatag ctctcttaaa taagctatga 4260 tattaatcag atcattacca gttagctttt aaagcacatt tgtttaagac tatgtttttg 4320 gaaaaatacg ctacagaatt tttttttaag ctacaaataa atgagatgct actaattgtt 4380 ttggaatctg ttgtttctgc caaaggtaaa ttaactaaag atttattcag gaatccccat 4440 ttgaatttgt atgattcaat aaaagaaaac accaagtaag ttatataaaa t 4491 <210> SEQ ID NO 34 <211> LENGTH: 335 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 42, 43, 53, 89, 90, 91, 97, 128, 182, 324 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 34 gagaatttaa gcttttatta ataaatcatg attttctatt gnntacataa tanagtacaa 60 ttaacaataa cataacatta caacattann nattaanact ttcagaatca ccttgatcaa 120 tatataangc tttagttcct tatttcaaca gtgttcttct catatgcaaa acagcttccc 180 anaataagag attcgtgaat gaaattttat aaagcttcct gtgtaccaaa gagattgact 240 ccacatcaac tgtcccctac tgaaaatcca aaccatacag gcttgaagga ccagaactga 300 gccacattct attaaagtta tcanagataa aatct 335 <210> SEQ ID NO 35 <211> LENGTH: 410 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 35 ttcagaaaac taagaagtaa gtgtaacttt taaagtaagt atatatcagt gagagtaggc 60 ttgttttaca actatttcta gccagtgagt tgtgttttca tgtctcatca aaagacaata 120 ccacattgca tcattttaca aaatatgttg tcattttcat ttcagttgta acataggaaa 180 atagatattt cctagatgat ttctgagttt cttactgcaa agaacagtta taaattggta 240 tacatgtgtc tctgtaatag ggataatatt gatatatctg ttgctacata tttaagaatc 300 attctatctt atggttgtct tgaggccaag atttaccacc gtttgcccag tgtattgaat 360 tggtggtaga aggtagttcc atgttccatt ggtagatcct taagatttta 410 <210> SEQ ID NO 36 <211> LENGTH: 455 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 423, 429, 453 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 36 ccaactctgc gtatgtattt gaactttcta caaccattaa taacagaaat aattgaatgc 60 tagactaata ctgtgtaaag gagcaatggt caatcttaat ctgattacaa aagtttgaaa 120 aaagaagcct cactcttctg attgccatta taataagtga tggctatact attgaatttg 180 taaagttatc ctaatcaaat actacttttc taatttatat atatttttat atacatgact 240 ccaaataaga ctgtttataa aatgggttcc atccagtaca agtttttaaa ctattgttgt 300 aacacataaa tttgtgctgc ctccaacagc aatgattcaa ctgttagtct ggattacatc 360 attcacatta tcaccaagta tatcccccta aaagtggtcc aattatcccc tttaataaag 420 gcncattcnc aaaggttttg gcattcatca ccnct 455 <210> SEQ ID NO 37 <211> LENGTH: 279 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 276 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 37 ctaaataagg atggaacatt tattgaatga aaaatgcact tttgtttttc cattttttta 60 aataataaaa atcagacaaa caggaactgg gtagtggtga tgaatgcaaa actttgtgaa 120 tgtgctttat aaaagtgata attagacact ttagaggata tacttggtga taatgtgaat 180 gatgtaatca gactaacagt tgaatcattg ctgttggagg cagcacaaat ttatgtgtta 240 caacaatagt ttaaaaactt gtactggatg ggcccnccc 279 <210> SEQ ID NO 38 <211> LENGTH: 247 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 3, 5, 239 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 38 tananagatt aagcccgatt tgcaacattt attgaaataa atgtcatcta ctaaaaacaa 60 ggttaattta taactggatc tcaacttgtt taatagcaat tgaattttga cataaaaatt 120 gcaaaacttc agctaaagaa caaataaaac attcagacac aagtttacac ttcaaaaatt 180 ctatcaactt caacaaataa tgaatgactg tatattaatt tacattagtc ctgtggtcna 240 gaggtca 247 <210> SEQ ID NO 39 <211> LENGTH: 164 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 95 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 39 tcagacaaac aatggtccaa gtctaacagg attgactact atagcagctc atctagtcaa 60 gcaagccaac aaagaatatt tgctggggag tactngcaga agaaaaagca atcgttcagc 120 agtggttaga atacagggtc actcaagtag atgggcactc cagt 164 <210> SEQ ID NO 40 <211> LENGTH: 840 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 40 ggcgtctgcc aggagctacg gccggaagat ggcggcggcc gcagagttgt cgctactgga 60 gaagtccctg ggactgagta aggggaataa atacagtgct cagggcgagc gacagattcc 120 agttcttcag acaaacaatg gtccaagtct aacaggattg actactatag cagctcatct 180 agtcaagcaa gccaacaaag aatatttgct ggggagtact gcagaagaaa aagcaatcgt 240 tcagcagtgg ttagaataca gggtcactca agtagatggg cactccagta aaaatgacat 300 ccacacactg ttgaaggatc ttaattcata tcttgaagat aaagtctacc ttacagggta 360 taactttaca ttagcagata tactattgta ctatggactt catcgcttta tagttgacct 420 gacagttcaa gaaaaggaga aatatcttaa tgtgtctcgc tggttttgtc acattcagca 480 ttatccaggc atcaggcaac atctgtctag tgttgtcttc atcaagaaca gactatatac 540 taattcccac tagaagctgt ccatgccata cagaagatct attaaaaatg ttttaaatgg 600 aaaatgtact ctagaccaca ggactaatgt aaattaatat acagtcattc attatttgtt 660 gaagttgata gaatttttga agtgtaaact tgtgtctgaa tgttttattt gttctttagc 720 tgaagttttg caatttttat gtcaaaattc aattgctatt aaacaagttg agatccagtt 780 ataaattaac cttgttttta gtagatgaca tttatttcaa taaaagttgc aaatcgggaa 840 <210> SEQ ID NO 41 <211> LENGTH: 375 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 299, 329, 351, 367 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 41 ctcttcataa aaaaatattt attagtttga acatcgattt aaaaaaaaat cagtcacata 60 aaaaaaaccc ttcatgacat gtcttttccc tccacgcctc ctgagatgga cgtgctcacc 120 tgggcctcgg aaatcccaca ctcttcagtc ggcaaactcg cgaacaagaa caggaaatct 180 gccacgcagc aaacacttgg ggaggtcagt gggacactgt tggttttagg gaagaaaatg 240 cccctgtagc tccggcgggg aaccccaaaa cggtcagcaa aggcaggcca cacggagtng 300 ccgggcaaaa ttgagcagga catccttant tttgaagggg aagcggggcc nggtccttgg 360 caaggtngcc tctag 375 <210> SEQ ID NO 42 <211> LENGTH: 481 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 424, 443, 478 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 42 ggcaagccca tgtgtgttga gagcttctca gactatccac ctttgggtcg ctttgctgtt 60 cgtgatatga gacagacagt tgcggtgggt gtcatcaaag cagtggacaa gaaggctgct 120 ggagctggca aggtcaccaa gtctgcccag aaagctcaga aggctaaatg aatattatcc 180 ctaatacctg ccaccccact cttaatcagt ggtggaagaa cggtctcaga actgtttgtt 240 tcaattggcc atttaagttt agtagtaaaa gactggttaa tgataacaat gcatcgtaaa 300 accttcagaa ggaaaggaga atgttttgtg gaccactttg gttttccttt ttttgccgtg 360 tggcagtttt aaagttaatt aagtttttaa aaatcagtac cttttttatt ggaacaactt 420 tggnccaaaa atttgtcccc agnatttttg agaccccttt aaaaagttta aatggggnaa 480 a 481 <210> SEQ ID NO 43 <211> LENGTH: 409 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 409 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 43 tggacacgtt acgaagaaat atcacatagg taagagtaag aaaactgaac agcctgccac 60 attaaaatga tggagaacaa agaaaatctg gcccagtttt tctagaaatc tcctccttaa 120 ggtgtgagat gagagcccct agtggaatta agtcctattt ctctctacat ccttgctgca 180 atgaagttta cagcaggttc ccttatagag agcccactct cctaagcaga tggagttaca 240 aatgaaaacc catagccaca cacacacaca cacacacaca aaaggagaaa taagagcagc 300 aagatcatcc aagaatacta catgtgctgc cagaataatt cctttaaaag tcaaatccag 360 gaagcacaga tcaacatctc acaaaaaact ttagcagtgg gaggccccn 409 <210> SEQ ID NO 44 <211> LENGTH: 474 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 44 gagccaaggt atgtagggtg tgtggctggc catcagtgga gcacgaagag agaatgggat 60 accattgtgg gaagagaaga aaagttcctc aggggcctcc cactgctaaa gttttttgtg 120 agatgttgat ctgtgcttcc tggatttgac ttttaaagga attattctgg cagcacatgt 180 agtattcttg gatgatcttg ctgctcttat ttctcctttt gtgtgtgtgt gtgtgtgtgt 240 gtggctatgg gttttcattt gtaactccat ctgcttagga gagtgggctc tctataaggg 300 aacctgctgt aaacttcatt gcagcaagga tgtagagaga aataggactt aattccacta 360 ggggctctca tctcacacct taaggaggag atttctagaa aaactgggcc agattttctt 420 tgttctccat cattttaatg tggcaggctg ttcagttttc ttactcttac ctat 474 <210> SEQ ID NO 45 <211> LENGTH: 465 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 45 ggtatttaaa caataaatgt gcagttttaa ctaacaggat atttaatgac aaccttctgg 60 ttggtaggga catctgtttc taaatgttta ttatgtacaa tacagaaaaa aattttataa 120 aattaagcaa tgtgaaactg aattggagag tgataataca agtcctttag tcttacccag 180 tgaatcattc tgttccatgt ctttggacaa ccatgacctt ggacaatcat gaaatatgca 240 tctcactgga tgcaaagaaa atcagatgga gcatgaatgg tactgtaccg gttcatctgg 300 actgccccag aaaaataact tcaagcaaac atcctatcaa caacaaggtt gttctgcata 360 ccaagctgag cacagaagat gggaacactg gtggaggatg gaaaggctcg ctcaatcaag 420 aaaattctga gactattaat aaataagact gtagtgtaga tactg 465 <210> SEQ ID NO 46 <211> LENGTH: 646 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 539, 567, 619, 628 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 46 tatctcacac tgtactttat ttttcttcac aatattaact agacagacaa ggaaagttta 60 atggcaatgt gactttttcc aacaacacaa acaaagtgcc attatagcta atggtggcca 120 actggagact tactttacct taaccatgta aagtatcctt accgtatttt ttatgtgtac 180 agtgttgcag aatatcagcc acctcttaaa agtatcaatc ttaaaaagag ccatggaagg 240 taaaagtatg aaaatcttga taacaaaagc tttcaataca aaaacactta ttgtacactt 300 atttttattt aaaacaaaaa taaccccagt aactcaaaac aaaagcaaac cttggttgaa 360 aacttaagaa ggtataataa acaaaaccac caaaagaaag cttccccaaa agaaatgcaa 420 tccactgtca ctcttgcaaa ttctaccttg gagggaaaaa cttaatgaaa tgagctatct 480 ggagggccca cggagatttt ccaaaaggtt taggtgcatg gatttactca gtatctacnt 540 acagtcttat ttattaatag ctcaganttc ctgattgagc gagcctttcc atctccacca 600 gtgtccccac ttctgtgcnc acttgggntg cagacaccct gtgttg 646 <210> SEQ ID NO 47 <211> LENGTH: 6030 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 47 gttggccccc gttacttttc ctctgggaaa tatggcgcac gctgggagaa cagggtacga 60 taaccgggag atagtgatga agtacatcca ttataagctg tcgcagaggg gctacgagtg 120 ggatgcggga gatgtgggcg ccgcgccccc gggggccgcc cccgcgccgg gcatcttctc 180 ctcgcagccc gggcacacgc cccatacagc cgcatcccgg gacccggtcg ccaggacctc 240 gccgctgcag accccggctg cccccggcgc cgccgcgggg cctgcgctca gcccggtgcc 300 acctgtggtc cacctgaccc tccgccaggc cggcgacgac ttctcccgcc gctaccgccg 360 cgacttcgcc gagatgtcca ggcagctgca cctgacgccc ttcaccgcgc ggggacgctt 420 tgccacggtg gtggaggagc tcttcaggga cggggtgaac tgggggagga ttgtggcctt 480 ctttgagttc ggtggggtca tgtgtgtgga gagcgtcaac cgggagatgt cgcccctggt 540 ggacaacatc gccctgtgga tgactgagta cctgaaccgg cacctgcaca cctggatcca 600 ggataacgga ggctgggatg cctttgtgga actgtacggc cccagcatgc ggcctctgtt 660 tgatttctcc tggctgtctc tgaagactct gctcagtttg gccctggtgg gagcttgcat 720 caccctgggt gcctatctgg gccacaagtg aagtcaacat gcctgcccca aacaaatatg 780 caaaaggttc actaaagcag tagaaataat atgcattgtc agtgatgttc catgaaacaa 840 agctgcaggc tgtttaagaa aaaataacac acatataaac atcacacaca cagacagaca 900 cacacacaca caacaattaa cagtcttcag gcaaaacgtc gaatcagcta tttactgcca 960 aagggaaata tcatttattt tttacattat taagaaaaaa agatttattt atttaagaca 1020 gtcccatcaa aactcctgtc tttggaaatc cgaccactaa ttgccaagca ccgcttcgtg 1080 tggctccacc tggatgttct gtgcctgtaa acatagattc gctttccatg ttgttggccg 1140 gatcaccatc tgaagagcag acggatggaa aaaggacctg atcattgggg aagctggctt 1200 tctggctgct ggaggctggg gagaaggtgt tcattcactt gcatttcttt gccctggggg 1260 ctgtgatatt aacagaggga gggttcctgt ggggggaagt ccatgcctcc ctggcctgaa 1320 gaagagactc tttgcatatg actcacatga tgcatacctg gtgggaggaa aagagttggg 1380 aacttcagat ggacctagta cccactgaga tttccacgcc gaaggacagc gatgggaaaa 1440 atgcccttaa atcataggaa agtatttttt taagctacca attgtgccga gaaaagcatt 1500 ttagcaattt atacaatatc atccagtacc ttaagccctg attgtgtata ttcatatatt 1560 ttggatacgc accccccaac tcccaatact ggctctgtct gagtaagaaa cagaatcctc 1620 tggaacttga ggaagtgaac atttcggtga cttccgcatc aggaaggcta gagttaccca 1680 gagcatcagg ccgccacaag tgcctgcttt taggagaccg aagtccgcag aacctgcctg 1740 tgtcccagct tggaggcctg gtcctggaac tgagccgggg ccctcactgg cctcctccag 1800 ggatgatcaa cagggcagtg tggtctccga atgtctggaa gctgatggag ctcagaattc 1860 cactgtcaag aaagagcagt agaggggtgt ggctgggcct gtcaccctgg ggccctccag 1920 gtaggcccgt tttcacgtgg agcatgggag ccacgaccct tcttaagaca tgtatcactg 1980 tagagggaag gaacagaggc cctgggccct tcctatcaga aggacatggt gaaggctggg 2040 aacgtgagga gaggcaatgg ccacggccca ttttggctgt agcacatggc acgttggctg 2100 tgtggccttg gcccacctgt gagtttaaag caaggcttta aatgactttg gagagggtca 2160 caaatcctaa aagaagcatt gaagtgaggt gtcatggatt aattgacccc tgtctatgga 2220 attacatgta aaacattatc ttgtcactgt agtttggttt tatttgaaaa cctgacaaaa 2280 aaaaagttcc aggtgtggaa tatgggggtt atctgtacat cctggggcat taaaaaaaaa 2340 atcaatggtg gggaactata aagaagtaac aaaagaagtg acatcttcag caaataaact 2400 aggaaatttt tttttcttcc agtttagaat cagccttgaa acattgatgg aataactctg 2460 tggcattatt gcattatata ccatttatct gtattaactt tggaatgtac tctgttcaat 2520 gtttaatgct gtggttgata tttcgaaagc tgctttaaaa aaatacatgc atctcagcgt 2580 ttttttgttt ttaattgtat ttagttatgg cctatacact atttgtgagc aaaggtgatc 2640 gttttctgtt tgagattttt atctcttgat tcttcaaaag cattctgaga aggtgagata 2700 agccctgagt ctcagctacc taagaaaaac ctggatgtca ctggccactg aggagctttg 2760 tttcaaccaa gtcatgtgca tttccacgtc aacagaattg tttattgtga cagttatatc 2820 tgttgtccct ttgaccttgt ttcttgaagg tttcctcgtc cctgggcaat tccgcattta 2880 attcatggta ttcaggatta catgcatgtt tggttaaacc catgagattc attcagttaa 2940 aaatccagat ggcaaatgac cagcagattc aaatctatgg tggtttgacc tttagagagt 3000 tgctttacgt ggcctgtttc aacacagacc cacccagagc cctcctgccc tccttccgcg 3060 ggggctttct catggctgtc cttcagggtc ttcctgaaat gcagtggtgc ttacgctcca 3120 ccaagaaagc aggaaacctg tggtatgaag ccagacctcc ccggcgggcc tcagggaaca 3180 gaatgatcag acctttgaat gattctaatt tttaagcaaa atattatttt atgaaaggtt 3240 tacattgtca aagtgatgaa tatggaatat ccaatcctgt gctgctatcc tgccaaaatc 3300 attttaatgg agtcagtttg cagtatgctc cacgtggtaa gatcctccaa gctgctttag 3360 aagtaacaat gaagaacgtg gacgctttta atataaagcc tgttttgtct tctgttgttg 3420 ttcaaacggg attcacagag tatttgaaaa atgtatatat attaagaggt cacgggggct 3480 aattgctggc tggctgcctt ttgctgtggg gttttgttac ctggttttaa taacagtaaa 3540 tgtgcccagc ctcttggccc cagaactgta cagtattgtg gctgcacttg ctctaagagt 3600 agttgatgtt gcattttcct tattgttaaa aacatgttag aagcaatgaa tgtatataaa 3660 agcctcaact agtcattttt ttctcctctt cttttttttc attatatcta attattttgc 3720 agttgggcaa cagagaacca tccctatttt gtattgaaga gggattcaca tctgcatctt 3780 aactgctctt tatgaatgaa aaaacagtcc tctgtatgta ctcctcttta cactggccag 3840 ggtcagagtt aaatagagta tatgcacttt ccaaattggg gacaagggct ctaaaaaaag 3900 ccccaaaagg agaagaacat ctgagaacct cctcggccct cccagtccct cgctgcacaa 3960 atactccgca agagaggcca gaatgacagc tgacagggtc tatggccatc gggtcgtctc 4020 cgaagatttg gcaggggcag aaaactctgg caggcttaag atttggaata aagtcacaga 4080 atcaaggaag cacctcaatt tagttcaaac aagacgccaa cattctctcc acagctcact 4140 tacctctctg tgttcagatg tggccttcca tttatatgtg atctttgttt tattagtaaa 4200 tgcttatcat ctaaagatgt agctctggcc cagtgggaaa aattaggaag tgattataaa 4260 tcgagaggag ttataataat caagattaaa tgtaaataat cagggcaatc ccaacacatg 4320 tctagctttc acctccagga tctattgagt gaacagaatt gcaaatagtc tctatttgta 4380 attgaactta tcctaaaaca aatagtttat aaatgtgaac ttaaactcta attaattcca 4440 actgtacttt taaggcagtg gctgttttta gactttctta tcacttatag ttagtaatgt 4500 acacctactc tatcagagaa aaacaggaaa ggctcgaaat acaagccatt ctaaggaaat 4560 tagggagtca gttgaaattc tattctgatc ttattctgtg gtgtcttttg cagcccagac 4620 aaatgtggtt acacactttt taagaaatac aattctacat tgtcaagctt atgaaggttc 4680 caatcagatc tttattgtta ttcaatttgg atctttcagg gatttttttt ttaaattatt 4740 atgggacaaa ggacatttgt tggaggggtg ggagggagga acaattttta aatataaaac 4800 attcccaagt ttggatcagg gagttggaag ttttcagaat aaccagaact aagggtatga 4860 aggacctgta ttggggtcga tgtgatgcct ctgcgaagaa ccttgtgtga caaatgagaa 4920 acattttgaa gtttgtggta cgacctttag attccagaga catcagcatg gctcaaagtg 4980 cagctccgtt tggcagtgca atggtataaa tttcaagctg gatatgtcta atgggtattt 5040 aaacaataaa tgtgcagttt taactaacag gatatttaat gacaaccttc tggttggtag 5100 ggacatctgt ttctaaatgt ttattatgta caatacagaa aaaaatttta taaaattaag 5160 caatgtgaaa ctgaattgga gagtgataat acaagtcctt tagtcttacc cagtgaatca 5220 ttctgttcca tgtctttgga caaccatgac cttggacaat catgaaatat gcatctcact 5280 ggatgcaaag aaaatcagat ggagcatgaa tggtactgta ccggttcatc tggactgccc 5340 cagaaaaata acttcaagca aacatcctat caacaacaag gttgttctgc ataccaagct 5400 gagcacagaa gatgggaaca ctggtggagg atggaaaggc tcgctcaatc aagaaaattc 5460 tgagactatt aataaataag actgtagtgt agatactgag taaatccatg cacctaaacc 5520 ttttggaaaa tctgccgtgg gccctccaga tagctcattt cattaagttt ttccctccaa 5580 ggtagaattt gcaagagtga cagtggattg catttctttt ggggaagctt tcttttggtg 5640 gttttgttta ttataccttc ttaagttttc aaccaaggtt tgcttttgtt ttgagttact 5700 ggggttattt ttgttttaaa taaaaataag tgtacaataa gtgtttttgt attgaaagct 5760 tttgttatca agattttcat acttttacct tccatggctc tttttaagat tgatactttt 5820 aagaggtggc tgatattctg caacactgta cacataaaaa atacggtaag gatactttac 5880 atggttaagg taaagtaagt ctccagttgg ccaccattag ctataatggc actttgtttg 5940 tgttgttgga aaaagtcaca ttgccattaa actttccttg tctgtctagt taatattgtg 6000 aagaaaaata aagtacagtg tgagatactg 6030 <210> SEQ ID NO 48 <211> LENGTH: 911 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 48 tgattgaaga caccccctcg tccaagaatg caaagcacat ccaataaaat agctggatta 60 taactcctct tctttctctg ggggccgtgg ggtgggagct ggggcgagag gtgccgttgg 120 cccccgttgc ttttcctctg ggaaggatgg cgcacgctgg gagaacgggg tacgacaacc 180 gggagatagt gatgaagtac atccattata agctgtcgca gaggggctac gagtgggatg 240 cgggagatgt gggcgccgcg cccccggggg ccgcccccgc accgggcatc ttctcctccc 300 agcccgggca cacgccccat ccagccgcat cccgcgaccc ggtcgccagg acctcgccgc 360 tgcagacccc ggctgccccc ggcgccgccg cggggcctgc gctcagcccg gtgccacctg 420 tggtccacct ggccctccgc caagccggcg acgacttctc ccgccgctac cgcggcgact 480 tcgccgagat gtccagccag ctgcacctga cgcccttcac cgcgcgggga cgctttgcca 540 cggtggtgga ggagctcttc agggacgggg tgaactgggg gaggattgtg gccttctttg 600 agttcggtgg ggtcatgtgt gtggagagcg tcaaccggga gatgtcgccc ctggtggaca 660 acatcgccct gtggatgact gagtacctga accggcacct gcacacctgg atccaggata 720 acggaggctg ggtaggtgca tctggtgatg tgagtctggg ctgaggccac aggtccgaga 780 tcgggggttg gagtgcgggt gggctcctgg gcaatgggag gctgtggagc cggcgaaata 840 aaatcagagt tgttgcttcc cggcgtgtcc ctacctcctc ctctggacaa agcgttcact 900 cccaacctga c 911 <210> SEQ ID NO 49 <211> LENGTH: 402 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 49 cagcatttag gaaactttat tgcacttatc catttacatg tcctaatttt ccagtaacat 60 aaaagcaaga agcaaatatt accattttag taagaccaac agttagagaa ggaaataaaa 120 gtagaaagaa taactaaatg agtcaataaa ttccccagtt cgtttctctg cttgtctgct 180 ggtgcttggt ttcacccaat taatagaaac accaccacac gaacacaaac acacacacac 240 attaaccttg cagaaggtcc tcctaaaact ttcctggaca gacccagccc ccaaaagttt 300 tctccaagta ctgggccaca gccagggtca gatgatcatt aaagggtcca gccacaacct 360 gggatgccta aagggagtcc tttggcattc agtcccagtg gg 402 <210> SEQ ID NO 50 <211> LENGTH: 463 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 14, 30, 32, 55, 60, 79, 91 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 50 gcgaccgcgc ggtngaccga cgccggcatn gnaccgagtg ggggccccgc gcggngcctn 60 ccctctccgc gccgccaanc cggggactgc ncgcgggtcg ggtttcccgc cagctcaggt 120 ggatctcgag ccagagggga aagtatttgt ggtaataacc cttaccggga gtttcactga 180 agctactctc cagagagacc ggatcttcaa acattttacc aggaagcgcc aaagggctat 240 gcgaaggcga gtccaccaga tcaatggaca caagttcatg gccacgtatc tgaggcagcc 300 cacctactgc tctcactgca gggaagttta tctggggagt gtttgggaaa cagggttatc 360 agtgccaagt tgtgcacctg tgtccgtcca taaacgctgc catcatctaa tttgttacag 420 cctgtacttg ccaaaacaat attaacaaag tggattcaaa gat 463 <210> SEQ ID NO 51 <211> LENGTH: 2389 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 51 gaattcggac ggaggaggca gaatggccag tcgaggggcg cttaggcgtg gcctttcccc 60 agggctgcct cgactcctgc acctgtcccg agggctggcc tgagacggga ctcccggttc 120 tcccgctgcg aagcaggccc cccggggccg gggcagcggc gccggcatgt cgtctggcac 180 catgaagttc aatggctatt tgagggtccg catcggtgag gcagtggggc tgcagcccac 240 ccgctggtcc ctgcgccact cgctcttcaa gaagggccac cagctgctgg acccctatct 300 gacggtgagc gtggaccagg tgcgcgtggg ccagaccagc accaagcaga agaccaacaa 360 acccacgtac aacgaggagt tttgcgctaa cgtcaccgac ggcggccacc tcgagttggc 420 cgtcttccac gagacccccc tgggctacga cttcgtggcc aactgcaccc tgcagttcca 480 ggagctcgtc ggcacgaccg gcgcctcgga caccttcgag ggttgggtgg atctcgagcc 540 agaggggaaa gtatttgtgg taataaccct taccgggagt ttcactgaag ctactctcca 600 gagagaccgg atcttcaaac attttaccag gaagcgccaa agggctatgc gaaggcgagt 660 ccaccagatc aatggacaca agttcatggc cacgtatctg aggcagccca cctactgctc 720 tcactgcagg gagtttatct ggggagtgtt tgggaaacag ggttatcagt gccaagtgtg 780 cacctgtgtc gtccataaac gctgccatca tctaattgtt acagcctgta cttgccaaaa 840 caatattaac aaagtggatt caaagattgc agaacagagg ttcgggatca acatcccaca 900 caagttcagc atccacaact acaaagtgcc aacattctgc gatcactgtg gctcactgct 960 ctggggaata atgcgacaag gacttcagtg taaaatatgt aaaatgaatg tgcatattcg 1020 atgtcaagcg aacgtggccc ctaactgtgg ggtaaatgcg gtggaacttg ccaagaccct 1080 ggcagggatg ggtctccaac ccggaaatat ttctccaacc tcgaaactcg tttccagatc 1140 gaccctaaga cgacagggaa aggagagcag caaagaagga aatgggattg gggttaattc 1200 ttccaaccga cttggtatcg acaactttga gttcatccga gtgttgggga aggggagttt 1260 tgggaaggtg atgcttgcaa gagtaaaaga aacaggagac ctctatgctg tgaaggtgct 1320 gaagaaggac gtgattctgc tggatgatga tgtggaatgc accatgaccg agaaaaggat 1380 cctgtctctg gcccgcaatc accccttcct cactcagttg ttctgctgct ttcagacccc 1440 cgatcgtctg ttttttgtga tggagtttgt gaatgggggt gacttgatgt tccacattca 1500 gaagtctcgt cgttttgatg aagcacgagc tcgcttctat gctgcagaaa tcatttcggc 1560 tctcatgttc ctccatgata aaggaatcat ctatagagat ctgaaactgg acaatgtcct 1620 gttggaccac gagggtcact gtaaactggc agacttcgga atgtgcaagg aggggatttg 1680 caatggtgtc accacggcca cattctgtgg cacgccagac tatatcgctc cagagatcct 1740 ccaggaaatg ctgtacgggc ctgcagtaga ctggtgggca atgggcgtgt tgctctatga 1800 gatgctctgt ggtcacgcgc cttttgaggc agagaatgaa gatgacctct ttgaggccat 1860 actgaatgat gaggtggtct accctacctg gctccatgaa gatgccacag ggatcctaaa 1920 atctttcatg accaagaacc ccaccatgcg cttgggcagc ctgactcagg gaggcgagca 1980 cgccatcttg agacatcctt tttttaagga aatcgactgg gcccagctga accatcgcca 2040 aatagaaccg cctttcagac ccagaatcaa atcccgagaa gatgtcagta attttgaccc 2100 tgacttcata aaggaagagc cagttttaac tccaattgat gagggacatc ttccaatgat 2160 taaccaggat gagtttagaa acttttccta tgtgtctcca gaattgcaac catagcctta 2220 tggggagtga gagagagggc acgagaaccc aaaggaatag agattctcca ggaatttcct 2280 ctatcggacc ttcccagcat cagccttaga acaagaacct taccttcaag gagcaagtga 