CN112289450A - Prediction system for prognosis survival period of intrahepatic cholangiocellular carcinoma patient - Google Patents

Abstract

The application provides a prediction system for prognosis survival period of a patient with intrahepatic cholangiocellular carcinoma, which comprises the following steps: the device comprises an acquisition module and a prediction module, wherein the acquisition module is connected with the prediction module in a wireless and/or wired mode. The prediction system can predict the survival period of the prognosis of the intrahepatic cholangiocellular carcinoma patient by adopting the promoter methylation score as a unique variable, can also predict the survival period of the prognosis of the intrahepatic cholangiocellular carcinoma patient based on a plurality of variables including the promoter methylation score, and has the advantages of high accuracy, strong reliability and stable prediction.

Description

Prediction system for prognosis survival period of intrahepatic cholangiocellular carcinoma patient

Technical Field

The application relates to the technical field of bioinformatics, in particular to a prediction system for prognosis survival period of intrahepatic cholangiocellular carcinoma patients.

Background

Intrahepatic Cholangiocellular Carcinoma (ICC) accounts for 4.4% to 12.0% of primary liver cancer, and is the second most common malignancy with poor prognosis of the liver itself. It has been found that complete surgical resection is the only opportunity for long-lived ICC patients that can undergo surgical resection, and that the overall survival rate five years after surgery is approximately 25.0% to 39.8% in the patients selected.

Due to highly aggressive biological behavior, and the lack of specific symptoms and signs, most ICC patients exhibit relatively advanced disease at the initial visit, and therefore, only a few ICC patients have the opportunity to undergo surgical resection therapy and then survive for a long time. However, therapeutically effective treatments (e.g., liver transplantation, liver resection, radiofrequency ablation, etc.) have a high rate of recurrence, leading to poor prognosis problems. Even with radical resection, 57.9% to 73.4% of ICC patients relapse, and 41.3% to 42.5% die of them.

For ICC patients who can be treated by surgical resection, the method has important clinical, scientific and social values for accurately predicting the prognosis survival period. Accurate prognosis survival prediction can guide doctors to make personalized examination and treatment schemes for high-risk ICC patients, guide the ICC patients to follow treatment plans to avoid over-treatment, and effectively reduce the risk of relapse. In addition, accurate prognostic survival prediction can provide important evidence for the development of novel ICC treatment regimens.

At present, no ideal prognosis survival prediction means exists in ICC clinical practice, and a comprehensive, reliable and stable prediction system for the prognosis survival of ICC patients is urgently needed to be developed.

Disclosure of Invention

The application provides a prognosis survival period prediction system for a patient with intrahepatic cholangiocellular carcinoma, which is used for accurately detecting the prognosis survival period of an ICC (acute coronary syndrome) patient and providing guidance for medical services.

A system for predicting prognosis of survival of a patient with intrahepatic cholangiocellular carcinoma, comprising:

the acquisition module is used for acquiring variables related to the prognosis survival period of the intrahepatic cholangiocellular carcinoma patient; and

the prediction module is used for predicting a prognosis parameter of the intrahepatic cholangiocellular carcinoma patient according to the at least one variable obtained by the acquisition module and outputting the prognosis parameter;

wherein the variables comprise promoter methylation scores that are based on methylation levels of at least 24 promoter regions; the 24 promoter regions are a set of polynucleotide sequences shown in SEQ ID No.1 to SEQ ID No.24 or a set of polynucleotide sequences complementary to SEQ ID No.1 to SEQ ID No. 24;

the acquisition module and the prediction module are connected in a wireless and/or wired mode.

In some embodiments of the present application, the obtaining module is for obtaining a promoter methylation score, the obtaining module comprising:

an analysis unit at least for analyzing the methylation level of the 24 promoter regions in an ex vivo sample of a patient with intrahepatic cholangiocellular carcinoma; and

a scoring unit for calculating a promoter methylation score based on at least the methylation levels of the 24 promoter regions;

wherein, the analysis unit is connected with the scoring unit in a wired and/or wireless mode.

In some embodiments of the present application, the obtaining module further comprises: an output unit for transmitting the promoter methylation score to the prediction module; the output unit is connected with the scoring unit in a wired and/or wireless mode.

In some embodiments of the present application, the promoter methylation score is calculated according to the following formula (1):

promoter methylation score = (-1.778426) × M (SEQ ID No. 1) + (-0.5188023) × M (SEQ ID No. 2) + (-0.007917956) × M (SEQ ID No. 3) + (-4.853461) × M (SEQ ID No. 4) + (0.442986) × M (SEQ ID No. 5) + (-1.512141) × M (SEQ ID No. 6) + (-0.503913) × M (SEQ ID No. 7) + (-2.622882) × M (SEQ ID No. 8) + (-5.796018E-14) × M (SEQ ID No. 9) + (-2.918528) × M (SEQ ID No. 10) + (-1.456336) × M (SEQ ID No. 11) + (-0.02070397) × M (SEQ ID No. 12) + (-0.4516687) × M (SEQ ID No. 13) + (-0.5262961) × M (SEQ ID No. 14) + (-0.01533871) (-3615) (-3985) × M (SEQ ID No. 3) (-0.3580827) (-3615) × M (SEQ ID No. 3) (-18) SEQ ID NO. 17) + (-0.03428591) × M (SEQ ID NO. 18) + (-0.183213) × M (SEQ ID NO. 19) + (-0.6439997) × M (SEQ ID NO. 20) + (-0.9643823) × M (SEQ ID NO. 21) + (-0.4090321) × M (SEQ ID NO. 22) + (-1.727257E-14) × M (SEQ ID NO. 23) + (-0.1818805) × M (SEQ ID NO. 24) (1)

Wherein "x" refers to a multiple, and M refers to the average methylation level of all CpG dinucleotides contained in the corresponding polynucleotide sequence.

In some embodiments of the present application, the variables further include: ascites status, tumor size, macrovascular invasion status, lymph node metastasis status, degree of tumor differentiation, and CA19-9 saccharide antigen concentration.

In some embodiments of the present application, the prognostic parameter includes: a prognostic survival risk grouping, and/or a survival probability value for a specified age.

In some embodiments of the present application, the prognostic risk grouping is to obtain a prognostic classification of the intrahepatic cholangiocellular carcinoma patient based on a preset threshold. For example: if the promoter methylation score is greater than or equal to a preset threshold value, dividing intrahepatic cholangiocellular carcinoma patients into high-risk groups; and if the promoter methylation score is smaller than a preset threshold value, classifying the intrahepatic cholangiocellular carcinoma patients into a low-risk group. For another example: if the promoter methylation score is larger than a preset threshold value, dividing intrahepatic cholangiocellular carcinoma patients into high-risk groups; if the promoter methylation score is equal to a preset threshold value, dividing intrahepatic cholangiocellular carcinoma patients into middle-risk groups; and if the promoter methylation score is smaller than a preset threshold value, classifying the intrahepatic cholangiocellular carcinoma patients into a low-risk group.

In some embodiments of the present application, the survival probability value for the specified age comprises: the prognostic survival is a probability value of three years and the prognostic survival is a probability value of five years.

In some embodiments of the present application, the method for predicting and outputting the prognosis parameter by the prediction module is: and importing the acquired variables into a pre-established Cox regression model, calculating the prognosis parameters through the Cox regression model, and visually presenting a prediction result.

In some embodiments of the present application, the prediction module and the acquisition module are respectively a processor, a server or a computer host; or, the prediction module and the acquisition module are integrated in the same processor, the same server or the same computer host.

The application provides a prediction system for prognosis survival of a patient with intrahepatic cholangiocellular carcinoma, which can predict the prognosis survival of the patient with intrahepatic cholangiocellular carcinoma by taking a promoter methylation score as a unique variable and can also predict the prognosis survival of the patient with intrahepatic cholangiocellular carcinoma based on a plurality of variables, wherein the variables comprise the promoter methylation score. Compared with the existing prognosis survival period prediction system for the intrahepatic cholangiocellular carcinoma patient, the prediction system has the advantages of high accuracy, strong reliability and stable prediction, and can be applied to clinical practice to guide the treatment scheme for the prognosis of the intrahepatic cholangiocellular carcinoma patient.

Drawings

Fig. 1 is a block diagram of a prediction system for prognosis survival of ICC patients according to an embodiment of the present application.

Fig. 2 is a block diagram of a prediction system for prognosis of survival of ICC patients according to another embodiment of the present application.

Fig. 3 is a block diagram of a prediction system for prognosis of survival of ICC patients according to another embodiment of the present application.

Fig. 4 is a schematic diagram illustrating a scenario of a prediction system for prognosis survival of an ICC patient according to an embodiment of the present application.

FIG. 5 is a time-dependent ROC plot (A) and a Kaplan-meier plot (B) of a training queue based on a PMS prediction system, and a time-dependent ROC plot (C) and a Kaplan-meier plot (D) of a validation queue based on a PMS prediction system.

Fig. 6 is a time-dependent ROC graph and a Kaplan-meier graph of five system prediction samples in the experimental example of the present application, where a is a time-dependent ROC graph of AUC of five systems in one year, B is a time-dependent ROC graph of AUC of five systems in two years, C is a time-dependent ROC graph of AUC of five systems in three years, D is a Kaplan-meier graph of prediction samples of PMS prediction systems, E is a Kaplan-meier graph of prediction samples of WCHSU prediction systems, F is a Kaplan-meier graph of prediction samples of jhesm prediction systems, G is a Kaplan-meier graph of prediction samples of bsh prediction systems, and H is a Kaplan-meier graph of prediction samples of AJCC TNM staged systems.

FIG. 7 is a prediction result map of a prediction sample by using the WCHSU-PMS prediction system, wherein A is a nomogram of the prediction sample by the WCHSU-PMS prediction system, B is a calibration curve of the three-year survival rate of the prognosis sample by the WCHSU-PMS prediction system, C is a calibration curve of the five-year survival rate of the prognosis sample by the WCHSU-PMS prediction system, and D is a time-dependent ROC curve of the prediction sample by the WCHSU-PMS prediction system.

Detailed Description

The terms and technical means used in the present application are explained below:

the term "prognosis" refers to providing a prognosis or prediction of the possible course or outcome of ICC. The term includes reference to predicting ICC progress (such as relapse or metastatic spread), survival, resistance, partial or complete remission, or good or poor outcome (good or poor prognosis, respectively). The term also includes a time limit for predicting any of the above (e.g., more than, less than, or equal to a given number of years, such as 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years), for example: providing a prognosis can include predicting a patient's survival as greater than, less than, or equal to a given number of years.

If survival, recurrence, metastatic spread, or other event (e.g., more than, less than, equal to, or within a given time period, etc.) is described herein in connection with a given time period, the given time period is preferably a time point within one of the following ranges: 0 to 18 years, 0 to 17 years, 0 to 16 years, 0 to 15 years, 0 to 14 years, 0 to 13 years, 0 to 12 years, 0 to 11 years, 0 to 10 years, 0 to 9 years, 0 to 8 years, 0 to 7 years, 0 to 6 years, 0 to 5 years, 0 to 4 years, 0 to 3 years, 0 to 2 years, 0 to 1 year, 1 to 18 years, 1 to 16 years, 1 to 14 years, 1 to 12 years, 1 to 10 years, 1 to 9 years, 1 to 8 years, 1 to 7 years, 1 to 6 years, 1 to 5 years, 1 to 4 years, 1 to 3 years, 1 to 2 years, 2 to 18 years, 2 to 16 years, 2 to 14 years, 2 to 12 years, 2 to 10 years, 2 to 9 years, 2 to 8 years, 2 to 7 years, 2 to 6 years, 2 to 5 years, 2 to 4 years, 2 to 3, 3 to 16 years, 3 to 3 years, 3 to 12 years, 2 to 10 years, 2 to 9 years, 2 to 8 years, 2 to 7 years, 2 to 6 years, 2 to 5 years, 2 to 4 years, 2 to 3, 3 to 3 years, 3 to 12 years, 3 to 3 years, 3 to 13 years, 3 to 3 years, 3 to 9 years, 3 to 8 years, 3 to 7 years, 3 to 6 years, 3 to 5 years, 3 to 4 years, 4 to 10 years, 4 to 9 years, 4 to 8 years, 4 to 7 years, 4 to 6 years, or 4 to 5 years. The foregoing ranges are inclusive, so that those skilled in the art will appreciate that, for example, a time point in the range of 4-5 years will be understood to include both endpoints of the range, such that the time point may, for example, be 4 years or 5 years (or any time point falling between the endpoints, such as 4.5 years). Thus, in at least some embodiments, providing a prognosis can include predicting that the patient has (i) survival that is greater than, less than, or equal to 3 years; or (ii) greater than, less than, or equal to 5 years. In some embodiments of the invention, the method comprises predicting patient survival for more than, less than, or equal to 3 or 5 years.

The term "patient" includes human patients and other mammals, and also includes any individual who has or has had ICC, or who wishes to be analyzed or treated using the methods of the invention. Suitable mammals falling within the scope of the present application include, but are not limited to: primates, livestock (e.g., sheep, cattle, horses, monkeys, pigs), laboratory test animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), pets (e.g., cats, dogs), and captive wild animals (e.g., foxes, deer, macadamia dogs). Preferably, the patient is a human patient. Optionally, the patient may be receiving ICC therapy; alternatively, the patient is in stage I, II, III or IV of ICC; still alternatively, the patient may be: (a) stage I or II patients; (b) stage II or III patients; or (c) stage III or IV patients.

The term "ex vivo sample" may include, for example, tumor material, tissue or bodily fluid, such as blood or biopsy, derived from a surgical resection or biopsy (e.g., cells from a patient biopsy). The tissue may be removed by any suitable method, such as punch biopsy, aspiration, scraping, excision with surgical resection. Suitable samples contain total tumor material, i.e., Tumor Infiltrating Leukocytes (TILs), stroma, and tumor cells. Optionally, the ex vivo sample may be excised tumor fragments. Ex vivo samples may be obtained at one or more time points. Optionally, the ex vivo sample may be processed (e.g., fixed, stored, frozen, lysed, homogenized, DNA or RNA extracted, cDNA transformed, ultrafiltered, diluted (e.g., with saline, buffer, or physiologically acceptable diluent, etc.), concentrated, evaporated, centrifuged, isolated, filtered, etc., using one or more post-collection preparation or storage techniques, prior to analyzing the ex vivo sample using the predictive system of the present application.

The term "promoter" refers to a nucleotide sequence recognized, bound and initiated by RNA polymerase that contains conserved sequences required for specific binding of RNA polymerase and initiation of transcription, which is not transcribed per se. In the present application, "promoter" and "promoter region" may be used interchangeably.

The term "methylation level" represents the proportion of one or more sites in a polynucleotide sequence that are in a methylated state. The methylation level of a region is the average of the methylation levels of all sites in the region, which can be, for example, a promoter region. An increase or decrease in methylation level of a region does not indicate an increase or decrease in methylation level at all sites in the region. Procedures are known in the art for converting the results obtained from methods for detecting DNA methylation (e.g., simplified methylation sequencing) to methylation levels. Exemplary embodiments utilize the moibs software to obtain methylation level parameters for CpG sites; for example, the methylation level parameter of the CpG sites represented by the M coefficient in formula (1) is obtained using MOABS software.

All statistics involved in the examples of the present application were performed by Rstudio 1.1.463, SPSS 25.0, and GraphPad Prism 8 software.

All time-dependent ROC curves in the examples of the present application were measured by the "survivvalroc" package for Area Under the Curve (AUC).

The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present application. The preferred embodiments and materials described herein are exemplary only, and are not intended to limit the scope of the present application.

Unless otherwise indicated, the starting materials and reagents used in the following examples are all commercially available or may be prepared by methods known in the art.

The whole genome extraction, the construction of a WGBS (whole genome sulfite sequencing) library, the WGBS sequencing and the data processing referred to in the examples of the present application were all performed by beijing knoo genesis science and technology ltd.

The kit Tiangen DP304 related to the examples of the present application was purchased from Tiangen Biochemical technology (Beijing) Ltd; the DNA analysis kit Qubit 2.0 Fluorometer is purchased from California Life technologies, Inc. USA; agilent Bioanalyzer 2100 was purchased from Agilent.

All operations in the examples of this application are in accordance with the manufacturer's specifications.

As shown in fig. 1, the present embodiment provides a system for predicting survival prognosis of an Intrahepatic Cholangiocellular Carcinoma (ICC) patient, where the system mainly includes: the device comprises an acquisition module 1 and a prediction module 2, wherein the acquisition module 1 is connected with the prediction module 2 in a wireless and/or wired mode.

In particular, the acquisition module 1 is used to acquire variables related to the prognosis survival of an ICC patient, the variables comprising promoter methylation scores. A promoter methylation score is based on the methylation levels of at least 24 promoter regions; the 24 promoter regions are a set of polynucleotide sequences shown in SEQ ID No.1 to SEQ ID No.24 or a set of polynucleotide sequences complementary to SEQ ID No.1 to SEQ ID No. 24.

The prediction module 2 is used for predicting a prognosis parameter of the ICC patient according to the at least one variable obtained by the obtaining module 1 and outputting the prognosis parameter. The method for predicting and outputting the prediction parameters by the prediction module 2 is as follows: and importing the obtained one or more variables into a pre-established Cox regression model, calculating the prognosis parameters through the Cox regression model, and generating a survival probability nomogram by adopting an R language RMS (root mean square) operation package to visually present a prediction result.

The prognostic parameters include a prognostic survival risk grouping, and/or a survival probability value for a specified age. The prognosis survival risk grouping is to obtain a prognosis classification of the ICC patient based on a preset threshold, for example: dividing ICC patients into high-risk groups if the promoter methylation score is greater than or equal to a preset threshold value; and if the promoter methylation score is smaller than a preset threshold value, dividing the ICC patients into low-risk groups. The probability of survival value for the specified age may be, for example, a probability of three years of prognostic survival and a probability of five years of prognostic survival.