2340 agaactctgt cgaaggatgg aactttcaga tatcaactat ttagagtcc 2389 <210> SEQ ID NO 52 <211> LENGTH: 412 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 52 aggtgtccaa ggatgatcga agtgatattg agtctagctc agatgaggag gactcagaac 60 ctccgggaaa gaatccccac actgcgacaa ccaccaatgg gaccagtggt accaacgggt 120 atctcctgac tggctcctgc tccatggatg attaattact caaaactaca agtcccaagc 180 aaagtgaact atttgttcct ggaagtattt aataagttgc aaatgcagtt cctttcataa 240 tatctcagca ccagaaacaa aaattaagat tatcaaacgc attttgaata cgtgcactgc 300 catgtgtcct gtctgtgaat gaagaagaat taccattctc tctttgtagg catgctgtat 360 gtaatttgac acaagggaac agtatttgca tttgtactgt cttagaatat ta 412 <210> SEQ ID NO 53 <211> LENGTH: 449 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 42, 355, 449 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 53 tttaatttga actgctaatt gaacatgaag agtgaaaatt anacacctag ttcgtccggt 60 ttaaatggtc actaagactg tataggcaat ttcaaaatgg gcactgtaac taaaagaaag 120 caaacctatt tagagctgaa cgagactctt gcactgggtt ttgcttgctc taagtgacaa 180 agtaagctga tgctcatagc acattggact acagcaagag aaagggggag aagcagatgg 240 agcatctcct tcactgtcat gagcccagtg agtaaaagga gtgaggaaac cctcttttgt 300 ccacagattt acaaatacaa aaaaataaat aatattctaa gacagtacaa atgcnaatac 360 tgttcccttg tgtcaattac atacagcatg cctacaaaga gagaatggta attcttcttc 420 attcacagac aggacacatg gcagtgcan 449 <210> SEQ ID NO 54 <211> LENGTH: 449 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 299, 423, 431, 442 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 54 aaaattggtc tgcaattaga acatgtaaga ggagattagg aattaaaatg gattctgaga 60 ggcaatttct aactactgaa cttttataac aggagtatct ttgattaaat aaggagctag 120 tctaaactaa aagcaaaact gtaccataat aacccaactt aattatcttt gcagaataca 180 tttataaatg attggctcat ttctaccttt acttgactaa gtaaatatgc ctcttaaatt 240 ctcaaacatt gaaaattctg attctcacag ttgcacagac ttatctaaat caaaacttnc 300 aaaaagttac aatataatta ctgactccca ttggctaaga tgccagtaca agttccaagt 360 aaggaagttt aagctctggt aacttccact cctcaaccta gaacctccaa ggtcacttgt 420 tcnggttaaa ngggtggggc gnttttatt 449 <210> SEQ ID NO 55 <211> LENGTH: 521 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 55 caaatcataa ggaagttttt attgggtcct gtacagaaga gaaatgctcc gttgtcaaaa 60 aactacaaag ggatccctgg ctctgggtgt gctatgaaga caactccctc cccagtgagc 120 ccagggaaca ggctggatgc tggacaaagt tagggaggga gctccaggcc cagggtcctc 180 cacttggggt ctccccttta tgtttgtaaa aaccgcagac ttggagtatt tagaggactc 240 tgtccccctg caagtattgc cgttggatat gaaacacaca gagcaaaacc ccaaggtgac 300 aaatgagtga aaacctaagg tgacaagtgg acagacgccc cccagatgga ggagacactg 360 gctagctggc gacctctgcc cctacgtaac ttgtcagtcc ttgaaggcac agcagcattg 420 gccagagatg gcccctcccg cggccagggc tggattgcag ttccctgcct tgctcacctg 480 tggccacagc tcataccccc agttacccca cagccaggga c 521 <210> SEQ ID NO 56 <211> LENGTH: 639 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 56 acatactttt tcttttataa aaacacacag gtcaatgttt tttaaaaaca cagcataatt 60 gtacaagggg aaacattttg ttagtataat cttaccaata atgtaagaga ggaaagactg 120 ccatactgaa atacattttg ctgctgccaa agacggtcct attgtgaaga aatgagaaag 180 aaatagcaag cgccagggcc aattaagcat ccctctcccc gtttttctga atacaacaca 240 gtgatcctca ccgtaacccc tacacatgtt aatggattgt tagagtatca aattattttc 300 aatgtgcttt cttgttgtat aaaccttaac ctgcactttc tatttagggg gcaaaaaggg 360 aatgtgagtg taaaaaccct gctcagtgtg tgtgtgttgg actttggagc aattcaacaa 420 acaagcctgc tctctttaaa ctaattatgg agtggaaggc ttacaaaatt ctcccctcag 480 ctcctatata aaagaccatg actggaagga cagccacctc tgggtgtgct ggagaaactt 540 tgagatttaa acgggttttg attgcatgag agaaagcaaa cggttagtct ctcgtcagtc 600 ctcaagaact tacttaattg tggtggtgac taagcataa 639 <210> SEQ ID NO 57 <211> LENGTH: 5433 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 57 ggggagattc gggaccatgg cacctgtgca cggcgacgac tctctgtcag attcagggag 60 ttttgtatct tctcgagccc ggcgagaaaa aaaatcaaag aaggggcgcc aagaagccct 120 agaaagactg aaaaaggcta aagctggtga gaagtataaa tatgaagtcg aggacttcac 180 aggtgtttat gaagaagttg atgaagaaca gtattcgaag ctggttcagg cacgccagga 240 tgatgactgg attgtggatg atgatggtat tggctatgtg gaagatggcc gagagatttt 300 tgatgatgac cttgaagatg atgcccttga tgctgatgag aaaggaaaag atggtaaagc 360 acgcaataaa gacaagagga atgtaaagaa gctcgcagtg acaaaaccga acaacattaa 420 gtcaatgttc attgcttgtg ctggaaagaa aactgcagat aaagctgtag acttgtccaa 480 ggatggtctg ctaggtgaca ttctacagga tcttaacact gagacacctc aaataactcc 540 accacctgta atgatactga agaagaaaag atccattgga gcttcaccga atcctttctc 600 tgtgcacacc gccacggcag ttccttcagg aaaaattgct tcccctgtct ccagaaagga 660 gcctccatta actcctgttc ctcttaaacg tgctgaattt gctggcgatg atgtacaggt 720 cgagagtaca gaagaagagc aggagtcagg ggcaatggag tttgaagatg gtgactttga 780 tgagcccatg gaagttgaag aggtggacct ggagcctatg gctgccaagg cttgggacaa 840 agagagtgag ccagcagagg aagtgaaaca agaggcggat tctgggaaag ggaccgtgtc 900 ctacttagga agttttctcc cggatgtctc ttgttgggac attgatcaag aaggtgatag 960 cagtttctca gtgcaagaag ttcaagtgga ttccagtcac ctcccattgg taaaaggggc 1020 agatgaggaa caagtattcc acttttattg gttggatgct tatgaggatc agtacaacca 1080 accaggtgtg gtatttctgt ttgggaaagt ttggattgaa tcagccgaga cccatgtgag 1140 ctgttgtgtc atggtgaaaa atatcgagcg aacgctttac ttccttcccc gtgaaatgaa 1200 aattgatcta aatacgggga aagaaacagg aactccaatt tcaatgaagg atgtttatga 1260 ggaatttgat gagaaaatag caacaaaata taaaattatg aagttcaagt ctaagccagt 1320 ggaaaagaac tatgcttttg agatacctga tgttccagaa aaatctgagt acttggaagt 1380 taaatactcg gctgaaatgc cacagcttcc tcaagatttg aaaggagaaa ctttttctca 1440 tgtatttggg accaacacat ctagcctgga actgttcttg atgaacagaa agatcaaagg 1500 accttgttgg cttgaagtaa aaaagtccac agctcttaat cagccagtca gttggtgtaa 1560 agttgaggca atggctttga aaccagacct ggtgaatgta attaaggatg tcagtccacc 1620 accgcttgtc gtgatggctt tcagcatgaa gacaatgcag aatgcaaaga accatcaaaa 1680 tgagattatt gctatggcag ctttggtcca tcacagtttt gcattggata aagcagcccc 1740 aaagcctccc tttcagtcac acttctgtgt tgtgtctaaa ccaaaggact gtatttttcc 1800 atatgctttc aaagaagtca ttgagaaaaa gaatgtgaag gttgaggttg ctgcaacaga 1860 aagaacactg ctaggttttt tccttgcaaa agttcacaaa attgatcctg atatcattgt 1920 gggtcataat atttatgggt ttgaactgga agtactactg cagagaatta atgtgtgcaa 1980 agctcctcac tggtccaaga taggtcgact gaagcgatcc aacatgccaa agcttggggg 2040 ccggagtgga tttggtgaaa gaaatgctac ctgtggtcga atgatctgtg atgtggaaat 2100 ttcagcaaag gaattgattc gttgtaaaag ctaccatctg tctgaacttg ttcagcagat 2160 tctaaaaact gaaagggttg taatcccaat ggaaaatata caaaatatgt acagtgaatc 2220 ttctcaactg ttatacctgt tggaacacac ctggaaagat gccaagttca ttttgcagat 2280 catgtgtgag ctaaatgttc ttccattagc attgcagatc actaacatcg ctgggaacat 2340 tatgtccagg acgctgatgg gtggacgatc cgagcgtaac gagttcttgt tgcttcatgc 2400 attttacgaa aacaactata ttgtgcctga caagcagatt ttcagaaagc ctcagcaaaa 2460 actgggagat gaagatgaag aaattgatgg agataccaat aaatacaaga aaggacgtaa 2520 gaaaggagct tatgctggag gcttggtttt ggaccccaaa gttggttttt atgataagtt 2580 cattttgctt ctggacttca acagtctata tccttccatc attcaggaat ttaacatttg 2640 ttttacaaca gtacaaagag ttgcttcaga ggcacagaaa gttacagagg atggagaaca 2700 agaacagatc cctgagttgc cagatccaag cttagaaatg ggcattttgc ccagagagat 2760 ccggaaactg gtagaacgga gaaaacaagt caaacagcta atgaaacagc aagacttaaa 2820 tccagacctt attcttcagt atgacattcg acagaaggct ttgaagctca cagcgaacag 2880 tatgtatggt tgcctgggat tttcctatag cagattttac gccaaaccac tggctgcctt 2940 ggtgacatac aaaggaaggg agattttgat gcatacgaaa gagatggtac aaaagatgaa 3000 tcttgaagtt atttatggag atacagattc aattatgata aacaccaata gcaccaatct 3060 ggaagaagta tttaagttgg gaaacaaggt aaaaagtgaa gtgaataagt tgtacaaact 3120 gcttgaaata gacattgatg gggttttcaa gtctctgcta ctgctgaaaa aaaagaagta 3180 cgctgctctg gttgttgagc caacgtcgga tgggaattat gtcaccaaac aggagctcaa 3240 aggattagat atagttagaa gagattggtg tgatcttgct aaagacactg gaaactttgt 3300 gattggccag attctttctg atcaaagccg ggacactata gtggaaaaca ttcagaagag 3360 gctgatagaa attggagaaa atgtgctaaa tggcagtgtc ccagtgagcc agtttgaaat 3420 taacaaggca ttgacaaagg atccccagga ttaccctgat aaaaaaagcc tacctcatgt 3480 acatgttgcc ctctggataa attctcaagg aggcagaaag gtgaaagctg gagatactgt 3540 gtcatatgtc atctgtcagg atggatcaaa cctcactgca agtcagaggg cctatgcgcc 3600 tgagcagctg cagaaacagg ataatctaac cattgacacc cagtactacc tggcccagca 3660 gatccaccca gtcgtggctc ggatctgtga accaatagac ggaattgatg ctgtcctcat 3720 tgcaacgtgg ttgggacttg accccaccca atttagagtt catcattatc ataaagatga 3780 agagaatgat gctctacttg gtggcccagc acagctcact gatgaagaga aatacaggga 3840 ctgtgaaaga ttcaaatgtc catgccctac atgtggaact gagaatattt atgataatgt 3900 ctttgatggt tcgggaacag atatggagcc cagcttgtat cgttgcagta acatcgattg 3960 taaggcttca cctctgacct ttacagtaca actgagcaac aaattgatca tggacattag 4020 acgtttcatt aaaaagtact atgatggctg gttgatatgt gaagagccaa cctgtcgcaa 4080 tcgaactcgt caccttcccc ttcaattctc ccgaactggg cctctttgcc cagcctgcat 4140 gaaagctaca cttcaaccag agtattctga caagtccctg tacacccagc tgtgctttta 4200 ccggtacatt tttgatgcgg agtgtgcact ggagaaactt actaccgatc atgagaaaga 4260 taaattgaag aagcaatttt ttacccccaa agttctgcag gactacagaa aactcaagaa 4320 cacagcagag caattcttgt cccgaagtgg ctactccgaa gtgaatctga gcaaactctt 4380 cgctggttgt gccgtgaaat cctaagggaa tcccaggagt aaccaaggag ggggtagttg 4440 aaaaatccca gcttcctctg tgcctccact ctggccctaa atgctcctcc agcatctgtt 4500 tctcccttgg gactgtgtct catgtttgtg tgaatgtaga ccaggaaagg gggctgcaaa 4560 aatgttgagt ctaatgttcg taagcatcat agaaattcct gtcttcatat taagatgtac 4620 tgctttaaaa cacaactcca gagcccctcc ccaagctccc ctccccaagc tcctgaagac 4680 ccggtttctg agggagggaa attgctactt ggattgagag tagctggaat gtaagtgacc 4740 ccaggctttg ctcagggcct ttagcctatg tcccccccac ataaagagag cttctcagag 4800 cctgactgaa gagctgacgt tttgcttttt catatgccaa ttaaacccgg tctaaatcca 4860 aatgcttctc cagccatcca ggagtggctg tccttttcag tcttgtcttt tatataggta 4920 gctgaggggg aagatttaga agccttgcac tcactaaata gattaaacag agcaggcttg 4980 tttgttgaat tgctccaaag tccaacagac acacactgag caggtgtttt acactcacat 5040 tccctttttg ccccttaaat agaaagtgca ggtaaaggtt tatacaacaa gaaagcacat 5100 tgaaaataat ttgatactct aacaatccat taacatgtgt aggggttacg gtgaggatca 5160 tgtgttgtat tcgaaaaacg gggagaggga tgcttaattg gccctcgctt gctatttttt 5220 tctcatttct tcacaatagg accgtctttg gcagcagcaa aatgtatttc agtatggcag 5280 tctttcctct cttacattat tggtaagatt atactaacaa aatgtttccc cttgtacaat 5340 tatgctgtgt ttttaaaaaa cattgacctg tgtgttttta taaaagaaaa agtatgttgt 5400 gccttcttct taagaataaa gttttctaaa ggg 5433 <210> SEQ ID NO 58 <211> LENGTH: 126 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 58 gaaaactgca aaaggtggca aaaggtgaga atgggaggag actcatctgt gactaactcc 60 cccatcagcc tcacgggtgg gtgacttgga gctccccaac ccaatgggac ttccttcttt 120 cgccta 126 <210> SEQ ID NO 59 <211> LENGTH: 294 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 59 tcagacgatc ttcctttaat acaaagtcga tatatctaca tacacggggg tgggaaaacc 60 accggctgct tccgctggaa taaacagtgt tgaaagtaac cgcagatctg cccttgtaca 120 aagaggaaca actcgcttgc tcagggtagg cgggtagagg ggggcctgtc cttctggttt 180 tgctcccaaa ctgccccata gtcccagggg gaaagggtcc ctgatgtggg gcagaacagc 240 catacagcca ctggtccccg aagaagtagg atcctctctg tctccttggg ggcg 294 <210> SEQ ID NO 60 <211> LENGTH: 397 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 1, 2, 202, 206, 305, 375, 387 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 60 nntgacattt catttttttt aaatagtgta ttttttttcc attttttttt ttaagagaaa 60 caaaagactc gccagtcaat gactttcaaa gagaactaac tttggcttat tcatattctg 120 ttcaaagaca gtctattttt tcactgtaga aagcgtcctt gtgtgatagt tacgttcgca 180 aacgcgcacg ccaggcccat gnctgntacc ttggcttttt tttttttttt tttttttttt 240 aatttttcct accatcagaa agtgtgcttt gctcacagaa gaatgggatg tccttttttc 300 tttcntggct ttttttttcc ccctttttgt ttcattttta taaattaaat tttcagacat 360 atcaaataag gttcngaggg gtaaggncat gggggaa 397 <210> SEQ ID NO 61 <211> LENGTH: 326 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 275, 301, 313, 318 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 61 tttttttttt tttttaccac acagaattga cttgtttaat accacccctc ccttgccctc 60 tgcctccagc atactcccta gagtagtaca ggcagggtag atctaactat tggaaggaat 120 ccctaacact tttccagggt agaattctgg ctagtccaaa aagggtcctt cttttaaggg 180 ttttgagaaa ctagacactg caacttatta gtatcggcga cgtttgtttg gggcaaattc 240 agctccagga gctgcacggg ttgaatgcag gaggnagttc caccaattgc cccaattccc 300 ntccatttgg tangcaancc ttgacc 326 <210> SEQ ID NO 62 <211> LENGTH: 156 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 62 ggccgtcgta gcgtcgccgt tactccgagg agataccagt cggtagaggg gtgcaaaaat 60 gcagagtaat aaaactttta acttggagaa gcaaaaccat actccaagaa agcatcatca 120 acatcaccac cagcagcagc accaccagca gcaaca 156 <210> SEQ ID NO 63 <211> LENGTH: 2690 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 63 gctcttttct cgggacggga gaggccgtgt agcgtcgccg ttactccgag gagataccag 60 tcggtagagg agaagtcgag gttagaggga actgggaggc actttgctgt ctgcaatcga 120 agttgagggt gcaaaaatgc agagtaataa aacttttaac ttggagaagc aaaaccatac 180 tccaagaaag catcatcaac atcaccacca gcagcagcac caccagcagc aacagcagca 240 gccgccacca ccgccaatac ctgcaaatgg gcaacaggcc agcagccaaa atgaaggctt 300 gactattgac ctgaagaatt ttagaaaacc aggagagaag accttcaccc aacgaagccg 360 tctttttgtg ggaaatcttc ctcccgacat cactgaggaa gaaatgagga aactatttga 420 gaaatatgga aaggcaggcg aagtcttcat tcataaggat aaaggatttg gctttatccg 480 cttggaaacc cgaaccctag cggagattgc caaagtggag ctggacaata tgccactccg 540 tggaaagcag ctgcgtgtgc gctttgcctg ccatagtgca tcccttacag ttcgaaacct 600 tcctcagtat gtgtccaacg aactgctgga agaagccttt tctgtgtttg gccaggtaga 660 gagggctgta gtcattgtgg atgatcgagg aaggccctca ggaaaaggca ttgttgagtt 720 ctcagggaag ccagctgctc ggaaagctct ggacagatgc agtgaaggct ccttcctgct 780 aaccacattt cctcgtcctg tgactgtgga gcccatggac cagttagatg atgaagaggg 840 acttccagag aagctggtta taaaaaacca gcaatttcac aaggaacgag agcagccacc 900 cagatttgca cagcctggct cctttgagta tgaatatgcc atgcgctgga aggcactcat 960 tgagatggag aagcagcagc aggaccaagt ggaccgcaac atcaaggagg ctcgtgagaa 1020 gctggagatg gagatggaag ctgcacgcca tgagcaccag gtcatgctaa tgagacagga 1080 tttgatgagg cgccaagaag aacttcggag gatggaagag ctgcacaacc aagaggtgca 1140 aaaacgaaag caactggagc tcaggcagga ggaagagcgc aggcgccgtg aagaagagat 1200 gcggcggcac gaagaagaaa tgatgcggcg acacgaggaa ggattcaagg gaaccttccc 1260 tgatgcgaga gagcaggaga ttcggatggg tcagatggct atgggaggtg ctatgggcat 1320 aaacaacaga ggtgccatgc cccctgctcc tgtgccagct ggtaccccag ctcctccagg 1380 acctgccact atgatgccgg atggaacttt gggattgacc ccaccaacaa ctgaacgctt 1440 tggtcaggct gctacaatgg aaggaattgg ggcaattggt ggaactcctc ctgcattcaa 1500 ccgtgcagct cctggagctg aatttgcccc aaacaaacgt cgccgatact aataagttgc 1560 agtgtctagt ttctcaaaac ccttaaaaga aggacccttt ttggactagc cagaattcta 1620 ccctggaaaa gtgttaggga ttccttccaa tagttagatc taccctgcct gtactactct 1680 aagggattcc ttccaatagt tagatctacc ctgcctgtac tactctaggg agtatgctgg 1740 aggcagaggg caagggaggg gtggtattaa acaatgcaat tctgtgtggt atattgttta 1800 atcagttctg tgtggtgcat tcctgaagtc tctaatgtga ctgttgaggg cctggggaaa 1860 ccatggcaaa gtggatccag ttagagccca ttaatcttga tcattccggt tttttttttt 1920 tttgtccatc ttgtttcatt tgcttgcccc gcccccgaga cggagtctta ctctgtcgcc 1980 caggctggag tgtagtggca tgatctcggc tcactgcaat ctctgcctcc cgggttcaag 2040 cttgtccagg ttgatcttga actcctgacc tcgtgatcta cccacctcgg tctcccaaaa 2100 tgctgggatt acaggggtga gccaccgtgc ccaacctcac ttgcttctta tccttacact 2160 cccccagccc cagagaaact gccacataca ccacaaaaac caaacatgcc ccaatgacct 2220 tagccccatt gctccattca ctcccaggtg agaattcagg caaacgtcca caaaggtcac 2280 aggcagcgta catacggttc tgttataccc catatattac cccttcatgt cctaaagaag 2340 acattttctc ttagagattt tcattttagt gtatctttaa aaaaaaaatc ttgtgttaac 2400 ttgcctccat ctttttcttg gggtgaggga caccagggaa tgaccctttt gtgtctatga 2460 tgttgctgtt cacagctttt cttgataggc ctagtacaat cttgggaaca gggttactgt 2520 atactgaagg tctgacagta gctcttagac tcgcctatct taggtagtca tgctgtgcat 2580 tttttttttc attggtgtac tgtgtttgat ttgtctcata tatttggagt ttttctgaaa 2640 aatggagcag taatgcagca tcaacctatt aaaatacttt taagcctttt 2690 <210> SEQ ID NO 64 <211> LENGTH: 367 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 41, 71, 341, 367 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 64 attttagtat ttcctgtttt ggtttatttg catcttagaa nagcataatg acattgtttg 60 atgaagccta nttatgctgg actgttttga cctggtttaa cccttctgat aggtagttgt 120 ggatgctggg gatgagaact gaataatctt tgcctggagt gacactacac tctagaattt 180 ccactttgga gaatactcag ttccaacttg tgattcctga tagaacagac tttacttttc 240 tagcccagca ttgatctaga agcagaggaa tcccagcgcc ttttaaaagt tgttatgtgg 300 gttttctttt aaaaagctcc tgtttttgga aagtagaatt natgggtaca acgtatgttc 360 attattn 367 <210> SEQ ID NO 65 <211> LENGTH: 1487 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 65 ctggtctaac agacccgcga gaacgaagga cgcttgcctt tttccggtcg gggaaggggg 60 aagaaggtaa cttccggtga cggggttgca tcacttcctc tcaagcttgg cgtttgtttg 120 gtggggttac acgcgggttc aacatgcgta tcgaaaagtg ttatttctgt tcggggccca 180 tctatcctgg acacggcatg atgttcgtcc gcaacgattg caaggtgttc agattttgca 240 aatctaaatg tcataaaaac tttaaaaaga agcgcaatcc tcgcaaagtt aggtggacca 300 aagcattccg gaaagcagct ggtaaagagc ttacagtgga taattcattt gaatttgaaa 360 aacgtagaaa tgaacctatc aaataccagc gagagctatg gaataaaact attgatgcga 420 tgaagagagt tgaagaaatc aaacagaagc gccaagctaa atttataatg aacagattga 480 agaaaaataa agagctacag aaagttcagg atatcaaaga agtcaagcaa aacatccatc 540 ttatccgagc ccctcttgca ggcaaaggga aacagttgga agagaaaatg gtacagcagt 600 tacaagagga tgtggacatg gaagatgctc cttaaaaatc tctgtaacca tttcttttat 660 gtacatttga aaatgccctt tggatacttg gaactgctaa attattttat tttttacata 720 aggtcactta aatgaaaagc gattaaaaga catctttcct gcattgccat ctacataata 780 tcagatatta cggatgttag attgcatctc agtgttaaat ctttactgat agatgtactt 840 aagtaaatca tgaaaattct acttgtaact atagaagtga attgtggacg taaaatggtt 900 gtgctatttg gataatggca ctaggcagca tttgtatagt aactaatggc aaaaattcat 960 ggctagtgat gtataaaata aaatattctt tgcagtaaaa tattcccttt gttaatgtta 1020 tagaaggggg gatacaaaaa ggaactaaca atttgtatgg cagtgtcaga tatttttatt 1080 ttagtatttc ctgttttggt ttatttgcat cttagaagag cataatgaca ttgtttgatg 1140 aagcctaatt atgctggact gttttgacct ggtttaaccc ttctgatagg tagttgtgga 1200 tgctggggat gagaactgaa taatctttgc ctggagtgac actacactct agaatttcca 1260 ctttggagaa tactcagttc caacttgtga ttcctgatag aacagacttt acttttctag 1320 cccagcattg atctagaagc agaggaatcc cagcgccttt taaaagttgt tatgtggttt 1380 tcttttaaaa agctcctgtt tttggaaagt agaatttatg ggtacaacgt atgttcatta 1440 tttgtacata aaataaaacc atttaaaaag taaaaaaaaa aaaaaaa 1487 <210> SEQ ID NO 66 <211> LENGTH: 366 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 66 ccgcctccag caaaacaacg atgttcactc ctccaaatat ccaaattgaa gatctaccaa 60 aacaaaaaca aaaacaaaag cccacagaga aataaaaagg aacaaaaatc acattctaat 120 ggggggggtc agtgcattta gcagtcttcg ctgtgctgtc taaccatcct tcagctgact 180 ttcaaaaaaa aaaacaccct aagctcatca aaatatacat tttccatttg cttttttaaa 240 ttaaaaataa ttattaaaaa aaggaaaact ttaaggaatt cacaatcaat tgcctgactc 300 attttgatgt catgtacagc atatggaggt caggaaggct atttgcagca catgtgatta 360 ggggct 366 <210> SEQ ID NO 67 <211> LENGTH: 410 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 389 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 67 aaagatgtac tcattctggg aggtggagac ggaggcatat tgtgtgaaat agtcaaacta 60 aaaccaaaga tggtcactat ggtagagatt gaccaaatgg tgattgatgg gtgtaagaaa 120 tacatgcgaa aaacgtgtgg cgatgtctta gacaatctta aaggagactg ctatcaggtt 180 ctaatagaag actgtatccc ggtacctgaa gaggtacgcc aaagaaggga gagaatttga 240 ttatgtgatt aatgatttga cagctgttcc aatctccacc gtctccagaa gaagattcca 300 catgggagtt tctcagactg attcttgacc tctcaatgaa agtgttgaaa caggatgggg 360 aaatatttta cacaggggga actgtgtcna tctgacagaa gcactgtcgc 410 <210> SEQ ID NO 68 <211> LENGTH: 1612 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 68 tagtgaggcg aggccctgtg ccatgcctgg ggcagcagca cggcacagca cgctcgactt 60 catgctcggc gccaaagctg atggtgagac cattctaaaa ggcctccagt ccattttcca 120 ggagcagggg atggcggagt cggtgcacac ctggcaggac catggctatt tagcaaccta 180 cacaaacaag aacggcagct ttgccaattt gagaatttac ccacatggat tggtgttgct 240 ggaccttcag agttatgatg gtgatgcgca aggcaaagaa gagatcgaca gtattttgaa 300 caaagtagag gaaagaatga aagaattgag tcaggacagt actgggcggg tgaaacgatt 360 accacccata gtgcgaggag gagccatcga cagatactgg cccaccgccg acgggcgcct 420 ggttgaatat gacatagatg aagtggtata tgacgaagat tcaccttatc aaaatataaa 480 aattctacac tcgaagcagt ttggaaatat tctcatcctt agtggggatg ttaatttggc 540 agagagtgat ttggcatata cccgggccat catgggcagt ggcaaagaag attacactgg 600 caaagatgta ctcattctgg gaggtggaga cggaggcata ttgtgtgaaa tagtcaaact 660 aaaaccaaag atggtcacta tggtagagat tgaccaaatg gtgattgatg ggtgtaagaa 720 atacatgcga aaaacgtgtg gcgatgtctt agacaatctt aaaggagact gctatcaggt 780 tctaatagaa gactgtatcc cggtactgaa gaggtacgcc aaagaaggga gagaatttga 840 ttatgtgatt aatgatttga cagctgttcc aatctccacg tctccagaag aagattccac 900 atgggagttt ctcagactga ttcttgacct ctcaatgaaa gtgttgaaac aggatgggaa 960 atattttaca caggggaact gtgtcaatct gacagaagca ctgtcgctct atgaagaaca 1020 gctggggcgc ctgtattgtc ctgtggaatt ttcaaaggag atcgtctgtg tcccttcata 1080 cttggaattg tgggtatttt acactgtttg gaagaaagct aaaccctgaa gatcagtagc 1140 ccctaatcac atgtgctgca aatagccttc ctgacctcca tatgctgtac atgacatcaa 1200 aatgagtcag gcaattgatt gtgaattcct taaagttttc ctttttttaa taattatttt 1260 taatttaaaa aagcaaatgg aaaatgtata ttttgatgag cttagggtgt tttttttttg 1320 aaagtcagct gaaggatggt tagacagcac agcgaagact gctaaatgca ctgacccccc 1380 ccattagaat gtgatttttg ttccttttta tttctctgtg ggcttttgtt tttgtttttg 1440 ttttggtaga tcttcaattt ggatatttgg aggagtgaac atcgttgttt tgctggaggg 1500 aagatcttga tggtgtttct ttccccaaaa attgacttag atattaaaat ttggtgctta 1560 taagagagag ttaaaaaaaa ataggattgc ttcaattaaa attacaaaag ag 1612 <210> SEQ ID NO 69 <211> LENGTH: 267 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 239, 243, 244 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 69 tttttttttt tttttttttt tttggggatt caaatccttt attgacggtg gtggtgaggc 60 cagccctccc tggcaggctc tgggtgcatc tccctagtat gttctgctgg gagccgggca 120 ccggggcagg cgtaggggca gcgagtggcc taggactcgg actcaaacat cttcttccgg 180 ccctccatgc cagacttctc ctcgatgttc ttcctccagt cacccacgtc tcgcaggtnc 240 cgnnccttct ctgtggtcct ccttctt 267 <210> SEQ ID NO 70 <211> LENGTH: 596 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 54, 56, 127, 130, 151, 154, 164, 421, 449, 474, 487, 516, 530, 540, 546, 562, 573 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 70 tcaggacctc aggatgggag atgaggagaa gcggaacagg gccatcacgg cgcnanggca 60 gcacctgaag agtgtgatgc tgcagatagc ggccacggag ctggagaagg aggagagccg 120 ccgtgangan gaagcagaac tacctggcgg nacntgcccg cgcntgcata tcccgggctc 180 catgtctgaa gtgcaggagc tctcaaacag ctgcacgcca agatcgatgc ggctgaagag 240 gagaagtacg acatggaggt gagggtgcag aagaccagca aggagctgga ggacatgaac 300 cagaagctat ttgatctgcg gggcaagttc aagcggcccc cactgcggag ggtgcgcatg 360 tcgaccgatg ccatgctcaa ggccctgctg cttcgaagca caaggtgttc atggacctga 420 nggcaacctg aagcaggttc aagaaggang acacagagaa ggagccggga cctncgagac 480 gttggtnact tgaagaagaa catcgaggga gaagtntggc atgaaggccn gaagaagatn 540 ttttanttcg agtctagcca tngctgccct aanctgcccg ttccggttcc agcaga 596 <210> SEQ ID NO 71 <211> LENGTH: 701 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 71 ctaggctcca agctcaggac ctcaggatgg gagatgagga gaagcggaac agggccatca 60 cggcccgcag gcagcacctg aagagcgtga tgctgcagat agcggccacg gagctggaga 120 aggaggagag ccgccgtgag gcagagaagc agaactacct ggcggagcac tgcccgccgc 180 tgcatatccc gggctccatg tctgaagtgc aggagctctg caaacagctg cacgccaaga 240 tcgatgcggc tgaagaggag aagtacgaca tggaggtgag ggtgcagaag accagcaagg 300 agctggagga catgaaccag aagctatttg atctgcgggg caagttcaag cggcccccac 360 tgcggagggt gcgcatgtcg gccgatgcca tgctcaaggc cctgctgggc tcgaagcaca 420 aggtgtgcat ggacctgagg gccaacctga agcaggtcaa gaaggaggac acagagaagg 480 agcgggacct gcgagacgtg ggtgactgga ggaagaacat cgaggagaag tctggcatgg 540 agggccggaa gaagatgttt gagtccgagt cctaggccac tcgctgcccc tacgcctgcc 600 ccggtgcccg gctcccagca gaacatacta gggagatgca cccagagcct gccagggagg 660 gctggcctca ccaccaccgt caataaagga tttgaatccc c 701 <210> SEQ ID NO 72 <211> LENGTH: 282 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 72 tttttttttt tttggatttc acgaactcac atttattcac agacagacaa agggacaagg 60 acagaccttt gctcactggg gacccccagg gtctggcagt tccaaagagg tgatggtgtc 120 cagtgtgtga aacgggggac agggaggcgg gggcgtccca ccagtctcca tccctctggc 180 caactgtccg ccgccttttt ttccaagtcg tcctgcctta agacacatgt tggggtgagc 240 ggttcctaac cagcatcagg ggttctgggg gcgggcgatg gg 282 <210> SEQ ID NO 73 <211> LENGTH: 443 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 419 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 73 agacagcaaa ctcacctgcg cgggctgggg ggcctggctc ctgaccttcg ccgccctgcc 60 ctccgccgct ccgcctgagc tccccggttt gcagaatgga ggagggaagt tgaaggagcc 120 acctcctctg tctacccacc cgtccccttc acgcccttga cactaaggag tggggggccc 180 tggactgccc cttcctcccc catcgcccgc ccccagaacc cctgatgctg gttaggaacc 240 gctcacccca acatgtgtct taaggcagga cgacttggaa aaaaaggcgg cggacagttg 300 gccagaggga tggagactgg tggggacgcc ccgcctccct gtcccccgtt tcacacactg 360 gacaccatca cctctttgga actgccagac cctgggggtc ccagtgagca aaggtctgnt 420 ccttgtcctt tgtctgtctg tga 443 <210> SEQ ID NO 74 <211> LENGTH: 310 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 74 ctaacgtgga ctagagaaac ttggcctgct gtgagtgggc cttctgttca acttaccctc 60 caccgctgac cctgtgtgaa gagagatggt gcgttactgc catctaatgg gaaaagagaa 120 aactgcagtt gggaaaagca gctgtcattt aagggtaggg ctttctgaag gatttctgat 180 acagtccaga aaagggaaaa tgatgacaca gcagttgcca tcttgaaaaa tgccctttcc 240 tgcggaaagg gtgttttgaa gtctaataca actatcatca caaggtccct ggactaaggc 300 tggatcgtgt 310 <210> SEQ ID NO 75 <211> LENGTH: 408 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 75 ggaataatgt ttatttaaag ttacatttca gaggaaacta tcttcaggag ggcatgaagc 60 ctatattggc tactgcaaaa caaccagaag ttttataaaa tatttctgat ttaaattact 120 aaggcactat agataggcac ctatattaca tacaatcttc aaacattttt aaaagttgaa 180 actatgtatt agttgatatc taaaatatta aagcccctga caaactgaac ggctaagaac 240 ttgacaaaat gagatgcctg tttcaatgat tcttgttgcc atgcatatta atttaaaatt 300 acaattttgg aggatttcta aattacacga tcccagcctt taagttccag ggggaccctt 360 gtgattggat aggtttggaa ttaggacttt tcaaaaacac cccccttt 408 <210> SEQ ID NO 76 <211> LENGTH: 439 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 76 aaagacgtac atttatattc ttcagccatg acaaaatcac aaatattttg aaatttttcc 60 acattctctt tttcaacgta caccaaagaa ttttaataca gttcaatctt taccttcgtt 120 tacttgatac ccagtcctta aatttaagtc caggtagttc catccaactt ccaaagctga 180 ttgtcaacat ggagccttcc atattatgcc aagccccacc aggtggacct ttaccaagaa 240 ctacgtgagg gatataatga tgttgctcta atttccaatg caaaacggat ggataatcat 300 acccaaagtc agcatctgga tgaagaagtg tatcgaaaag tactgcaact ggattggatg 360 atcggccctc aaggcgctca gacaagtatt ctaagtcctg atcaacaatg gaaagatgtc 420 ttgcttcttc taatttact 439 <210> SEQ ID NO 77 <211> LENGTH: 427 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 77 agaaactata gtgacactga aactgaagga gagattttta attccttagt gcaatacttt 60 ggtgacaact tggggcgaaa agttaaagcg atgccattag ttgaagaaac ttctttactg 120 gaagattcgt cagtgacttt tcctgtggta ataataggaa atggaccctc aggaatatgc 180 ctttcttata tgttatcagg ctacagaccg tatttatcat cagaagcaat acacccaaat 240 acaatcttaa atagtaaatt agaagaagca agacatcttt ccattgttga tcaggactta 300 gaatacttgt ctgagggcct tgagggccga tcatccaatc cagttgcagt acttttcgat 360 acacttcttc atccagatgc tgactttggg tatgattatc catccgtttt gcattggaaa 420 ttagagc 427 <210> SEQ ID NO 78 <211> LENGTH: 4199 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 78 tggggcgggc tgatgagcac ctggattttc acccggcgtg ctggtaattc ctacacttgt 60 gggtgtttga gagacatgaa gaggggagga tgacctcttc ccggaagcgg gacttccata 120 aaagaagcgt ggtgggcggg tcccgggcac ctgtggtttg gtgagtcctc caggtaactg 180 tgatgcgggg gtcagcggga gaggcacccg gaagctcccg gcgtctgcac cccggcagcg 240 cgaggaaatg cccaaagaaa ctatagtgac actgaaactg aaggagagat ttttaattcc 300 ttagtgcaat actttggtga caacttgggg cgaaaagtta aagcgatgcc attagttgaa 360 gaaacttctt tattggaaga ttcgtcagtg acttttcctg tggtaataat aggaaatgga 420 ccctcaggaa tatgcctttc ttatatgtta tcaggctaca gaccgtattt atcatcagaa 480 gcaatacacc caaatacaat cttaaatagt aaattagaag aagcaagaca tctttccatt 540 gttgatcagg acttagaata cttgtctgag ggccttgagg gccgatcatc caatccagtt 600 gcagtacttt tcgatacact tcttcatcca gatgctgact ttgggtatga ttatccatcc 660 gttttgcatt ggaaattaga gcaacatcat tatatccctc acgtagttct tggtaaaggt 720 ccacctggtg gggcttggca taatatggaa ggctccatgt tgacaatcag ctttggaagt 780 tggatggaac tacctggact taaatttaag gactgggtat caagtaaacg aaggagccta 840 aaaggggatc gagttatgcc agaggaaata gctcgctact ataaacatta tgtaaaagtc 900 atgggtcttc agaagaattt cagagagaat acttacataa cttccgtatc aagactctac 960 agagatcaag atgatgatga tattcaagac agagatattt caacaaagca tttacagata 1020 gagaagtcaa actttatcaa gagaaactgg gaaattaggg gttatcagcg aatagctgat 1080 ggttctcatg ttcccttctg cctctttgct gagaatgtag cgctggcaac tggaacgctg 1140 gattctcctg cccatctgga aattgaaggg gaagattttc cttttgtgtt tcattcaatg 1200 cctgaatttg gagctgctat aaacaaagga aagttgcgtg gcaaagtgga tccagtgtta 1260 attgtaggtt ctgggcttac tgccgctgac gcagtactgt gtgcttacaa cagtaatatc 1320 cctgtgattc atgtgtttcg cagacgagta actgatccaa gcttaatttt caaacagctt 1380 cccaaaaagc tgtatcctga atatcataaa gtctatcata tgatgtgtac tcagtcatat 1440 tctgtagact caaatctttt atctgattat accagctttc ccgagcaccg tgtgctttcc 1500 tttaagtcgg acatgaaatg tgttctccaa agcgtttctg gattgaagaa aatatttaag 1560 ctgtctgcag cagtagtatt gataggttct catcctaatc tgtcttttct gaaggatcaa 1620 gggtgttacc taggccataa gtcaagccag ccaatcacat gtaagggtaa tcctgtggaa 1680 atagatacat atacctatga gtgtattaaa gaagccaacc tttttgcatt gggtcctttg 1740 gttggagaca attttgttcg atttttaaag ggaggggcgc tgggtgttac acgctgttta 1800 gctacaagac agaagaaaaa gcatttgttt gttgaaagag gaggaggaga tgggatagct 1860 taaagcaagt ttacaagtaa ttaaaatgga cagtttgcca ttaaagattt ttaatagtgg 1920 ttttgcagtg tactggcttg aattttctgg acttgagtta actgaaggag agcctcaaac 1980 tatagtaact tcatttttaa aagttactag aatttggtat cctgatttat attgcagtgt 2040 ttcaaaggtg tcactgtcag acaaatagaa acactgccaa cttggtgtaa cttaagcttt 2100 catttaacta aaacattctt ttcttgcaaa acttattttt catgatcatt tttggttatt 2160 tattatactt gattccaaaa tagtacagcc ttgaatctat aaaactgtgc agtcattatg 2220 ccagaaatta tcttaaatat ataatgggtc accttgctgt tcaaagggtg gtgcaaggtc 2280 ctgcagcatc ttacatctgt agcttgttag aaatgtaaac tctcaggccc cacaacttac 2340 ttcctgcatt ttaacaagat ccccaaggga tatgtatgct cataaaaatt tgagacactg 2400 gtttaaatga aaatggatat aaggtatgta taactggggg tggggtgagg gtaggaggca 2460 tttacaactc agattttatt tattttgaaa ttatcaattg tataaatcta atttattacc 2520 aaatagggtc ttttaaaaaa tatttttatc gttgaaacct tgacaggtac ttcatattct 2580 tctaataatt taaacagtcc aataatgtgg tatacacttt gacatccaag aactcaccaa 2640 gatgtttttc agagatttat tctcgattta actatcatag catttaatga atctgatttg 2700 tagttcaata aattgtgggt tgaactactt atccctgtgt gaacattgaa ttactttctg 2760 tcactgaaac tgaggtattt gggtgtggta agtacttcga aaattgtaat actgtttggg 2820 cattgtctaa attattaaag gttaaaatag aaaataaagt cagaattttt cttttccatt 2880 ccaaaggtgt acttagagat ctctattagt attcattcga gatgacatag cagctcatat 2940 catggttgtt tattggattt atctgttcta attatataag tgtgtttact gtctgtgttt 3000 tcacacaaac tgctagaatt tttaatgtta agacgaaaac atctgaagtt ctccatggca 3060 aattgaattt ttcagtcatt ttcttttctt tttttggtac aattacttca tctggaatgt 3120 cttcattgaa ctcgttattc tatttttctt agaattaaaa gtggattaat gtgggttttt 3180 ctgttcattt tattgcagta ttaaatgctt aagcttatta ggaccataat tcactttaaa 3240 tataattgta tagaatatat ttgcgtcgat caaataattg cttcagatga attcttagac 3300 tcttgataat atcacaccta atttaacttg attttacaag ctgtacaatc cagttttagt 3360 tttctattgt gataataact tttttcaaac cagtttcaca tcttaatgaa ataacattct 3420 ctgactgcac ttgcttcagt actctcttgc ctgcctgttt ttgacctctg catgagttgg 3480 attagatgtt tttcttactg tcacttctaa atagaaaatg acagtgttat aaaaaaggga 3540 aggataaaac ctttgacatc cccttgtgtc tcaaaagtcc acagttattc aaacaatggc 3600 tttttttgtg atgagagtat ttgttaaaaa aaaaaaaaga cttcaagaaa aataaaagtt 3660 cagtggagct gcaaataaat ctggtgaata atttcatctt tggtaatctc ccatttcctg 3720 agttcttcct caatccaagc tgtcctgtgt agtatataac atttgggcat tttctctgat 3780 atactatact ctcatgttct ataaatttct gtcccgtaat tctaacactt tacatttttt 3840 ctttgctatc agctatagct attcatggaa gggaagaatc actaaatact tgtctagtta 3900 tagcatgatg tgagcatctc ctccttatcc ctcgatgcct ggcttggtgt ctggcaaaca 3960 gtccataatt agcagatgtt gaaagaccgt ttacaaagca gaatttgggg atttaaagtg 4020 caatgataca acaaaaagat ttaattacag cttccagtgt tttgactatg tgaaccatat 4080 ccaactactt ttttgaaaat ctagttctat gtaatatatt tctgtggcat caaattttag 4140 ttgattgtat tagtcaatag gaagtggtgg aaaatttcta aataaattca actattaaa 4199 <210> SEQ ID NO 79 <211> LENGTH: 541 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 79 ttttgagagg ctagtaacat cagttttatt gggttggggt ggcaacatag cctggctggg 60 ggtggggctg gcctcacagg ttgttgagtt ccagcagggt ctggtccaag gtctggtgaa 120 tctcgacgtt ctcctccttg gcactggcaa ggtctcttct aggtcatcga tggttttctc 180 caactttgcc acagacctct cggcaaactc tgctcgggtc tcagcctcct tcagcttctc 240 ctccaacagt ttgatctcct cttcatattt atcttctttg gtggaatact tgtccgcctg 300 ggcctccagg gatttcaagt tgttggtaac aattttcagc tcctcctcta ggtccccaca 360 tttactcctc ctctgaggcc atcagggact tgagggcctg gtccatggtt cgaagttcct 420 cctccagctg tctggctcgg ctctcggcca cctcagccct ctcctccgag cgctccagct 480 ctccttccag gatcaccagc ttcctggcca cctcttcata tttgcggtct gaatcctcag 540 c 541 <210> SEQ ID NO 80 <211> LENGTH: 368 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 80 ccgacccccc ggcgcggccg tgcttctgcc cctacaaggt ttgggccgag gtgggggagg 60 gtcctggttg ccggccccgc cgtcacctcc ccgcctttta ggcaccgcgt ggccgggacg 120 tcccagtcgc ctccgtcctc ctcgcctgcc accggtgcac ccagtccgct cacccagccc 180 agtccgtccg gtcctcaccg cctgccggcc ggcccacccc ccaccgcagc catggacgcc 240 atcaagaaga agatgcagat gctgaagctg gacaaggaga acgccatcga ccgcgccgag 300 caggcgaagc cgacaagaag caagctgagg accgctgcaa cagctggagg aggagcagca 360 ggccctcc 368 <210> SEQ ID NO 81 <211> LENGTH: 1044 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 81 tgctgctctc ctcccgctcc gtcctcctcg cctgccaccg gtgcacccag tccgctcacc 60 cagcccagtc cgtccggtcc tcaccgcctg ccggccggcc caccccccac cgcaggccat 120 ggacgccatc aagaagaaga tgcagatgct gaagctggac aaggagaacg ccatcgaccg 180 cgccgagcag gccgaagccg acaagaagca agctgaggac cgctgcaagc agctggagga 240 ggagcagcag gccctccaga agaagctgaa ggggacagag gatgaggtgg aaaagtattc 300 tgaatccgtg aaggaggccc aggagaaact ggagcaggcc gagaagaagg ccactgatgc 360 tgaggcagat gtggcctccc tgaaccgccg cattcagctg gttgaggagg agctggaccg 420 ggcccaggag cgcctggcta cagccctgca gaagctggag gaggccgaga aggcggctga 480 tgagagcgag agaggaatga aggtcatcga aaaccgggcc atgaaggatg aggagaagat 540 ggaactgcag gagatgcagc tgaaggaggc caagcacatc gctgaggatt cagaccgcaa 600 atatgaagag gtggccagga agctggtgat cctggaagga gagctggagc gctcggagga 660 gagggctgag gtggccgaga gccgagccag acagctggag gaggaacttc gaaccatgga 720 ccaggccctc aagtccctga tggcctcaga ggaggagtat tccaccaaag aagataaata 780 tgaagaggag atcaaactgt tggaggagaa gctgaaggag gctgagaccc gagcagagtt 840 tgccgagagg tctgtggcaa agttggagaa aaccatcgat gacctagaag agaccttggc 900 cagtgccaag gaggagaacg tcgagattca ccagaccttg gaccagaccc tgctggaact 960 caacaacctg tgagggccag ccccaccccc agccaggcta tggttgccac cccaacccaa 1020 taaaactgat gttactagcc tctc 1044 <210> SEQ ID NO 82 <211> LENGTH: 447 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 82 taggttggac tcttcacaga aattggggcc atgtcctgct tcatccctcg acaatccatc 60 ccttcagaga tggagtttga atctaactcc aacccaccat gttacaagac aatggatgag 120 gatattgtga ttcagcagga cgatgagatc cgcttaaaga ttgtggggac ccgtgtggac 180 aagaatgaca tttttgctat tggctccctg atggacgatt acttggggct tgtaagctga 240 gcctggtggc ctcctaccct tggtcctact ctaggaagtg tgattgtcac acttatcatg 300 ttgtccagag gtccagtctg gctgctgttg tggaggcaag gaaggcaact catcccagaa 360 ggcatctggt gcttcttgta gcttaactac tgcctcctca tttttcagta tgtgttctaa 420 gtataaaaag tccttggttc tcaaaaa 447 <210> SEQ ID NO 83 <211> LENGTH: 433 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 83 gagaaccaag gactttttat acttagaaca catactgaaa aatgaggagg caggagttaa 60 gccacaagaa gcaccagatg ccctctggga agaggtgccc tcccggcctc cacaacagca 120 gccagactgg acctctggac aacatgataa gtgtgacaat cacacttcct agagtaggac 180 caagggtagg aggccaccag gctcagctta caagccccaa gtaatcgtcc atcagggagc 240 caatagcaaa aatgtcattc ttgtccacac gggtccccac aatctttaag cggatctcat 300 cgtcctgctg aatcacaata tcctcatcca ttgtcttgta acatggtggg ttggagttag 360 gatcaaactc catctctgaa gggatggaat gtcgagagat gtagccagac atgggcccca 420 tttctggtga gag 433 <210> SEQ ID NO 84 <211> LENGTH: 828 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 84 tagtcgcacc aagcgcggaa ctggggttgc ggcgtctaag tgtttccggt ggattcccag 60 ggactgtcgg aggtgtggac tctgcctgcc tacctggtct gggaagatgt tctaccatat 120 ctccctagag cacgaaatcc tgctgcaccc gcgctacttc ggccccaact tgctcaacac 180 ggtgaagcag aagctcttca ccgaggtgga ggggacctgc acagggaagt atggctttgt 240 aattgctgtc accaccattg acaatattgg tgctggtgtg atccagccag gccgaggctt 300 tgtcctttat ccagttaagt acaaggccat tgttttccgg ccatttaaag gggaggtcgt 360 ggatgctgtt gtcactcagg tcaacaaggt tggactcttc acagaaattg ggcccatgtc 420 ttgcttcatc tctcgacatt ccatcccttc agagatggag tttgatccta actccaaccc 480 accatgttac aagacaatgg atgaggatat tgtgattcag caggacgatg agatccgctt 540 aaagattgtg gggacccgtg tggacaagaa tgacattttt gctattggct ccctgatgga 600 cgattacttg gggcttgtaa gctgagcctg gtggcctcct acccttggtc ctactctagg 660 aagtgtgatt gtcacactta tcatgttgtc cagaggtcca gtctggctgc tgttgtggag 720 gcaaggaagg caactcatcc cagaaggcat ctggtgcttc ttgtagctta actactgcct 780 cctcattttt cagtatgtgt tctaagtata aaaagtcctt tggttctc 828 <210> SEQ ID NO 85 <211> LENGTH: 336 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 85 tttgacgaat tcaggagtcc tttattagcc ggcagccgag agacagctag cgctcgaaat 60 tctcttggcc ccgaagaagg agctagattt tcttttatac tttggtttag acaggaggag 120 agggggagtc tagttgaaac aatcttacag aagtaaagta ggcaaaaagt taaaaggata 180 aacggttaca ggaaagtaaa cagttccagg tgcagaggct ttaagtctat cctaaggtga 240 tggacgccgg gctttgggcg ttatcaaccg gacacaaacg caggggctct gggtgctatt 300 aaccgggcga attcctggga actgcggata tagctt 336 <210> SEQ ID NO 86 <211> LENGTH: 391 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 86 gaagagccca catgtagccc tgaggtttcc ttcccaggac agctgcaggg tagagatcat 60 tttaagtgct tgtggagttg acatccctat tgactctttc ccagctgata tcagagactt 120 agacccagca ctccttggat tagctctgca gagtgtcttg gttgagagaa taacctcata 180 gtaccaacat gacatgtgac ttggaaagag actagaggcc acacttgata aatcatgggg 240 cacagatatg ttcccaccca acaaatgtga taagtgattg tgcagccaga gccagccttc 300 cttcaatcaa ggtttccagg cagagcaaat accctagaga ttctctgtga tataggaaat 360 ttggatcaag gaagctaaaa gaattacagg g 391 <210> SEQ ID NO 87 <211> LENGTH: 440 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 87 gcattattaa cacatttatt gaacaactag aacttgacaa ccacttgcca agtagagggg 60 atacagtggt gagcaataat agtgatgata atgaggagca gttttcccta gcaggcagca 120 gttgaaagga atatgggttt aacatccacc aatgaccagg agtggacaga cctatttcca 180 ggagactgag tccatagtgg gattaaaaac atccctgtaa ttcttttagc ttccttgatc 240 caaatttcct atatcacaga gaatctctag ggtatttgct ctgcctggaa accttgattg 300 aaggaaggct ggctctggct gcacaatcac ttatcacatt tgttgggtgg gaacatatct 360 gtgccccatg atttatcaag tgtggcctct agtctctttc caagtcacat gtcatgttgg 420 tactatgagg ttattctctc 440 <210> SEQ ID NO 88 <211> LENGTH: 2937 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 88 acgcgtccgc ttcggaatga gagactcaac cataatagaa agaatggaga actattaacc 60 accattcttc agtgggctgt gattttcaga ggggaatact aagaaatggt tttccatact 120 ggaacccaaa ggtaaagaca ctcaaggaca gacatttttg gcagagcata gatgaaaatg 180 gcaagttccc tggctttcct tctgctcaac tttcatgtct ccctcttctt ggtccagctg 240 ctcactcctt gctcagctca gttttctgtg cttggaccct ctgggcccat cctggccatg 300 gtgggtgaag acgctgatct gccctgtcac ctgttcccga ccatgagtgc agagaccatg 360 gagctgaggt gggtgagttc cagcctaagg caggtggtga acgtgtatgc agatggaaag 420 gaagtggaag acaggcagag tgcaccatat cgagggagaa cttcgattct gcgggatggc 480 atcactgcag ggaaggctgc tctccgaata cacaacgtca cagcctctga cagtggaaag 540 tacttgtgtt atttccaaga tggtgacttc tacgaaaaag ccctggtgga gctgaaggtt 600 gcagcattgg gttctgatct tcacattgaa gtgaagggtt atgaggatgg agggatccat 660 ctggagtgca ggtccactgg ctggtacccc caaccccaaa taaagtggag cgacaccaag 720 ggagagaaca tcccggctgt ggaagcacct gtggttgcag atggagtggg cctgtatgca 780 gtagcagcat ctgtgatcat gagaggcagc tctggtgggg gtgtatcctg catcatcaga 840 aattccctcc tcggcctgga aaagacagcc agcatatcca tcgcagaccc cttcttcagg 900 agcgcccagc cctggatcgc ggccctggca gggaccctgc ctatctcgtt gctgcttctc 960 gcaggagcca gttacttctt gtggagacaa cagaaggaaa aaattgctct gtccagggag 1020 acagaaagag agcgagagat gaaagaaatg ggatacgctg caacagagca agaaataagc 1080 ctaagagaga agctccagga ggaactcaag tggaggaaaa tccagtacat ggctcgtgga 1140 gagaagtctt tggcctatca tgaatggaaa atggccctct tcaaacctgc ggatgtgatt 1200 ctggatccag acacggcaaa cgccatcctc cttgtttctg aggaccagag gagtgtgcag 1260 cgtgctgaag agccgcggga tctgccagac aaccctgaga gatttgaatg gcgttactgt 1320 gtccttggct gtgaaaactt cacatcaggg agacattact gggaggtgga agtgggggac 1380 agaaaagagt ggcatattgg ggtatgtagt aagaacgtgg agaggaaaaa aggttgggtc 1440 aaaatgacac cggagaacgg atactggact atgggcctga ctgatgggaa taagtatcgg 1500 gctctcactg agcccagaac caacctgaaa cttcctgagc ctcctaggaa agtggggatc 1560 ttcctggact atgagactgg agagatctcg ttctataatg ccacagatgg atctcatatc 1620 tacacctttc cgcacgcctc tttctctgag cctctatatc ctgttttcag aattttgacc 1680 ttggagccca ctgccctgac catttgccca ataccaaaag aagtagagag ttcccccgat 1740 cctgacctag tgcctgatca ttccctggag acaccactga ccccgggctt agctaatgaa 1800 agtggggagc ctcaggctga agtaacatct ctgcttctcc ctgcccaccc tggagctgag 1860 gtctcccctt ctgcaacaac caatcagaac cataagctac aggcacgcac tgaagcactt 1920 tactgatatt cattccatta ttccatatga cagttgtttt gagtttcgta ccaccttatt 1980 gtccccttat acagataagg aaactggggt gcagaaaggt gaattaactt tacaaagtag 2040 acatgacaag tgaacagcag agctgggatc taaacagcaa taactaacat taacagagaa 2100 tttaaaatgt tcttagtgct gtgttataag ctttggtgga tgtcactcct ttaatcctca 2160 caacaccctg tcgggtagtc atattttgca agtatggaag ctgaggcagg gcaacatgaa 2220 gtaacttaca taattcatac agtaatttgt gcagttggga gatgttcagc cttagtccct 2280 ggctaattgc ctgttctttt ccagcctgat tttttttccc acaggaagag cccacatgta 2340 gccctgaggt ttccttccca ggacagctgc agggtagaga tcattttaag tgcttgtgga 2400 gttgacatcc ctattgactc tttcccagct gatatcagag acttagaccc agcactcctt 2460 ggattagctc tgcagagtgt cttggttgag agaataacct catagtacca acatgacatg 2520 tgacttggaa agagactaga ggccacactt gataaatcat ggggcacaga tatgttccca 2580 cccaacaaat gtgataagtg attgtgcagc cagagccagc cttccttcaa tcaaggtttc 2640 caggcagagc aaatacccta gagattctct gtgatatagg aaatttggat caaggaagct 2700 aaaagaatta cagggatgtt tttaatccca ctatggactc agtctcctgg aaataggtct 2760 gtccactcct ggtcattggt ggatgttaaa cccatattcc tttcaactgc tgcctgctag 2820 ggaaaactgc tcctcattat catcactatt attgctcacc actgtatccc ctctacttgg 2880 caagtggttg tcaagttcta gttgttcaat aaatgtgtta ataatgaaaa aaaaaaa 2937 <210> SEQ ID NO 89 <211> LENGTH: 490 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 108, 110, 111, 188 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 89 tatttttaat tttgttaaat ttttattatt agggtttgaa ataaattcag tgttcacatt 60 tctataaaga agtaacccag tttcaggaaa ccctgcccca gcagcagntn naagcaacac 120 tctccctgcc cacatctagt ttgatttcac gccctgatgc ttcaaggtgc ccagaaaagc 180 ggcacttngt ggaagaggaa atctatgccc ggcccgtgct tggggcccag ggctcagtaa 240 gctttcgaga aagcagaggg gaagactagc ttactgcaaa aaccttttta aaaaatattc 300 atacacttca