The promoter methylation score can be used as an independent predictor of the prognosis survival of ICC patients. Other variables that are relevant to the prognostic survival of ICC patients may be, for example: ascites status, tumor size, macrovascular invasion status, lymph node metastasis status, degree of tumor differentiation, and CA19-9 saccharide antigen concentration.

In one embodiment of the present application, the prediction system uses promoter methylation scores as the only prediction variables, as shown in fig. 2, and the obtaining module 1 is only used for obtaining promoter methylation scores, and comprises: the analysis unit 11 and the scoring unit 12 are connected with each other in a wired and/or wireless mode, and the analysis unit 11 and the scoring unit 12 are connected with each other in a wired and/or wireless mode. Wherein, the analysis unit 11 is at least used for analyzing the methylation levels of 24 promoter regions in an in vitro sample of a patient with intrahepatic cholangiocellular carcinoma, and the scoring unit 12 is used for calculating a promoter methylation score according to the methylation levels of the 24 promoter regions.

In one embodiment of the present application, the obtaining module 1 further includes an output unit 13, the output unit 13 is connected to the scoring unit 12 in a wired and/or wireless manner, and the output unit 13 is configured to transmit the promoter methylation score to the predicting module 2.

In an embodiment of the present application, the prognostic parameters include a probability value that the prognostic survival time is three years and a probability value that the prognostic survival time is five years, and correspondingly, the method for predicting and outputting the prognostic parameters by the prediction module 2 is as follows: importing the obtained promoter methylation scores into a pre-established Cox regression model, wherein the Cox regression model is only used for analyzing the influence of the promoter methylation scores on the prognosis survival of an ICC patient; and calculating to obtain a prognosis parameter through the Cox regression model, and generating a survival probability nomogram by adopting an R language RMS (root mean square) operation package to visually present a prediction result. The survival probability nomogram is sequentially provided with a promoter methylation score nomogram, a total risk score nomogram, a three-year survival rate nomogram and a five-year survival rate nomogram, the obtained promoter methylation scores are mapped to an abscissa of the promoter methylation score nomogram, a numerical value of a position, corresponding to the abscissa, on the total risk score nomogram is the total risk score, a numerical value of a position, corresponding to the total risk score, on the three-year survival rate nomogram is a probability value that the prognosis survival period is three years, and a numerical value of a position, corresponding to the total risk score, on the five-year survival rate nomogram is a probability value that the prognosis survival period is five years.

In another embodiment of the present application, the prognosis parameter is a prognosis survival risk group, and correspondingly, the method for predicting and outputting the prognosis parameter by the prediction module 2 is as follows: importing the obtained promoter methylation scores into a pre-established Cox regression model, wherein the Cox regression model is only used for analyzing the influence of the promoter methylation scores on the prognosis survival of ICC patients, and the optimal threshold values of the promoter methylation scores in the Cox regression model are determined through a survivvalROC software package; if the obtained promoter methylation score is larger than the optimal threshold value, dividing the corresponding ICC patients into high-risk groups and outputting the groups; and if the obtained promoter methylation score is smaller than the optimal threshold value, dividing the corresponding ICC patients into low-risk groups and outputting the groups.

In another embodiment of the present application, as shown in fig. 3, the obtaining module 1 includes a promoter methylation score obtaining submodule 111, an ascites status obtaining submodule 112, a tumor size obtaining submodule 113, a large blood vessel invasion status obtaining submodule 114, a lymph node metastasis status obtaining submodule 115, a tumor differentiation degree obtaining submodule 116, and a CA19-9 sugar antigen concentration obtaining submodule 117, which are independent of each other.

The prognosis parameters are a probability value that the prognosis survival time is three years and a probability value that the prognosis survival time is five years, and correspondingly, the method for predicting and outputting the prognosis parameters by the prediction module 2 is as follows: importing the obtained multiple variables into a pre-established Cox regression model, wherein the Cox regression model is used for analyzing the influence of the multiple variables on the prognosis survival period of the ICC patient; and calculating to obtain a prognosis parameter through the Cox regression model, and generating a survival probability nomogram by adopting an R language RMS operation package to visually present a prediction result. A score column line, a column line for each of the plurality of variables, a total risk score column line, a three-year survival rate column line, and a five-year survival rate column line are presented in the probability-of-survival nomogram. The acquired variables are respectively mapped to the abscissa of the corresponding variable column line, the score of each variable in the variables is obtained through the score column line, the total risk score is calculated, the total risk score is the accumulated sum of the scores of the variables, the total risk score is mapped to the total risk score column line, the numerical value of the position, corresponding to the total risk score, on the three-year survival rate column line is the probability value of the prognosis survival period being three years, and the numerical value of the position, corresponding to the total risk score, on the five-year survival rate column line is the probability value of the prognosis survival period being five years.

The Wireless connection may be a bluetooth connection, a Wireless-Fidelity (WiFi) connection, an infrared connection, a mobile data network connection, or the like, and the wired connection may be a hardwired connection, a Universal Serial Bus (USB) connection, or the like. In addition, the form of the obtaining module is not particularly limited as long as the variable related to the prognosis survival time of the ICC patient can be obtained, and the obtaining module can be selected according to actual needs.

In some embodiments of the present application, the promoter methylation score is calculated according to the following formula (1):

promoter methylation score = (-1.778426) × M (SEQ ID No. 1) + (-0.5188023) × M (SEQ ID No. 2) + (-0.007917956) × M (SEQ ID No. 3) + (-4.853461) × M (SEQ ID No. 4) + (0.442986) × M (SEQ ID No. 5) + (-1.512141) × M (SEQ ID No. 6) + (-0.503913) × M (SEQ ID No. 7) + (-2.622882) × M (SEQ ID No. 8) + (-5.796018E-14) × M (SEQ ID No. 9) + (-2.918528) × M (SEQ ID No. 10) + (-1.456336) × M (SEQ ID No. 11) + (-0.02070397) × M (SEQ ID No. 12) + (-0.4516687) × M (SEQ ID No. 13) + (-0.5262961) × M (SEQ ID No. 14) + (-0.01533871) (-3615) (-3985) × M (SEQ ID No. 3) (-0.3580827) (-3615) × M (SEQ ID No. 3) (-18) SEQ ID NO. 17) + (-0.03428591) × M (SEQ ID NO. 18) + (-0.183213) × M (SEQ ID NO. 19) + (-0.6439997) × M (SEQ ID NO. 20) + (-0.9643823) × M (SEQ ID NO. 21) + (-0.4090321) × M (SEQ ID NO. 22) + (-1.727257E-14) × M (SEQ ID NO. 23) + (-0.1818805) × M (SEQ ID NO. 24) (1)

Where "×" refers to the multiplication number, M refers to the average methylation level of all CpG dinucleotides contained in the corresponding polynucleotide sequence, and M can be obtained by the moebs software. For example: m (SEQ ID NO. 1) refers to the average methylation level of all CpG dinucleotides contained in the polynucleotide sequence as shown in SEQ ID NO. 1.

The prediction module 2 and the acquisition module 1 are respectively a processor, a server or a computer host; alternatively, the prediction module and the acquisition module are integrated in the same processor, the same server or the same computer host.

For example, the server described in this embodiment includes but is not limited to a computer, a network host, a single network server, a plurality of network server sets, or a cloud server formed by a plurality of servers. Among them, the Cloud server is constituted by a large number of computers or web servers based on Cloud Computing (Cloud Computing).

The Processor may include one or more Processing cores, and the Processor described in the embodiments of the present Application may be a Central Processing Unit (CPU), other general purpose Processor, a Digital Signal Processor (DSP), an Application Specific Integrated Circuit (ASIC), an off-the-shelf Programmable Gate Array (FPGA) or other Programmable logic device, a discrete Gate or transistor logic device, a discrete hardware component, or the like. The general purpose processor may be a microprocessor or the processor may be any conventional processor or the like, preferably the processor may integrate an application processor, which handles primarily the operating system, user interfaces, application programs, etc., and a modem processor, which handles primarily wireless communications. It will be appreciated that the modem processor described above may not be integrated into the processor.

In one embodiment of the present application, as shown in fig. 4, the prediction system for prognosis of survival of ICC patients comprises: a server 100 and a terminal 200, wherein the server 100 integrates an acquisition module and a prediction module. The server 100 and the terminal 200 may communicate with each other through any communication method, including but not limited to mobile communication based on 3rd Generation Partnership Project (3 GPP), Long Term Evolution (LTE), Worldwide Interoperability for Microwave Access (WiMAX), or computer network communication based on TCP/IP Protocol Suite (TCP/IP), User Datagram Protocol (UDP), and so on.

The server 100 includes: a plurality of processors; a memory; and a plurality of application programs, wherein the plurality of application programs are stored in the memory and configured to be executed by the processor.

The memory may be used to store software programs and modules, and the processor may execute various functional applications and data processing by operating the software programs and modules stored in the memory. The memory may mainly include, for example, a storage program area and a storage data area, wherein the storage program area may store an operating system, an application program required by at least one function (such as a sound playing function, an image playing function, etc.), and the like; the storage data area may store data created according to the use of the server, and the like. Further, the memory may include high speed random access memory, and may also include non-volatile memory, such as at least one magnetic disk storage device, flash memory device, or other volatile solid state storage device. Accordingly, the memory may also include a memory controller to provide the processor access to the memory.

The terminal 200 may be a general-purpose computer device or a special-purpose computer device. In a specific implementation, the terminal 200 may be a desktop, a laptop, a web server, a Personal Digital Assistant (PDA), a mobile phone, a tablet computer, a wireless terminal device, a communication device, an embedded device, and the like, and the type of the terminal 200 is not limited in this embodiment.

One skilled in the art will appreciate that the server may also include one or more of a power supply, an analysis module, and an output module. The power supply is used for supplying power to each component of the server, and preferably, the power supply can be logically connected with the processor through the power management system, so that functions of charging, discharging, power consumption management and the like can be managed through the power management system. The power supply may also include one or more dc or ac power sources, recharging systems, power failure detection circuitry, power converters or inverters, power status indicators, and any other components. The analysis module is used for receiving input digital or character information and can be a keyboard, a mouse, an operating rod, a human-computer interaction laser pen and the like. The output module is used for visualizing or audio-processing the prognosis parameter of the ICC patient, and can be a display screen, a printer or an audio output device.

It should be noted that the prediction systems shown in fig. 1-4 do not constitute a specific limitation of the prediction system of the present application, and may include more or fewer components than those shown, or some components in combination, or a different arrangement of components.

In an embodiment of the present application, the processor in the prediction system loads the executable files corresponding to the processes of the plurality of applications into the memory according to the following instructions, and the processor runs the applications stored in the memory, so as to implement various functions, as follows:

obtaining variables associated with prognostic survival of an ICC patient, said variables comprising promoter methylation scores; and

and introducing the obtained variables into a pre-established Cox regression model, calculating to obtain a prognosis parameter through the Cox regression model, and visually presenting a prediction result.

The prediction system of the present application will be described below with reference to specific examples.

Example 1: PMS prediction system

The present embodiment provides a prediction system of ICC patient prognostic survival, which is a prediction system as shown in fig. 2 and predicts based on Promoter Methylation Score (PMS) only, and thus, the prediction system is named PMS prediction system.

PMS is based on the methylation level of 24 promoter regions, the 24 promoter regions are a collection of polynucleotide sequences shown in SEQ ID No.1 to SEQ ID No.24, and the specific information is detailed in Table 1 below. Any of these 24 promoter regions is a 4000bps total polynucleotide sequence consisting of 2000bps upstream and 2000bps downstream based on the transcription start site.

Table 124 relevant information tables of promoter regions

The method for predicting the prognosis survival period of the ICC patient by the PMS prediction system comprises the following steps:

s1, providing an in vitro sample of an ICC patient, and sequentially performing whole genome extraction, WGBS library construction, WGBS sequencing and WGBS sequencing result data processing operations on the in vitro sample to obtain the methylation level of any one of 24 promoter regions;

s2, calculating the PMS of the in-vitro sample by adopting a formula (1);

and S3, introducing the PMS into a pre-established Cox regression model, calculating to obtain the ICC patient prognosis survival risk group based on the optimal threshold value of the Cox regression model, if the PMS obtained in the step S2 is larger than the optimal threshold value, dividing the corresponding ICC patients into high-risk groups and outputting the high-risk groups, and if the PMS obtained in the step S2 is smaller than the optimal threshold value, dividing the corresponding ICC patients into low-risk groups and outputting the low-risk groups.

The specific flow of step S1 is as follows:

s11, genomic DNA was isolated using the tiangen dp304 kit, and DNA degradation and contamination was monitored using agarose gel. The DNA purity was measured with a spectrophotometer (IMPLEN, CA, USA). DNA concentration was confirmed using the DNA analysis kit in the Qubit 2.0 Fluorometer, sonicated to 200 + 300bp with Covaris S220, followed by end repair and adenylation, and genomic DNA spiked with 26 ng λ DNA in a total amount of 5.2 μ g was fragmented. The cytosine methylated barcode was ligated to the sonicated DNA according to the kit manufacturer's instructions. The ligated DNA fragments were treated twice with bisulfite using EZ DNA Methylation-GoldTM kit (Zymo Research). The bisulfite treated single stranded DNA fragment was PCR amplified using the KAPA HiFi HotStart Uracil + ReadyMix (2X) kit. Library concentrations were quantified by a Qubit 2.0 fluorometer (Life Technologies, CA, USA) and quantitative PCR, and insert sizes were determined on the Agilent Bioanalyzer 2100 system.

S12, sequencing the prepared gene library on the Illumina NovaSeq platform and generating a 150bp paired end reading. Image analysis and base detection were performed using the Illumina CASAVA pipeline, ultimately yielding a paired end read of 150 bp. The sequencing depth of each sample was at least 30 ×.

S13, generate a quality report of the original WGBS sequencing reads using FastQC (Andrews, 2010). Fastp is used for quality control and low quality read filtering for C + + development, which performs fast quality control and data filtering on high-throughput sequencing reads (Chen et al, 2018). The adapter is pruned from the original reads (AGATCGGAAGAGCACACGTCTGAACTCCAGTCA, AGATCGGAAGAGCGTCGTGTAGGGAAAGAGTGT). Both ends with quality less than 3 or N cardinalities are also pruned (each ready: cut _ front, cut _ front _ window _ size 1, cut _ front _ mean _ quality 3, cut _ tail, cut _ tail _ window _ size 1, cut _ tail _ mean _ quality 3 is filtered by a quality value). The average quality is checked using a 4-benchmark sliding window and the cardinality is clipped to make its average quality below 15 (cut _ right, cut _ right _ window _ size 4, cut _ right _ mean _ quality 15). Since the first 10 bps were treated with biased cytosine sulphite, the two end reads were trimmed from the front by 10 bps (trim _ front 110, trim _ front 210). The minimum length of the trim reads is reserved to 36 bps (length _ required 36). Only correctly paired reads were retained for downstream analysis, which were clean reads of the WGBS library.

S14, DNA methylation analysis is carried out by using MOABS software. The BSMAP module of MOABS was used to align clean reads to the reference genome (hg 38). The mcal module of MOABS performed a single sample analysis to report the methylation levels of CpG dinucleotides throughout the genome, as well as CpG depth coverage and average methylation levels. To check the methylation level of the promoter region, the Gencode transcription annotation was downloaded from the UCSC table browser (V33). A promoter region was defined at 2,000 bps upstream and 2,000 bps downstream of the transcription initiation site, resulting in a total length of 4,000 bps promoter region. The mean methylation level containing CpG sites is used to represent the methylation level of the promoter region (SEQ ID No.1-SEQ ID No. 24).

The method for establishing the Cox regression model comprises the following steps:

s21, obtaining in vitro samples of 334 ICC patients from biological banks of Huaxi hospital of Sichuan university, Zhongshan hospital of Fudan university and tumor hospital of Tianjin medical university, and freezing and storing the obtained in vitro samples at-80 ℃ or in liquid nitrogen. 334 ICC patients are divided into a training queue and a verification queue, wherein the training queue is used for constructing a Cox regression model, the verification queue is used for verifying the effectiveness of the Cox regression model, and specific classification information is detailed in the following table 2:

TABLE 2334 ICC patient Classification List

Baseline characteristics of 334 ICC patients are detailed in table 3:

table 3334 baseline profile of ICC patients

As shown in table 3, some baseline characteristics are not balanced between the two queues. This difference can be explained by a explanation of both geodesic and economic factors, as socioeconomic status of the southwest continent (training cohort) lags behind the eastern coastal region of china (validation cohort).

S22, sequentially carrying out whole genome extraction, WGBS library construction, WGBS sequencing and WGBS sequencing result data processing operations on the 334 in-vitro samples to obtain DNA methylation data of each in-vitro sample.

S23, analyzing DNA methylation data of 334 in vitro samples, and screening 24 promoter regions (shown in Table 1) related to ICC, wherein the specific screening process is as follows:

the 175976 promoter regions obtained by WGBS in the training cohort were identified, the 175976 promoter regions corresponding to 198074 transcripts of 42737 genes (coding and non-coding). As can be seen from the WGBS data, the methylation levels of any of the 175976 promoter regions were continuous and quantitative, the methylation levels of the promoter regions were determined to be significantly correlated with overall survival (P < 0.01) using the single predictor Cox method, and 36938 of the 175976 promoter regions were found to be significant in the single predictor Cox analysis.

Calculating the consistency index (C-index) of any one promoter region in the 175976 promoter regions, and selecting 5000 promoter regions ranked before the C-index;

calculating the Coefficient of Variation (CV) of each promoter region of each in vitro sample in the training queue, and filtering the promoter region with the CV value less than 0.05;

3596 promoter regions which meet the standard (P <0.01 and C-index 5000 at top in single predictor Cox analysis and CV > 0.05) were selected and then further screened using the LASSO Cox algorithm for 3596 promoter regions, finally obtaining 24 promoter regions as shown in Table 1, corresponding to the polynucleotide sequences as shown in SEQ ID No.1 to SEQ ID No. 24.

S24, constructing a PMS calculation formula according to the average methylation level of all CpG dinucleotides contained in any promoter region in the 24 promoter regions, wherein the PMS calculation formula is shown as formula (1).