gtgagcgcct gttgagacgt taggggaaca agagcttgga aacatcccgt 360 ccaggccatt gggaggcagc gtcttcctca caccccgtcc ctggatgtcg ggggtgcagg 420 gggaaggtcc cggctcttcc actggagaaa ggagactcac ctggcttcct agttcatgtt 480 tgactatttc 490 <210> SEQ ID NO 90 <211> LENGTH: 484 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 90 attgaagccc acccgtggct gaagcattaa ccggtgggcc ccgtgcctcc ccgccccact 60 ttcccttctt caaaggacaa agtgccctca aagggaattg aatttttttt tttacacact 120 taatcttagc ggattacttc agatgttttt aaaaagtata ttaagatgcc ttttcactgt 180 agtatttaaa tatctgttac aggtttccaa ggtggacttg aacagatggc cttatattac 240 caaaactttt atattctagt tgtttttgta ctttttttgc atacaagccg aacgtttgtg 300 cttcccgtgc atgcagtcaa agactcagca caggttttag aggaaatagt caaacatgaa 360 ctaggaagcc aggtgagtct cctttctcca gtggaagagc cgggaccttc cccctgcacc 420 cccgacatcc agggacgggg tgtgaggaag acgctgcctc ccaatggcct ggacgggatg 480 tttc 484 <210> SEQ ID NO 91 <211> LENGTH: 501 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 91 tttacccaaa tttagtcgaa ttttagcaac tttgggatat aaaccagcac agatgacagc 60 tttaattatc ttctcattat ctgaatttat attagattct ggatctttag gatttctact 120 gcttacaaat ccagctccaa gaagatgctc agcaaactgt cctttcatgt tatgcagcat 180 ctgcagtgtg tttgaagaca gaaaatattc ccagcaatag tccttttcgt atctgaaacc 240 acgtcgccta gcctcttccc agccctcaaa cgcattcaca actgttaagt gatcacttct 300 agtatccttt gccaattcct ttcttcttgc atctgcaatc ttttcttttc ccagtggaat 360 gacaaatgga tctttgaaac tgagactagc agcaatagtg agtactgggt ctaagcagca 420 gaacagtgct ccaaaaagaa tcatttttcc aatatgtggc tcaacgggta atcgtgccaa 480 gtggacttca agaggtgtca a 501 <210> SEQ ID NO 92 <211> LENGTH: 502 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 92 gagagggagg gggaagagca gaagttagag aaaaaaagcc accggagaag aggaaaaaac 60 atcggccaac ctagaaacgt tttcattcgt cattccaaga gagagagagg aaagaaaaat 120 acaactttca ttctttcttt gcacgttcat aaacattcta catacgtatt ctcttttgtc 180 tcttcattta taactgctgt gaattgtaca tttctgtgtt ttttggaggt gcagttaaac 240 ttttaagctt aagtgtgaca ggactgataa atagaagatc aagagtagat ccgactttag 300 aagcctactt tgtgaccaag gagctcaatt tttgttttga agctttacta atctaccaga 360 gcattgtaga tatttttttt ttacatctat tgtttaaaat agatgattat aacggggcag 420 agaactttct tttctctgca agaatgttac atattgtata gataaatgag tgacatttca 480 taccatgtat atatagagat gt 502 <210> SEQ ID NO 93 <211> LENGTH: 425 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 93 tacaagacag agaaatctac tttaatattc acatgtaaaa gttacacatc acaagagatt 60 ggacagtagc ttagcgtaac atagctatag tgaaaatcat ttttataaaa aaataatcta 120 gatgcggtca tcagaatttt tggtctgctt aagttaatgt ttgaagatcg acttttatcc 180 ctgcttgaag gatttgccat tatgcctttt tttttctccc actgttgcct attaattctt 240 tggaggaagg aaagcagaaa gtgttcattt ccaagagttt gtcctttggt agcaagcaga 300 gaacattttt ttcatttcca tgatttaaat aatctgtaca gacatgaaac ttagtgacat 360 taagctttag tgtaaaatga agagtaataa gcaatttttt ttcactttga taaaacagca 420 gattc 425 <210> SEQ ID NO 94 <211> LENGTH: 1322 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 94 ggaattccgg gcgcggttgt gagtagtacc gggagtgggg tgatcccggg ctaggggagc 60 gcggcgcccg atcgggctta gtcggagctc cgaagggagt gactaggaca cccgggtggg 120 ctacttttct tccggtgctt ttgctttttt tttcctttgg gctcgggctg agtgtcgccc 180 actgagcaaa gattccctcg taaaacccag agcgaccctc ccgtcaattg ttgggctcgg 240 gagtgtcgcg gtgccccgag cgcgccgggc gcggaggcaa agggagcgga gccggccgcg 300 gacggggccc ggagcttgcc tgcctccctc gctcgcccca gcgggttcgc tcgcgtagag 360 cgcagggcgc gcgcgatgaa ggcggtgagc ccggtgcgcc cctcgggccg caaggcgccg 420 tcgggctgcg gcggcgggga gctggcgctg cgctgcctgg ccgagcacgg ccacagcctg 480 ggtggctccg cagccgcggc ggcggcggcg gcggcagcgc gctgtaaggc ggccgaggcg 540 gcggccgacg agccggcgct gtgcctgcag tgcgatatga acgactgcta tagccgcctg 600 cggaggctgg tgcccaccat cccgcccaac aagaaagtca gcaaagtgga gatcctgcag 660 cacgttatcg actacatcct ggacctgcag ctggcgctgg agacgcaccc ggccctgctg 720 aggcagccac caccgcccgc gccgccacac cacccggccg ggacctgtcc agccgcgccg 780 ccgcggaccc cgctcactgc gctcaacacc gacccggccg gcgcggtgaa caagcagggc 840 gacagcattc tgtgccgctg agccgcgctg tccaggtgtg cggccgcctg agcccgagcc 900 aggagcacta gagagggagg gggaagagca gaagttagag aaaaaaagcc accggaggaa 960 aggaaaaaac atcggccaac ctagaaacgt tttcattcgt cattccaaga gagagagagg 1020 aaagaaaaat acaactttca ttctttcttt gcacgttcat aaacattcta catacgtatt 1080 ctcttttgtc tcttcattta taactgctgt gaattgtaca tttctgtgtt ttttggaggt 1140 gcagttaaac ttttaagctt aagtgtgaca ggactgataa atagaagatc aagagtagat 1200 ccgactttag aagcctactt tgtgaccaag gagctcaatt tttgttttga agctttacta 1260 atctaccaga gcattgtaga tatttttttt ttacatctat tgtttaaaat agccggaatt 1320 cc 1322 <210> SEQ ID NO 95 <211> LENGTH: 397 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 95 tttttttttt tttttttttt tttttcattt taaagagctt tattacagga tattaatatt 60 taggacactt cagagcacct tatacttcta atcagatttt gggtaactgg ttttaaagtg 120 ttacttgaat atttttctca tactgtcttt caggtaaagt acttctcaga gactgtttaa 180 gagatgttaa tttgattaaa cagtttatcc ttaataacct gagacatcaa tccatggata 240 gcttctatgg tagttttaca gctgtctctt gtagctttgg caagtttgtc ttctgatttt 300 cggtcatgcg tttctaaacc caacatgaaa ctccctcgtc ccagctgggc ttctgactgc 360 tctaactttt cagacaaatc aaagacctga ccagtgg 397 <210> SEQ ID NO 96 <211> LENGTH: 505 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 96 atagctgccc gctgctctcg gttcgccagt acgctggccg gggacttggt caactcgttc 60 tcctgctgtg cccaggggct attaaactgt gggggccact tctcaggcta aatctattgc 120 agcctctcca gccgtcccat gcaccagcca gcttaggaac agttcaccat tactttaagt 180 actgcaaaat ctcagcattg gctctgctga agatggtgat gcatgccaga tcgggaggca 240 acttggaagt gatgggtctg atgctaggaa aggtggatgg tgaaccatga tcattatgga 300 cagttttgct ttgcctgtgg agggcactga aacccgagta aatgctcagg ctgctgcata 360 tgaatacatg gctgcataca tagaaaatgc aaaacaggtt ggccgccttg aaaatgcaat 420 cgggtggtat catagccacc ctggctatgg ctgctggctt tctgggattg atgttagtac 480 tcagatgctc aatcagcagt tccag 505 <210> SEQ ID NO 97 <211> LENGTH: 1277 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 97 caagagtcta ggtaagagtt tgttcccgtg gtgcggaggg tcaaggccca cacccggaaa 60 cctagcgagg taaagttgcg tcttggttgt agagacgaca acttctccgc ttcctcggcg 120 atggcggcgt ccgggagcgg tatggcccag aaaacctggg aactggccaa caacatgcag 180 gaagctcaga gtatcgatga aatctacaaa tacgacaaga aacagcagca agaaatcctg 240 gcggcgaacc ttgggactaa ggatcaccat tactttaagt actgcaaaat ctcagcattg 300 gctcttctga agatggtgat gcatgccaga tcgggaggca atttggaagt gatgggtctg 360 atgctaggaa aggtggatgg tgaaaccatg atcattatgg acagttttgc tttgcctgtg 420 gagggcactg aaacccgagt aaatgctcag gctgctgcat atgaatacat ggctgcatac 480 atagaaaatg caaaacaggt tggccgcctt gaaaatgcaa tcgggtggta tcatagccac 540 cctggctatg gctgctggct ttctgggatt gatgttagta ctcagatgct caatcagcag 600 ttccaggaac catttgtagc agtggtgatt gatccaacaa gaacaatatc cgcagggaaa 660 gtgaatcttg gcgcctttag gacataccca aagggctaca aacctcctga tgaaggacct 720 tctgagtacc agactattcc acttaataaa atagaagatt ttggtgtaca ctgcaaacaa 780 tattatgcct tagaagtctc atatttcaaa tcctctttgg atcgcaaatt gcttgagctg 840 ttgtggaata aatactgggt gaatacgttg agttcttcta gcttgcttac taatgcagac 900 tataccactg gtcaggtctt tgatttgtct gaaaagttag agcagtcaga agcccagctg 960 ggacgaggga gtttcatgtt gggtttagaa acgcatgacc gaaaatcaga agacaaactt 1020 gccaaagcta caagagacag ctgtaaaact accatagaag ctatccatgg attgatgtct 1080 caggttatta aggataaact gtttaatcaa attaacatct cttaaacagt ctctgagaag 1140 tactttacct gaaagacagt atgagaaaaa tattcaagta acactttaaa accagttacc 1200 caaaatctga ttagaagtat aaggtgctct gaagtgtcct aaatattaat atcctgtaat 1260 aaagctcttt aaaatga 1277 <210> SEQ ID NO 98 <211> LENGTH: 247 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 98 gttctggatc tcaaagcggc tgtgagtact ttggctgtga gcaaaaaagg agaatttatg 60 atatcaccaa tgtcttagag ggaattgact tgattgaaaa aaagtcaaaa aacagtatcc 120 agtggaaagg tgtaggtgct ggctgtaata ctaaagaagt catagataga ttaagatatc 180 ttaaagctga aattgaagat ctagaactga aggaaagaga acttgatcag cagaagttgt 240 ggctaca 247 <210> SEQ ID NO 99 <211> LENGTH: 342 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 99 tgaatgtttt atacaatttt atttttaaaa atcttgttaa tgtacaggca ttggcacatt 60 ttaaaaacaa actacataaa cagatctttc ctataaccta ggaaagtgga atgtcagaag 120 tcaacaaaat gtgataaact taaagtgcta aaacagaagg cacttcacaa aatctgttca 180 ctgaaacagt tatatatcct cgtttacatc cttcacttta caagtggcag tgaacgtctg 240 tttggataga aggacataca gaaatacagg cagtttagtg gcagtaaaaa tataagacaa 300 gtaatgagtc cttggccaac ttgtttttga tgacctgtag tg 342 <210> SEQ ID NO 100 <211> LENGTH: 1752 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 100 cgggggggcc cgaccaccgc ggggccggga cgcgatggcg gcggcagagc ccgcgagctc 60 gggccagcag gcgccggcag ggcaggggca gggccagcgg ccgccgccgc agcctccgca 120 ggcgcaagcc ccgcagccgc ccccgccgcc gcagctcggg ggcgcggggg gcggcagcag 180 caggcacgag aagagcctgg ggctgctcac taccaagttc gtgtcgctgc tgcaggaggc 240 caaggacggc gttctggatc tcaaagcggc tgctgatact ttggctgtga ggcaaaaaag 300 gagaatttat gatatcacca atgtcttaga gggaattgac ttgattgaaa aaaagtcaaa 360 aaacagtatc cagtggaaag gtgtaggtgc tggctgtaat actaaagaag tcatagatag 420 attaagatat cttaaagctg aaattgaaga tctagaactg aaggaaagag aacttgatca 480 gcagaagttg ttgctacagc aaagcatcaa aaatgtgatg gacgattcca ttaataatag 540 attttcctat gtaactcatg aagacatctg taattgcttt aatggtgata cacttttggc 600 cattcaggca ccttctggta cacaactgga ggtacccatt ccagaaatgg gtcagaatgg 660 acaaaagaaa taccagatca atctaaagag tcattcagga cctatccatg tgctgcttat 720 aaataaagag tcgagttcat ctaagcccgt ggtttttcct gttcccccac ctgatgacct 780 cacacagcct tcctcccagt ccttgactcc agtgactcca cagaaatcca gcatggcaac 840 tcaaaatctg cctgagcaac atgtctctga aagaagccag gctctgcagc agacatcagc 900 tacagatata tcttcagcag gatctattag tggagatatc attgatgagt taatgtcttc 960 tgacgtgttt cctctcttaa ggctttctcc taccccggca gatgactaca actttaattt 1020 agatgataac gaaggagttt gtgatctgtt tgatgtccag atactaaatt attagattcc 1080 atggaaactt gggactgtta tctacctcta actgtgtaac attttagact tcttaataac 1140 ctaaatattt aaaataatga atgtaacacc ttttttagtt cactgattct gaagtgttct 1200 tccctaatac tttctttact tcacaaaact tcaaccataa aaacaaaggg ctctgattgc 1260 tttaggggat aagtgattta atattcacaa acgtccccac tcccaaaagt aactatattc 1320 tggatttcaa cttttcttct aattgtgaat ccttccgttt tttcttctta aggaggaaag 1380 ttaaaggaca ctacaggtca tcaaaaacaa gttggccaag gactcattac ttgtcttata 1440 tttttactgc cactaaactg cctgtatttc tgtatgtcct tctatccaaa cagacgttca 1500 ctgccacttg taaagtgaag gatgtaaacg aggatatata actgtttcag tgaacagatt 1560 ttgtgaagtg ccttctgttt tagcacttta agtttatcac attttgttga cttctgacat 1620 tccactttcc taggttatag gaaagatctg tttatgtagt ttgtttttaa aatgtgccaa 1680 tgcctgtaca ttaacagatt tttaaaaata aaattgtata aaacattaaa aaaaaaaaaa 1740 aaaaaaaaaa aa 1752 <210> SEQ ID NO 101 <211> LENGTH: 456 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 101 tgtgttccaa caaaacttta tttacaaaaa caggaagcag gcacgtttgg ccctcagact 60 gtaatcttcc catcactact cttaatgata ctcagatgac ctggctgcct gagggggctg 120 tggccatgtc tgattctctg tgagatggaa accactctag ggtctcctgg tgcgctgagg 180 ctttacacac cggcagaaca gggcactgcg tttggaagtt tctgaccaag tggtgacagc 240 agagggcaaa acgtgaaggc tgtgctggat aaggctgaac cttcctcata agcaacacca 300 actgctttat tccaggtcag ggccaactct tccgccatga tacatacatg gtccctggcg 360 ggcactgtcc ttactgggcc cctaggagtc cctgcgttgt ggcctgacca ccagcccctc 420 tctggtgatg gcccagttgt agttcttccg ggagtc 456 <210> SEQ ID NO 102 <211> LENGTH: 317 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 102 tgcggccgca agacccgcca cgacccgctg gccaaatcca agatcgagcg agtgaacatg 60 ccgcccgccg tggaccctgc ggagttcttc gtgctgatgg agcgttacca gcactaccgc 120 cagaccgtgc gcgccctcag gatggagttc gtgtccgagg tgcagaggaa ggtgcacgag 180 gcccgagccg gggttctggc ggacggcaag gccctgaagg acgccgccga gcaccgcgag 240 ctgatggcct ggaaccaggc ggagaaccgg cggctgcacg agctgcggat agcgaggctg 300 cggcaggagg agcggga 317 <210> SEQ ID NO 103 <211> LENGTH: 1038 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 103 ggcacgaggc tcggccatgc tacgcgcgct gagccgcctg ggcgcgggga ccccgtgcag 60 gccccgggcc cctctggtgc tgccagcgcg cggccgcaag acccgccacg acccgctggc 120 caaatccaag atcgagcgag tgaacatgcc gcccgcggtg gaccctgcgg agttcttcgt 180 gctgatggag cgttaccagc actaccgcca gaccgtgcgc gccctcagga tggagttcgt 240 gtccgaggtg cagaggaagg tgcacgaggc ccgagccggg gttctggcgg agcgcaaggc 300 cctgaaggac gccgccgagc accgcgagct gatggcctgg aaccaggcgg agaaccggcg 360 gctgcacgag ctgcggatag cgaggctgcg gcaggaggag cgggagcagg agcagcggca 420 ggcgttggag caggcccgca aggccgaaga ggtgcaggcc tgggcgcagc gcaaggagcg 480 ggaagtgctg cagctgcagg aagaggtgaa aaacttcatc acccgagaga acctggaggc 540 acgggtggaa gcagcattgg actcccggaa gaactacaac tgggccatca ccagagaggg 600 gctggtggtc aggccacaac gcagggactc ctaggggccc agtaaggaca gtgcccgcca 660 gggaccatgt atgtatcatg gcggaagagt tggccctgac ctggaataaa gcagttggtg 720 ttgcttatga ggaaggttca gccttatcca gcacagcctt cacgttttgc cctctgctgt 780 caccacttgg tcagaaactt ccaaacgcag tgccctgttc tgccggtgtg tacagcctca 840 gcgcaccagg agaccctaga gtggtttcca tctcacagag aatcagacag ggccacagcc 900 ccctcaggca gccaggtcat ctgagtatca ttaagagtag tgatgggaag attacagtct 960 gagggccaaa cgtgcctgct tcctgttttt gtaaataaag ttttgttgga acacaaaaaa 1020 aaaaaaaaaa aaaaaaaa 1038 <210> SEQ ID NO 104 <211> LENGTH: 405 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 104 agtttgattt agaattgttt tatttgtgtt cctcatgcta caacacaacc ttcaaagtca 60 gcgaagttta taacattaat atgcttcctc aaaacatcaa tttaggcaac ccatagccag 120 agcttctaaa cttctacaat gcaacttcaa cattcacaag agcacaatat gcttcaaatc 180 ccatctcaat gcaaatttaa gaaaagcaaa gcaaattgta ttatcagtct accaaaactc 240 agtaagattc tgtaatttaa tatacctact tctcaactct ctaaatttgt ttctcaacac 300 tggggagttt ttaaagatat caatgcctga attctactcc aagccaatta aatcagaaca 360 attaaaatca gaatctctgt ggggcatctt tttttttttt taaag 405 <210> SEQ ID NO 105 <211> LENGTH: 1278 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 105 ggcacgagga ggtgtggacg ctgtgtatga aatgtctttc ctccaggacc caagtttctt 60 caccatgggg atgtggtcca ttggtgcagg agccctgggg gctgctgcct tggcattgct 120 gcttgccaac acagacgtgt ttctgtccaa gccccagaaa gcggccctgg agtacctgga 180 ggatatagac ctgaaaacac tggagaagga accaaggact ttcaaagcaa aggagctatg 240 ggaaaaaaat ggagctgtga ttatggccgt gcggaggcca ggctgtttcc tctgtcgaga 300 ggaagctgcg gatctgtcct ccctgaaaag catgttggac cagctgggcg tccccctcta 360 tgcagtggta aaggagcaca tcaggactga agtgaaggat ttccagcctt atttcaaagg 420 agaaatcttc ctggatgaaa agaaaaagtt ctatggtcca caaaggcgga agatgatgtt 480 tatgggattt atccgtctgg gagtgtggta caacttcttc cgagcctgga acggaggctt 540 ctctggaaac ctggaaggag aaggcttcat ccttggggga gttttcgtgg tgggatcagg 600 aaagcagggc attcttcttg agcaccgaga aaaagaattt ggagacaaag taaacctact 660 ttctgttctg gaagctgcta agatgatcaa accacagact ttggcctcag agaaaaaatg 720 attgtgtgaa actgcccagc tcagggataa ccagggacat tcacctgtgt tcatgggatg 780 tattgtttcc actcgtgtcc ctaaggagtg agaaacccat ttatactcta ctctcagtat 840 ggattattaa tgtattttaa tattctgttt aggcccacta aggcaaaata gccccaaaac 900 aagactgaca aaaatctgaa aaactaatga ggattattaa gctaaaacct gggaaatagg 960 aggcttaaaa ttgactgcca ggctgggtgc agtggctcac acctgtaatc ccagcacttt 1020 gggaggccaa ggtgagcaag tcacttgagg tcgggagttc gagaccagcc tgagcaacat 1080 ggcgaaaccc cgtctctact aaaaatacaa aaatcacccg ggtgtggtgg caggcacctg 1140 tagtcccagc tacccgggag gctgaggcag gagaatcact tgaacctggg aggtggaggt 1200 tgcggtgagc tgagatcaca ccactgtatt ccagcctggg tgactgagac tctaactaaa 1260 aaaaaaaaaa aaaaaaaa 1278 <210> SEQ ID NO 106 <211> LENGTH: 330 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 106 gcgtgtggtt ttgatggtgg ttgtagtttt gtttcgtttt gtttttaaga gatgagtctt 60 gaaggcagag ttgtaatggc cctcctctct cccctcccat tcccgaaatt agggtagctt 120 aacagaaagc caccttgacc acatggccag ggactgagat tcaatgggga aagaaagact 180 gtagctggaa tgtgaagaat ttgatttgca gttgattgca ggttgggttt ccggaagggc 240 agacagctca atgtagtgcc atcatagggc ctcagatgcc cacactccac ccccagagct 300 tcacaaaatg gaaggaccct ggagtcaccc 330 <210> SEQ ID NO 107 <211> LENGTH: 390 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 107 tttcacagcg taggcaacag agtgagaacc tagggctacc ctagctgatg gatgtgaggc 60 tgctgtctac aggagctcat cccagccctg ttaactggca gtggcaagga tactcgtcat 120 cggccattgc actggggaac tccctcaccc catggcttcc caacttgaaa cccagattta 180 cctccaggga gaggtgagaa aaaaattgta aatagacttg ctaaagagca actcagggtt 240 ggggtgtgtt ttaattctcc tgatcacttg aaataatctg taggctgagt gcttatgggg 300 gtgggggaga agggtgactc cagggtcctt ccattttgtg aagctctggg ggtggagtgt 360 gggcatctga ggccctatga tggcactaca 390 <210> SEQ ID NO 108 <211> LENGTH: 380 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 48, 58 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 108 cagcaggcac tccggagtgc acggcgaggg gggcctccta gagaccangc agggcccngg 60 gagcccccac ccagcctgcc accgagcgac tccccgtgcg caaggcccag cagccaccga 120 cgcgccctcc cgccccggca gactcgcagg cagggtccaa gcgtccaggt ttattgaccc 180 ggctgggtct cactcctcct tctcctcccc gtgggtgatc acgtagctga gcgccttgta 240 gtccaggttg cccgccacat cgatggaggc gaactggaac atctggtcca cctgcgggcg 300 ggggcgaaag ggctccttgc gggctccggg agcgaattac aagcgcgcac ctgcaaaaaa 360 aaaaaaaaaa aaaaaacccg 380 <210> SEQ ID NO 109 <211> LENGTH: 325 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 109 tttgcaggtg cgcgcttgta attcgctccc ggagcccgca aggagccctt tcgcccccgc 60 ccgcaggtgg accagatgtt ccagttcgcc tccatcgatg tggcgggcaa cctggactac 120 aaggcgctca gctacgtgat cacccacggg gaggagaagg aggagtgaga cccagccggg 180 tcaataaacc tggacgcttg gaccctgcct gcgagtctgc cggggcggga gggcgcgtcg 240 gtggctgctg ggccttgcgc acggggagtc gctcggtggc aggctgggtg ggggctcccg 300 ggccctctgg ggtcctctag cgagg 325 <210> SEQ ID NO 110 <211> LENGTH: 1619 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 110 cagtagtcct tggggcggaa ctggcccccc gtggcccggc ccggctcggc cccacctccg 60 cccgcaggcg gtcccggccc acgcgggaag gtccttaagc ccgggcggcc ggcgggaccg 120 gcggagaccc gtggaggccg ccgacgatgg cggggccgac ggaggccgag acggggttgg 180 ccgagccccg ggccctgtgc gcgcagcggg gccaccgcac ctacgcgcgc cgctgggtgt 240 tcctgctcgc gatcagcctg ctcaactgct ccaacgccac gatcaactgg ctgtcactgg 300 tctacctcgt ggtatccacc ccatttggcg tggcggccat ctggatcctg gactccgtcg 360 ggctccgtgc ggcgctcggt gtctatacca tccctgctgg cgtcgtctgc ctgctgtcca 420 ccatctgcct gtgggagagt gtgcccccca ccccgccctc tgccggggct gccagctcca 480 cctcagagaa gttcctggat gggctcaagc cgcagctcat gtggaacaag gcctatgtca 540 tcctggctgt gtgcttgggg ggaatgatcg ggatctctgc cagcttctca gccctcctgg 600 agcagatcct ctgtgcaagc ggccactcca gtgggttttc cggcctctgt ggcgctctct 660 tcatcacgtt tgggatcctg ggggcactgg ctctcggccc ctatgtggac cggaccaagc 720 acttcactga ggccaccaag attggcctgt gcctgttctc tctggcctgc gtgccctttg 780 ccctggtgtc ccagctgcag ggacagaccc ttgccctggc tgccacctgc tcgctgctcg 840 ggctgtttgg cttctcggtg ggccccgtgg ccatggagtt ggcggtcgag tgttccttcc 900 ccgtggggga gggggctgcc acaggcatga tctttgtgct ggggcaggcc gagggaatac 960 tcatcatgct ggcaatgacg gcactgactg tgcgacgctc ggagctgtcc ttgtccacct 1020 gccagcaggg ggaggatcca cttgactgga cagtgtctct gctgctgatg gccggcctgt 1080 gcaccttctt cagctgcatc ctggcggtct tcttccacac cccataccgg cgcctgcagg 1140 ccgagtctgg ggagcccccc tccacccgta acgccgtggg cggcgcagac tcagggccgg 1200 gtgtggaccg agggggagca ggaagggctg gggtcctggg gcccagcacg gcgactccgg 1260 agtgcacggc gaggggggcc tcgctagagg accccagagg gcccgggagc ccccacccag 1320 cctgccaccg agcgactccc cgtgcgcaag gcccagcagc caccgacgcg ccctcccgcc 1380 ccggcagact cgcaggcagg gtccaagcgt ccaggtttat tgacccggct gggtctcact 1440 cctccttctc ctccccgtgg gtgatcacgt agctgagcgc cttgtagtcc aggttgcccg 1500 ccacatcgat ggaggcgaac tggaacatct ggtccacctg cgggcggggg cgaaagggct 1560 ccttgcgggc tccgggagcg aattacaagc gcgcacctgc aaaaaaaaaa aaaaaaaaa 1619 <210> SEQ ID NO 111 <211> LENGTH: 338 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 111 accccaacaa caaaaaagaa tgttttggta taggagaagg gatggtcagt tagcctgtct 60 gtcacacgac ggaatggata ctgggcccgg ggaccacttt catactcacg tcctcatcct 120 tggataccca ggggagggcg aaccgttttc gctcgtgtgt ctgtacgcag catgttggga 180 tcgggagttt cggcacagac tatcccatca agccgttggt cctttcagct actacgttac 240 cacgttccta aaacgcaagc tctccggacc agacggacac agggagaagc tagtttcttt 300 catgtgattg aaatgatgac tctactccta aaagggaa 338 <210> SEQ ID NO 112 <211> LENGTH: 413 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 112 tttttttttt ttttttaagt ttaatacaaa ttttatacaa agaaaatgtg aaaaaatact 60 tccatatgct aaaagcaatt atgcttcaca aataaggcca gctaggctat tttttttttt 120 gacaactgca attcacaaat gttctttctc tcctgttttc ttctaatact ctcttatttc 180 ttctctaata tgggtaacta gctggaaact gtacagttcg catcctctta acaatgaaga 240 gaaagtaaac aagactaaaa tgtacaacaa aacgtactgg aatgatatcg tacaattaat 300 tttctcatat acatacatca ccttttgctt tttcatcaat gctttttgtt ttacacaaca 360 tacaaaatgg ctctacagca tacgtagtgt tacggacagc atgacgggcc ttg 413 <210> SEQ ID NO 113 <211> LENGTH: 1845 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 113 atggatttga aggagctgag cgagtcggtc cagcaacagt ccacccctgt tcctctcatc 60 tctcccaagc gccagattcg tagcaggttc cagctgaatc ttgacaagac catagagagt 120 tgcaaagcac aattaggcat aaatgaaatc tcggaagatg tctatacggc cgtagagcac 180 agcgattcgg aggattctga gaagtcagat agtagcgata gtgagtatat cagtgatgat 240 gagcagaagt ctaagaacga gccagaagac acagaggaca aagaaggttg tcagatggac 300 aaagagccat ctgctgttaa aaaaaagccc aagcctacaa acccagtgga gattaaagag 360 gagctgaaaa gcacgtcacc agccagcgag aaggcagacc ctggagcagt caaggacaag 420 gccagccctg agcctgagaa ggacttttcc gaaaaggcaa aaccttcacc tcaccccata 480 aaggataaac tgaagggaaa agatgagacg gattccccaa cagtccattt gggcctggac 540 tctgattcag agagcgaact tgtcatagat ttaggagaag accattctgg gcgggagggt 600 cgaaaaaata agaaggaacc caaagaacca tctcccaaac aggatgttgt aggtaaaaca 660 ccaccatcca cgacggtggg cagccattct cccccggaaa caccggtgct cacccgctct 720 tccgcccaaa cttccgcggc tggcgccaca gccaccacca gcacgtcctc cacggtcacc 780 gtcacggccc cggcccccgc cgccacagga agcccagtga aaaagcagag gccgctttta 840 ccgaaggaga ctgccccggc cgtgcagcgg gtcgtgtgga actcatcaag tgtccagcag 900 aaggagatca cacagagccc atccacgtcc accatcaccc tggtgaccag cacacagtca 960 tcgcccctgg tcaccagctc ggggtccatg agcacccttg tgtcctcagt caacgctgac 1020 ctgcccatcg ccactgcctc agctgatgtc gccgctgata ttgccaagta cactagcaaa 1080 atgatggatg caataaaagg aacaatgaca gaaatataca acgatctttc taaaaacact 1140 actggaagca caatagctga gattcgcagg ctgaggatcg agatagagaa gctccagtgg 1200 ctgcaccagc aagagctctc cgaaatgaaa cacaacttag agctgaccat ggcggagatg 1260 cggcagagcc tggagcagga gcgggaccgg ctcatcgccg aggtgaagaa gcagctggag 1320 ttggagaagc agcaggcggt ggatgagacc aagaagaagc agtggtgcgc caactgcaag 1380 aaggaggcca tcttttactg ctgttggaac accagctact gtgactaccc ctgccagcaa 1440 gcccactggc ctgagcacat gaagtcctgc acccagtcag ctactgctcc tcagcaggaa 1500 gcggatgctg aggtgaacac agaaacacta aataagtcct cccaggggag ctcctcgagc 1560 acacaatcag caccttcaga aacggccagc gcctccaaag agaaggagac gtcagctgag 1620 aaaagcaagg agagtggctc gacccttgac ctttctggct ccagagagac gccctcctcc 1680 attctcttag gctccaacca aggctctgac cattcccgga gtaataaatc cagttggagc 1740 agcagtgatg agaagagggg atcgacacgt tccgatcaca acaccagtac cagcacgaag 1800 agcctcctcc cgaaagagtc tcggctggac accttctggg actag 1845 <210> SEQ ID NO 114 <211> LENGTH: 348 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 114 gaaaaagttg caagcctttt aattcattga cctcttttga ctgattggaa tttttaccat 60 tctgtacact ctgaattata actaaacaac tacatgttac tgacaaattt gtgattcttt 120 gagtctaaac aacacagaaa ctagaagatc cctttcctag atttatatac ttgattttct 180 tataaaaata acttcagtta ttatgtcaat atttatctga aaaaggcagc cctctgacag 240 taaactagta actggaataa ctacagtatc attataagct acagtaaaac aacctgtaaa 300 gtaatttttc ctatttgaat aataaataga ctggacagga gtgaaaaa 348 <210> SEQ ID NO 115 <211> LENGTH: 186 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 115 tttttttttt tttttttttt ttttttttga cgttaagaca tttattacat acagagcaga 60 tatgtgggtt tgcttgcagg gccaaagcct gaggagaatc gtcacccctc ccccagccgc 120 cccactgctc agcccggagt cacttcgaga tcctggggga acagacgagg gagcggacat 180 tcatca 186 <210> SEQ ID NO 116 <211> LENGTH: 355 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 116 agttcttacg gaaacacccc aggacacaat tgaattaaac agattgaatt tagaatcttc 60 caattcaaag tactccttga atacagattc ctcagtgtct tatattgatt cagctgtaat 120 ttcacctgat actgtcccac tgggaacagg aacttccata ttatctatac aggttcaaaa 180 taaaccaaaa actggtcgaa gtttattagg aggaccagca gctcttagtc cattaacccc 240 aagttttggg attttgccat tagaaacccc aagtcctgga gatgggtcta tttacgaaac 300 tacactaata cacctcctgt aattggtgtg cctccatcgg ggcccttcag aaaag 355 <210> SEQ ID NO 117 <211> LENGTH: 4029 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 117 atgatggaga tccagatgga cgagggcggc ggcgtggtgg tgtaccagga cgactactgc 60 tccggctcgg tgatgtcgga gcgggtgtcg ggcctggcgg gctccatcta ccgcgagttc 120 gagcgcctca tccactgcta cgacgaggag gtggtcaagg agctcatgcc gctggtggtg 180 aacgtgctgg agaacctaga ctcggtgctc agcgagaacc aggagcacga ggtggagctg 240 gagctgctgc gcgaggacaa cgagcagctg ctcacccagt acgagcgtga gaaggcgctg 300 cgcaggcagg cggaggagaa attcattgag tttgaagatg ctctggaaca agagaagaaa 360 gagctgcaaa tccaggtgga gcactacgag ttccagacgc gccagctgga gctgaaggcc 420 aagaactatg ccgatcagat ttcccggttg gaggagcggg agtcggagat gaagaaggag 480 tacaatgccc tgcaccagcg gcacacagag atgatacaga cctacgtgga gcacattgag 540 aggtccaaga tgcagcaggt cggaggaaac agccagaccg agagcagcct gccggggcgg 600 agcaggaagg agcgccccac ctccctgaac gtgttccccc tggctgacgg cacggtacgt 660 gcacagatcg ggggcaagct cgtgcctgcg ggggaccact ggcacctgag tgacctcggc 720 cagctgcagt ccagctccag ctaccagtgt ccacaggatg aaatgtccga gtcaggccag 780 tcctcggcgg ccgccacacc cagcaccaca ggcaccaagt ccaacacgcc cacatcctcc 840 gtgccctcgg ccgccgtcac acccctcaac gagagcctgc agcccctggg ggactatggc 900 gtgggctcca agaacagcaa gcgtgcccgg gagaagcgcg acagccgcaa catggaagta 960 caggtcaccc aggagatgcg caacgtcagt ataggcatgg gcagcagtga cgagtggtct 1020 gatgttcaag acattattga ctccacgcca gagctggaca tgtgtccaga gacccgcctg 1080 gaccgcacag gaagcagccc aacccagggc atcgtgaaca aagctttcgg catcaacacc 1140 gactccctgt accatgagct gtcgacggca gggtctgagg tcatcgggga tgtggacgaa 1200 ggggccgacc tcctaggtga aacctccgca ccttctgttt caggaatggg caaagaagtg 1260 gggaatctgc tactggaaaa ctcacagctt ctggaaacca aaaacgcctt gaatgtggtg 1320 aagaatgacc tgattgccaa ggtcgaccag ctgtccgggg agcaggaggt gctgaggggc 1380 gagttggagg ctgctaagca ggccaaagtc aagctggaaa accgtatcaa ggagctggaa 1440 gaggaactga aaagagtgaa gtccgaggcc atcatcgccc gccgtgaacc caaagaagag 1500 gcggaggatg taagcagcta tctctgtaca gaatcggaca aaatccccat ggcccagcgc 1560 cgccgcttca cgcgggtgga gatggcccgt gtgctcatgg agcggaacca gtacaaggag 1620 cggctgatgg agctgcagga ggctgtgcgg tggactgaga tgatcagagc gtcccgagag 1680 cacccatccg tccaggagaa gaagaagtcg accatctggc agttcttcag ccgcctcttc 1740 agctcttcct ccagcccccc tccggccaag cgcccctatc cctcggtgaa catccactac 1800 aagtcaccca ccactgccgg cttcagccag cgccgcaacc atgccatgtg cccgatctcg 1860 gcaggcagcc ggcccctgga attcttccct gacgacgact gcacgtcctc cgcccgtcga 1920 gagcagaagc gcgagcagta ccgccaggtg cgtgagcacg tgcgtaacga cgacggccgt 1980 ctgcaggcct gcggctggag cctgcccgcc aagtacaagc agctgagtcc caacgggggc 2040 caggaggaca cgcggatgaa gaacgtgccg gtgccggtgt actgccgccc tctggtggag 2100 aaggacccca ccatgaagct gtggtgtgcc gcgggcgtca acctgagcgg gtggaggccc 2160 aatgaggacg acgctgggaa tggagtcaag ccagcgccag gccgcgatcc cctgacctgc 2220 gaccgcgaag gagacggcga gcccaagagc gcccacacgt ctcccgagaa gaagaaggcc 2280 aaggagctcc ctgaaatgga cgccacctcc agccgggtgt ggatcctgac cagcaccctg 2340 accaccagca aggtggtgat catcgacgcc aaccagccgg gcacggtggt ggaccagttc 2400 accgtctgca acgcgcacgt gctgtgcatc tccagcatcc ccgcggccag cgacagcgac 2460 taccctcccg gggagatgtt cctggacagc gacgtgaacc cagaggaccc gggcgcagat 2520 ggcgtgctgg ccggtatcac cctggtgggc tgtgccaccc gctgcaacgt gccgcggagc 2580 aactgctcct cccgagggga caccccagtg ctagacaagg ggcaggggga ggtggccacc 2640 atcgccaacg ggaaggtcaa cccgtcccag tccacagagg aggccacaga ggccacggag 2700 gtgccagacc ctgggcccag cgagccagag acagccacat tgcggcccgg gcctctcaca 2760 gagcacgtct tcactgaccc agccccgacc ccgtcctctg gcccccagcc tggcagcgag 2820 aacgggccag agcctgacag cagcagcaca cggccagagc cagagcccag cggggacccc 2880 acgggagcag gcagcagtgc tgcacccacc atgtggctgg gagcccagaa cggctggctc 2940 tatgtgcact cggctgtggc caactggaag aagtgcctgc actccatcaa gctgaaggat 3000 tctgtgctga gcctggtgca tgtcaaaggc cgtgtgctgg tggctctggc ggacgggacc 3060 ctggccatct tccaccgtgg tgaagatggc cagtgggatc tgagcaacta tcacctaatg 3120 gacctgggcc acccgcacca ctccatccgc tgcatggctg ttgtgtacga ccgcgtgtgg 3180 tgtggctaca agaacaaggt gcacgtcatc cagcccaaga ccatgcagat agaggcgacc 3240 atgactccac agaagtcatt tgacgcccac ccgcggcggg agagccaggt gcggcagctg 3300 gcgtggatcg gcgatggcgt atgggtgtcc atccgcctgg actccaccct gaggctctac 3360 catgcacaca cgcaccagca tctacaggac gtggacattg agccctacgt cagcaagatg 3420 ctaggcactg gcaagctggg tttctccttc gtacgcatca cggccctgct tgtcgcgggc 3480 agccggctct gggtgggcac cggcaacgga gtggtcatct ccatccccct gacagagact 3540 gtggtcctgc accgaggcca gctcctgggg ctccgagcca ataagacatc ccccacctct 3600 ggggagggcg cccgtcccgg gggcatcatc cacgtgtatg gcgatgacag cagtgacagg 3660 gcggccagca gcttcatccc ctactgctcc atggcccagg cccagctatg cttccatggg 3720 caccgcgatg ccgtgaagtt ctttgtctcg gtgccaggga acgtgctggc caccctgaat 3780 ggcagtgtgc tggacagccc agccgagggc cctgggccag ctgcccctgc ctcggaggtc 3840 gagggccaga agctgcggaa cgtgctggtg ctgagcggcg gggagggcta catcgacttc 3900 cgcattggag acggagagga cgacgagacg gaggagggcg caggggacat gagccaggtg 3960 aagcccgtgc tgtccaaggc agagcgcagt cacatcatcg tgtggcaggt gtcctacacc 4020 cccgagtga 4029 <210> SEQ ID NO 118 <211> LENGTH: 385 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 118 actcaaattg accctggaca acagtagtct agtctcctgg aagacatggt gcaaacagaa 60 atgcaatgtg gtggtatact catagtcaaa gtgggtgcac aagtgatggt ccaactttgt 120 ggaatggtaa ggatttttag ggttgtttgg ccagaacaag agaaataact gcagaaaaca 180 catatggttg gaaaccatgc gcttgtgact ttttctgtag cctatgggag tggacagagt 240 gggtaaccca agatgttttt aagactgact ggactaagaa tgacgtactt atagccaact 300 actttccccc taatgtgact gaagggattc ataatgatca caattagcat tacggttaag 360 tattttaggg ttgacgtcta agctc 385 <210> SEQ ID NO 119 <211> LENGTH: 438 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 119 aggtcctcct tggggacgcc gcctgccgca gccacccgcc cccttggtgc tcagttctgg 60 ttctgttaat tcgccccacc aaaacgtgcc gagcacgctc tgtgctgggg ttgcggaagt 120 gactgaacgc ggctccgtgg gcgcagtggt gggggttggg ctagctgtcc ccggcagttg 180 gtgcagagcc attttcattc ccggcggttt ccttgttttt gttggggaac taagatggac 240 ggatacagtc gtcttattgt acttaaagcg gatgatattt aatacacagt ttgatttcac 300 aggtaagcca agatgggtgc atacaagtac atccaggagc tatggagaaa gaagcagtct 360 gatgtcatgc gctttcttct gagggtccgc tgctggcagt accgccagct ctctgctctc 420 cacagggctc ccgcccca 438 <210> SEQ ID NO 120 <211> LENGTH: 2018 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 120 cctttccgtc tggcggcagc catcaggtaa gccaagatgg gtgcatacaa gtacatccag 60 gagctatgga gaaagaagca gtctgatgtc atgcgctttc ttctgagggt ccgctgctgg 120 cagtaccgcc agctctctgc tctccacagg gctccccgcc ccacccggcc tgataaagcg 180 cgccgactgg gctacaaggc caagcaaggt tacgttatat ataggattcg tgttcgccgt 240 ggtggccgaa aacgcccagt tcctaagggt gcaacttacg gcaagcctgt ccatcatggt 300 gttaaccagc taaagtttgc tcgaagcctt cagtccgttg cagaggagcg agctggacgc 360 cactgtgggg ctctgagagt cctgaattct tactgggttg gtgaagattc cacatacaaa 420 ttttttgagg ttatcctcat tgatccattc cataaagcta tcagaagaaa tcctgacacc 480 cagtggatca ccaaaccagt ccacaagcac agggagatgc gtgggctgac atctgcaggc 540 cgaaagagcc gtggccttgg aaagggccac aagttccacc acactattgg tggctctcgc 600 cgggcagctt ggagaaggcg caatactctc cagctccacc gttaccgcta atataagtaa 660 agtttgtaaa attcatactt aataaacaat ttaggacagt catgtctgct tacaggtgtt 720 atttgtctgt taaaactagt ctgcagatgt ttcttgaatg ctttgtcaaa ttaagaaagt 780 taaagtgcaa taatgtttga agacaataag tggtggtgta tcttgtttct aataagataa 840 acttttttgt ctttgcttta tcttattagg gagttgtatg tcagtgtata aaacatactg 900 tgtggtataa caggcttaat aaattcttta aaaggagaga actgaaacta gccctgtaga 960 tttgtctggt gcatgtgatg aaacctgcag ctttatcgga gtgatggcaa tgctctgctg 1020 gtttattttc aagtggctgc gtttttttta gtttggcagg tgtagacttt ttaagttggg 1080 ctttagaaaa tctgggttag cctgaagaaa attgcctcag cctccacagt accattttaa 1140 attcacataa aaggtgaaag ctcctggttc agtgccatgg cttcatggca ttcagtgatt 1200 agtggtaatg gtaaacactg gtgtgttttg aagttgaatg tgcgataaaa ttattagcct 1260 taagattggt aagctagcaa tgaatgctag ggtgggaagc tggtgagcca gtggccatta 1320 gataaatacc tttcaagtgt gagcttagac gtcaacccta aaatacttaa ccgtaatgct 1380 aattgtgatc attatgaatc ccttcagtca cattaggggg aaagtagttg gctataagta 1440 cgtcattctt agtccagtca gtcttaaaaa catcttgggt tacccactct gtccactccc 1500 ataggctaca gaaaaagtca caagcgcatg gtttccaacc atatgtgttt tctgcagtta 1560 tttctcttgt tctggccaaa caaccctaaa aatccttacc attccacaaa gttggaccat 1620 cacttgtgca cccactttga ctatgagtat accaccacat tgcatttctg tttgcaccat 1680 gtcttccagg agactagact actgttgtcc agggtcaatt tgagtgtaaa gaaaatgtag 1740 acaaggaatt gcccaatttt aaattctgac tttgctgact taatttaaat gctcgttctg 1800 aaccaatttt ctcctatctt ctctaggggt ttcaaaagac tcagttaatt gatttccagg 1860 aagtactcat agcaagttca taaaagttct tgagacctaa atttcttcac aaaaaaagaa 1920 aagatcttaa gtcatacatt ttaattgtgt agaggttgtt caactgaagg aataaatgtc 1980 tattaaacta aaaaaaaaaa aaaaaaaaaa aaaaaaaa 2018 <210> SEQ ID NO 121 <211> LENGTH: 720 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 121 tttttttttt tttttttagt gtaaagtgta gcatgatgtt aagccatttt agcttttgca 60 catacatgtt gcacttctgg ctgataatgg aggaaaattt gcagcattat actgttaagc 120 taggttgcat ccatcccttt aaatggcatc aatatcgatg tcgtcatcct tgttgtctga 180 ctttacagtc tcaactttcg gtacactggc agccttcgaa tacaccacct caatgttctc 240 atcttcatct tcttcttcgc caccagaaga ttcttcctct gcctccttca accattttat 300 aaatggttct gctttgacac gaatctcttt ggcaagttct ttggagacat atttcttaga 360 ggccttttcc gaccagctga tgaagaaccc ctcctccaaa aaggtcgaat cgtaaatctc 420 cttcaagaaa tgtggaatct tggagataag ctgagcttga tgcattgcta ccacacactc 480 caaaccatga agaaggtacc gttgggcttt tttgttgttg tgacaaaatc gtaggaaatg 540 gcgcctgtat ttcttaatct gttctctaat cttctcatta aaaagaactt cagttagaac 600 aagagggccc atggctttta catccagtcc ttctgcttca gcaacgattt ccttgtcaga 660 tgaatcaata acaccctctg tcttcctttt cttaacaaaa tcaaagagga tattgagcct 720 <210> SEQ ID NO 122 <211> LENGTH: 1826 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 122 tacctgaccc cagccatttc ccttctagaa attgttctac agacatatgt aataacatat 60 acaaaaggtt attctttcag cagtgtttgt cagagcgaga acattccaga gagctgttgc 120 gcagccattg gtacctgtat tggggaaaca tagcatacaa tcaagaagct tacagcctca 180 gtggcgaaaa ttttttcatg tcagagaccg agaactcttg cagtcgttta tgtcatccct 240 tcttctccag acagaagata ccaaaaagtt gcaatcaaag atctcttcat cttattgata 300 aagccactaa taagccaaaa tgtctgtcaa tgtcaaccgc agcgtgtcag accagttcta 360 tcgctacaag atgccccgtc tgattgccaa ggttgagggc aaaggcaatg gaatcaagac 420 agttatagtc aacatggttg acgttgcaaa ggcgcttaat cggcctccaa cgtatcccac 480 caaatatttt ggttgtgagc tgggagcaca gacccagttt gatgttaaga atgaccgtta 540 cattgtcaat ggatctcatg aggcgaataa gctgcaagac atgttggatg gattcattaa 600 aaaatttgtt ctctgtcctg aatgtgagaa tcctgaaaca gatttgcatg tcaatccaaa 660 gaagcaaaca ataggtaatt cttgtaaagc ctgtggctat cgaggcatgc ttgacacaca 720 tcataaactc tgcacattca ttctcaaaaa cccacctgag aatagtgaca gtggtacagg 780 aaagaaagaa aaagaaaaga aaaacagaaa gggcaaagac aaggaaaatg gctccgtatc 840 cagcagtgag acaccaccac caccaccacc accaaatgaa attaatcctc ctccacatac 900 aatggaagaa gaggaggatg atgactcggg agaagataca actgaggaag ctcaaaggcg 960 tcgaatggat gaaatcagtg accatgcaaa agttctgaca ctcagtgatg atttggaaag 1020 aacaattgag gagagggtca atatcctctt tgattttgtt aagaaaaaga aagaagaggg 1080 tgttattgat tcatctgaca aagaaatcgt tgctgaagca gaaagactgg atgtaaaagc 1140 catgggccct cttgttctaa ctgaagttct ttttaatgag aagattagag aacagattaa 1200 gaaatacagg cgccatttcc tacgattttg tcacaacaac aaaaaagccc aacggtacct 1260 tcttcatggt ttggagtgtg tggtagcaat gcatcaagct cagcttatct ccaagattcc 1320 acatatcttg aaggagatgt acgatgcaga ccttttagaa gaagaggtca tcatcagctg 1380 gtcggaaaag gcctctaaga aatatgtctc caaagaactt gccaaagaga ttcgtgtcaa 1440 agcagaacca tttataaaat ggttgaagga ggcagaggaa gaatcttctg gtggcgaaga 1500 agaagatgaa gatgagaaca ttgaggtggt gtattcgaag gctgccagtg taccgaaagt 1560 tgagactgta aagtcagaca acaaggatga cgacatcgat attgatgcca tttaaaggga 1620 tggatgcaac ctagcttaac agtataatgc tgcaaatttt cctccattat cagccagaag 1680 tgcaacatgt atgtgcaaaa gctaaaatgg cttaacatca tgctacactt tacactaaaa 1740 atctattact gtgagtgtga aaaactagtg gtggacacat ttggatcaca tttatacagt 1800 tataaaaata aaggtttgat tttggt 1826 <210> SEQ ID NO 123 <211> LENGTH: 486 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 123 tggttgtttt gccttaaaac atcaatatgc tggattgtgg cgtgaggtat ttttattccc 60 tttgttagta ctggaaaccg tctggtacat cttgtaaggc aaatgattaa cacacggcag 120 gctcttcgtc cgtttgcaag ttgctgtttg tttccaggta caccagtcag agctccacag 180 agagggtgcg ttcctggttc tcaggtgggc aggtgctatg gtgcggggcg ctggaaagaa 240 tggggttgaa ttggccctcg cctccgcttg tttgagactc tcgttagaaa gggcttagga 300 aaaccaaggg aatggcagcc accccatcac catcgagaac aggcagacgt ttcccgagta 360 ggggccaaag cactggaaac cgtgttccct gtgcagtccg actgacacta ccccatgcct 420 ggggggaatg agtataaaaa ggtaaatgtt tttgaagaca ggcacgatat atactactag 480 agaatg 486 <210> SEQ ID NO 124 <211> LENGTH: 3442 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 124 cgccgcagcc gccggcgctg tggagatatt ctctaagccg ctttcatcat gggagaaata 60 gagcagaggc cgaccccagg atcacgactg ggggccccgg aaaattcggg gatcagtacc 120 ttggaacgtg gacagaagcc gcccccaaca ccttcaggaa aactcgtgtc catcaaaatc 180 cagatgctgg atgacaccca ggaggcattt gaagttccac aaagagctcc tgggaaggtg 240 ctgctggatg cagtttgcaa ccacctcaac ctcgtggaag gtgactattt tggcctcgag 300 tttcctgatc acaaaaagat cacggtgtgg ctggatctcc taaaacccat tgtgaaacag 360 attagaaggc caaagcacgt tgttgttaag tttgtggtga aattctttcc gcctgaccac 420 acacaactcc aagaagaact cacaaggtac ctgttcgcgc tgcaggtgaa gcaggacttg 480 gctcaaggca ggttgacgtg taatgacacc agcgcagctc tcttgatttc acacattgtg 540 caatctgaga ttggggattt tgatgaagcc ttggacagag agcacttagc aaaaaataaa 600 tacatacctc agcaagacgc actagaggac aaaatcgtgg aatttcacca taaccacatt 660 ggacaaacac cagcagaatc agatttccag ctcctagaga ttgcccgtcg gctagagatg 720 tatggaatcc ggttgcaccc ggccaaggac agggaaggca cgaagatcaa tctggccgtt 780 gccaacacgg gaattctagt gtttcagggt ttcactaaga tcaatgcctt caactgggcc 840 aaggtgcgga agctgagctt caagaggaag cgctttctca tcaagctccg gccagatgcc 900 aatagtgcgt accaggatac cttggaattc ctgatggcca gtcgggattt ctgcaagtcc 960 ttctggaaaa tctgtgttga acatcatgcc ttctttagac tttttgaaga gcccaaacca 1020 aagcccaagc ccgtcctctt tagccggggg tcatcatttc ggttcagtgg tcggactcag 1080 aagcaggttc tcgactatgt taaagaagga ggacataaga aggtgcagtt tgaaaggaag 1140 cacagcaaga ttcattctat ccggagcctt gcttcacagc ctacagaact gaattcggaa 1200 gtgctggagc agtctcagca gagcaccagc cttacatttg gagaaggtgc cgaatctcca 1260 gggggccaga gctgccggcg aggaaaggaa ccgaaggttt ccgccgggga gccggggtcg 1320 cacccgagcc ctgcgccgag gagaagcccc gcgggtaaca agcaggcgga cggagccgcc 1380 tcggcgccca cggaggaaga ggaggaggtc gttaaggata ggacccagca gagtaaacct 1440 cagcccccgc agccaagcac aggctccctg actggcagtc ctcacctttc cgagctgtct 1500 gtgaactcgc aggggggagt ggcccctgcc aacgtgacct tgtctcccaa cctgagcccc 1560 gacaccaagc aggcctctcc cttgatcagc ccgctgctga atgaccaggc ctgcccccgg 1620 acggacgatg aggatgaggg ccggaggaag agattcccaa ctgataaagc gtacttcata 1680 gctaaggaag tgtctaccac cgagcgaaca tatctgaagg atctcgaagt tatcacttcg 1740 tggtttcaga gcacagtgag caaagaggac gccatgccgg aagcactgaa aagtctcata 1800 ttcccgaatt ttgaaccttt gcacaaattt catactaatt ttctcaagga aattgagcaa 1860 cgacttgccc tgtgggaagg ccgctcaaat gcccaaatca gagattacca aagaatcggc 1920 gatgtcatgc tgaagaacat tcagggcatg aagcacctgg cggctcacct gtggaagcac 1980 agcgaggcct tggaggccct ggagaatgga atcaagagct cccggcggct ggagaacttc 2040 tgcagagact ttgagctgca gaaggtgtgt tacctaccgc tcaacacctt cctcctgcgg 2100 ccactgcacc ggctcatgca ctacaagcag gtcctggagc ggctgtgcaa acaccacccg 2160 ccgagccacg ccgacttcag ggactgccga gccgctttgg cagagatcac ggagatggtg 2220 gcacagctcc acggtacgat gatcaagatg gagaatttcc agaagctgca cgaactcaag 2280 aaagatttga ttggcattga caatcttgtg gttccgggaa gggagttcat ccgtctgggc 2340 agcctcagca agctctcggg gaaggggctc cagcagcgca tgttcttcct gttcaacgac 2400 gtcctgctat acacgagccg ggggctgacg gcctccaatc agtttaaagt ccacgggcag 2460 ctcccgctct atggcatgac gattgaggag agcgaagacg agtggggggt gccccactgc 2520 ctgaccctcc ggggccagcg gcagtccatc atcgtggccg ccagttctcg gtccgagatg 2580 gagaagtggg ttgaggacat ccagatggcc attgacctgg cggagaagag cagcagcccc 2640 gcccctgagt tcctggccag cagcccccct gacaacaagt cccctgatga agccaccgcg 2700 gctgaccagg agtcagagga tgacctgagc gcctcgcgca catcgctgga gcgccaggcc 2760 ccgcaccgcg gcaacacaat ggtgcacgtg tgctggcacc gcaacaccag cgtctccatg 2820 gtggacttca gcatcgcagt ggagaatcag ttgtctggaa acctgctgag gaaattcaaa 2880 aacagcaacg ggtggcagaa gctgtgggtg gtgttcacaa acttctgcct gttcttctac 2940 aaatcacacc aggacaatca tccccttgcc agcctgcctc tgctcggcta ctcgctcacc 3000 atcccctctg agtccgagaa catccagaaa gactacgtgt tcaagctgca cttcaagtcc 3060 cacgtctact acttcagggc ggaaagcgag tacacgttcg aaaggtggat ggaagtgatc 3120 cgcagtgcca ccagctctgc ctcgcgaccc cacgtgttga gccacaaaga gtctcttgtg 3180 tattgatggc cggacacact cgtttccgca gtggctgctt tcctggaaga cgtttccttt 3240 cttctgtatt aatgaagcct ggtaaaatta acacctgtct gaaaatcaaa aacatggctt 3300 cccagcagct ctcctgtctc cacagccgcg ttttttaacc ccgacctctc agcgtttgaa 3360 tgaacagcgc tcccacctcc agtcctggca tccgctgggg gcgctgttct ttagctagtg 3420 ccagtattaa aacattgtca tt 3442 <210> SEQ ID NO 125 <211> LENGTH: 360 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 125 tttacattta caaatattaa atttattata actaaaatga atttaattgt tctcagattt 60 ggccacctta tagctccgtt taaggagggg atttgttaaa aacaaaaatg cattataact 120 tggtcaaatt actttcacat taaggaaaaa aacttctaaa aaggaaaaca agaaaagcaa 180 ctcttcagtt tcacataatt aaaagaacag gagaaagcac gcaagctaca tatagctaaa 240 tttacgaaac caaccaaagc cagggggatt tctcttctga ttatgtgtca taaaaaggtc 300 cactgtctta tatacacatg tatataatgt tacattccat cactgtaaaa agtccccttt 360 <210> SEQ ID NO 126 <211> LENGTH: 3624 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 126 gcaggttggg agggaaagtc gggggaggac gcggaagagg agctgtggga agggggagga 60 gggagggagg aaaagaggag gagacggagg agaactgagc agagcagagc atcgagccaa 120 aggggagatg agtttgtctg tcctctgctg aggctacggc cgggcctagg gaactgggag 180 cttgggtgga agcgacaccc gtggaagtgg gaggaggtgg cgccgggact ttaacccctt 240 gtgggctctg cggcagggga tttaaccctt tgtggatctg gcccctcgga ggcagcgtca 300 tcggtagttt taaccccttc ggggctgggt ttcacgcact ggacttaccc tcatcacctt 360 gctcaccaac tcctttattg gggtgctccg cttggaggtt tgaggcccac ctccgcccat 420 tacgtactgt tcctgccgct gcaccccctt ggacccgcta gctggccgca ctgtgggcgc 480 ttaacccttt actgacttga gctccccaga ttgcagttgg agtttgctga tagaaggact 540 agctaaaggc gtcactgcag gaattacaaa ctgaagagga ctctgttgga ctgttttttt 600 tttctttttc ttttttttaa gaaaaaccca tttttttcct taaggactta ctagccaaaa 660 tttcttaaac ttcgaggact ctactagcca tggccgagcc attcttgtca gaatatcaac 720 accagcctca aactagcaac tgtacaggtg ctgctgctgt ccaggaagag ctgaaccctg 780 agcgcccccc aggcgcggag gagcgggtgc ccgaggagga cagtaggtgg caatcgagag 840 cgttccccca gttgggtggc cgtccggggc cggaggggga agggagcctg gaatcccaac 900 cacctccctt gcagacccag gcctgtccag aatctagctg cctgagagag ggcgagaagg 960 gccagaatgg ggacgactcg tccgctggcg gcgacttccc gccgccggca gaagtggaac 1020 cgacgcccga ggccgagctg ctcgcccagc cttgtcatga ctccgaggcc agtaagttgg 1080 gggctcctgc cgcagggggc gaagaggagt ggggacagca gcagagacag ctggggaaga 1140 aaaaacatag gagacgcccg tccaagaaga agcggcattg gaaaccgtac tacaagctga 1200 cctgggaaga gaagaaaaag ttcgacgaga aacagagcct tcgagcttca aggatccgag 1260 ccgagatgtt cgccaagggc cagccggtcg cgccctataa caccacgcag ttcctcatgg 