And S25, constructing a Cox regression model by adopting the PMS of the training queue.

And S26, verifying the effectiveness of the Cox regression model by adopting a verification queue.

The Cox regression model has one or more optimal thresholds based on which all ICC patients in the validation cohort are assigned to one of the high PMS and the low PMS.

For 164 ICC patients in the training cohort, the C-index for Overall Survival (OS) was 0.772 (95% CI: 0.731-0.813) and the optimal threshold for PMS was-11.20716. For 170 patients in the validation cohort, the C-index of the OS was 0.735 (95% CI: 0.676-0.793), the PMS in the validation cohort was calculated by the same coefficients as the PMS in the training cohort, and the groupings were defined by the same thresholds.

The prognostic survival profiles of the training cohort and validation cohort are detailed in table 4 below:

TABLE 4 Pre-and post-lifecycle condition List for training and validation queues

As shown in fig. 5 and table 4, the AUC for the training cohort for 1 year, 2 years and 3 years of overall survival was 0.844, 0.830 and 0.883, respectively. There were 96 and 68 patients with low PMS and high PMS, respectively. The overall survival rate for the low PMS group was significantly higher than for the high PMS group (P <0.001, HR = 4.261, 95% CI: 2.743-6.619). Median survival in the low PMS group was 55.2 ± 3.3 months, with overall survival rates of 92.7%, 71.3% and 45.2% for one, three and five years of prognosis, respectively. Meanwhile, median survival in the high PMS group was 11.8 ± 2.5 months, with overall survival rates of 48.5%, 13.9% and 4.9% for one, three and five years of prognosis, respectively.

For the validation cohort, the AUC for 1, 2 and 3 years of overall survival were 0.773, 0.770 and 0.779. There are 109 and 61 PMS low and high groups, respectively. The overall survival in the low PMS group was significantly higher than the high PMS group (P <0.001, HR = 3.999, 95% CI: 2.283-7.004). Median survival in the low PMS group was 53.0 ± 11.6 months with overall survival rates of 92.9%, 71.3% and 42.1% for 1, 3 and 5 years of prognosis, respectively. In contrast, median survival in the high PMS group was 16.9 ± 2.0 months, while the prognostic 1-year, 3-year and 5-year overall survival was 66.1%, 23.7% and 23.7%, respectively.

Taken together, the overall survival C-index for PMS in the training cohort was 0.772, and median survival was significantly higher for the low PMS group than for the high PMS group; the total life cycle C-index of PMS in the verification queue is 0.735, and the median life cycle of the low PMS group is obviously higher than that of the PMS high group. The effectiveness of the constructed Cox regression model is fully demonstrated by the prognostic prediction data of the training queue and the verification queue, so that the PMS can accurately predict the prognostic survival of the ICC patients, and the effectiveness of the prediction system of the embodiment is further proved.

Experimental example: comparing PMS prediction system, WCHSU prediction system, JUSM prediction system, EHBSH prediction system and AJCC TNM staging system

The WCHSU prediction system is mainly different from the PMS prediction system in that: the WCHSU prediction system adopts six variables, namely ascites state, tumor size, large vessel invasion state, lymph node metastasis state, tumor differentiation degree and CA19-9 saccharide antigen concentration.

The JUSM prediction system is mainly different from the PMS prediction system in that: the JUSM prediction system adopts six variables, namely age, tumor size, tumor number, lymph node state, large vessel invasion state and liver cirrhosis, and the specific content of the JUSM prediction system is referred to as a reference document:

Y Wang et al, Prognostic Nomogram for Intrahepatic Cholangiocarcinoma After Partial Hepatectomy, J. Clin. Oncol. 31（2013）1188-1195。

the EHBSH prediction system differs from the PMS prediction system mainly in that: the EHBSH prediction system uses six variables, age, tumor size, number of tumors, cirrhosis, lymph node metastasis status, and macrovascular invasion status, specific contents of EHBSH prediction system references: o Hyder, H Marques et al, A Nomogram to Predict Long-term overview review for Intrahepatic Cholangiocarpioma, JAMA Surg.149 (2014) 432.

The AJCC TNM staging system and the PMS forecasting system are mainly characterized in that: the T stage in the AJCC TNM stage system mainly comprises three variables of tumor number, vascular invasion and direct extrahepatic invasion; the N stage in the AJCC TNM staging system is based on a variable, i.e., whether there is metastasis of one or more regional lymph nodes; the M staging in the AJCC TNM staging system is based on a variable, i.e. the presence or absence of distant metastasis. Specific contents of the AJCC TNM staging system refer to the eighth edition TNM staging system for ICC, promulgated by the American Joint Committee on Cancer, AJCC.

The PMS prediction system, the WCHSU prediction system, the jhausm prediction system, the EHBSH prediction system, and the AJCC TNM staging system were used to predict 334 ICC patients in example 1, the 334 ICC patients were taken as a whole without classification, and the variable information is detailed in table 5 below:

table 5 list of variable information

The prediction results of the PMS prediction system, the WCHSU prediction system, the jhausm prediction system, the EHBSH prediction system, and the AJCC TNM staging system are shown in fig. 6 and the following table 6:

TABLE 6 time-dependent ROC graph Performance generated by five System predictions

As can be seen from table 6 and fig. 6, the Kaplan-meier plots of the five systems each have four clearly separated Kaplan-meier curves (overall P < 0.001), and the Kaplan-meier plots of the five systems all show the same trend, fully illustrating the effectiveness of the PMS prediction system. The C-index of the PMS prediction system is obviously higher than that of a WCHSU prediction system, a JUSM prediction system, an EHBSH prediction system and an AJCC TNM staging system, the AUCs of the PMS prediction system in one year, two years and three years are also higher than those of the WCHSU prediction system, the JUSM prediction system, the EHBSH prediction system and the AJCC TNM staging system, and the fact that compared with the other four systems, the PMS prediction system has higher accuracy is fully demonstrated. Therefore, the PMS prediction system is superior to the other four systems.

Example 2: WCHSU-PMS prediction system

The embodiment provides a prediction system for prognosis survival period of an ICC patient, PMS is added into a WCHSU prediction system as a new variable, and the WCHSU-PMS prediction system is obtained. The WCHSU-PMS prediction system is a prediction system as shown in fig. 3, which has seven variables, respectively: PMS, ascites state, tumor size, macrovascular invasion state, lymph node metastasis state, degree of tumor differentiation, and CA19-9 saccharide antigen concentration.

The method for predicting the prognosis survival period of the ICC patient by the WCHSU-PMS prediction system comprises the following steps:

s1, providing an ICC patient in-vitro sample, and sequentially performing whole genome extraction, WGBS library construction, WGBS sequencing and WGBS sequencing result data processing operations on the in-vitro sample to obtain the methylation level of any one of the 24 promoter regions;

s2, calculating the PMS of the in-vitro sample by adopting a formula (1);

s3, introducing the PMS obtained in the step S2, the ascites state, the tumor size, the large vessel invasion state, the lymph node metastasis state, the tumor differentiation degree and the CA19-9 carbohydrate antigen concentration of the ICC patient (the judgment standards of the six variables refer to a WCHSU prediction system) into a pre-established Cox regression model to calculate a probability value that the prognosis survival time is three years and a probability value that the prognosis survival time is five years, and generating a survival probability nomogram by adopting an R language RMS (root mean square) operation package to visually present a prediction result, wherein the Cox regression model is obtained by adding PMS variables on the basis of the Cox regression model of the WCHSU prediction system.

As shown in a in fig. 7, the survival probability nomogram is presented with score, ascites status, tumor size, large vessel invasion, lymph node metastasis status, tumor differentiation degree, CA19-9 carbohydrate antigen concentration, PMS, total risk score, three-year survival rate, and five-year survival rate nomograms. And mapping the seven variables obtained in the step S3 to the abscissa of the corresponding variable row line, obtaining the scores of the variables through the score row line, and calculating the total risk score, which is the cumulative sum of the scores of the variables, mapping the total risk score to the total risk score row line, where the value at the position corresponding to the total risk score on the three-year survival rate row line is the probability value of the prognosis survival period of three years, and the value at the position corresponding to the total risk score on the five-year survival rate row line is the probability value of the prognosis survival period of five years.

The prognostic survival of 334 ICC patients in example 1 was predicted using the WCHSU-PMS prediction system. As shown in FIG. 7, the C-index of the Cox regression model of the WCHSU-PMS prediction system is 0.799 (95% CI: 0.769-0.829), and the 3-year and 5-year AUC of the time-dependent ROC curve are 0.874 and 0.854, respectively; for the 334 ICC patients, a satisfactory agreement was achieved between the predicted outcome of the WCHSU-PMS prediction system and the actual prognostic survival observed.

The WCHSU-PMS prediction system has better performance than a PMS prediction system, a WCHSU prediction system, a JUSM prediction system, an EHBSH prediction system and an AJCC TNM staging system because: the prediction system of the embodiment considers various variables including PMS, and has higher accuracy.

In the foregoing embodiments, the descriptions of the respective embodiments have respective emphasis, and for parts that are not described in detail in a certain embodiment, reference may be made to related descriptions of other embodiments.

The system for predicting the survival period of the intrahepatic cholangiocellular carcinoma patient after prognosis provided by the embodiment of the application is described in detail above. The principle and the implementation of the present application are explained by applying specific examples, and the above description of the embodiments is only used to help understanding the technical solution and the core idea of the present application; those of ordinary skill in the art will understand that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; such modifications or substitutions do not depart from the spirit and scope of the present disclosure as defined by the appended claims.

Sequence listing

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aaaagtagaa ggacaaatgt ataataacaa ggtttcatct ctgatcatat gaatgagtat 2580