1320 atgatcacga ccaggaggag ccggatctca aaaccggcct gtactccaag cgggccgccg 1380 ccaaatccga cgacaccagc gatgacgact tcatggaaga agggggtgag gaggatgggg 1440 gcagcgatgg gatgggaggg gacggcagcg agtttctgca gcgggacttc tcggagacgt 1500 acgagcggta ccacacggag agcctgcaga acatgagcaa gcaggagctc atcaaggagt 1560 acctggaact ggagaagtgc ctctcgcgca tggaggacga gaacaaccgg ctgcggctgg 1620 agagcaagcg gctgggtggc gacgacgcgc gtgtgcggga gctggagctg gagctggacc 1680 ggctgcgcgc cgagaacctc cagctgctga ccgagaacga actgcaccgg cagcaggagc 1740 gagcgccgct ttccaagttt ggagactaga ctgaaacttt tttgggggag ggggcaaagg 1800 ggacttttta cagtgatgga atgtaacatt atatacatgt gtatataaga cagtggacct 1860 ttttatgaca cataatcaga agagaaatcc ccctggcttt ggttggtttc gtaaatttag 1920 ctatatgtag cttgcgtgct ttctcctgtt cttttaatta tgtgaaactg aagagttgct 1980 tttcttgttt tcctttttag aagttttttt ccttaatgtg aaagtaattt gaccaagtta 2040 taatgcattt ttgtttttaa caaatcccct ccttaaacgg agctataagg tggccaaatc 2100 tgagaacaat taaattcatt ttagttataa taaatttaat atttgtaaat gtaacatagt 2160 ttcagtgtga tttctagagc taattcaaaa tagtattgat atattttatg tgactgcatt 2220 tttggggagg ggtaccgaaa tcgttaaatt tgtcagtttg caaaaatatc aatctttaat 2280 gggagaattt tcaatttgcc aattttttcc ttgaatgggt ttaagtatgc tacaatatac 2340 agttcaggca aaatttaaga tgtaattatc ttcaatactt aagtgtgctt gctttctagt 2400 gccttggttt tctttcttga tgctggaaaa ataaacaaac cggtattgag tgtttaggcg 2460 agtggaaagt ggctacaatc caaaatttta aatttaactc tgcctcggcc attcaaaagt 2520 ctaataacaa aaaatgtaaa cctaatttgg cagtttgtta ggttagacaa ctgacagcct 2580 catttcattc ctacaagttg gttttcagta atctcttcct tccccccagt aaggctggaa 2640 gaggctcttg gcaaacttct tagcgcaagc aatggttaga ttaatttgtg aggcagctct 2700 ttaagacgtt cagaggtaag aaatactgga tttataaagc aaatggctgt ttgggggatt 2760 ccaaggattt acctaattgt ccaattctac gtgctctcta taccaaaaca aaaaaaaagc 2820 tatccacctt tccatgtggg tcaaactaaa attagaaatg tcccctcact gcagatcaaa 2880 tgtaaagctt ccagttaagg agctaaatga ggtcctcagc tgaatgagga accctgtaca 2940 tccccttgca cagccctatt ctaaatcgct taaactatgc tgatagctgc ttaggttctt 3000 gagtagttct gctcttaaac gtagggaggc cctgagaact aaattttgcc ccaaaataaa 3060 aacagaaatt atgagattgc ctcctgtcat tttggttaac ccagtccttc acctgccctg 3120 tgtcagtgtc ttctgagggc aattgcgttg ctcaaatcac tagcacagag gttccttaat 3180 ttggggcctt agaaaccatt gtgggccttg gggtccatga accccatgaa attatttgta 3240 gacttgtatg tacatttttc tggggagaag gttcaagaga ttcataagat tgtcaaactc 3300 cttgaaggtt cagaacctct gcagggaagg gggaagaaaa ccctcccatt aggaagcatg 3360 cttttgcagt taaatggcga tggtggaggt gatagggact tcaagagtaa aatgcacctt 3420 gtattgcata agaagcatac acaaatcaat aaatcaaggg agattatacc agtaggactg 3480 aatcagggcc ttcaaagctg gactgagttg gtcctgttct ggcacatatg gtccactgga 3540 gacaatgtat gattgagctt ttctttggtc taaaaattat attaaacatt tattttgaaa 3600 aaaaaaaaaa aaaaaaaaaa aaaa 3624 <210> SEQ ID NO 127 <211> LENGTH: 316 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 127 tagtggtgcc atgaagttta ctaggaagtg attgtgaata agtaatagat ctaacattcg 60 cgtcatagag gaggtgttgg gacaccacag aatcttgttt gaatttatga attgagtcca 120 gttccccagt actttcagtg tctccaatcc tcctgcacac ctgtgtggtt tgtcttagga 180 ctcagtggtc tttgaggatg tggctgtgga cttcaccctg gaggagtggg ctttgctgga 240 ttctgctcag agggacctct acagagatgt gatgctggag accttccgga acctggcctc 300 agtaggtgag gatggc 316 <210> SEQ ID NO 128 <211> LENGTH: 270 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 128 caaccgcatc gaggtggcca acctcaatgg cacatcccgg aaggtgctct tctggcagga 60 ccttgaccag ccgagggcca tcgccttgga ccccgctcac gggtacatgt actggacaga 120 ctggggtgag acgccccgga ttgagcgggc agggatggat ggcagcaccc ggaagatcat 180 tgtggactcg gacatttact ggcccaatgg actgaccatc gacctggagg agcagaagct 240 ctactgggct gacgcaagct cagcttcatc 270 <210> SEQ ID NO 129 <211> LENGTH: 5100 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 129 atggagcccg agtgagcgcg gcgcgggccc gtccggccgc cggacaacat ggaggcagcg 60 ccgcccgggc cgccgtggcc gctgctgctg ctgctgctgc tgctgctggc gctgtgcggc 120 tgcccggccc ccgccgcggc ctcgccgctc ctgctatttg ccaaccgccg ggacgtacgg 180 ctggtggacg ccggcggagt caagctggag tccaccatcg tggtcagcgg cctggaggat 240 gcggccgcag tggacttcca gttttccaag ggagccgtgt actggacaga cgtgagcgag 300 gaggccatca agcagaccta cctgaaccag acgggggccg ccgtgcagaa cgtggtcatc 360 tccggcctgg tctctcccga cggcctcgcc tgcgactggg tgggcaagaa gctgtactgg 420 acggactcag agaccaaccg catcgaggtg gccaacctca atggcacatc ccggaaggtg 480 ctcttctggc aggaccttga ccagccgagg gccatcgcct tggaccccgc tcacgggtac 540 atgtactgga cagactgggg tgagacgccc cggattgagc gggcagggat ggatggcagc 600 acccggaaga tcattgtgga ctcggacatt tactggccca atggactgac catcgacctg 660 gaggagcaga agctctactg ggctgacgcc aagctcagct tcatccaccg tgccaacctg 720 gacggctcgt tccggcagaa ggtggtggag ggcagcctga cgcacccctt cgccctgacg 780 ctctccgggg acactctgta ctggacagac tggcagaccc gctccatcca tgcctgcaac 840 aagcgcactg gggggaagag gaaggagatc ctgagtgccc tctactcacc catggacatc 900 caggtgctga gccaggagcg gcagcctttc ttccacactc gctgtgagga ggacaatggc 960 ggctgctccc acctgtgcct gctgtcccca agcgagcctt tctacacatg cgcctgcccc 1020 acgggtgtgc agctgcagga caacggcagg acgtgtaagg caggagccga ggaggtgctg 1080 ctgctggccc ggcggacgga cctacggagg atctcgctgg acacgccgga ctttaccgac 1140 atcgtgctgc aggtggacga catccggcac gccattgcca tcgactacga cccgctagag 1200 ggctatgtct actggacaga tgacgaggtg cgggccatcc gcagggcgta cctggacggg 1260 tctggggcgc agacgctggt caacaccgag atcaacgacc ccgatggcat cgcggtcgac 1320 tgggtggccc gaaacctcta ctggaccgac acgggcacgg accgcatcga ggtgacgcgc 1380 ctcaacggca cctcccgcaa gatcctggtg tcggaggacc tggacgagcc ccgagccatc 1440 gcactgcacc ccgtgatggg cctcatgtac tggacagact ggggagagaa ccctaaaatc 1500 gagtgtgcca acttggatgg gcaggagcgg cgtgtgctgg tcaatgcctc cctcgggtgg 1560 cccaacggcc tggccctgga cctgcaggag gggaagctct actggggaga cgccaagaca 1620 gacaagatcg aggtgatcaa tgttgatggg acgaagaggc ggaccctcct ggaggacaag 1680 ctcccgcaca ttttcgggtt cacgctgctg ggggacttca tctactggac tgactggcag 1740 cgccgcagca tcgagcgggt gcacaaggtc aaggccagcc gggacgtcat cattgaccag 1800 ctgcccgacc tgatggggct caaagctgtg aatgtggcca aggtcgtcgg aaccaacccg 1860 tgtgcggaca ggaacggggg gtgcagccac ctgtgcttct tcacacccca cgcaacccgg 1920 tgtggctgcc ccatcggcct ggagctgctg agtgacatga agacctgcat cgtgcctgag 1980 gccttcttgg tcttcaccag cagagccgcc atccacagga tctccctcga gaccaataac 2040 aacgacgtgg ccatcccgct cacgggcgtc aaggaggcct cagccctgga ctttgatgtg 2100 tccaacaacc acatctactg gacagacgtc agcctgaaga ccatcagccg cgccttcatg 2160 aacgggagct cggtggagca cgtggtggag tttggccttg actaccccga gggcatggcc 2220 gttgactgga tgggcaagaa cctctactgg gccgacactg ggaccaacag aatcgaagtg 2280 gcgcggctgg acgggcagtt ccggcaagtc ctcgtgtgga gggacttgga caacccgagg 2340 tcgctggccc tggatcccac caagggctac atctactgga ccgagtgggg cggcaagccg 2400 aggatcgtgc gggccttcat ggacgggacc aactgcatga cgctggtgga caaggtgggc 2460 cgggccaacg acctcaccat tgactacgct gaccagcgcc tctactggac cgacctggac 2520 accaacatga tcgagtcgtc caacatgctg ggtcaggagc gggtcgtgat tgccgacgat 2580 ctcccgcacc cgttcggtct gacgcagtac agcgattata tctactggac agactggaat 2640 ctgcacagca ttgagcgggc cgacaagact agcggccgga accgcaccct catccagggc 2700 cacctggact tcgtgatgga catcctggtg ttccactcct cccgccagga tggcctcaat 2760 gactgtatgc acaacaacgg gcagtgtggg cagctgtgcc ttgccatccc cggcggccac 2820 cgctgcggct gcgcctcaca ctacaccctg gaccccagca gccgcaactg cagcccgccc 2880 accaccttct tgctgttcag ccagaaatct gccatcagtc ggatgatccc ggacgaccag 2940 cacagcccgg atctcatcct gcccctgcat ggactgagga acgtcaaagc catcgactat 3000 gacccactgg acaagttcat ctactgggtg gatgggcgcc agaacatcaa gcgagccaag 3060 gacgacggga cccagccctt tgttttgacc tctctgagcc aaggccaaaa cccagacagg 3120 cagccccacg acctcagcat cgacatctac agccggacac tgttctggac gtgcgaggcc 3180 accaatacca tcaacgtcca caggctgagc ggggaagcca tgggggtggt gctgcgtggg 3240 gaccgcgaca agcccagggc catcgtcgtc aacgcggagc gagggtacct gtacttcacc 3300 aacatgcagg accgggcagc caagatcgaa cgcgcagccc tggacggcac cgagcgcgag 3360 gtcctcttca ccaccggcct catccgccct gtggccctgg tggtagacaa cacactgggc 3420 aagctgttct gggtggacgc ggacctgaag cgcattgaga gctgtgacct gtcaggggcc 3480 aaccgcctga ccctggagga cgccaacatc gtgcagcctc tgggcctgac catccttggc 3540 aagcatctct actggatcga ccgccagcag cagatgatcg agcgtgtgga gaagaccacc 3600 ggggacaagc ggactcgcat ccagggccgt gtcgcccacc tcactggcat ccatgcagtg 3660 gaggaagtca gcctggagga gttctcagcc cacccatgtg cccgtgacaa tggtggctgc 3720 tcccacatct gtattgccaa gggtgatggg acaccacggt gctcatgccc agtccacctc 3780 gtgctcctgc agaacctgct gacctgtgga gagccgccca cctgctcccc ggaccagttt 3840 gcatgtgcca caggggagat cgactgtatc cccggggcct ggcgctgtga cggctttccc 3900 gagtgcgatg accagagcga cgaggagggc tgccccgtgt gctccgccgc ccagttcccc 3960 tgcgcgcggg gtcagtgtgt ggacctgcgc ctgcgctgcg acggcgaggc agactgtcag 4020 gaccgctcag acgaggcgga ctgtgacgcc atctgcctgc ccaaccagtt ccggtgtgcg 4080 agcggccagt gtgtcctcat caaacagcag tgcgactcct tccccgactg tatcgacggc 4140 tccgacgagc tcatgtgtga aatcaccaag ccgccctcag acgacagccc ggcccacagc 4200 agtgccatcg ggcccgtcat tggcatcatc ctctctctct tcgtcatggg tggtgtctat 4260 tttgtgtgcc agcgcgtggt gtgccagcgc tatgcggggg ccaacgggcc cttcccgcac 4320 gagtatgtca gcgggacccc gcacgtgccc ctcaatttca tagccccggg cggttcccag 4380 catggcccct tcacaggcat cgcatgcgga aagtccatga tgagctccgt gagcctgatg 4440 gggggccggg gcggggtgcc cctctacgac cggaaccacg tcacaggggc ctcgtccagc 4500 agctcgtcca gcacgaaggc cacgctgtac ccgccgatcc tgaacccgcc gccctccccg 4560 gccacggacc cctccctgta caacatggac atgttctact cttcaaacat tccggccact 4620 gtgagaccgt acaggcccta catcattcga ggaatggcgc ccccgacgac gccctgcagc 4680 accgacgtgt gtgacagcga ctacagcgcc agccgctgga aggccagcaa gtactacctg 4740 gatttgaact cggactcaga cccctatcca cccccaccca cgccccacag ccagtacctg 4800 tcggcggagg acagctgccc gccctcgccc gccaccgaga ggagctactt ccatctcttc 4860 ccgccccctc cgtccccctg cacggactca tcctgacctc ggccgggcca ctctggcttc 4920 tctgtgcccc tgtaaatagt tttaaatatg aacaaagaaa aaaatatatt ttatgattta 4980 aaaaataaat ataattggga ttttaaaaac atgagaaatg tgaactgtga tggggtgggc 5040 agggctggga gaactttgta cagtggaaca aatatttata aacttaattt tgtaaaacag 5100 <210> SEQ ID NO 130 <211> LENGTH: 282 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 130 tttaaataaa aatgctgcaa ggtttccgcc tctgcgttcc ccttgtgatg gctggcaggt 60 ggtctggaag cgtcccggat ggcggccaag cgacaatggg gcaggtgtcc tggcagcgaa 120 gggcagcccg gccgcacgcg atacactgca cagcggcgtc cgggtggctc tggtatcgct 180 gcctccaaac ctcctggatc ttcctgcacc acttgtgtgc gttcccgctg gggtccatca 240 gataatacgt cctgttaggc gtgtggacaa agaaagtttt aa 282 <210> SEQ ID NO 131 <211> LENGTH: 1891 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 131 ccgcttcggg gaggaggacg ctgaggaggc gccgagccgc gcagcgctgc gggggaggcg 60 cccgcgccga cgcggggccc atggccagga ccaccagcca gctgtatgac gccgtgccca 120 tccagtccag cgtggtgtta tgttcctgcc catccccatc aatggtgagg acccagactg 180 agtccagcac gccccctggc attcctggtg gcagcaggca gggccccgcc atggacggca 240 ctgcagccga gcctcggccc ggcgccggct ccctgcagca tgcccagcct ccgccgcagc 300 ctcggaagaa gcggcctgag gacttcaagt ttgggaaaat ccttggggaa ggctcttttt 360 ccacggttgt cctggctcga gaactggcaa cctccagaga atatgcgatt aaaattctgg 420 agaagcgaca tatcataaaa gagaacaagg tcccctatgt aaccagagag cgggatgtca 480 tgtcgcgcct ggatcacccc ttctttgtta agctttactt cacatttcag gacgacgaga 540 agctgtattt cggccttagt tatgccaaaa atggagaact acttaaatat attcgcaaaa 600 tcggttcatt cgatgagacc tgtacccgat tttacacggc tgagatcgtg tctgctttag 660 agtacttgca cggcaagggc atcattcaca gggaccttaa accggaaaac attttgttaa 720 atgaagatat gcacatccag atcacagatt ttggaacagc aaaagtctta tccccagaga 780 gcaaacaagc cagggccaac tcattcgtgg gaacagcgca gtacgtttct ccagagctgc 840 tcacggagaa gtccgcctgt aagagttcag acctttgggc tcttggatgc ataatatacc 900 agcttgtggc aggactccca ccattccgag ctggaaacga gtatcttata tttcagaaga 960 tcattaagtt ggaatatgac tttccagaaa aattcttccc taaggcaaga gacctcgtgg 1020 agaaactttt ggttttagat gccacaaagc ggttaggctg tgaggaaatg gaaggatacg 1080 gacctcttaa agcacacccg ttcttcgagt ccgtcacgtg ggagaacctg caccagcaga 1140 cgcctccgaa gctcaccgct tacctgccgg ctatgtcgga agacgacgag gactgctatg 1200 gcaattatga caatctcctg agccagtttg gctgcatgca ggtgtcttcg tcctcctcct 1260 cacactccct gtcagcctcc gacacgggcc tgccccagag gtcaggcagc aacatagagc 1320 agtacattca cgatctggac tcgaactcct ttgaactgga cttacagttt tccgaagatg 1380 agaagaggtt gttgttggag aagcaggctg gcggaaaccc ttggcaccag tttgtagaaa 1440 ataatttaat actaaagatg ggcccagtgg ataagcggaa gggtttattt gcaagacgac 1500 gacagctgtt gctcacagaa ggaccacatt tatattatgt ggatcctgtc aacaaagttc 1560 tgaaaggtga aattccttgg tcacaagaac ttcgaccaga ggccaagaat tttaaaactt 1620 tctttgtcca cacgcctaac aggacgtatt atctgatgga ccccagcggg aacgcacaca 1680 agtggtgcag gaagatccag gaggtttgga ggcagcgata ccagagccac ccggacgccg 1740 ctgtgcagtg acgtggcctg cggccgggct gcccttcgct gccaggacac ctgccccagc 1800 gcggcttggc cgccatccgg gacgcttcca gaccacctgc cagccatcac aaggggaacg 1860 cagaggcgga aaccttgcag catttttatt t 1891 <210> SEQ ID NO 132 <211> LENGTH: 410 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 132 cacaatataa accttaattt taatgacata ttggctagtc aataaacaag tcttatctca 60 tctcatctct tttctgataa caaacacccg atgtgttcaa tttgctttca tatttaagtc 120 tttcctgaat tgctgtcatc attcaacaac agttgcatgt cgccttgcta gctgtcaaag 180 tagacttcat ccccaaatgg atatctgtaa tgaaagaata caaaggtgaa attttattta 240 aaaatttttt aaaagaattt ggttttggat taaaaggcat gcaagcagca ttaattccac 300 tcacagttac agtctatcac ctggggcatt cactactttt cagagtcaga tcacagttca 360 aaagacagct ctcaccttgg gggcatattc cccagtcagt gtgaacatgt 410 <210> SEQ ID NO 133 <211> LENGTH: 278 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 133 tttttttttt ttatcaaaag tttgttttat tttcaataca agataaatac catgcttgtt 60 actagtgcag tttaaggccg acaatggcca tatatcaaac tgccgaacag tcacctaaat 120 gctaaagaaa ggaaagacaa agtaaacatt aaacacaaaa ttgcaattac aaacatttta 180 ataaaatgga atgagctttt taattgaagc taatatgaag tctaattctc atggacagca 240 aaaaaaaaaa aaaaaaaaag tctattagat caattatc 278 <210> SEQ ID NO 134 <211> LENGTH: 414 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 134 ttttttttta agaaatttgt tcttttcatt tcattactta ggaattacaa gagactttgc 60 agaagggtaa aaatggtgag aactgaagag taatgccatt gttctaacag tgtcggggag 120 ttcacctggg ccagagaatg actctttttt cactactgcc ccctgtaggg gagcgacatc 180 cctctgatag aaatgagatg caaagaccac gtgagttacc tgcccggtcc cagtaaggta 240 agtcataggt gccttcagtt tttttctttc tgtttctcca gtgccaagca cacactaata 300 tgagaatgag agtagtgagg accatgacca gcacagggac aagaactgca ggcagcgcta 360 catctttggt tacatttgga gttacggtag tatttctgat atcaggactg gcag 414 <210> SEQ ID NO 135 <211> LENGTH: 697 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 135 aattattaaa aacactttat tatgtataat ttgtacatgc ttcaatttgt gtcacttagg 60 gtgatttatt ttccaggttg taatgacatc taccgagatt agctagatct aattttcatt 120 ctgccatgcc acatacaaaa atacaatttt caaacaaagc ttcccttctt tacacaaagg 180 tacacaagag tttgtcagac aaataaaata agaatacttc acacacgtat caacaccata 240 caaggcatta ttcttcacac agtaacatct aatgtgttct tttatttttg aaacagcagg 300 aaaagagccc tttcccttca gaggaaaata aaaactttat ctgttgctta agccaaactc 360 cagggaggaa ggtgtggtcc tctggggaaa gcagagggat ggggatgtat ggaggagaat 420 ggacgcccct tcataagcac ttcaggagga aggaattgca ggaggttcct cggggacagt 480 cacacagctt cccgatcctt gcccctttcc tcactgcaca ctgctcaccg gcgtcacaca 540 tggggacttg gccatacttc ttctcataga tgggaacacg tttactcttg agcttcttca 600 agacttcttg cagcgcttcg atcagctcct tctcgtggga ggcatcatcc acggcagaat 660 agatgtccag agctcggggc tggagcttcg cgttctc 697 <210> SEQ ID NO 136 <211> LENGTH: 796 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 136 aacgacgagt ttcagaacga tggagagctc ccgcgtgagg ctgctgcccc tcctgggcgc 60 cgccctgctg ctgatgctac ctctgttggg tacccgtgcc caggaggacg ccgagctcca 120 gccccgagcc ctggacatct actctgccgt ggatgatgcc tcccacgaga aggagctgat 180 cgaagcgctg caagaagtct tgaagaagct caagagtaaa cgtgttccca tctatgagaa 240 gaagtatggc caagtcccca tgtgtgacgc cggtgagcag tgtgcagtga ggaaaggggc 300 aaggatcggg aagctgtgtg actgtccccg aggaacctcc tgcaattcct tcctcctgaa 360 gtgcttatga aggggcgtcc attctcctcc atacatcccc atccctctac tttccccaga 420 ggaccacacc ttcctccctg gagtttggct taagcaacag ataaagtttt tattttcctc 480 tgaagggaaa gggctctttt cctgctgttt caaaaataaa agaacacatt agatgttact 540 gtgtgaagaa taatgcctgt atggtgttga tacgtgtgtg aagtatctat ttattgtctg 600 acaaactctt gtgtaccttt gtgtaaagaa gggaagcttt gtttgaaaat tgtatttttg 660 tatgtggcat ggcagaatga aaattagatc tagctaatct cggtagatgt cattacaacc 720 tggaaaataa atcaccctaa gtgacacaaa ttgaagcatg tacaaattat acataataaa 780 gtgtttttaa taatta 796 <210> SEQ ID NO 137 <211> LENGTH: 333 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 137 ttttttggat gcacatttga ttttactggg ggtaggggac agggctgggc gttcaggagt 60 tctccgctat ggtgtcctcg atccacttca cataagacag cactctgacg gcgacagaag 120 gcttattggg ggtgccacaa gggacgtagc cccatgatgt gacaccttgg agcacaccat 180 cacacatcag cgggccccct gaatcaccca cacaggtgtc tttgccacct tccaggtgtc 240 cgacacacag catgaagtct gtcaccttct ggacgtggct cgggggtcgc gtaactagtt 300 agcatgccag agtctcgttc gttatcggaa tta 333 <210> SEQ ID NO 138 <211> LENGTH: 871 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 138 tcctccacct gctggcccct ggacacctct gtcaccatgt ggttcctggt tctgtgcctc 60 gccctgtccc tgggggggac tggtgctgcg cccccgattc agtcccggat tgtgggaggc 120 tgggagtgtg agcagcattc ccagccctgg caggcggctc tgtaccattt cagcactttc 180 cagtgtgggg gcatcctggt gcaccgccag tgggtgctca cagctgctca ttgcatcagc 240 gacaattacc agctctggct gggtcgccac aacttgtttg acgacgaaaa cacagcccag 300 tttgttcatg tcagtgagag cttcccacac cctggcttca acatgagcct cctggagaac 360 cacacccgcc aagcagacga ggactacagc cacgacctca tgctgctccg cctgacagag 420 cctgctgata ccatcacaga tgctgtgaag gtcgtggagt tgcccaccga ggaacccgaa 480 gtggggagca cctgtttggc ttccggctgg ggcagcatcg aaccagagaa tttctcattt 540 ccagatgatc tccagtgtgt ggacctcaaa atcctgccta atgatgagtg caaaaaagcc 600 cacgtccaga aggtgacaga cttcatgctg tgtgtcggac acctggaagg tggcaaagac 660 acctgtgtgg gtgattcagg gggcccgctg atgtgtgatg gtgtgctcca aggtgtcaca 720 tcatggggct acgtcccttg tggcaccccc aataagcctt ctgtcgccgt cagagtgctg 780 tcttatgtga agtggatcga ggacaccata gcggagaact cctgaacgcc cagccctgtc 840 ccctaccccc agtaaaatca aatgtgcatc c 871 <210> SEQ ID NO 139 <211> LENGTH: 395 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 139 cctacatttt tgttcaacta agagtgctta tttcttcttg aaggttaaca ttatgtttat 60 taagtatcaa aatggaatta tcttttaaaa aagaagacaa gttttccata ctgtcacagt 120 aagctccaaa gaactttgtc tttctcataa agtaatattc tttatttgca tccatttact 180 atgattccgt taatttgttg aattaaatgc ctttataaaa atatttacaa atgttttctt 240 gccttaaaat gtaacatttt ctacttaaat ttaatttcca agagagtgat tatttgcatt 300 acaaaggaat tcttaataat tcctgtaagc ctaggaaata ggaatgccaa agtaacattt 360 aatgtacttc tctataactt ttcataatca gaaat 395 <210> SEQ ID NO 140 <211> LENGTH: 483 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 446, 470 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 140 ttgctaatga catcacttgc tgtttatgtt tattttagac tatggaaatg atgttagaca 60 aaaacaaatc caagcgattt tcttatttga gttcaaaatg ggtcgtaaaa gaagcgcaga 120 caactcacga tataaacaaa gcatttgtct caggaattgc taacgaacat acagtgcatt 180 caagaagttc aagaagtttt gcaaaggaaa agagatcctt gtagatgagg agcatagtgg 240 ccagacatcg gaagtccaca atgaccattt gagagcaatc attgaagctg tttctctaac 300 aaccacatga gaagttgcca aaagaactca aacctttgac gattctacag ccctttaagc 360 attttggaag ccaaatttgg gaaagctggg gaaaatctcc gctaagtggg gtgcctcatg 420 agctgagcga aaatttaaaa aatccncgtt tttgaagtgg tcatccttcn cctaattcta 480 cac 483 <210> SEQ ID NO 141 <211> LENGTH: 452 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 64, 68, 418 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 141 gtctccagtg gttaaaaaga aaaaagaaac aaggaacatg tttaatatct taaaaaacag 60 cacntaancc tgcaaaaatg tgaattattt gataaatact taaaaaacat gttaatcatg 120 tttagatttg aaaatgtggc atcaatgtga agcagtgcat tcaaccctct gtatcaggag 180 acagcggtgc tgcctgccca agactgcaga gagcagagac acagctgcat ctctcagcac 240 tctccccggc ccccaagaag agattccaat cacagcatat tcatttaaaa agcattctaa 300 tatagtaatt agactcatca aatacaaact ttttttcccc tttaaactat actctaaatt 360 tggccaaact aagtacttga tataaaaatc ctggcaaaga gcaggggtcc ctgcgggntt 420 ggtggtgggc aaacccagac attctctcgc cc 452 <210> SEQ ID NO 142 <211> LENGTH: 355 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 142 tttggctgta caaaagcttt tatggttttg taatcccaca tgtccatttt tgcttttgtg 60 gcctgtgatt ttcatatcca tgaaatcatt accaagacta atgtgatgaa gctttcccct 120 atgttttctt ctgaaagttt tacagtttca gttcttatgt tcaagttttt aatccatttt 180 gaattgattt tttgtgtatg atgtaagatt ggggcccaat tttattcttt tgtatgggga 240 tatccagttt tgctaacact atttgttgaa gagactatcc tttccacttt gcgtattctt 300 ggcactcttg tcaaacatca gttgaccgta tcatgtgtgg atttatttgt gaact 355 <210> SEQ ID NO 143 <211> LENGTH: 412 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 392, 393, 394 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 143 tacacagtaa tgatataatt atgtgatgca aatattaact tcatcccttt ccttgtaaat 60 tcagcttttc tcaccagagc tcaggggcag tcatgacaat aaaaataaca atagtaatta 120 caagaaatgt gctctgagta cagagaaacc acaaggccca tctcaacaca caaatacaaa 180 aacaactcgc atttacgggg cgtttccagg agttaatagc atacagtacc atgggtaggg 240 tgtggttggc agaagctgtc cactttttct aagtgcaggt gttcgttgct gaggatcttg 300 ttgctctcct cccttcgttt tctagagtaa cttcccagag gaccctgcct ggagcctgcc 360 aagccagagt ccagcgtaaa ggcccggagg tnnnttgtgt ctttctggcc ct 412 <210> SEQ ID NO 144 <211> LENGTH: 4700 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 144 atggccccct cggcctgggc catttgctgg ctgctagggg gcctcctgct ccatgggggt 60 agctctggcc ccagccccgg ccccagtgtg ccccgcctgc ggctctccta ccgagacctc 120 ctgtctgcca accgctctgc catctttctg ggcccccagg gctccctgaa cctccaggcc 180 atgtacctag atgagtaccg agaccgcctc tttctgggtg gcctggacgc cctctactct 240 ctgcggctgg accaggcatg gccagatccc cgggaggtcc tgtggccacc gcagccagga 