tgcagagcca tgaatgaaat gtccttgttt gcctttttta ttttagcatt ttgtattata 2640

catattttat cattagactt acaatgttaa caatgtatat tttaaaataa accttgaatt 2700

cccataccta ttagtaaatt gtgtcaaaag tcttatgaaa cctgtttcgt tttctaatga 2760

attttctgcc agaaccaata aagagtcttt agtcatttaa aaccttaaga ttggcatttc 2820

agattctgag tagtttatag cttattcaca aaaacaaaaa gtagtttttt gcctttctta 2880

tagcaaggct agtttagact gaacaagaca gagttgtgac tctcagaagc agaaggcgca 2940

ggcatttagc ttctagttgt ttttggcatt ctgcctggag aggaaagaat tttcctgatg 3000

tcataaaata ccagaacaag tttttagctt aattgtaaac aataattttg tgccaagaaa 3060

atgaaatctc agaaatacaa tttttgacct aaaatggcca cctagttaga ataattactg 3120

atttactttt agataacatt atttatttag aaattttact atctaggtat agagaaaaac 3180

atgacaactt ccctttcctc tccctgccat acttttgttt tttgcattgt gagatcaaaa 3240

actagtgagc acagtaaagg aggataattt cagattatcc ttttctcatt ctgcatttta 3300

aatcaggttt gtccatcact tccatataaa cggggctatg aagtaagact attttaaatt 3360

gctaattgat aacacaaaaa actttaactt gtactgtttt ggggattttc aacttttaac 3420

atcaggacta agttatttta ttattagttt ttctcccaaa atactggctt tcaaatcact 3480

gtagctatga aaacttgtta tccctttgat tcctttatta catttaacat caaattttcc 3540

taattagaaa tatatcctta aaatatagtc aagcagtgac tgcttatttt gaatgaaaca 3600

aattaaatgt agacaagcag ggtgattgta tatagagggt tttttccttt ttgttttgtt 3660

tagctttttt ggtctatgag ttgcccaaaa ttgaagttta tgttgcaggt tttggtgtgg 3720

tgaggaccta cagtgtcagg ttcttacaaa gtaaatattg aaaaaggcaa atactgggca 3780

gttcaatctt gcatgatacc tatggccata ttacccaaaa tatcatgact tggtttatct 3840

caaaagctaa gcaggattct gagatactac caataatgta ctactatttc taaaggagta 3900

attttgtaat tttgtaaaga aattcacaaa catggaatga cactgtgaat tcctgtgaaa 3960

aagcagatat ccactgcttt gtatttaaaa tattttgcaa c 4001

<210> 3

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 3

cccggtcttc aggttctcta aaataattta ctgtgtcaag ttttgataat attcctagct 60

ctctgaaaat gattgaatca aataagtgtc tatttttttt ttctgcaaac actacccgcc 120

agaacaattt ccggttgtta aatagtaaag tcaccgttcc tttggtaagg aatatttaaa 180

ggaactccct tggaaatgaa ttttgtaata ggtgattttt attctgtttt tactctatgt 240

gatactgatc cttgcactgg atttcagttt ggcaatatgc tttttaaaac tgggagtctt 300

aaggtgactg gatattagca tttttcacta agttttttgg atttgaaagt accttttgat 360

attatttctt ggtgaggcta aaaaaattga taaatagctg acaaacctct gtaacctaca 420

ggtaggctag atcaatgtta tacatttcta atgtcatggt gttgttaaag tagagaattt 480

tgaagagtag aaaatcgtag ctgtcaaaat gcacaaagat gaacattcag aaagaattgc 540

tgaatcatca ttgcttggca tatagagtag gcgttctcat ttctttaaag gttaacacat 600

gattattacc ctttattata ttctaaacat atatgtacat tttcttttcc tcataaaggt 660

tttctaacat tttatttgga ctgtgtgcaa ttcttctgac ttttcttatt tatctctcta 720

atagaaatgg gaacattttt gaaaagatga gaaaaccata caggagataa aagatgagtt 780

atatacatag aaaatgtctc ataaatacct gaaatatgtt atactttcaa aagcaggcat 840

caaaagggta tataaatgct atgatctaac tttgttaaca aaaaattata aaactacagc 900

aaataaccat gaagatttat agaaaacaga attagaagta aatacagtaa tatttaacag 960

ggattaccta aaatgatatt atagggagat ttttaaaaac ttttttctgc gttttccaaa 1020

atctccaaca atgaatatat atttataatt agggaaatgt gtttttgaaa gaaaaaatat 1080

ttctcatatt actgcccctt aagtggcata tccaaatttt acattgatgc agttgcagtt 1140

aagtcttgta aggaacatga gtatgtactg tctgtaacct gatactttgt tctagctttc 1200

ctgcagcacc acagttcttt aaatagggat cctgtggggc ggctgcaggg gacgggggtt 1260

gaggggtggc agggacctca ttcagtttta gtttagttga agtaactaag ttcagatact 1320

aaaatttcaa aaataagtat ttgtttgcca gaactatgaa ctcatgtata ctagaaataa 1380

ctagttagct aaaatcatgt ttaagtcctt tacttatttt aaaataacgc atttgaattt 1440

tattatagat actcccttaa caatgtgaaa ctagtacaca aactttctgg cgtttctgat 1500

tgatagaccc caggaatttt gaagacgaca taaattactt ggaaatccta atttaaacaa 1560

cctgcgtttt ggtattatat acttaacaga caaatagctt aaaattaaaa aatccctaaa 1620

gtagaattgt cgttcctttt atctgtatat taactttaac ttcttttaac atagggtgtt 1680

taatgactgt gatgattttc acctagtatg gagtacataa atatatagtt gtgacattct 1740

gtgttgaaat attggcatgt taacccattt gtcctgttta attaggaaat aaagacggta 1800

gagctagtcg gaaaatgaat agttaatcgt ggaggaggag aaaacatagc tcagtacttt 1860

gactagaggc agctgggaaa gtgacgtcct gtagcatttg ctgttctaga aagtacagag 1920

acacgtagtg aaaatgggag gatctagaag gaggctgtct cctgtgtagt gtatatttat 1980

ctgtaagtga gccgttgggg aaggattgaa tacagagacg ctgtctgctt gctgccttaa 2040

gacagctagc tgaattgctg attaactttt aaaataccca gcttggttta tttttcttag 2100

aatctgttgc taagactggg gacgctgttt tcttttacaa agggaaatct aagttaattt 2160

caaggcattc gaaatgggga aagactatta ttgcattttg ggaattgaga aaggagcttc 2220

agatgaagat attaaaaagg cttaccgaaa acaagccctc aaatttcatc cggacaagaa 2280

caaatctcct caggcagagg aaaaatttaa agaggtcgca gaagcttatg aagtattgag 2340

tgatcctaaa aagagagaaa tatatgatca gtttggggag gaaggtaagt attctctgta 2400

tatctttctg tctcttcagc tctgtctctt tttttttttt ctctctctct gccagccttt 2460

ttcccctctc tctcagcttg ttaaggttat ccttaaattg gattctcagt catatcaaaa 2520

gtagaaggac aaatgtataa taacaaggtt tcatctctga tcatatgaat gagtattgca 2580

gagccatgaa tgaaatgtcc ttgtttgcct tttttatttt agcattttgt attatacata 2640

ttttatcatt agacttacaa tgttaacaat gtatatttta aaataaacct tgaattccca 2700

tacctattag taaattgtgt caaaagtctt atgaaacctg tttcgttttc taatgaattt 2760

tctgccagaa ccaataaaga gtctttagtc atttaaaacc ttaagattgg catttcagat 2820

tctgagtagt ttatagctta ttcacaaaaa caaaaagtag ttttttgcct ttcttatagc 2880

aaggctagtt tagactgaac aagacagagt tgtgactctc agaagcagaa ggcgcaggca 2940

tttagcttct agttgttttt ggcattctgc ctggagagga aagaattttc ctgatgtcat 3000

aaaataccag aacaagtttt tagcttaatt gtaaacaata attttgtgcc aagaaaatga 3060

aatctcagaa atacaatttt tgacctaaaa tggccaccta gttagaataa ttactgattt 3120

acttttagat aacattattt atttagaaat tttactatct aggtatagag aaaaacatga 3180

caacttccct ttcctctccc tgccatactt ttgttttttg cattgtgaga tcaaaaacta 3240

gtgagcacag taaaggagga taatttcaga ttatcctttt ctcattctgc attttaaatc 3300

aggtttgtcc atcacttcca tataaacggg gctatgaagt aagactattt taaattgcta 3360

attgataaca caaaaaactt taacttgtac tgttttgggg attttcaact tttaacatca 3420

ggactaagtt attttattat tagtttttct cccaaaatac tggctttcaa atcactgtag 3480

ctatgaaaac ttgttatccc tttgattcct ttattacatt taacatcaaa ttttcctaat 3540

tagaaatata tccttaaaat atagtcaagc agtgactgct tattttgaat gaaacaaatt 3600

aaatgtagac aagcagggtg attgtatata gagggttttt tcctttttgt tttgtttagc 3660

ttttttggtc tatgagttgc ccaaaattga agtttatgtt gcaggttttg gtgtggtgag 3720

gacctacagt gtcaggttct tacaaagtaa atattgaaaa aggcaaatac tgggcagttc 3780

aatcttgcat gatacctatg gccatattac ccaaaatatc atgacttggt ttatctcaaa 3840

agctaagcag gattctgaga tactaccaat aatgtactac tatttctaaa ggagtaattt 3900

tgtaattttg taaagaaatt cacaaacatg gaatgacact gtgaattcct gtgaaaaagc 3960

agatatccac tgctttgtat ttaaaatatt ttgcaacaat t 4001

<210> 4

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 4

acacacacac acacacatat atatatatag agagagagag agagagagag acagagacag 60

agacagagag atccttgtaa aatagtagaa aatgcacctg atttggaagc tcaaaatctg 120

tgttcaaatt tcagttcttg aagttgaata attgatctct tgagctttta gagtgtctgt 180

atgtctgcaa aagaaagata tcatgagaat tatatataag acatgccaag tatatgcata 240

tgttaaatat aatatattgt ataattacat atataattat ataatggaaa taaagatgtt 300

tagaataatt cttgtaatat tagcaggtaa ctaaagaata atgatacttt gacatttttg 360

tctttagcat aattgcaatc atttgagtct gccactatat tttacccatt ttaattctga 420

aacataataa atacttcaca ttcatcaaga ataccagaca tactagataa aaaactatgg 480

ccagcaaaaa agacctttct catatttaaa tggctatgaa tacttggagg tgtgagatct 540

gccataaatt ctaatttcag ttctgtcact tgattcataa tacatgcaat ctatatcaac 600

acataatatc tatatcaatc tactttctac ttcaatattt aaaaatccga agttaaaagt 660

tggccctaaa atgaaagtca tgtttcatat aaccataata ttacctaata gaaaaccatt 720

actaagttga ggcatagaaa tagttgaatt ctgtttcagt cattacagtg ataaattgta 780

aatgcaaacc atttattctg tttttatctg taaaacagaa aagaggacat ctacatatgc 840

tcaaggtcta aaattctgtg gttttataat cttctaattc tattaatttc ctaataaata 900

atttaaaata taaactagtt tcaaaatact tatgtttcaa ataatgcagg aagcattttc 960

agttttctac gttcatcaaa gatgaggctt acctttcttg ggctggcatc atatttcaga 1020

tatggcatgt catattcaac aacttaaaga tggctgggcg tgatggttca cacctgtaat 1080

cccagcactt tgggaagcca aggagggcag atcatgaggt caggagttcg agaccagcct 1140

gatcaacatg gcaaaacccc atcgctacta aaaatacaaa aattagccag gtgtggtggg 1200

gtgtgcctat aatcccagct actcaggagg ctgaggcagg agaatcgctt gaacccaaga 1260

ggtgtaggtt gcagtgagtc gcgatcatgc cactgcactc tagcctgggc aacagagcga 1320

gactccatct caaaaaaaca aaaaacaaac aacaacaaca acaacaaaac ttaaagacta 1380

gaggggttaa aatatggaag gaaattatat gttttaaaga aaaagacaaa ataataaaca 1440

aatgcattta atatctactt tatgagtaga agagaagact ggtctatttt ctagtgaaga 1500

aatggtcact gtgagcaaag cttctttcat tccacattgc ctttcttaag atttgtatca 1560

ttacatgttt gcaatgcact gtaatgtcac agtcattgtt atgaataatt acaaagtgag 1620

atgtgtattt tatgagactg ttacagagaa cgaatcagtg ggggaaatta aaaataaaag 1680

agcctagatg tcttcacagc agaaagtcag ttacctatgc tcctcttcag cttttattat 1740

aaaatgtttt tagtgctcag aacctcagct ttaatgatgt ttatttcttt ctccattttt 1800

cacaatgtga ccaaaaactg caccatcatt aacaaatcat cgattccaca tccccttctc 1860

tgactcactc ttttctattt ttccagcaca cttaatcaaa cttctcaatt ataacactta 1920

ccattgagaa gcttcatgca cttgcccctc tcccataatc ctcagtgtgt tttcagcttt 1980

cttcttttcc tgcttaagtt ccagagacaa tcattaaaat cattttgtta tcaatgtctt 2040

taatttctat gtccctctct ccatcccttc tcgcatgttg gtcaagaccc tactaatttc 2100

ctttgagctt acatcctgcc aattgagggt tgttagataa aatcacatag attggcatta 2160

tatattccta acagtattaa ttgagtagtc aacaatgtcc atcaatctta ctctattttc 2220

atatggtgct aaaatattta tatcaatgac tttttaatgc attttccaca ctaatcaaac 2280

ctctcactcc cttcatcttt tcatcacact ttttagctga tgacctcaat tactattttg 2340

taaaatcttg aagccatcag ataagaactc aactcatctc atcaccaaac tgtaaactta 2400

acctgaacag tcaccaatac tctctttatt cactcttgtt ataatggatg tcagagtttg 2460

gtttcccttc ttctataatc ctagcactct tattgtattt gggatcctat cttactcatt 2520

ttttagtcac atccattgac tatatcttcc ctttctacac attgttgtac gtgagtattc 2580

aaacattctc tggcatctcc catattaaag aaaaataaat ctctccttga atcccaaatt 2640

actttccata tgctataata ttttcttttt catttcaagt caaatttatt gggaagaatc 2700

tttatatatg ctactttatc tcctaagccc atgttgaatc tgaactgact ctccatctgg 2760

cttctacctt tgccattata tcaaaactgc tcctaccaaa gacaccaaaa atatgttctg 2820

cccaccccaa cctttcttga ataattggat aattcctatt caagtctcat attttgtttc 2880

ctcaatgata ccttaataat taattaaatt atgctgtcat agtactctgt atttattctt 2940

cttagcatat atctacatag attataattc aatacttgtt gttgctcaaa ggcacatcac 3000

tctatggtgg tacaattaaa taaaaattct gaccaagaag cattactgag tactgagagt 3060

aacactatca atacatagca aaacttatca aaagaaatct gcttattgca actcctcccc 3120

taaagattca ttcaacagtg tgatggctct aatccctttt tcacttttct ctgcctaaaa 3180

caatctgaat tgtacctcca cctaatcaac tatcctcttc atttcttact caattatctc 3240

gctacctctt tactatatat agaaatctag tctttttcag cagcattaaa aaaatgtctt 3300

ctaagaagga tagagacctt gtatccttct ataaatggga aagggttata aactcttcag 3360

taatgtttaa tttataacct tactacttac ttagtcccta tctttcttag atctcttacc 3420

tataattgag ggagtgaatg agtgaataaa tatttgaaaa agaaattggt aatgacatcg 3480

tgattcactg acaatatgcc aagaaagaag aatgaaaact gttagaatta aatatttgtg 3540

ttattttaag gttttgaaac tctgcccttt cttttagagg tctaagtcat tagatcccaa 3600

tatctttatt taatttttat atggtagaga tctaggaaga acataattga gacatgtcat 3660

ataattactt cctgatttga tgtgccattt taattaattt ggggttaagt tcccatacta 3720

taggataaaa tggtggggtt catgttatct ctttaatttt cccattactc tggggaggag 3780

aagggagagt acttaagctt ttcatattaa agtttctaag ctgataaaaa ttcaaggtta 3840

gcacagattt tgtgtggttc aagtaagaca cacactatct gaggaatatt taggcgatca 3900

aatatatttt tagaactgtc tcagagtttt ttttttctct gacaaaataa tacagtttct 3960

aggaaaccac tgaaagacta ttttttaagt tagcttcatg a 4001

<210> 5

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 5

acaaaaaaca gcaaatcagt gttgtatagg taaacatcgg aatgaagaaa aaggtcacag 60

gaatgaatat gaagaaagaa aagaatagat aggagagcaa agaccagaga gctagtatat 120

gaataatagg ggtccccaga gaggaaagca gaacaaatga agctgaaaca acaaaatcac 180

agcagaatat tttcctatcc tgtaaaaata aattgcagtt ttcagatagt cttgccatgt 240

tttgaagcaa aaatacattt aataacactg agcacttaat atattgctag aaagttatta 300

tatatattgt ttagtacttt gataagaaag agatagcaaa atatagtcct ttccctcaag 360

gggctaaaaa tctattggaa aaagcacata aaaatataat tgtttaatat atggcaaagt 420

cagtgatgga cataatgtag gtttgttgta gcaccaaagc aaggcaaagt attggttaag 480

ggcttaatgt gtctatggga gcaggcatcc aagacaatat gagatgtaaa taatgaatta 540

tgtccaagca ctagatgaag ggagatggaa agcatagcta ttcaagacag caggacaatg 600

tggaggaata tataataata accagataat attctatggg aaaatacaca gtttcttgtt 660

tctggatcaa agaaatccaa ggtgggagtt aagaagctca gggccagaaa agtgggcaaa 720

agtgagtttc aacgactgtg tgtgccatgt tgtgaagtag acactttatt ctgaggtgat 780

agaacatcac tgaagagttt tttgtagggt aaggaaaatt ttcatgtgac atgaagcact 840

gtttacttct cagagggtgt actagagaaa aggagactag ttgaaaggct attgccaaag 900

tctgggtaag aaataacaaa gactcaggat agaagggagt agttacagca gaaaacagga 960