300 cagagggagg agtgtgttcg aaagggaaga gatcctttga cagagtgcgc caacttcgtg 360 cgggtgctac agcctcacaa ccggacccac ctgctagcct gtggcactgg ggccttccag 420 cccacctgtg ccctcatcac agttggccac cgtggggagc atgtgctcca cctggagcct 480 ggcagtgtgg aaagtggccg ggggcggtgc cctcacgagc ccagccgtcc ctttgccagc 540 accttcatag acggggagct gtacacgggt ctcactgctg acttcctggg gcgagaggcc 600 atgatcttcc gaagtggagg tcctcggcca gctctgcgtt ccgactctga ccagagtctc 660 ttgcacgacc cccggtttgt gatggccgcc cggatccctg agaactctga ccaggacaat 720 gacaaggtgt acttcttctt ctcggagacg gtcccctcgc ccgatggtgg ctcgaaccat 780 gtcactgtca gccgcgtggg ccgcgtctgc gtgaatgatg ctgggggcca gcgggtgctg 840 gtgaacaaat ggagcacttt cctcaaggcc aggctggtct gctcggtgcc cggccctggt 900 ggtgccgaga cccactttga ccagctagag gatgtgttcc tgctgtggcc caaggccggg 960 aagagcctcg aggtgtacgc gctgttcagc accgtcagtg ccgtgttcca gggcttcgcc 1020 gtctgtgtgt accacatggc agacatctgg gaggttttca acgggccctt tgcccaccga 1080 gatgggcctc agcaccagtg ggggccctat gggggcaagg tgcccttccc tcgccctggc 1140 gtgtgcccca gcaagatgac cgcacagcca ggacggcctt ttggcagcac caaggactac 1200 ccagatgagg tgctgcagtt tgcccgagcc caccccctca tgttctggcc tgtgcggcct 1260 cgacatggcc gccctgtcct tgtcaagacc cacctggccc agcagctaca ccagatcgtg 1320 gtggaccgcg tggaggcaga ggatgggacc tacgatgtca ttttcctggg gactgactca 1380 gggtctgtgc tcaaagtcat cgctctccag gcagggggct cagctgaacc tgaggaagtg 1440 gttctggagg agctccaggt gtttaaggtg ccaacaccta tcaccgaaat ggagatctct 1500 gtcaaaaggc aaatgctata cgtgggctct cggctgggtg tggcccagct gcggctgcac 1560 caatgtgaga cttacggcac tgcctgtgca gagtgctgcc tggcccggga cccatactgt 1620 gcctgggatg gtgcctcctg tacccactac cgccccagcc ttggcaagcg ccggttccgc 1680 cggcaggaca tccggcacgg caaccctgcc ctgcagtgcc tgggccagag ccaggaagaa 1740 gaggcagtgg gacttgtggc agccaccatg gtctacggca cggagcacaa tagcaccttc 1800 ctggagtgcc tgcccaagtc tccccaggct gctgtgcgct ggctcttgca gaggccaggg 1860 gatgaggggc ctgaccaggt gaagacggac gagcgagtct tgcacacgga gcgggggctg 1920 ctgttccgca ggcttagccg tttcgatgcg ggcacctaca cctgcaccac tctggagcat 1980 ggcttctccc agactgtggt ccgcctggct ctggtggtga ttgtggcctc acagctggac 2040 aacctgttcc ctccggagcc aaagccagag gagcccccag cccggggagg cctggcttcc 2100 accccaccca aggcctggta caaggacatc ctgcagctca ttggcttcgc caacctgccc 2160 cgggtggatg agtactgtga gcgcgtgtgg tgcaggggca ccacggaatg ctcaggctgc 2220 ttccggagcc ggagccgggg caagcaggcc aggggcaaga gctgggcagg gctggagcta 2280 ggcaagaaga tgaagagccg ggtgcatgcc gagcacaatc ggacgccccg ggaggtggag 2340 gccacgtaga agggggcaga ggaggggtgg tcaggatggg ctggggggcc cactagcagc 2400 ccccagcatc tcccacccac ccagctaggg cagaggggtc aggatgtctg tttgcctctt 2460 agagacaggt gtctctgccc ccacaccgct actggggtct aatggagggg ctgggttctt 2520 gaagcctgtt ccctgccctt ctctgtgctc ttagacccag ctggagccag caccctctgg 2580 ctgctggcag ccccaaggga tctgccattt gttctcagag atggcctggc ttccgcaaca 2640 catttccggg tgtgcccaga ggcaagaggg ttgggtggtt ctttcccagc ctacagaaca 2700 atggccattc tgagtgaccc tcagagtggg tgtgtgggtg cgtctagggg gtatcccggt 2760 agggggcctg cagggagcca gagggtggaa atggcctcta agctagcacc ccgtaagaag 2820 agcctacctg accgacttgg ggagggaaca cagaggtgtt gggaaggtgg agcaacaatg 2880 cacctcccct cctgtcgcgc cgtgatatct tggtggctcc ctgccactgc ccaccgcctc 2940 ttctccatct gagaatcacg gagaggtgta gataatctag aggcatagac tgctagagcc 3000 cccagggatc tggggtggtc agggctcagg cttcactttg taaaccaggt gggggcatct 3060 cacagcctga cttcccttcc ccaggccagg gttgctggga tgcctgcccc tcctgagagg 3120 accccctccc cattgtcagg ctctccatgt ccacgagcgg ggaggggtgg gttctggggc 3180 attgttgtcc cttgtgtctg tggactagag atagggtggg ggagctgggg aagggtgcag 3240 gcgggaagag tgggctgtct ttcccagggt gatgcaagca tgccgcagcc ctggaggctg 3300 ggaatgtgga ggctctgtga gccctgcagc cctcagaatc agggccaggg atgcagaaga 3360 ttgagaggat atggagatgg atagagggca ggagaccctt aggatagatt gtgggaccca 3420 ggcaggaaca ggtgtccaca agaactcagg atggcatcag ttagctcaga agccacctgg 3480 aagacccagt gtttccatct ctggaatctc tgttttatgc taaatggatt taggaagact 3540 gtttttcttt taagggggaa acaaggtaga gaaaaggacg aagaagtgta agtcccgctg 3600 attctcgggg gtaaggctcg gatggcaagg acgcgttctg cctgggcatg taggggaggt 3660 gtttttgcca tcaccagttt ctcaggctgg ggagcacaga ggggaggagg aggactaaat 3720 gaaaagttgt tcccagcctg cacatgaaca cattcatgac acacaaaact ggctggaagg 3780 agataagagc actgggtttg agattccctc cattaaaaca accaagacaa agaaaggagg 3840 ggaaaaaaag ataaaaagca agccagggtt ccctgcccta ttgaaactca aacccagact 3900 gccttgggtt ttatctttcc cttacccctg gcacctccag agaactggga cctgaaatag 3960 tccctccgtt ctcccctttg accatgtaat aaatgaacca gaagcactga gattaaccta 4020 tcaacgccct gagaagcctt ccagcctgcg gtgctgtctg ctgggaggtc agctggtcaa 4080 ggcagaggag gagaggagga aaggatgggg gctgaagagc agaagggagg ggagacagag 4140 gggattaaag aggggaggag agagtgcaga gctccaggaa agggtatcag agctgcagcc 4200 agctctgccc tctaccctag ggaggccaga aagacacaaa cagccctccg ggcctttacg 4260 ctggactctg gcttggcagg ctccaggcag ggtcctctgg gaagttactc tagaaaacga 4320 agggaggagg agcacaagat cctcagcaac gaacacctgc acttagaaaa agtggacagc 4380 ttctgccaac cacaccctac ccatggtact gtatgctatt aactcctgga aacgccccgt 4440 aaatgcgagt tgtttttgta tttgtgtgtt gagatgggcc ttgtggtttc tctgtactca 4500 gagcacattt cttgtaatta ctattgttat ttttattgtc atgactgccc ctgagctctg 4560 gtgagaaaag ctgaatttac aaggaaaggg atgaagttaa tatttgcatc acataattat 4620 atcattactg tgtatctgtg tattgtacta aatggactga tgctgcgcac atgagctgaa 4680 aatgaagagc cctcccatcc 4700 <210> SEQ ID NO 145 <211> LENGTH: 453 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 68 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 145 tttgtttaaa ggcaatctaa cagattggaa ccctgataag atcatgcctg tgcagccctg 60 caccgacnga aggagactgt gatcaagtct gttactcgtt acagtactgt gaacgtcaac 120 aagaagaatt gctgcatgga aaacactgaa tataggcaga acaatctctc gcttacgata 180 ctgtgtgttg caaataatgc ctagaccaga gcaatgcagg cgctatgatt catcacaggc 240 aagatcaaca aaggaattgt taggacaaag aagaggctgc atgcagacct cccctgtcaa 300 aacacctcgc agctcattgg cttcatacag cctgccaaat gcaagggaag cagagagagg 360 gatggtgggt aggaagagaa aacttttttg cctgacaagc aacagccctc ttccccacaa 420 agcaggacag ttccttataa ctaagagtaa gtt 453 <210> SEQ ID NO 146 <211> LENGTH: 290 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 146 attgattacc catgtagtac aagtgtcgga tttaatgttc acacaccata gagaggcggc 60 agggacagat ggtgccttaa ctcttctttg atagatttta atggtgaaat attgatttct 120 gtctggccaa gacctgctgt taggggccaa agtcatttgt tgggtattgc cggacaccca 180 gttggcccag cgtaatcaat catttttggc aaggcaggtg aaaatccaga gagaagcacc 240 ttggaaccca aactggagcg tgatgtgtct gagtccagcc acctggattg 290 <210> SEQ ID NO 147 <211> LENGTH: 487 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 147 ttcggcactt gggagaagat gtttgaaaaa actgactctg ctaatgagcc tggactcaga 60 gctcaagtct gaactctacc tccagacaga atgaagttca tctcgacatc tctgcttctc 120 atgctgctgg tcagagcctc tctccagtcc aaggtgttct ggaggtctat tacacaagct 180 tgaggtgtag atgtgtccaa gagagctcag tctttatccc tagacgcttc attgatcgaa 240 ttcaaatctt gcccccgtgg taatggttgt ccaagaaaag aaatcatagt ctggaagaag 300 aacaagtcaa ttgtgtgtgt ggaccctcaa gctgaatgga tacaaagaat gatggaagta 360 ttgagaaaaa gaagttcttc aactctacca gttccagtgt ttaagagaaa gattccctga 420 tgctgatatt tccactaaga acacctgcat tcttccctta tccctgctct ggattttagt 480 tttgtgc 487 <210> SEQ ID NO 148 <211> LENGTH: 415 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 148 aagtaaaatg tttgctcaac tttattgaat gtcattagat ttataggaat cattaaagaa 60 ttagatacca gagtcccccc ggcccagacc cccacaaaaa aagtcagtga aaaagatgtg 120 agtgaaagaa gtttgtcaag gcaaatgtgt gaaaggatac atgtgtacat caccctttaa 180 atgctttccc tgagtattct atgaagtctg gggatcttcg aatgctatta atcttagaca 240 gtaaatttta taaagaaatt ctttaaaagt aggacttaat tctcctccgt agtgagtttt 300 taagcagagg atatctacta catggattcc tttgcctctt gacaggctca agttccatct 360 gcctcccagg cagctttttg agtctttcat agaagcctgc ttttaatata tgcca 415 <210> SEQ ID NO 149 <211> LENGTH: 1216 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 149 ttcggcactt gggagaagat gtttgaaaaa actgactctg ctaatgagcc tggactcaga 60 gctcaagtct gaactctacc tccagacaga atgaagttca tctcgacatc tctgcttctc 120 atgctgctgg tcagcagcct ctctccagtc caaggtgttc tggaggtcta ttacacaagc 180 ttgaggtgta gatgtgtcca agagagctca gtctttatcc ctagacgctt cattgatcga 240 attcaaatct tgccccgtgg gaatggttgt ccaagaaaag aaatcatagt ctggaagaag 300 aacaagtcaa ttgtgtgtgt ggaccctcaa gctgaatgga tacaaagaat gatggaagta 360 ttgagaaaaa gaagttcttc aactctacca gttccagtgt ttaagagaaa gattccctga 420 tgctgatatt tccactaaga acacctgcat tcttccctta tccctgctct ggattttagt 480 tttgtgctta gttaaatctt ttccagggag aaagaacttc cccatacaaa taaggcatga 540 ggactatgtg aaaaataacc ttgcaggagc tgatggggca aactcaagct tcttcactca 600 cagcacccta tatacacttg gagtttgcat tcttattcat cagggaggaa agtttctttg 660 aaaatagtta ttcagttata agtaatacag gattattttg attatatact tgttgtttaa 720 tgtttaaaat ttcttagaaa acaatggaat gagaatttaa gcctcaaatt tgaacatgtg 780 gcttgaatta agaagaaaat tatggcatat attaaaagca ggcttctatg aaagactcaa 840 aaagctgcct gggaggcaga tggaacttga gcctgtcaag aggcaaagga atccatgtag 900 tagatatcct ctgcttaaaa actcactacg gaggagaatt aagtcctact tttaaagaat 960 ttctttataa aatttactgt ctaagattaa tagcattcga agatccccag acttcataga 1020 atactcaggg aaagcattta aagggtgatg tacacatgta tcctttcaca catttgcctt 1080 gacaaacttc tttcactcac atctttttca ctgacttttt ttgtgggggc ggggccgggg 1140 ggactctggt atctaattct ttaatgattc ctataaatct aatgacattc aataaagttg 1200 agcaaacatt ttactt 1216 <210> SEQ ID NO 150 <211> LENGTH: 405 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 150 tttgtgtcaa aggcctttta ttcattaact gaacaatcat tggttgattt cttaaaaaat 60 tgtggtgaac caataaaagc taaagttcct tctaattgtg ggcttaactg aattacagtt 120 ttaaaatgtg gtgtcttcat tgccactcag ttcaatatat tttctaactt ccacttgatt 180 taaaagtcat gtttgatagt gtattgccag tttgtttaag acaggtatga ttaactgcat 240 cttagagaac tcgtctgtcc tggactgact gaagaatttc tgcactttgc catgttccat 300 ttttccatgg aaacagtgct ctgcagtgag cctctctctt caactccacc atgtcactgg 360 tctacctggt ctgggagcca gtagacttag ctgagacggg ctgta 405 <210> SEQ ID NO 151 <211> LENGTH: 343 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 151 ccgagaagga ggtccagcag tggtacaaag gcttcatcaa ggactgcccc agtggcagct 60 ggatgcggca ggctaccaga agatctacaa gcaattcttc ccgttcggag accccaccaa 120 gtttgccaca tttgttttca acgtctttga tgaaaacaag gacgggcgaa ttgagttctc 180 cgagttcatc caggcgctgt cggtgacctc acggggaacc ctggatgaga agctacggtg 240 ggccttcaag ctctacgact tggacaatga tggctacatc accaggaatg agatgctgga 300 cattgtggat gccatttacc agatggtggg gaataccgtg gag 343 <210> SEQ ID NO 152 <211> LENGTH: 4341 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 152 ccggcccggc ccgcccggcc cagccgctcc tgctgggcgc cccaaccggg tccggcccgg 60 gggggcgggg gccgcggccg ccgaggatgg ggaaatccaa cagcaagttg aagcccgaag 120 ttgtggagga gctgaccagg aagacctact ttaccgagaa ggaggtccag cagtggtaca 180 aaggcttcat caaggactgc cccagtgggc agctggatgc ggcaggcttc cagaagatct 240 acaagcaatt cttcccgttc ggagacccca ccaagtttgc cacatttgtt ttcaacgtct 300 ttgatgaaaa caaggacggg cgaattgagt tctccgagtt catccaggcg ctgtcggtga 360 cctcacgggg aaccctggat gagaagctac ggtgggcctt caagctctac gacttggaca 420 atgatggcta catcaccagg aatgagatgc tggacattgt ggatgccatt taccagatgg 480 tggggaatac cgtggagctc ccagaggagg agaacactcc tgagaagagg gtggaccgga 540 tctttgccat gatggataag aatgccgacg ggaagctgac cctgcaggag ttccaggagg 600 ggtccaaggc agacccgtcc attgtgcagg cgctgtccct ctacgacggg ctggtatagt 660 cccaggctgg agctggatgc ctgggaacca ctcacctcct tctgtgccat gaggccacct 720 cagccctgac accaaccccg tgcgtccacc cagccttctt ccgcatccac acacagccgg 780 ctgcccttga cccgggaggc cccggctctc ctctcccctg tcctgcaccc atcccccgcc 840 tgaagccacc ggctccaatt gccagcaacc tctgcttgtc cggaaaacga caacacgaaa 900 tggaaaaggc tacagccctc tgcataaacc aaggacttgg ctgcctcgca ggcagcctcc 960 gttcctcccg ctctcttgcg cgtgtgcttt tgttttttat tttgaacaga cgttttaaaa 1020 gaaaaaaaaa caactacctt ctgtcctaga agacacagac tgacagatgg ggtgaaggcc 1080 tggggacctc agagaactct gccttgccct cgtccctcgt ccttcggcag ccggagaggc 1140 tgtgggtggg ccgagggtgt ctaggggttc tgcctagtca acgttatttg tcgtcccatc 1200 ttttggcagc aaaaccacct gcgtggctag gatgattaat tatgaggatg atgatttttt 1260 ttgtgataac agtattgtgc tttttgtggg gaaagtgagg tttttttttt atatacatat 1320 ataattgata tctttaattt attggttgtt aactgttgct gctgcctggt gtgtcctcag 1380 ctcccagggc tgcgggccca ccgtttacat gtgcacgccc tgacccacct gcccacgccg 1440 acttgggagg atggtggcct gcagcggcca agaagccaaa aaaaattttt tttttttcag 1500 atactgtgct tgatttttgg agaggggaga ggtggaaatt cctaaatggc taatgcactg 1560 ttccctccag cccgaatgcc tcctgccaaa ccccttttcc ctgctgcctc tgtccccgca 1620 tccttgttct cccctgggtc cgtaacattt tttccgagga tgaacagggg acatctttag 1680 gtttctcaac tcttgctttg gtgtttgccg cagcatggaa aacagggcgc ctaaggctgg 1740 gagctggaag aaggggcatt gggtacccag gcagagtcag gagaggtggt ctttgaagta 1800 agttagcaga aatcaagggg acccccgcct ccttgggctg gggaggggat ttcaagatag 1860 ttcataactc tctcccgctc tgccttccct ccttcctatc tgctttttcc agtaaactgc 1920 atggtgtcct tccctggcct tctcttggct caaaggctgg gagggaggga aggagagaag 1980 agttccaggc aatcccatca atatagtccc tacacctggg gctgcggccc acatgtcttc 2040 acggaggctt ccagcggtgc ctgccactga ggcaggtgcg gccccaggac catcaccagg 2100 aatgcgaggc caccctggac cagaggtagg agcccaaggt ccggcccttg ctctttgatt 2160 gtgggcagcc tcctgccctc tctgggtctc agttgcccca tctgcagagc gaggaggccc 2220 gggctggttg gtcttgaagg cccttttcca tgccgacatc atgtcactct aggcctgggg 2280 ttcagtttcc tgtggctggt gatgctgtgg ttaagtttgc ttgaccccag cagcccgagg 2340 gactgtctga gtcacagcac agcccctatt gcgtggctgc tggtgtgtgg ggtcagttcc 2400 agcagatgaa tgtgtcatgt ggcacacctt gtcccttccc gcagcatttc ctggttcccc 2460 ccagaccctt gagcgctctt tgggacccag aaggagtcct tgcacaggga aggcttgagg 2520 tgagaagccg cttcccagac tgtcagggcc aggcctgggt ctagaattct tgctgctgct 2580 ttgcagagtc aacagcccat cagcccatgt tttagagggg acactttggt cctcggttcc 2640 caccctcagc aagcaggcct ccagcccgag gaaggcctct gccgtagtga cgttgccgtg 2700 tggggctgcg tggctgttcc ccttggctgg agcattcagc caaccccagc gtcccccctg 2760 aggcgttcat tggcagcccc ctaggactgc acgctggccc cacggtaacc ccccctcccc 2820 caccaacatc ctgcagggat ggggtcagtg gttccacctt cacaggccac tttgaagggt 2880 ggattctttg aggcccctgc cagtcggctc cctgctcagc tgctggcccg ggcgacctgg 2940 gactcagcac caacggctga agtttctcag ctgggctctg acctggggtc tggggcaggg 3000 aacgaacatg gtggctttgg gctgagagga tgagggaggt ctttcccagg tcaaattact 3060 ttcctttggc ctctgcctga ggctcgattt gcctctctgg tccaatggga ctgacactgt 3120 tgtacaacct gacctgtggc tgagggtgtc tgggcttaag catgtggacc ccttcggtgt 3180 gtctggcctt cctccatcgt cctgcccttt ggccttttgg tttgaagcca caggtgtggc 3240 ttctggcctt agcagatggt atgcttgcgg accgcagccc agcatgccgg tgggcccaca 3300 gcccgagcca gcccagagct gccggaaggg ccgcccttcc cggccctggc ggggtgctgg 3360 acactggcca ttttcactag agtttgcctg gcagggaccg atctctgccc cctcctctcc 3420 ccaggcctct ggctgcagtg atgccgcaga atcctgagcc aggtgcctcc tgagcagccc 3480 gtgcgcctct ccacagcggc gtttgccacc caatgcggct cgcttcagat gctctgatgc 3540 agagggcacg cccatagtcc ctctgcagag cctcgcactg gggccagggc aggcaccagc 3600 cccaggcggc cagtcggcca cggcctgtcc tcttcctcgt agcgtctgct cctcactttg 3660 tgttgatggt gacttaggag aatgttccga ttttccatga tctaagcagg ccacgtttaa 3720 aataacatca aggcaagcgt acgtgtcacc ctctgtactg acatctcctc ccctgaaatg 3780 cttttcagtt tgacagcccg tttcctagac aagtgcacct ggggtttcag gaactttgtg 3840 ttttttcgga gggggttggt ggggaggtcg ggatgcctgg gatcccttcc tggagaggca 3900 ggctgtctct ggaaaaagcc tccattgccc acccgccagg cggaaagtca ccctgttccc 3960 agcgcggttt cagcatttaa ttttaaggga gctaaggaag cgcggcgcgc cccctggtgg 4020 tggtaagccg ccaacgcacc tgggggctgc aaccccaccg gacgggtggt ccggagggag 4080 gctggagcgg ggaggcgagg agggggctgt gagtcctcag aggccctggg ccaccacatt 4140 tctggcagcg tttcccagac acccctctgc taggccatcc ctggatagca agtgaattaa 4200 cttaagggca ctgtgatggg aagccttgcc cccctctttt tttttttttt tttaatatct 4260 gcggaataaa cccaatggtt aatttttgaa tgaataaaag gcttttgttg aataaaaaaa 4320 aaaaaaaaaa aaaaaaaaaa a 4341 <210> SEQ ID NO 153 <211> LENGTH: 355 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 153 gctgacaccc tgctctccta ccgcattcct cttgctgaga cactgaaaat ggtaatcaat 60 aaactgaggg aactcagagg ccggtgcggt gctggtcctc cgtatgctga gtgccggtct 120 cctgggcccg ctgttctttc tctgtacttt gtctccgtgt cttatttctt ttctcagtct 180 ctcatcccac atatgaagaa ttctaatctt caaaaaattt tagaactcag tcagaacttg 240 agaacttctt tcagtaggtg tagtcccagg tagacaaaca acacggcctt cctcagcctc 300 tacccgagtc gtttcagaag agtgtgagcc atgagaaatc agagctgtta ttttc 355 <210> SEQ ID NO 154 <211> LENGTH: 372 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 149, 187, 290, 351, 361 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 154 ggctgctcca ccacagttag aggaggcagc cctgcttaca gactatagca ggtttttata 60 gggccagaac taggtcgggg tgggggagct gagttggggg tgcaggagaa ctgggttggg 120 gtgggggagc tgagtcgagg gtgcaggtnt cttgtctgca tcctggagat gttttttgcc 180 agctttntta tgcgaggtga acagacatgt taaccgcatc ctgtaactgt ctggacagtt 240 actggaggga tcagtgaagg ggggtttgtt ttttgccctg ggggtagctn tgcggagagc 300 aaaaggggac cctattgtaa gtccccttgg gaggggaagg gaaccggtct natcaagggt 360 naaccccaaa ca 372 <210> SEQ ID NO 155 <211> LENGTH: 230 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 207 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 155 acaagtctat ctttatttgt aaaaaataat atacaactaa agctaatttg atttttaaaa 60 tcgaagttca tttagtgata atgtacactt tataataaaa ttgtagtaaa atactgacat 120 ttgatagtta taaacaaagt atcattcatg taaaaatcat gttatagcat gtaaaattta 180 attagaaaat tcatagctca caaaagnaca tatattttgt tgatagctcc 230 <210> SEQ ID NO 156 <211> LENGTH: 177 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: 153, 161, 168 <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 156 ttgttttaaa gggggttttc acttacactt tttggtatga tgaatttttt gttaaataaa 60 cagatacaat agaattaaac taaggaccaa ttagtgcaaa aatgcattaa atacagctct 120 ccaggatttt taggatatgc ctcatttctg agnaataaaa ntttttangg ggaaaca 177 <210> SEQ ID NO 157 <211> LENGTH: 327 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 157 ctttagatga tgttgccatg gtacttgatg aagaagcaga agtttttata gtcaaaatgt 60 ggagattatt gatatatgaa acagaagcca agaaaattgg tcttgtgaag taaaactttt 120 tatatttaga gttccatttc agatttcttc tttgccaccc ttttaaggac tttgaatttt 180 tctttgtctt tgaagacatt gtgagatctg taattttttt tttttgtaga aaatgtgaat 240 tttttggtcc tctaatttgt tgttgccctg tgtactccct tggttgtaaa gtcatctgaa 300 tccttggttc tctttatact caccagg 327 <210> SEQ ID NO 158 <211> LENGTH: 512 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 158 tgtatctttt tttaacttat taaatggcta gtgggaaaga tttgtgcttg tgatcagctc 60 ttaacttcaa tttttacatc aaaacgtccc tgaaaacggt ctttctcact gtacccaatg 120 ttctcaccgt acgccttaca ctctatgcga atttcagtgt ccatggtaag attggtgaac 180 tgtacggcca gcaggggctg caggtatttg ggctgcagga gtttgccata gtacggataa 240 tactgcagag gaaaaccagg ggagttgcac agtccaaaat actccacatt tccaacttta 300 tccttatctt catctcgctt gccagtgcac tgaacgggaa ggacatttgg gttatacttc 360 atcactgggt aagtctccaa ggactcattc aatgggggct taggtttgaa gcctataaat 420 cggttgagcc ttataataat gcaagggttg tcctctttgt agccataagt ttcatcattt 480 aatccgagca atttcccggc catgcaaact tg 512 <210> SEQ ID NO 159 <211> LENGTH: 2208 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 159 gaattcatgc taaattgctg gaaggctgcg tctctgctgt ggtgtcagtt ccggatgcct 60 catcgccagg ggcgcgccgc agccacccac cctccggacc gcggcagctg ctgacccgcc 120 atcgccatgg cccgcgggaa agccaaggag gagggcagct ggaagaaatt catctggaac 180 tcagagaaga aggagtttct gggcaggacc ggtggcagtt ggtttaagat ccttctattc 240 tacgtaatat tttatggctg cctggctggc atcttcatcg gaaccatcca agtgatgctg 300 ctcaccatca gtgaatttaa gcccacatat caggaccgag tggccccgcc aggattaaca 360 cagattcctc agatccagaa gactgaaatt tcctttcgtc ctaatgatcc caagagctat 420 gaggcatatg tactgaacat agttaggttc ctggaaaagt acaaagattc agcccagagg 480 gatgacatga tttttgaaga ttgtggcgat gtgcccagtg aaccgaaaga acgaggagac 540 tttaatcatg aacgaggaga gcgaaaggtc tgcagattca agcttgaatg gctgggaaat 600 tgctctggat taaatgatga aacttatggc tacaaagagg gcaaaccgtg cattattata 660 aagctcaacc gagttctagg cttcaaacct aagcctccca agaatgagtc cttggagact 720 tacccagtga tgaagtataa cccaaatgtc cttcccgttc agtgcactgg caagcgagat 780 gaagataagg ataaagttgg aaatgtggag tattttggac tgggcaactc ccctggtttt 840 cctctgcagt attatccgta ctatggcaaa ctcctgcagc ccaaatacct gcagcccctg 900 ctggccgtac agttcaccaa tcttaccatg gacactgaaa ttcgcataga gtgtaaggcg 960 tacggtgaga acattgggta cagtgagaaa gaccgttttc agggacgttt tgatgtaaaa 1020 attgaagtta agagctgatc acaagcacaa atctttccca ctagccattt aataagttaa 1080 aaaaagatac aaaaacaaaa acctactagt cttgaacaaa ctgtcatacg tatgggacct 1140 acacttaatc tatatgcttt acactagctt tctgcattta ataggttaga atgtaaatta 1200 aagtgtagca atagcaacaa aatatttatt ctactgtaaa tgacaaaaga aaaagaaaaa 1260 ttgagccttg ggacgtgccc atttttactg taaattatga ttccgtaact gaccttgtag 1320 taagcagtgt ttctggcccc taagtattgc tgccttgtgt attttattta gtgtacagta 1380 ctacaggtgc atactctggt catttttcaa gccatgtttt attgtatctg ttttctactt 1440 tatgtgagca aggtttgctg tccaaggtgt aaatattcaa cgggaataaa actggcatgg 1500 taattttttt tttttgtttg ttttttgttt tttggctctt tcaaaggtaa tggcccatcg 1560 atgagcattt ttaacatact ccatagtctt ttcctgtggt gttaggtctt tatttttatt 1620 tttttcctgg gggctggggt gggggtttgt catgggggaa ctgcccttta aattttaagt 1680 gacactacag aaaaacacaa aaaggtgatg ggttgtgtta tgcttgtatt gaatgctgtc 1740 ttgacatctc ttgccttgtc ctccggtatg ttctaaagct gtgtctgaga tctggatctg 1800 cccatcactt tggcctaggg acagggctaa ttaatttgct ttatacattt tcttttactt 1860 tccttttttc ctttctggag gcatcacatg ctggtgctgt gtctttatga atgttttaac 1920 cattttcatg gtggaagaat tttatattta tgcagttgta caattttatt tttttctgca 1980 agaaaaagtg taatgtatga aataaaccaa agtcacttgt ttgaaaataa atctttattt 2040 tgaactttat aaaagcaatg cagtacccca tagactggtg ttaaatgttg tctacagtgc 2100 aaaatccatg ttctaacata tgtaataatt gccaggagta cagtgctctt gttgatcttg 2160 tattcagtca ggttaaaaca acggacaata aaagaatgaa ccgaattc 2208