tggatgtgag aaatgttcag ctgtgaaaat agaattaagt aactcatgga taggctgaag 1020

ggtaaaatgg gtaagaaggg ctcagtgatg ccttctgtat ttctagcttg atgactgtgt 1080

tatgaggctg gaacatgatg aacagagaaa taaaatgttg catattaaat ttgtaatcct 1140

ccctaagagg agatgcaaag ttattgtttt attcttaatt ttgataatta cttaaatata 1200

ggtttgactg ccatttaaca aaatctgaaa ctcgtcacta ggagaattac atgtttgtca 1260

acatgccaaa atcccataga aaattattta aaaatatagc ccatgtggtc aaatgctgag 1320

ccagatgaaa gagcaaagtg gcaaaaacaa aacagaaaaa gcacacccag aaagcgtgaa 1380

acaggattac agaatttaat ataggcagag ttttgaaaat aaatgtactt taaacacatt 1440

cattaaaaaa aaaaaactct caaattgggt taacaatata caacttcttg gatattatgg 1500

cagcagcctg gtcatgcctg acttaccttt catcactttc agttaaacac tccaaagtgt 1560

ccagcccgag ataaaagctg acagcaacac agctggttga tgaaaagaga agcccatatt 1620

caaattccag tactaagccc gctggcagga cgtttgatga gatgttccca gaagcacaaa 1680

cttgaccaga gaacagtctt ctctctggaa agaaattgat tgtgaaagtc accttccacc 1740

ttccactacc tggctgtctc ccatcccaca tcctggacac gtttcaatgt actctatctc 1800

agtcaagggc acagcgatct atcccgtttt tatacctggc tcctaacact ttctgtatta 1860

gtctgttatc atgctgctaa taaagacata ccaaacactg ggtaattaat aaaggaaaga 1920

ggtttaattg actcacagtt tagcatggct gtggagacct caggaaactt accaatatgg 1980

tggaaaggga agcaaacatg tccttcttaa caggagtgca ggggaactac cctttataaa 2040

accatcagat ctcgtgagac ttactcactg tcatgagaac agcacaggaa cctcatgatt 2100

ccattacttc ccatcaggtc cctcccacaa cacgtgggga ttatgggagc tacaattcaa 2160

gatgagatct aggtgacgaa ccaaccaaat catatcactg tccctttcct catgcctgct 2220

atccaatctg tcagcagttc tgagtatttt acctccaaac tcttttacat ttgattgctt 2280

ttctttctac caccatcacc atagtccaag ctactttcac tcctgaactt cttaagcaat 2340

tcccccacaa tctatttctt gctctttcat ttataaaggt tttcctggag tgccagagtt 2400

acattacacg tgcatgtcac tctttttggc accatagaga ccaaagtact gaacaagaca 2460

agatccctgg tctgaaagag cctacgtttt agttagattg acagctagtg tctgcttgta 2520

ttacctttca ccaggtaagc tacttgcttt ggggaaaacc aaacaggata aaggctgggt 2580

ccttcgtgaa gaaaagatct tggagaaagt agagtacaga gaccatagcc gaagtcttgg 2640

tagaatatgg ttggcttgaa tggggctatc actgggagtc ctggaaaata caaagcagca 2700

aaaaagcaga aaaaaaaatc actaaaatta cacaaaattt actggtagca agcacaatgc 2760

atcgtataca tattgttttc tttgaaaatt ttgatctaac aacttttgat ctaacactct 2820

ttggaaacta aaaaagcaat actcacacat gtgtaaatat tagatagtta agaatattct 2880

ttgcagcact actgctgcaa gatatggtaa gaaaaggatt agctcagaat atatttgcag 2940

agaagagcca tggaatttga actggacgtg gaatgtgagg gaaagaggac tccttattga 3000

atgaaagaaa ggtgatacta aattggtgga gctatttgtt tgaagtgtga gacttgggga 3060

agaagtctgc tgcacaagtg gaaataattc aatggtattc ttggactttt tttgataata 3120

gagagatact aatattttgt acatatcaac ttttgtagaa agtcttaaaa tgtcttaatc 3180

cactttacac tttattaagt ggagtctaat gaagaaattg agtatttatt ttctgcctga 3240

tgctcttgcg agtcattatc gttgttctga atatcagttg tcactattca ggcctctgac 3300

atgagatatg caagatgaag gagattctag acaaatagaa gaaccacagt gcttgatttc 3360

aaaattttca aagaaaacag tatgtatacg gtgcactgtg cttgctacca gtaaattgtg 3420

taattttagt gatttttatt ctgctttttt gctactttgc attttccagg actcccaatg 3480

atagcaaaat ctgtgggtcc tcaagtccct tgtgtaaaat gatgtggtat ttgcataaac 3540

tatgtcatca tctcatatat tctaagtcat ctcaagatta cttaaaatac ctaatacaat 3600

ttaaatgctg ggtaaatagt tgttatactg tattgtttca ggagtaatga caagaaaaaa 3660

tgtctgcaca tgttcagaca gatacaacca tccatatttc ttctgaatat tttcagttca 3720

caaatcggtt gactccaaat agatgtggaa cccatggata ccaattgact attacagtgt 3780

aataattttg tgtgcttatt cagctataat atgtaaatac atttttcact ttttaagatc 3840

caggtactac ttaaatattc agaatcaaga tatgaaagtg cttcctaaga ctctccttca 3900

gatacccatg tcaggaaatt cagatgttca catttcactg tatattgttc tggggatttt 3960

ccccatgcct tcaaatatgt ctatcatgtc ttcttaagtt t 4001

<210> 6

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 6

acagcaaatc agtgttgtat aggtaaacat cggaatgaag aaaaaggtca caggaatgaa 60

tatgaagaaa gaaaagaata gataggagag caaagaccag agagctagta tatgaataat 120

aggggtcccc agagaggaaa gcagaacaaa tgaagctgaa acaacaaaat cacagcagaa 180

tattttccta tcctgtaaaa ataaattgca gttttcagat agtcttgcca tgttttgaag 240

caaaaataca tttaataaca ctgagcactt aatatattgc tagaaagtta ttatatatat 300

tgtttagtac tttgataaga aagagatagc aaaatatagt cctttccctc aaggggctaa 360

aaatctattg gaaaaagcac ataaaaatat aattgtttaa tatatggcaa agtcagtgat 420

ggacataatg taggtttgtt gtagcaccaa agcaaggcaa agtattggtt aagggcttaa 480

tgtgtctatg ggagcaggca tccaagacaa tatgagatgt aaataatgaa ttatgtccaa 540

gcactagatg aagggagatg gaaagcatag ctattcaaga cagcaggaca atgtggagga 600

atatataata ataaccagat aatattctat gggaaaatac acagtttctt gtttctggat 660

caaagaaatc caaggtggga gttaagaagc tcagggccag aaaagtgggc aaaagtgagt 720

ttcaacgact gtgtgtgcca tgttgtgaag tagacacttt attctgaggt gatagaacat 780

cactgaagag ttttttgtag ggtaaggaaa attttcatgt gacatgaagc actgtttact 840

tctcagaggg tgtactagag aaaaggagac tagttgaaag gctattgcca aagtctgggt 900

aagaaataac aaagactcag gatagaaggg agtagttaca gcagaaaaca ggatggatgt 960

gagaaatgtt cagctgtgaa aatagaatta agtaactcat ggataggctg aagggtaaaa 1020

tgggtaagaa gggctcagtg atgccttctg tatttctagc ttgatgactg tgttatgagg 1080

ctggaacatg atgaacagag aaataaaatg ttgcatatta aatttgtaat cctccctaag 1140

aggagatgca aagttattgt tttattctta attttgataa ttacttaaat ataggtttga 1200

ctgccattta acaaaatctg aaactcgtca ctaggagaat tacatgtttg tcaacatgcc 1260

aaaatcccat agaaaattat ttaaaaatat agcccatgtg gtcaaatgct gagccagatg 1320

aaagagcaaa gtggcaaaaa caaaacagaa aaagcacacc cagaaagcgt gaaacaggat 1380

tacagaattt aatataggca gagttttgaa aataaatgta ctttaaacac attcattaaa 1440

aaaaaaaaac tctcaaattg ggttaacaat atacaacttc ttggatatta tggcagcagc 1500

ctggtcatgc ctgacttacc tttcatcact ttcagttaaa cactccaaag tgtccagccc 1560

gagataaaag ctgacagcaa cacagctggt tgatgaaaag agaagcccat attcaaattc 1620

cagtactaag cccgctggca ggacgtttga tgagatgttc ccagaagcac aaacttgacc 1680

agagaacagt cttctctctg gaaagaaatt gattgtgaaa gtcaccttcc accttccact 1740

acctggctgt ctcccatccc acatcctgga cacgtttcaa tgtactctat ctcagtcaag 1800

ggcacagcga tctatcccgt ttttatacct ggctcctaac actttctgta ttagtctgtt 1860

atcatgctgc taataaagac ataccaaaca ctgggtaatt aataaaggaa agaggtttaa 1920

ttgactcaca gtttagcatg gctgtggaga cctcaggaaa cttaccaata tggtggaaag 1980

ggaagcaaac atgtccttct taacaggagt gcaggggaac taccctttat aaaaccatca 2040

gatctcgtga gacttactca ctgtcatgag aacagcacag gaacctcatg attccattac 2100

ttcccatcag gtccctccca caacacgtgg ggattatggg agctacaatt caagatgaga 2160

tctaggtgac gaaccaacca aatcatatca ctgtcccttt cctcatgcct gctatccaat 2220

ctgtcagcag ttctgagtat tttacctcca aactctttta catttgattg cttttctttc 2280

taccaccatc accatagtcc aagctacttt cactcctgaa cttcttaagc aattccccca 2340

caatctattt cttgctcttt catttataaa ggttttcctg gagtgccaga gttacattac 2400

acgtgcatgt cactcttttt ggcaccatag agaccaaagt actgaacaag acaagatccc 2460

tggtctgaaa gagcctacgt tttagttaga ttgacagcta gtgtctgctt gtattacctt 2520

tcaccaggta agctacttgc tttggggaaa accaaacagg ataaaggctg ggtccttcgt 2580

gaagaaaaga tcttggagaa agtagagtac agagaccata gccgaagtct tggtagaata 2640

tggttggctt gaatggggct atcactggga gtcctggaaa atacaaagca gcaaaaaagc 2700

agaaaaaaaa atcactaaaa ttacacaaaa tttactggta gcaagcacaa tgcatcgtat 2760

acatattgtt ttctttgaaa attttgatct aacaactttt gatctaacac tctttggaaa 2820

ctaaaaaagc aatactcaca catgtgtaaa tattagatag ttaagaatat tctttgcagc 2880

actactgctg caagatatgg taagaaaagg attagctcag aatatatttg cagagaagag 2940

ccatggaatt tgaactggac gtggaatgtg agggaaagag gactccttat tgaatgaaag 3000

aaaggtgata ctaaattggt ggagctattt gtttgaagtg tgagacttgg ggaagaagtc 3060

tgctgcacaa gtggaaataa ttcaatggta ttcttggact ttttttgata atagagagat 3120

actaatattt tgtacatatc aacttttgta gaaagtctta aaatgtctta atccacttta 3180

cactttatta agtggagtct aatgaagaaa ttgagtattt attttctgcc tgatgctctt 3240

gcgagtcatt atcgttgttc tgaatatcag ttgtcactat tcaggcctct gacatgagat 3300

atgcaagatg aaggagattc tagacaaata gaagaaccac agtgcttgat ttcaaaattt 3360

tcaaagaaaa cagtatgtat acggtgcact gtgcttgcta ccagtaaatt gtgtaatttt 3420

agtgattttt attctgcttt tttgctactt tgcattttcc aggactccca atgatagcaa 3480

aatctgtggg tcctcaagtc ccttgtgtaa aatgatgtgg tatttgcata aactatgtca 3540

tcatctcata tattctaagt catctcaaga ttacttaaaa tacctaatac aatttaaatg 3600

ctgggtaaat agttgttata ctgtattgtt tcaggagtaa tgacaagaaa aaatgtctgc 3660

acatgttcag acagatacaa ccatccatat ttcttctgaa tattttcagt tcacaaatcg 3720

gttgactcca aatagatgtg gaacccatgg ataccaattg actattacag tgtaataatt 3780

ttgtgtgctt attcagctat aatatgtaaa tacatttttc actttttaag atccaggtac 3840

tacttaaata ttcagaatca agatatgaaa gtgcttccta agactctcct tcagataccc 3900

atgtcaggaa attcagatgt tcacatttca ctgtatattg ttctggggat tttccccatg 3960

ccttcaaata tgtctatcat gtcttcttaa gtttttctaa a 4001

<210> 7

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 7

acatcggaat gaagaaaaag gtcacaggaa tgaatatgaa gaaagaaaag aatagatagg 60

agagcaaaga ccagagagct agtatatgaa taataggggt ccccagagag gaaagcagaa 120

caaatgaagc tgaaacaaca aaatcacagc agaatatttt cctatcctgt aaaaataaat 180

tgcagttttc agatagtctt gccatgtttt gaagcaaaaa tacatttaat aacactgagc 240

acttaatata ttgctagaaa gttattatat atattgttta gtactttgat aagaaagaga 300

tagcaaaata tagtcctttc cctcaagggg ctaaaaatct attggaaaaa gcacataaaa 360

atataattgt ttaatatatg gcaaagtcag tgatggacat aatgtaggtt tgttgtagca 420

ccaaagcaag gcaaagtatt ggttaagggc ttaatgtgtc tatgggagca ggcatccaag 480

acaatatgag atgtaaataa tgaattatgt ccaagcacta gatgaaggga gatggaaagc 540

atagctattc aagacagcag gacaatgtgg aggaatatat aataataacc agataatatt 600

ctatgggaaa atacacagtt tcttgtttct ggatcaaaga aatccaaggt gggagttaag 660

aagctcaggg ccagaaaagt gggcaaaagt gagtttcaac gactgtgtgt gccatgttgt 720

gaagtagaca ctttattctg aggtgataga acatcactga agagtttttt gtagggtaag 780

gaaaattttc atgtgacatg aagcactgtt tacttctcag agggtgtact agagaaaagg 840

agactagttg aaaggctatt gccaaagtct gggtaagaaa taacaaagac tcaggataga 900

agggagtagt tacagcagaa aacaggatgg atgtgagaaa tgttcagctg tgaaaataga 960

attaagtaac tcatggatag gctgaagggt aaaatgggta agaagggctc agtgatgcct 1020

tctgtatttc tagcttgatg actgtgttat gaggctggaa catgatgaac agagaaataa 1080

aatgttgcat attaaatttg taatcctccc taagaggaga tgcaaagtta ttgttttatt 1140

cttaattttg ataattactt aaatataggt ttgactgcca tttaacaaaa tctgaaactc 1200

gtcactagga gaattacatg tttgtcaaca tgccaaaatc ccatagaaaa ttatttaaaa 1260

atatagccca tgtggtcaaa tgctgagcca gatgaaagag caaagtggca aaaacaaaac 1320

agaaaaagca cacccagaaa gcgtgaaaca ggattacaga atttaatata ggcagagttt 1380

tgaaaataaa tgtactttaa acacattcat taaaaaaaaa aaactctcaa attgggttaa 1440

caatatacaa cttcttggat attatggcag cagcctggtc atgcctgact tacctttcat 1500

cactttcagt taaacactcc aaagtgtcca gcccgagata aaagctgaca gcaacacagc 1560

tggttgatga aaagagaagc ccatattcaa attccagtac taagcccgct ggcaggacgt 1620

ttgatgagat gttcccagaa gcacaaactt gaccagagaa cagtcttctc tctggaaaga 1680

aattgattgt gaaagtcacc ttccaccttc cactacctgg ctgtctccca tcccacatcc 1740

tggacacgtt tcaatgtact ctatctcagt caagggcaca gcgatctatc ccgtttttat 1800

acctggctcc taacactttc tgtattagtc tgttatcatg ctgctaataa agacatacca 1860

aacactgggt aattaataaa ggaaagaggt ttaattgact cacagtttag catggctgtg 1920

gagacctcag gaaacttacc aatatggtgg aaagggaagc aaacatgtcc ttcttaacag 1980

gagtgcaggg gaactaccct ttataaaacc atcagatctc gtgagactta ctcactgtca 2040

tgagaacagc acaggaacct catgattcca ttacttccca tcaggtccct cccacaacac 2100

gtggggatta tgggagctac aattcaagat gagatctagg tgacgaacca accaaatcat 2160

atcactgtcc ctttcctcat gcctgctatc caatctgtca gcagttctga gtattttacc 2220

tccaaactct tttacatttg attgcttttc tttctaccac catcaccata gtccaagcta 2280

ctttcactcc tgaacttctt aagcaattcc cccacaatct atttcttgct ctttcattta 2340

taaaggtttt cctggagtgc cagagttaca ttacacgtgc atgtcactct ttttggcacc 2400

atagagacca aagtactgaa caagacaaga tccctggtct gaaagagcct acgttttagt 2460

tagattgaca gctagtgtct gcttgtatta cctttcacca ggtaagctac ttgctttggg 2520

gaaaaccaaa caggataaag gctgggtcct tcgtgaagaa aagatcttgg agaaagtaga 2580

gtacagagac catagccgaa gtcttggtag aatatggttg gcttgaatgg ggctatcact 2640

gggagtcctg gaaaatacaa agcagcaaaa aagcagaaaa aaaaatcact aaaattacac 2700

aaaatttact ggtagcaagc acaatgcatc gtatacatat tgttttcttt gaaaattttg 2760

atctaacaac ttttgatcta acactctttg gaaactaaaa aagcaatact cacacatgtg 2820

taaatattag atagttaaga atattctttg cagcactact gctgcaagat atggtaagaa 2880

aaggattagc tcagaatata tttgcagaga agagccatgg aatttgaact ggacgtggaa 2940

tgtgagggaa agaggactcc ttattgaatg aaagaaaggt gatactaaat tggtggagct 3000

atttgtttga agtgtgagac ttggggaaga agtctgctgc acaagtggaa ataattcaat 3060

ggtattcttg gacttttttt gataatagag agatactaat attttgtaca tatcaacttt 3120

tgtagaaagt cttaaaatgt cttaatccac tttacacttt attaagtgga gtctaatgaa 3180

gaaattgagt atttattttc tgcctgatgc tcttgcgagt cattatcgtt gttctgaata 3240

tcagttgtca ctattcaggc ctctgacatg agatatgcaa gatgaaggag attctagaca 3300

aatagaagaa ccacagtgct tgatttcaaa attttcaaag aaaacagtat gtatacggtg 3360

cactgtgctt gctaccagta aattgtgtaa ttttagtgat ttttattctg cttttttgct 3420

actttgcatt ttccaggact cccaatgata gcaaaatctg tgggtcctca agtcccttgt 3480

gtaaaatgat gtggtatttg cataaactat gtcatcatct catatattct aagtcatctc 3540

aagattactt aaaataccta atacaattta aatgctgggt aaatagttgt tatactgtat 3600

tgtttcagga gtaatgacaa gaaaaaatgt ctgcacatgt tcagacagat acaaccatcc 3660

atatttcttc tgaatatttt cagttcacaa atcggttgac tccaaataga tgtggaaccc 3720

atggatacca attgactatt acagtgtaat aattttgtgt gcttattcag ctataatatg 3780

taaatacatt tttcactttt taagatccag gtactactta aatattcaga atcaagatat 3840

gaaagtgctt cctaagactc tccttcagat acccatgtca ggaaattcag atgttcacat 3900

ttcactgtat attgttctgg ggattttccc catgccttca aatatgtcta tcatgtcttc 3960

ttaagttttt ctaaatatct gtatctacac aaatatatat c 4001

<210> 8

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 8

agcgagtccc aactatacaa atcacagaaa aacaagacac agaaagtgtc actaaatcaa 60

gaactttaaa ataaatgttt tttttatccc tgactataat catttaccat aggcctcaag 120

gaaaaaaaaa atgctaccat gaaacctaat gtttccgtga aagcacagga aattagttat 180

tctgtcttta aaataaaaca aaattaatgt atatttttct aatgaatttg ataaagtgaa 240

ccctaagttg agtgtggcat tcaccaaaac tataagaaaa aaccccgttt actataagat 300

ggcaaaatat gggtcttagt tcaagctaac acttttaaag tagcctttct ttcacaactt 360

aaaaaaatgt tgttaataaa aaatggccct cactttgaat ctgaagtatt ttttaatgtc 420

accaagtgct attattaaat gtgtactata tatgcatgta tacacacata aaaataagca 480

ctacagatgt gggcatgaaa attcttagca aaacccccac atatttcaaa tactgttctt 540

cttcattatt gtcctctacc ataattagca cgttacagca taacaggtgg ctttcattta 600

tagaatgcaa aattaatgaa atttagagat ggtcttgtct ccaaaaacaa attggccatt 660

ctataaaaag tacacccctt aatctacaaa acaaacagaa acaaactccc ttcatgctgg 720

ttttccaaat tataggaatt tctgaatgta gttaagtaaa ttgaatgcat ttactgacag 780

cttaaaattc atacacttca aggaaaacaa gtcattatta tggattttat aagaaagggg 840

aagagaaaca aagattgccg atttttccag cttggtaacc ccagatctgt ttaatgctct 900

ctgagtgata acaggattta ctgctataca ctgggctgct ccacaaatgc taaatcttag 960

gcaaatttgt gggcagttgt gttataggtc ctgacctagc cattctggac agacagacca 1020

ggaaagcata aatagtactg ctataaacta actatagcat ctgtccctaa caagcaagac 1080

tcacaaagta tttttttaaa atatgaggag acactgaata gactgtcaac acacatagga 1140

atgtttaata cactcaaata aataagatat gtgctttaac tagtcagaca ttgtttaaat 1200

ttagtgggtg aagaaagaga gagggtcaga caggcagaca cagcctccca attatgcaga 1260

atgatccttc agatcatgtg aacgctataa ttaaatgttg ctaccaaatc cccactaccc 1320

tttctcccac ctagaaaaag ttaatgcatg aattcagtat gagcaaattg tgatttataa 1380

aaacaaacaa acaaacaaac aaacaaaacc caccctattc actccgtagg ggaataaagc 1440

tttcttgcat taagtcacgc atcatggggg taggaaaaaa gcacagtact gaaagaaatc 1500

caacgtaaca caatagtaat tgttagacca cctccttcag ctcacctctg cttattcatt 1560

tgttttaaag ctctacacta cccacccaag aggtatacca tctctgcaag ctgtttccta 1620

ggcagcatct tttagattca ggacttaata ataaaaaaca acaacaacaa caacaaaaca 1680

tttctatcag aatatctaag gagaaatttg ttttcagaaa gaggcatgag aggctaagag 1740

ctctgtgtct atcaacagac cagaggttac ctatctgtcc ttgcacgtgg gcacacacaa 1800

atacaaacac atacacactg tggtcctcta caactaggat aaattttctc ctttaaaaaa 1860

atgctaaaag caggcaccag aaaggttaag aataagagaa caatgaaaaa ataaagttca 1920

tgtaaacagt aagcacgtac ctgccaggcg atgccatttc ctctacattg tggagcccga 1980

gtgctgggta ttagcattat tgctactata aagcttccga taaaaatgga tcgtctcttg 2040

ctgacctgag aaccagctgg ctgcctgaga agtggtttcc cccatatatg attcagtctc 2100

cttgacaaat atactgcatt gtaccggatg agtcatccga gggttagtcc gcattttata 2160

ggcctgttgt gtcattactc acattcaaca tcctgcttct caaaagtgga aactggaagc 2220

ctgacagctg acagatgcgt tttccaatta aaatattgtt ttaaaaattc ctgtaagtta 2280

tgattaccaa tcattgatga aaggatgaaa tgcccaggaa gcaaatggca cagttcaata 2340

cctgagatta cattctggag aaccacaagt gcaaattctt cacctgcccc cagccccaaa 2400

ccaaagaatt tcgtccaaag ttgagagcaa ggatccctct ctttaaagtt atcagctgaa 2460

ttcgtgtagg catggacttg ttgattcttg tgctgtgagg ttacccagct gcagaagcta 2520

tgtaaaaagt atacatcaaa attttggtcc tggattaatt ttataggtgg gatagtggca 2580

ttgtgtttat aaaatgtcta cttttttaga gaggcatgtt gaagtatgtt aggggtaaaa 2640

tgatatgata tctggggttt gttgtgaata ttttagcaaa aaataaataa gggacggggt 2700

aaagaaatgt ggcaaaatct tgataaatgg ttgcatctgt gtagtgcgta tatgcaggct 2760

gactgtattt ctcttttttg aagtatcttt gaaaattttc ataataaaat gtttttaaaa 2820

attaaaaaaa attttttttt cagtccctgc aatctaattt atacctaaac aaggcacttt 2880

tctagttagg tatagagcta ccacacatgt gagtgtggga gctgaacttg aagttgtttc 2940

tgccttccag ctgggaggta tgatacatgt atcctgcggc tgttgtgagt gttgcatcaa 3000

cctcctgaac aaacgcctag tgccttctcc tcccagggcg atctggtgat tgtttcctta 3060

tgcattctct gaggacacaa gccctggctt catggctcag tgttaacgtt atgaaggaga 3120

ggtgactata cccagcttcc ttacaaggtt ttggaaatgc tccatgagag gttatgtaag 3180

tcacatccat agtctcttaa accagcaggc cctttggtaa tgtggcacag ggtttgcttg 3240

actcacttaa tgttcaaatt gggtgtctta aaccatctgg aggaggaaga gctttgattt 3300

agtggctgac aaaaaaaaaa tccagatatg gaagctccaa tgtatgtgaa ataaaaccac 3360

tgttgaaact ggctgtcact ttaaaaacta tccatattga tgcgctgtga aaacatgaca 3420

agtcaccaca ggaaacaaaa tagaggggtc actaaagccc agagctcctg catggccccc 3480

ttagtcctga aacttaaaaa tggaagcatg tttcaggctg aggttcacac ctcagcaaac 3540

agctgactct aattcttaaa ggaccctgtc taataggact tcaaactggc tccaaatggt 3600

tgggacagtc ccatccaaca tcaaattaca acctcactaa tccagactga ttaggattgt 3660

gcatgggcct caactgaaga cttccttggc tttgacaatt ctttcctcct cacgaggact 3720

gcaggctgca gccttatcaa aatgtttcct tgaaatttta taacttttca cacacttgaa 3780

aagcataatt taccttaatg cagcaggtag aaatggggga aattaataaa cttgtagtct 3840

aatttgagtt tctatagtat tttggagaaa taagttcaca gttcattgaa gaattttata 3900

attcagattt cagtaatgaa aaatacaaaa ataatagcaa taataatgtg tgcacacatg 3960

cacaaacaat gagaataagg caaagatagt aaaatggtaa c 4001

<210> 9

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 9

ggtctggttc aaagcaaaga tgacctaaaa gaaaggtctc ttttaagttc actaacaagg 60

caactgtttg ctgccatctt atttcttttg tccatggctg gaaatacctt cacctttgtg 120

ctcgttatgt aaggacgtgg atagtgctac ttaaaaaagg gaacacaaat ccctggacag 180

catccaaaga aaaggagaac agtccttccc aaatcagccc caatcagaca cacctaggga 240

actgccttat ggaggacaca gacaacctgg aactcttcca tgagtgtgac caagaggtga 300

gggaacccaa gagctggctt gtgaggaata gaagctagga ggtggggcag cgagagggct 360

ggggactcac agacacacct accagtgggt cccaattatg taaaggactg ggcagaaacc 420

agtgcattat ccacatcttt tctaaccatc aatgcagcat tcccagctaa tggcgtcatt 480

agatccatgg gatattaagg gaagttaatg tgaaaaaatg ggaaatgaag gctaaagaaa 540

attaaacacc agcctggcca acatggtgaa acatgtctct actaaaaata caaaaattag 600

ctgggcatgg tggcatgtgc ctctagtccc agctacttgg gaggctaagg ctagagaatc 660

gtttgaaccc aggagacaga ggttgcagta agccaagatt gtgccattgt actccaggct 720

ggatgacagt gagactctgt ctcaaaaaaa aaaaaaagaa aagaaaagaa aattaaacag 780

gttttaattt tacagaactt ctcagagtct ttaatatact aatgtgcgat gtgggtctcc 840

ttgatgggga acagagtatg ccaggtttcc caaacatatt tgaggcatac atcacaagag 900

aaagctttgt tgaaacatat tttgggaaaa tccagattca agatcctgat gccaggaacc 960

ctatctctcc agctctgacc cagatctcca gtgtccagga gaattcattt tacaaagcag 1020

ggaattctcc tgggcactgg agagctgggt cagaggtggg gaggtagggt tcctggtatc 1080

aggtgggtag tggggctggc caccccctac gaggctccag acaacactta caacccgtgg 1140

aattttctct ctcactttcc ccaggtacag atgcagctct atagcctctg acagctcccc 1200

tttcttgtgc ttccccagta atcagcatac aggatgctgc ctttgctgga atatctcctc 1260

actctttgct gcaatacaga caggcttggt ccatctgtgt tgcagcaaag actgactatg 1320

aggtctttag caagatgttt caactctcca gagacaacgc attagaggtc ttaagtcagc 1380

aaatgaccct acccagcccc aacccctttc tcctttcaca tgttctcctc attctgagtg 1440

gtgaggagac aaggcttcct ggtttgcctc ccatgggcca aggtggcaca ggcccactgc 1500

gtaccccttg tctcagtcca tttgtgctgc tacaacaaaa tgcctgagac tgggtaattt 1560

atgaggaaca gaaatatatt tctcaccatt ctggaggctg ggaagtccga gatcaaggca 1620

ctggcctttg gtctggtgag ggccttcttg ctgcatcctc acatggaaga agacagaagg 1680

gcaagctaac tgaatggctg catgacacct cttttattag ggccttaatc ccataaaggc 1740

cttataaaga ggagtcttaa tcccaaaaag gtccttataa agaggagcct tcatggctta 1800

atcacctcct aaaggcctca ccttttaata ccatcacact agcaacatct gaattttgga 1860

ggggacacat tcaaaccaca gcatccctcc ttccacatag tttacctccc tcagttactc 1920

taatatttcc tgtgcctgtg atgcaacctt aaccaaagga gacagatctc tctgtaaaac 1980

ccctccatcc tctcttctct caatacctcc tccttttctc tggcagaggc acctccagtc 2040

tctctggaag gcgtctcccc aaggttctgc acaatagcct cttctgtctt ggtaccctct 2100

agaccatact gtgttcccat ccttcccatc cctctattgg tcacaagcca gagcaggtaa 2160

caaatctgct tggtcatgcg gtgatttggt ttggctgtgt tcccacccaa atctcatctt 2220

gaattgtagc tcctagaatt cccacgtgtt gtgagaggga cccagtggga ggtaattgaa 2280

tcatggaggt aggtctttcc catgccgttc tcgtgatagt gaataagtct cgtggttcta 2340

taaaggggag ttcccctgca cacgctctct tgccttccac catgtaagac acgcctttcc 2400

tcctccttca ccttccgcca tgattgtgag gcctccccag gcaagtggaa ctgtgagtcc 2460

attaaacccc tttcctttac agattaccca gtcttgggta tgtcttcatt agcagtgtga 2520

gaacagactg gtacatgtgg gatcacagcc ttgccagaaa agcagataca cccgggtgct 2580

tgtctgcaaa ctgatctaaa tgagacaact cagccttcca caggtataag cccctgcatt 2640

ctaaagccat acaattaggg cctacccaca acaactggga attgccaact gacttcagat 2700

cagctggagg aacaaacctt caaaggtttg ggagggaaga gagaggggca ttatgaaaca 2760

cctatcaggt atgcctggcc ccaggcccaa gtcccacata ttctgtctcc atctaactca 2820

tccaagccaa atcctcagtc tgactggctc acaaatacct gctgatgagc tttgctattc 2880

tcttaaaggc attgagcaca agcccaggtt acctggtgct taaatacctt cctcaaagag 2940

tgtccattaa ttttgaaaca tttttctttc ttaaggtttt cttggtattt ggagaagatt 3000

gagttaccca ttgtaacaga catgtcagtc tgcaaactgg ggcagactgt gtatgggcca 3060

catcacagat taaataagaa ctttaggcca ggcgcggtgg ctcacacctg tgatcccagc 3120

actttgggag gccgatgcag gtggatccct tgaggtcagg agttcaagac cagcctggcc 3180

aacatggtaa aaccctgtct ctactaaaaa tacaaaaatt agccaggcat ggtggcaggt 3240

gcctgtaatc ccagctactt gggaggctga agcacgagaa tcgcttttaa cctgggaggc 3300

agaggttgca gtgagctgag attgtgccac tgcactccag cctgggcaac agagcaagat 3360

tccttctcaa aaaataaata aataaaatga ctactggaga gttttgtgca ttataatgat 3420

ttaagatatc aggtactccc ctactgagaa ttacacacaa tccctggtgg aagatggaca 3480

ttaggacagt gacctggcta atggtgttca tcagtgacag gtttctggcc ctgtggtcct 3540

caaggaccag aaggcctggg aacagcaaag ttgggggaga caagggcggg ggaagaaggg 3600

tagcaaaatg ccaactgtga tcctgagtta ctctaggatt ctggaaactg agtggttgat 3660

agactgaaca tcaagaatgg aagggcataa gggatgatga agggtatcat gagagttcat 3720

tctgtgtcaa ctaatcaagg acagaatcaa ggcaagtcac agtactaaat gatcctaaat 3780

ttcaatcatt catcccttct attcattaat tcagtcaata aatagttatt atatgcccac 3840

tgttccaagc actgaagata cagtcatgaa caagacaaga tccttgcctt taatggagct 3900

ttcattttac ctgaaaaagg gggcattttt caagaaaaat cttgaaaaga tgggtggaaa 3960

ggaggtctag tgtatcatag aagcttctgg gaggagaagg a 4001

<210> 10

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 10

agaaggaata gaaaaagtgt ttattgaata tatttgccaa gcacataatc accaaaaaga 60

ctgatttgca agcccttgtt tggtattatc tacttgtctc aaactagggt cagcgtctgg 120

ctttagttac taggtaataa gtttgggact tttaatcaac agtgaaaaag gcaatgtcat 180

acattaggaa atatgttgta tttgagaaag caacattttg tctctagacc taaattttct 240

tatctgagaa atataggaag agaggtcatg ttttctagca tacaaatgtg cctcccatat 300

ttacatagtt ttgaacaaat agaaagaata agcagaaact cggaggtttc agaggctaag 360

cagatagggt gttccagccc tctactaata tttttctaat gtttcactgt aaatgttgag 420

cggcacttgg aaatttccca agtctcaaag ctgttgttct cttgctttct cctcccattg 480

gatggaaata tgatgtttga gcttaatgtc aagaacatgg gtcatgagaa aactaacagg 540

tggcttcaaa ttctttttac aagtcttaat tatggaaaca gatttattac aaagtagaat 600

acctaatgtt ttgggtctaa aacttcagga tattagacct ctcatccaga ggtcctattt 660

ccacaatact tgctaaactc tgagaatttt ccaaaatggt ttaaaacagc ccaagaagaa 720

ggtttgcatt acagaaaagg gaatttatgc agtagaatat aatggaaatt tacacagtca 780

tttgagcctg agtcaaagtc tttaatatca agtcaatctc agaaaaacta aagtcactcg 840

tggaatccct tttatttgct ttgttcattc cacaccttta tttaacctgg catgctcttt 900

tgatattgcc aaaattcaga actctattta aatggcattc tattcttttt ttttcctttt 960

ttttaagatg gagtctcact cttgtcaccc aggttggagt gcagtggcac aatctcagct 1020

cactgcaacc tctgcctccc agattgaagc gattcttctg cctcagcctc ctgagtagct 1080

ggtattatag gcgcccgcca ccatggggtt tcaccatgtt ggccaggctg gtctcaggtg 1140

atccacctgc atcggcctcc caaagtgctg ggattacagg agtgagccac tgcacccggc 1200

tggcattcta ttcttttcat ggatcctttc ttggcccctt ttaataaaaa atatgtatct 1260

ctgcttcact cctgttgcac tttatttaca cctcatcttc tggcatttgc cccaagttat 1320

aagaagccat cctatacatg ctcatgatgt tttcttagtc ataagcacaa gtaagacagg 1380

gaatattagc atgatgcttg agacatgcta aggtttcagt tgctgagtga gataggaaat 1440

ctgtgttgaa tctatttctc tgtatcacat cacctactta tggtcactga ggaaatgaag 1500

ctttactgaa actggctttc atatccataa gtaaaaatat atttttggtt atataatcta 1560

tacaatttat atttgcataa ctgagggctt taaaaaacac aatcattgca accactaata 1620

atttttttaa ttaaaggtat tttgtgtgta ctttataaaa atccaagcta tcgactattt 1680