Claims

1. A method for determining whether an agent can be used to reduce the growth of ovarian cancer, comprising the steps of:a. Obtaining a sample of ovarian cancer cells;b. Determining the expression profile of a marker set, wherein the marker set is selected from those set forth in Tables 2-15; andc. Identifying that the agent is or is not appropriate to reduce the growth of the ovarian cancer cells based on the expression profile.

2. The method of claim 1, wherein the ovarian cancer cells are selected from the group consisting of ovarian cancer cell lines and ovarian cancer cells obtained from a patient.

3. The method of claim 1, wherein the expression profile of the marker set in the sample is assessed by detecting the presence in the sample of polynucleotides or portions thereof, wherein the polynucleotides comprise the marker set.

4. The method of claim 1, wherein the expression profile of the marker set in the sample is assessed by detecting the presence in the sample of proteins or protein fragments corresponding to the marker set.

5. The method of claim 1, wherein the agent is a chemotherapeutic compound.

6. The method of claim 5, wherein the chemotherapeutic compound is a taxane compound.

7. The method of claim 5, wherein the chemotherapeutic compound is a platinum compound.

8. The method of claim 5, wherein the chemotherapeutic compound is a combination of a taxane compound and a platinum compound.

9. The method of claim 6, wherein the taxane compound is TAXOL or an analog of TAXOL.

10. The method of claim 7, wherein the platinum compound is cisplatin or an analog of cisplatin.

11. A method for determining whether treatment with an anti-cancer agent should be continued in an ovarian cancer patient, comprising the steps of:a. Obtaining two or more samples of ovarian cancer cells from a patient at different times during the course of anti-cancer agent treatment;b. Determining the expression profile of a marker set, in the two or more samples, wherein the marker set is selected from those set forth in Tables 2-15; andc. Continuing or discontinuing the treatment based on the evaluation.

12. The method of claim 11, wherein the ovarian cancer cells are selected from the group consisting of ovarian cancer cell lines and ovarian cancer cells obtained from a patient.

13. The method of claim 11, wherein the expression profile of the marker set in the sample is assessed by detecting the presence in the sample of polynucleotides or portions thereof, wherein the polynucleotides comprise the marker set.

14. The method of claim 11, wherein the expression profile of the marker set in the sample is assessed by detecting the presence in the sample of proteins or protein fragments corresponding to the marker set.

15. The method of claim 11, wherein the agent is a chemotherapeutic compound.

16. The method of claim 15, wherein the chemotherapeutic compound is a taxane compound.

17. The method of claim 15, wherein the chemotherapeutic compound is a platinum compound.

18. The method of claim 15, wherein the chemotherapeutic compound is a combination of a taxane compound and a platinum compound.

19. The method of claim 16, wherein the taxane compound is TAXOL or an analog of TAXOL.

20. The method of claim 17, wherein the platinum compound is cisplatin or an analog of cisplatin.

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