tgctgtaaaa aatataggct tttatcatac aagtgacttc taaaaaataa tatttaatgc 1740

taaatatata aaagggagaa taagaaagag ataactgttt ttggaaaaag taaatagttt 1800

gcttttctcg gggtgagatt catattatca gtacacttga agataactaa cttaaaatat 1860

atagtttaaa agaaactcaa gtttgtactc accgattttc aaaacataac acgcattcat 1920

tgggataagt atttccatca gtcccacaga cagggtcata tatcttggtg catccattaa 1980

gttcattgta acatttggcc taaaaatgga attaaacaga atcatttccc attattctcc 2040

attcttgagt tcatagcaaa atctctgaaa tggttttatt tctctgggga ataactgtga 2100

ttgggagaat gatactgtgt gttgtaagag aaataaccta ctatctggag acagaaaacc 2160

ttgttttaag tcatgcctct gctatttcta agctgtgtga cattagtaag tcctatggcc 2220

cttctgaaac tcagtcagtt catctgcaaa acagtgatga tattaccatt tcccacctat 2280

ctcatagtgt tgttgtgaga tttacatgga tgggtgagat aatgttcaag tttgcaatta 2340

ctgcgggtgc tggcatctct caggttggcc acatcttggg gcacgttctt ccttgtacac 2400

tgtagtccac acacactggt cttctattag gcacttaaag gcactaggca ttgtcgggtg 2460

ttggaagtct ttgcattcta ctccagtaag agtttataat catcaaatga ttgtcattgt 2520

cctagacatt gttctagtgc tttttatata ttattctgtt taaacctcct aactatcctg 2580

tgaactaagt attatattct tcttcaggtg aagataatga ggcacaaagc aataaaatta 2640

gccaaggcca cccagctaag gaattcctaa attcagaatt caaacctagt cagagttcct 2700

gagctttagc tcttaagtac tttattctac tacatctccc caccagtttt gttttactaa 2760

cactcatttt ttttttttgg ctcaaaataa cccctcagtt acttcggagc accctccctg 2820

atttttctaa ctaggctaag ttcctaacgg cagcagaact ttttcataac acttatcaca 2880

aatgtaatat tgcattcatt catgaacttt tggtctatca gctgtctctg actagatata 2940

aatgtactga gaacagggac acttcttcct ctggtctcca aatttactga aattacctct 3000

taaacaaaaa aatatgaaaa ggttagagtt agaatatttt tctagaagga gaacctagtt 3060

tattattttc tgtcattcat tataaattag agccacacct tggtgattgg gagagctgca 3120

tgccaacatg gtcaaactgg ctgtaaggag gaagggctac ttggagtgaa gttgagaagg 3180

cttccacccc aaatacttgt ctacagctat cactagtcta tataaaaacc ccttcacagc 3240

aagcactgta ggactatatg gaacttgctt atacatcagt gaaattgtcc ttcaatatac 3300

gcctgtgggt tggaactact actaccattt gcatttctca cgttaaccct ccctagcatt 3360

catactcctc ttaacttcag gctaaactga aaggtgacag caaggctgca tttttgttgg 3420

atcaaactgt tccagtctga gaaataagaa attacaaata tctctttacc tctcttccca 3480

gggagtcagc tccagtgtta cctagaaata aatcagatat ggtaagttgg gtcctaaatg 3540

aaagaagtca gatctattct tcatcagaat tctctgcttt cattgcagac tgtgacttct 3600

ttactaggct ctttcattcc ccaccctttc tgatttctct aatcttccaa aagtatctga 3660

ctgattttcc tgtacccctt ccttggcaaa accttaaaaa gtttgagtaa aactttgatt 3720

atgaccaaag tatctcgatt tgatgtttta ggaagttgat ctatttcctt gaaaacagaa 3780

attatgcact tactgctgga aatgaatcag gcactgagca aattatcttt tgaatactca 3840

caaacattct caaaaccagt tactagatct ttaatctcac aattagtgaa gtataatttt 3900

tatctcagtt tacagatgaa agtatggaga gtttttataa ctagctgtga aacagttatc 3960

ataagcagta accaggtctt ctgatgcaaa gttagctttt t 4001

<210> 11

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 11

acagacaagg caaatacatc aaaatcttaa catttatccc tggcactggg actgattttt 60

gcttttgtct ttatccctta gttatgttaa catataatag gtttgtatta ttaagtgaat 120

atttttaaaa tgtcttagtt ttaatttctc atatagcaaa catcaataga cataacccac 180

ataaacaaaa cctctttgga gttctatttg taaggatgtc tgagaccaaa aggtttaagg 240

aatgctggct tagagagttg aaatctaaac caaggccgtc aatcccagcc cctgtaaaat 300

accagacaaa aacaatccag agaaagtgaa aaaatcataa caaaatgata aaaacatatt 360

aaacattaaa caaccataaa gatggcacct ggtggtccct agcagcctct ccaggctcat 420

ggaaatgagt cacattcagg agccaagacc tccaacccaa ggtctggagg ccatttctga 480

acctcagact ccaaaagaag tttgggcaca ctggttttaa caataagttt ttatatttct 540

ttttcctgtc tgttgaaaac acattcaagt tgcctcaaga ggtgaaagga agccagaggt 600

agcctccaac catcctcaac gctgtctttc aggagaggcc gcgtccctct ctgtctccct 660

ctcagaggag tggcccaagc gcagcatgcc acagctgttc aacatggaca gcatgctttg 720

gctctttccc tgctaaaact gaagctaaga gttcacagac ctataaaata cttagacttt 780

gatagaccaa aacctgcaag tatgctcaag aggatataaa taaccaagtt tacaatcctt 840

attttttggt tcctgttatc tcccccatct acctctgaat tcagcaaact cttgacactc 900

actcataact gaggtccagg aaggaagaga aaagtcacca tcctatggta tttagggaca 960

gagcgggtgt cagcatctcc acttcccagg gctctgaccc atgatgtggc ccagggctca 1020

cgctgctgaa tgctaggtaa ggagcagtcc tgactaacag ctgttatttt attagttgaa 1080

aaacaagaag gccctgaaaa tcccccctct tcccggttac ttggttaagg gtccatgttc 1140

tttgttcatt catacttgga gtctcactct gttgcccagg ctggagtgca gtggtgtgat 1200

ctcggctcac tgcaacctcc acctcctggt tcaagcgatt ctcaggcttc agcctcacga 1260

gtagctggga ttacagatgc gtgccaccac acctggctac tttttttgta tttttagtag 1320

agatggggtt ttgccatatt ggctgggctg ggttggccag gctggtctcg aactcctgac 1380

ctcaagtgat ccgcccacct tggccgccca aagtgctggg attataggcg tgagctactg 1440

cgcgcagcct ggttcattta tacttgacat aaatccaaaa gaaggccacc cctgcacgat 1500

ctccaagagc ctctgtggaa agctctagtt taaccctagg aaggagaaca gctcacctct 1560

ggcatgatct cgatcttctc gtaccgacgt ttgaagggca gggcgagaac ctcagcccgc 1620

cgataggaca tggcgggggg ctggcagtcg atcatgaggt ccatcctgtg ggactgggct 1680

gggggcggct gagtgtactg ctcaggacac accacgtgca ggggctgagg aaccaatggg 1740

acagttgaga aaggtggtgt gaagtacagt ggcccctgtg gaaggcccat tcctgacccc 1800

gatccactcc ccgccattac aggctcacca cttccaggcc aaggtgaact ttcatcctct 1860

caagcccaat gaaccgtaga caggagaggg aacgtgaagg cactggggca gaagaaacat 1920

ctcggaaacc cctaaactgc ctcagcttaa tttatctttc ttactcttta cataagtttc 1980

acggtaactt ccatgtgtct gctcccagcg gtctctgggc ttcctcgggg cacggtcttt 2040

ctctaacatt cccacatgcc tgctattata agctcttggc tgattaccaa gagctgtggc 2100

ttttcgtgcc gggctggcgc tgtgggtttg gagtttccgc tggatctgca ggtcagctgg 2160

tattaggcag tgggcactcc tcagctcatg tgctcaccat gtgcaaccaa ggagcagagg 2220

cagagttttt tttttttgtt ttttttttta aacaaaatgt ctctttttgt tatcttgaga 2280

aaaaaagatt agtaaaccaa tttttacttt gcacaaatat cacccaaatg aaaaggaatg 2340

ctggcagccc acaggggcac tgtgttgtcc ctgcttctac ttaagagctt ggaccaagcc 2400

ctgaattccc tgctgaagac ggctttccac caggctgacc gggctgagct tccaaaagca 2460

cttgttcctt agggctaata cttttctcct ccaaactgcc ctttgctcct cctcttgacc 2520

tgtctcaaag catctcatgc cacaggtgca gtctgatggc ttctcccagg ttttcctcac 2580

ctaaagtgga gaccaggtgg cctccagttt ccaggattag cacctgacag aggggcgtca 2640

agagctggtt tagggactgg gatttgaagt taataatgaa aagcaacacg cctttcactg 2700

ctgcttctaa cgtggatgag catacattgg ggtagcgaat cactgtagac aggccccacg 2760

tttgctgtct gctctcatca tacctagaga gtgccagtat tctttcttca ttgggcaagc 2820

acattaataa tcaccagaat ccgctcttgg ggccctcctg gggttctccg gctttctctg 2880

tttcctgttc ccctgcctta gagttttgtg aaagggcctc tctcatcctg aggttgaagg 2940

tgctgtgctg ggcccctcca ccctcatctc actcctggga acaccaggga gtggaaaggg 3000

agagctcttc ctcgccggtg tcagctgtcc tccttgccaa ttccagttcc tctcccgact 3060

ctcaagagcc agaaacccag cgagcagtgg ctgagccagc acagtggttc cgtggccctg 3120

ccttcctgct acgcgcgcct cctggtctac actgcacccc agctacttct tccctttctc 3180

cagggcagaa aatgtgaagt gaaacaaatg accaaaaact gccacaaaac ccaaacccga 3240

cagcactgtt tgtggtacca gcctacacgt gcgacacggc cccagtaacg cgtttcattt 3300

aaactgtctc agcttagtga gtatgtttct agaatgactt tttttttttt tggcaggggt 3360

gagagggttt gcttttaagc ggacacagat ggttttcttt cccttccaca tctgatttct 3420

ttagaatgga aactgcggtc agggtgtaaa gaccactcct tttcagtgtg gaggggggct 3480

ggcatgtgtc ccagcattct gcagatgcgt gagaactgaa gacaagaatc aaacacagct 3540

agatctctct cccctcaccc cacacaagca tgagccacac caaggtgaca tgactacgtg 3600

aaggcacaag cagtgtcctt cattacctgc acttctttaa gcagctttga cacctggatg 3660

aagttcagcc gggtgtcgat ggggcagtag atgcatttca tggccagcgg ctggtaagga 3720

gccagggctt ccaggtagga gaagtctggt tctagggaaa gtacaagaaa gaaatcttac 3780

aatgcagact acacaggagc tgccaagcca gacagcaact ggggcgctga gggcccacag 3840

acagtcaggg ggtcaggagg gagccaggaa gcacacgtgg gggacggagg tcaaaggggc 3900

cccgtggaag gaggggcagg ctgggatgga ccctgtgggt gggctccaag cttcagcaga 3960

ggcagatgag gtaaatgagg gagaaataca tatgtggggg a 4001

<210> 12

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 12

aaatgtactc cttcttataa gtctccactc tcaaatgact tgtttctgtt ccttttttct 60

cttttaaatg tgtatctggt agaatgagca tttagaagca taatacatgt atacactttg 120

tgtttaattt tctatggcat aagtaagcag tttttatgaa ttgctggtat tgcttatgag 180

caattattac aaacattgag agaagggaac ccctgtgaac ctttaacatt tctcaggagt 240

tagtggtaaa cccatgaaca tgtattttta aaccaaatta cccacctctt ggagttcaat 300

ctctgttaat tctttattaa agtagtgaag tatcagttgt tccaatgata taatgatcaa 360

gcaaccctgg aaattaaatc ccaaagcagt gcacctttag tttgttcagt gatagtagga 420

catcccacga gccatcatat attttcaagt ttttatactc aatctacttt ttcagcaatc 480

ttttgggaac tatcccaaga taatttactg cataagtgca tctatcttct aaaagacatt 540

tggaatattt cttagtctga cctctgcacc ctgagacact ctataaagga aacaatcaga 600

aaaatttaac aaagaaataa ataggttaag aagaaagcaa tctaggcgtt tgcactgagt 660

ttgcaacagt gccattgcta catttaagag ctgtagttct tcctcacatt ttaactgaga 720

gccactagtt atgttactta aaatctcccc attaaataag acagttgctg aacaactaaa 780

aagtacaaaa tatcacaaaa tcaaaaagta gcaagtcata aggggatttc cgcatcctag 840

catgtgtgtg tgtgtgtgtg tgtgtgtgtg tgaaagaaaa cgttacagtt aaccgttaca 900

attgctctca ctccactcca ccacctcatc ctgtgtagtc tgcctgcgga acccgcggga 960

atctctcctc agtgtagtaa gagcaaaggc cagcatcctg tgcaaaggtg ctctgcagcg 1020

tcgtgatcca gggattttag catctgtcgt cgcttgcaca tcctctctta cccctctgct 1080

atctggtgga gttgggcgag ggtctccagg gcttccagag agtgtcgttt acgcatgtga 1140

cttgccatgc gctcaaacta aagcgccgcc ggggacttac tgaagcccac ctcggccctc 1200

ctccactttg tcctcagtct tcaggttttc ctttctgccg ctagggccta agttgtgggt 1260

tcaccataac tcctcagcag acattggagt gaacgcatcg actgccgtca cccaagtgct 1320

aatcactgcc ttctcccact cagcgctgga gtgggagatt catccatcgg aagattcgta 1380

gccaccaggt ccagtcaagg atttcatatg cactttccct cagaaaaccc tgaaaagcaa 1440

acgacccctg gaatgtcaca cactcctaaa tatccctgga aatccgcttc tctgtgtttc 1500

gcttcatggt gagtgtcgag ggccagataa gacaaagaaa aaaatgtatg gaaggttatt 1560

cccggtcggc tcctccttcc tgtgagtctc agacaggctt gcaggcttac aggctttccg 1620

ccgctccccg ttggcagcct tcatcgaatt aggtgggtgg gggtgggaaa ttgggtaaga 1680

aaataaagtc gttgtgggcg gctggggaac ctggcgtcag tcccccgtgg ctgtgcgcag 1740

gtaccctgca acgtcgcggt ggccccgctc ctcggccaag tccacgggca gacgacccca 1800

ggcatcgcgc acgtccagcc gcgccccggc ccggtgcagc accaccagcg tgtccaggaa 1860

gccctcccgg gcagcatcat gcaccggtcg ggtgagagtg gcagggtctg cgcagttggg 1920

ctccgcgccg tggagcagca gcagctccgc cacgcgggcg ctgcccatca tcatgacctg 1980

ccagagagag cagagtggtc agagccaggg tgggggcagg tatgggagat gccggccggg 2040

gcaaggcagg tggagccatt taaagaaaca cctaattgca aagttttcac ccagtgcaga 2100

ggtgttcagg tctctgatgt ctggtgtttc ttcatttgct gatgcaatcc actttcccac 2160

cccaccttca ggttatactc agtacaaatt aaatgccatt ttattctcta aacgtgcaga 2220

gacaagaaag ttgatggtaa agtgatgatc atcattatgg aaaaacaaat cttgatttcc 2280

attggaacat gggaatctat tttgttaaat gatttagggg cagagttaaa tttattcggc 2340

ttttaaagtt ttaaattatt tgccttgctg acccctcctc cataatccag gtctacaaat 2400

atttattagg tagtcaacta ctgtttgtta gaagttggga gtaatggttt aggggagaaa 2460

ataaacaact aagttttttt ctttcttttt tttttaattt atttagttct catagcaaat 2520

cccgtgcgga aggcttttgt ttgtcatgtg tctgagctca taactggctt gtagtgtgat 2580

aatttgagcc aaagttggag attagaaggg aaaagtaaat taaatcatgc aaaatcttat 2640

aaaattataa taaatgattt ttccttaaca gttcatcatt ttaaatttag actataatat 2700

ttttaatgta atataaaact aactatattt gtatactaca ggattttata atagctaaga 2760

tttaaaaatg ttaaacagta aatattttgc tatataaaaa gagcttgggc caggcccagt 2820

ggcttatgcc tgtaatccca gcactttggg aggccatagc aggcagatca cctgaggtca 2880

ggagttcgag accagcctgg ccaacatggt gaaatcccgt ctctactaca aaaaataaaa 2940

aattagctgg gcatggtggg gcgtgcctgt agtcccagca actcaggagg ctgaggcagg 3000

agaatcgctt gcatcctgga agaggttgca gtgagctgag attgtgccac tgcactccag 3060

cctgtccgac agagtgaggc ctcatctcaa aaaaaataaa ataaataaat aaataaatag 3120

agcttggatg ttagcagtca atcaggatga tgcataactt agaaaaaatg atgttttgca 3180

ggagtaatcc tgtagcagcc atttgtgtac atgaacatta tgaaaacatt tgctgtcata 3240

tttaaagtca attataagac aatttttggt aactaaatgt ctaaaatcga gttatttgtt 3300

atgggtttat gcactttaaa atataccatt taattgaaag gcagtatact tctcatgttt 3360

tgttggcttg tttcattaat attagaaatg ttcatttcat ctcttaaaaa ccgtgataag 3420

ttatatctac tagtgatgta aggatatttt acatagaaaa aaaggggaaa atagctgctg 3480

ttagtatttc agaaaatggt gaattacata tataacttgt ttttataatt attaataaaa 3540

ttttaagttt ttaagatgca ctttacaata tttttgctcc tttaaaaatc cctcatttgt 3600

tataccatta ttctaagaat tcaaaagaaa tgaacacttc tttaaaatct atactattaa 3660

caagatccct taatattagc ttagttttag agggtgatag tgaggtgagt actgaatatg 3720

accactagcc aacggtaaag tacaaaagag ttgtccgaga ttgtaaaaga aataaaaaat 3780

atcagtacta attaaagcag gattcgtact taaacattga ataagtgtat tttaacaatg 3840

aagataaaga tgcattattt atgaagatcc tttgccattc aaaaaggacc taacagttgc 3900

tgcaggaata tttttgtaat ctgggcactg agtatgataa ttaaagaatg agaaacctat 3960

agaactatat attttttctc ttatgcatca ctcataagac a 4001

<210> 13

<211> 4001

<212> DNA

<213> Homo sapiens

<220>

<221> misc_feature

<222> (2050)..(2050)

<223> n is a, c, g, or t

<400> 13

ttctcctttg catataagtc aatctctagg gacctttagg gaaacattta ctttttcagg 60

catctagaat attattagga atagtaaaat cacaatgtat taatataaat caataggcat 120

tcctctatta acagaaaccc catgagtact ctcaaattct cattacaaga cactggcaca 180

caggaggaaa tgtctatgct gagcaacttg aggacgttgt ttctttacct cggtatacta 240

aaacaactgt caattttcac tattcaatat ttcctgagtg ttactgattc ccagtccgtg 300

cacaaggcta tgagagaata cagattctct ctctaacatc taggaattca caattcagtg 360

gggagaaagg cacacaaaca aagtaggtaa aaataaaagt agtggaaaat gtcgctttga 420

gaaatagcat atactcaaat taatacttat ccattttcta aaagccttga gttgtttcag 480

caaacacaat acatggtgaa aaaatacagt actcaaagga agaactcttg gtttcacaat 540

tcttaacata ttgtaacgtg acttcaggca cgtcattctt aaccagggtt ggccttagtc 600

acctcgtcta aaaatgtcag tattagcaac ctaaacccga atcgttttac cggcataaac 660

taaattgtct ctagtggctc ttccgggtca aagatccaca atactcacat actcatccat 720

cagattaccc cagtaatcat ggcccaggga accactacgg gtaaactaga tgaattagag 780

ttcctaaact gagataggct ttaaacttgt gaactcagaa aatgtattac agtggccatg 840

atacagcctt ataaaatgaa caagaatagc tgaacatttt gtgtatcatt ctggtacaat 900

atgcgtgtga atttcccacc aggaatccga gtttctgcac tactggaacc acgcctccca 960

gagaaatcaa ggagacacca gaaaaacctc ctcaagggac agggaaaaat cacggacaag 1020

ctttcttccc ttctcacctc cccctaaaaa agcccagtgt ttttcttccc ctccagctat 1080

gcagctgcac ccagcagaga agtactagat tagcatcatc tgcatttcat tccttttctt 1140

ttgcaatagc tactcgccta taataaacag accttgtgct caagggagaa tttacttccc 1200

cgtccagtaa aaatgaagtt ccttattttc actaacaacg ccgtctccaa tcaacaccca 1260

acctccctgg ggggtgggtg agaccagaca cgcctctccc tgccacccgt gctgcaagcc 1320

tgacgaccca caccctagga attgtcccac tttccgagcc ccttctgctc gagtggcgag 1380

gcttcggggg acagcggaag aggccaggga tttggcgtgc acaccagggg ggcgtccagg 1440

caggcccgag agcgctaggc tgcctccgct gacagggggc tcgcacaggc ggaaggggag 1500

cggcgagacc tatgccaccc ccacttaccc actttgtcct tcccgtacat gtgcccggcc 1560

acctgatgcg agaggggcac gcagccgttg aggaagcgga gtctgccgcc cgccggctgc 1620

ggggtgccct caggggtgga ctcgatcgcc ggtgaggtcc gcatttctgg ggggcccggc 1680

gcctcgaccc ggagggggga tggtggctct gttgccataa cggagagcag aagcggtaac 1740

ggcagcgaga gtaggaaaaa aaatagggcg agggaggggg cgccggagaa cccgagggtc 1800

gctcaggctc gggcgcgagg aggcccgggg gttcccgcgg ctggtgccct ctgaagcgcg 1860

gggagggggc ccatgacgcc gccggggcgc gggcgctcct ctgcccaact ctcggcggaa 1920

cgcggctccc ggctcctgtt cctctgccgc cgcagccgcc ggccccggcg ctgcccggta 1980

gacagaaccg agccgaagaa cagcagcagc ggcgccccgc gctccctggg gccctgacgg 2040

cgacggcggn cccacctcct gcgcccccgc cccctcccgc cgtcctccag tcccctcagc 2100

tgccgcgcgc gcgtcaccgc cgcccgcacc gccgctgccg ccgctactga gcatgcccag 2160

aggccgtcca acgggattcc ggccccccaa gtcagcgggg cgggcgcgcc gtgctgccag 2220

gacctggcga cggcgacagg gatagggcga gcgcacccct gtttcttctc acccccaccc 2280

cgcgggcatt tcgaagtcac gcgtgctgct gtggcctcat tcattcaaca cgcttctcag 2340

cgcgtcagct cagagaagcc agggacttct aagtgtgcgg agcagtccgg caagaattgg 2400

aaggcactag cattgccaag ggtggctcta aaggccaccc ctaactgcac tcaactccct 2460

ccaactccca ccccgcacga aaacaacaga agtaaaagca ggcagcttat tagagatgcg 2520

ccttcaaaat acccttcgag ttaatctcag cccccctccc cggattgctg tctctaaacc 2580

gctcttacca aaaagtaaaa cacataaaaa taaaataaaa ttggaaccga cacgaatttc 2640

agactgtaga agacagagaa aacttctaat ttttttaagt gaacatgttt tttaaagaaa 2700

ggagcaagtt ttttctctcc cactcgacct ttaagatagt gcaggttcca aggtcctgag 2760

tagataatta tatcaaaagc agaaagggat ggacaccggt agctacgcga ggttctggaa 2820

tgggactcag tcattgattc ctgtatgtcc gccgctggca tgttatataa aagctggacc 2880

tggccttgaa ggtaaatcgt cacaagcccc gagcaagaaa aactggggtc aaatcttagg 2940

tatctgatta aagtaagtgt cctattaaca cctgtttctg cccccagaag cccacacacc 3000

tggaagagac gtaaaatctg gcctggattc cctaatccca gggccctgcc cctcggcttc 3060

agggccccgc ccctcggctt cagggccccg cccctcggcg ttgcgcaaac tctgttgcta 3120

cctaagtctt ttcctcctcc cacctcccgt agctgtcaaa atccggagtc cagacttcct 3180

tatggccagg acagctccac gcatgctcag cacctaccag ggtcgagctc acacacgtgc 3240

ctacgacccg ccgcggcgcc tgcgcggtag catcgcggag tcggtgcttt agtacgccgc 3300

tggcaccttt actctcgccg gccgcgcgaa cccgtttgag ctcggtatcc tagtgcacac 3360

gccttgcaag cgacggcgcc atgagtctga cttccagttc cagcgtacga ggtgaagtgg 3420

ggcctgggag cgggtgaggc tggtgaggct cagcggttgc cgcgcccgca gttcgactgg 3480

gttgttttac cactgcccta cgcgcccgcc ggtcctataa ccttgagatg cagaagggca 3540

agcgctcggc ccggctgcgg gctccgggcc ggacagcgaa agggggcgag gtcagggatg 3600

gattgatggt ttggggccat gccggaccag agtccacgtt taccccagct agccaaaccc 3660

taacacctaa tgaccgcgcc gctagctttt cttgttcacc cctaagacgc tttcatgtcc 3720

ttaagtcaca tagcctggaa aagaaggaaa ggtgggagaa aacaacagca aacctgtttg 3780

cccttctcat gtttcagtca gcgtcgggcc acaacgtcga tttcctgcaa tcctgaagca 3840

ttgcgtgact aatcacatct tagttttgca gatttttttt taagggatga aacgcaatcc 3900

gaggttttca gttttcccgg ttttttatta ttcctctggc atctgacact cggtggcagt 3960

agtccaggat aaaggattga aaactgcgtt cgttgaacct t 4001

<210> 14

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 14

gtccggacag ggcaggtgga gattgtggag cactttctat ccctgggcct ggaaatcaat 60

gccagagaca gggtgagtgc tagcctgtcc gctgctcacc cgccatgggt gtgtgggcag 120

cctgcgggcc cctacaggtg gtgtccttcc tcctggggcc ttcaggactt ggctcctgag 180

cagggtctcc agcccacctc ccatcaccct tgcctcctcc cactgcccac aagggccata 240

gtgagtgcca cactgactct aggaagggga tactgccctg catgacgctg tgaggctcaa 300

ccgctacaaa atcatcaaac tgctgctcct gcatggggct gacatgatga ccaagaacct 360

ggtaagctca ttccctcctt gattcagtca ctggcgtgag cactcataca gtggaggtgc 420

tgtcctggtc cctggagcag cccccgccta gggacatgta tcattggctc tggccagcac 480

catagtacat aaacttgtcc tcttccagag caccattcca actgtccgcc ccattctcta 540

tgtgtgtcta tgtccagagt gcaagtgcag agagacagca ggaggggcag caagaggact 600

tcccaaagac ccccaagtag gccagagggg gtcctcaagt actggcccaa ggaggccaga 660

atcatgaaag gccagagctg gaagggaccg agcactcagc tggcatgaca gttcctagca 720

ccccatgtca gctcctgtgg tctttgagtt ttcttaggat ctaggcagga agtccttgga 780

aggggaaggt gcccagggaa caccttggac tagggaacac ttagtccaag ttcttctttg 840

gggcccagag cattcacaaa aggaggccat gggagagtcc ctcgggctca agaaaggcta 900

aagggataat gagaaaagca ggaaaatatg gagaaggtat aaatgagggg ttttcaccct 960

cagcattatt gacatttagg gctgggtgat tgtttgttgt aggggaccat cctatgcctt 1020

gtaggatatt taagcaacat tcttggcctc tgcccactag atgccagtag tacccatccc 1080

ctagtgtgac aaccaaaagt atcttcacac aatgccagtt gcccccattt gagaagcact 1140

ggtggtgtca atgagggtac cttctgtgaa agccttcagg acagttaaca gattttctct 1200

tgccaacccc cacgccccgt cccgccccct ccaggcagga aagaccccga cggacctggt 1260

gcagctctgg caggctgata cccggcacgc cctggagcat cctgagccgg gggctgagca 1320

taacgggctg gaggggccta atgatagtgg gcgagagacc cctcagcctg tgccagccca 1380

gtgaatgcgt gccccagccc agccagctac ccagcccctc tctgtgtgca gccggagggt 1440

cctaagaatg gctcccggag ctaactgagg gcccagcctt ttttctgcat gatccaggag 1500

cacataccac aaactaccac aataaaaaag ctgtttttgc taattgcgat gttcatttcc 1560

acttgtgtct gaaatctttg ggaatgaagg aagactgggg gcaaatgctg gtttggggag 1620

gagggaaact gggagccggt tggccctctg agccagccct gcagcttctt tactgtggtc 1680

tcttttcctt tcctccctgc cactcaactt ttcctgcccc ttctcacatc tccagggcca 1740

ggcttggccc ctgcatggat tgacttggta atacactcat cctggccccc ttcctggtgc 1800

ctgctgtcct gtggggctgt gagtggctag cacaggcttg tcacgtggct gccttggcag 1860

gaggagcctg gtaagggagc ggggcagggg atggacagcc tgtcacaggc agcttcttgc 1920

ccagccttgc cacacctccc acagggcagg acctgctcag ccaatcagct ccaccaacct 1980

cagaactgcc cgtggaaacc tggctgggct tctggcttca gagctgggaa ttgtgggagg 2040

agggcccaga tcccactgga gataccgaag gagatactct ttagtattgg gatcccagaa 2100

accagtccta tatctggcca gagggacact gggttgtggc atctctctag ctgctaccca 2160

gaaggaacag ggccccctgg ggcctatagg ccttgcccct gaccctggga acacccagct 2220

caggcctgcc ccagtggcca caagtcaggg aggccgcaaa tttttaacta gaaacattga 2280

tcattaatag ggggttagaa agagttcaaa ctaagtctca ctctgggaca tagaccaatt 2340

gtgcttcagg cctcctgcag agatgctggg tccccaagtc tggtcttctg tgaggcaggg 2400

gctaagcagg agcttgtcca ggaatgtggg ggtctgggcc tcaggggagg ggaagaaggt 2460

ggacattgcg ggtatctacc cccctgtgac cacccccttc actgccactg cagaggtgga 2520

ctatgggaaa ctggaggaga atctgcacaa actgggcacc ttccccttcc gaggtaagtg 2580

gggctgtcct ctgtgggacc tggggagatg tgagtggccc tttagccaga gaccaaggga 2640

gggtacacag gctctgtcaa gctgtccagg gatagtctgg tactcagtgg gtcattttat 2700

tatgggagag gaacagggga gactggtctg gagtcaggag acaggcagga agctccacgc 2760

tggcctgtaa ccttaagcta aacctcacct gcttcagttt acccagctgt aaactgttaa 2820

agtgcctttg tagctcccag agtgattctg aggttggact ggataatggg cgtgaaagtc 2880

cttgtcaacc ttgtcacttg gtgcagatgt gaaggcatgt ggctggggtc acgtggcagc 2940

ccagccacag tcccagttcc ctccaaagtt tgtttgtaca ttctcttctg gacaaagcct 3000

ccttgccaga attagttctc ctgtgacccc ttggctcctg tgactcctgt tgtggctcct 3060

gtgaccccat ctctctttac acatgggtct ccccaactct gaggttaggg accagatgat 3120

atttgcaaca atcaacatgt aacagagtcc caggcacaat aaatgaaggt agaagaaaat 3180

gtcaaattct gcctgccctg ctccgcccat ccccattcct tactgcacaa tcccctgagg 3240

cagtgctctc tgtaggacca tcccacagat gggaatctgg gcctcagagt gacatggtca 3300

ctgcccaagg tcattcggct aacacatagc tgagctgagg tttgcacctc gtctgactgc 3360

atggcccatg ctccatttta ctccctcgct gactctcatt ataaaccctt tggagctgct 3420

aggccacact atttcaacgg agtgtctggt cagcactagc tttgttgtgg ctgctattga 3480

ggcagtatcg tgtagactgt ggactctggt ttcaaatcac agctctggag tgagcgcctg 3540

taatcccaac actttgggag gccgaggcgg agggatcatg aggtcaggag ttcaagacca 3600

gcctggccaa catagtgaaa ccccgtctct actaaaaatg caaaaattag ctgggcgtgg 3660

tggtgtgtgc ctgtaatccc agctactcgg gagactgagg caggagaatc gcttgaaccc 3720

gggaggcaga gattgcagtg agctgagatc ataccattgc actctagccc gggcgacaga 3780

gcaagactcc atctcaaaaa aaaaaaaaaa aatcaaatca catctctggc actgacttag 3840

tgtgggatga ttgctgtccc tatcggacac atgggagtga taatgctcat attatgggat 3900

ggttggacaa aaaaatctga gagaatgcaa gtgaaatcgt gctataaatt gtggagtaat 3960

atacattgga aggtactgat tccaatggta ataatgatta a 4001

<210> 15

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 15

gatttgcttt ctgcagagga gccagagagg gtatccatgt tgaacttgta tatccatagg 60

aggaaaccag tcccatggcc cctgaagggt cctggcagtg ggaaggggag aggtctgcat 120

gtgcatgtac tggacagcat attccatgtg ggtcatggag tgatgactgt gggcctcttt 180

cgggcattgt agcaggcccc catttcattt catgatgacc tcggggtgct gggacaggaa 240

tgtgattgcg ggtccacgtg cttctgcaac tcctcagact gacttggttt ggaaggtctg 300

tgttcaggac cctctgtgag atgcttgtct ccattaggca tttgagctta tatcggccca 360

gggtttctac ctatcgtagg ttgtgcatac tttgcctctg aaccactcag gcacctcgat 420

gcagtcaacg tgcccgatta taagagtgtg acttcccata tcctggtgat ctctactcgg 480

aaacatggtc caggaaggtc tctgtgctta aataccttag tagctcgtga tgttaggtta 540

ttttctaatt cctcctaatt cttcccagga gtcttctttg tgaaatagtc atcttgttgt 600

aggacagggc tggtatccac aggcagtgat gcataggttt tgcactgcgc ggccatgttc 660

aaaggcaagt gccttaaaat gtatggtgtt ctcagccaca gtgccttaga agccatgtgg 720

gattcagtgt gtctggtggt cctctgagct gcacctgtga ggaagacgct gaggtagagg 780

ttaagttgtt attgaacgtt tttctcaatc tgaaaagtgt tcaagcagcc cagggtgaaa 840

agtcttcaag actgaaggaa aattgccttt tgtactggaa gagtttttcc ccaaaactct 900

cctcatttaa atagccctgt ggcttgtgtc ttctctgatg accaagagga gggcttttga 960

gtcagtgatg gcaaatgagt ggttttgaga gagttcttac acttagggct ctgtagcttg 1020

atggtgcctt caaaattaac acgtgcctgc tatcttcatt cctgggtaga cccatacacc 1080

catcccaaaa ggggagtagc ctgtgggaag cacatatggg atataccaca gtgagtcgag 1140

tggaatggcc cttttgacat gtgtacctgc ctcccgttct taagcacacc cgtttttcct 1200

ctgcacttcc caggtgttgt ggccatggaa gtaaggccag tggctacgag ggacagtctt 1260

catcttggga gatccctaga gagggcaggg agccccttga catgtggaat gtgatctctg 1320

ttgggtgctg gtggatccca caggttggta aatgtccatt ttccaaaagc ccctgatgtt 1380

ccttctttgc agggataaag actgtgcatg gatcgatgat gacctcaata catgcattcc 1440

ttggaaagct gaacaaaatg agtgaaaact ctataccgtc gtcctcgtca aactgaggtc 1500

cagcacgtgg ctccaactgg agctggagag agagagacaa cttccattgg ttgatgtggg 1560

ttgcactaag ccatccatcc aggcttagga tggggtccac tttggatcaa agggagtcac 1620

agggcagtag gtgctcctgt gcagaggaga ttccttgtgt gaaggacttc tctttgtgag 1680

gctgggtagc acgcacaatg tctgcaggac tgggtgaatg tgcaggtggc acagaagagt 1740

tagccggtaa cccgcctctg tgtggccagg tttgtccttg agtgctggct ctgggttccc 1800

ttgttcccca gaggtagata gctccttgtg gttgggaaga gagcccaagg ccacatcttt 1860

gttgttcttt ggctcatttt ttttcatggc tgaggacttt ttagtgccca tggtgttttc 1920

gtagcagcag tggaagtcag ttgtgaggag gttggtgatg cttattttct ttctggagag 1980

taccctgtag atcggctcca tttatgattt gtgtgtctcc agggagaaac tgaaatccca 2040

tggctggtga tggatactcc aggtgggaat gagaaagcgc catacatgtg ttgacttggt 2100

accctaagat ggggatggtc cgccacattt gcgcgtctgt tttgcatggt gtgtactgca 2160

catcacaaat gccatgttgg ccttagggtg ctgggaatgg aatatgatct gatgtctaca 2220

tgggagggcc tttcagcaga ttgcttttgt ttcctgacag tctttgctcc atccccagtc 2280

acacgtgttt ttctccaggg aacattttat tggagtatat caggtcgata tcagaaaaaa 2340

aaatgttgtg gttatcccaa cattaagtgt ggtgatgtaa cagcagtgtg gatggtagct 2400

caagtgaaca gtggcaaaac caaaatatat tggtttacgt aagtgaccct attctctcct 2460

atgtttgaag tctggtatgc atctctttct gcaataatct cagtgatctg gaaactttca 2520

ggaggtcttt tttagatatt ttatgtcctt gtggttgtac tcatactccc tgcagtgcta 2580

agtctgagtc attctgctat cctagtgcta ctggaatttc tattgttttg ggggcactgt 2640

ctggtcattg tggatacctc tcttggggcc ctttaataag aagtatgtta gaggtcggtt 2700

ttggggcagt gttgacctcc tgcctaaggt caaaggcagt tttcttccta aatcttattg 2760

caggattcac tgcctggggg ttgtgtgaca gggagagcac aaaattaggg tatcccatgt 2820

ggacttgtgt ccagtatcaa ggcagtgttg gataattttc tatatccaca aggctcccac 2880

tggactcttt atgtccagca gacattcaca ggccaacttt tctcttacac agggggcctc 2940

attcctgcca tgtgtagctt ccatggaacc atccttcagg ttttaagtgc aaggatttct 3000

ctcaagagtt taatttgttt ctttaagaca ccgttttctt ttctataaat tctgctttct 3060

gtggtttgta gcacagatga aattgccagg tcatattcta catttctgcc caatcttgga 3120

ttagtgagcc tttgaaatat gttccttgat cactggcaat ggttcttgga ataccagaac 3180

ttagttacaa gcattgcaga cctacagagg tttgttgtta tttttaactg catgaagcag 3240

tgggtttgtt tgtatcttgt cactcacggc tgtcagcaaa acttaggtgt tgctaaacca 3300

gaccacaccc atgaattata gtgcctctgg ttccttctgt agtagcctgt gggaagtaga 3360

tacaggatgc accacaaggg aatgaatggc atggcccttg agacctgtgt acctgcttgc 3420

ctttctcaag cacacctgtt ttgcctctaa ttcctaggtg gtctggcatg gaagaaggcc 3480

agaggctgcg atggatcatc tttgtcttgg gagattcctg gagatggtgg ggagcccctg 3540

ggcacgtgca gcatatgtgg cgtgggcttc ttcaggtgct ggtggatccc tcaggatggt 3600

aaatgtccat tttccaaaat cttctgatat tccatctttg taggtacaaa gactgtgcat 3660

ggatcgatga tgacttttat acatgcattc cttggaaagc tgaacaaaat gagtgaaaac 3720

tctataccgt catcttcgtt gaactgaggt ccagcacatt gctccaacag tgggtagata 3780

gagagggaaa acttccattt gttgacgcag gttccattga ggggtttgtc caggcttagg 3840

atggggtccc ctttgggcaa agggagtcac aggggagtgc ggcctcctgt gcacaggaga 3900

ttccttgtgt gaaggattta cctctgtgag agcagggtag cacacataac tatgcaggag 3960

caggtgaatg tgcaggtggc acaggaagag ttagatggca g 4001

<210> 16

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 16

caacatgatg aaaccccgtc tctactaaaa atacaaaatt tagctgggca tggtggtggg 60

cagctgtaat cccagctact taggaggctg gggcaggaga attgcttgaa cccgggaggc 120

ggaggttgca gtgagccgag atcacaccac tgcactccag cttgggcaat agagtgagac 180

tccatcttaa aaaatccaaa caacaacaaa aaacaacgca gctgaaaaat gttcctttcc 240

agtccctaaa ctgggcagac agaactggct tcatcagtat cagctgctct gaaatgaact 300

aaaatatctt ataacaccaa ttactgaaga atttgtaaca aggtcaatag aggcacattc 360

atttgaatat aatttttaag actgctacag aaggccatac ttacattgta agcagtactt 420

aatttgtgtt tctctggcgc aagtttttat ctttgtgatt gttggtagag ttggttttcc 480

tttggaggaa aaattgcatt acatgagtta aactcagtca ataacttttc aaagtataac 540

acatggaaat acagggactc tttcacttac tgccatccct ggtgtagtga gaaattttgt 600

ggcacaatat gagtgcataa aaaaacattc cttaagtagc tacaggttaa gtatccctca 660

tctgaaatgc ttgggatcag aaatgtttca gattttgaat ttttttagat tttggaatat 720

ctgcattata cttaccagtt cagcatccct aatctgaaaa tccaaaattc aaaatgctcc 780

aatgagcatt tcctttgagc ctcatgtgag cacacaaaaa aaacttcaga ttttggagca 840

tttcagatta tggattttgg tagtaggtag actcaacctg tatatacctc attttatcct 900

ccttttgacc cccaaggcag acgagtactt tcccttcgaa tccggaacta taattacgat 960

acaggtgaga atatgtaaaa cttttctcca ctgaacacaa caccactgtc ccttcttgat 1020

aaaaggtaat cataagctgg cagtgctggg ccctctggta cttaacaaat ttgggtgctg 1080

tttgtctgct tctcactctt tagtccaact ctaggagatt ctgccgatct tagattgatt 1140

ccatacctgc agtaccctct ctcttggata cgagcaattg ttaatggggc tagacagttt 1200

atccaggcta tagttcagcc tcaaattgca ttacatgagt taaactcggt cagtaacaac 1260

ttttgaaagt ataacacatg gaaatacagg gaccctttta ctaccatccc tggtgtagtg 1320

agaaattttg tggcacaata tgagtgcata aaaaaacatt ccttaagtag ctacaggttg 1380

agtattcctc atctgaaatg cttgggatca gaaacgtttt aacattgaca aaaccgggag 1440

cctcagatat actggccatt tcccccacat tttaagtata tcaaatacac aaaatttgaa 1500

aaaaaaaaaa gttttttgca tggtattcca ctttgtatgg ccactggaaa acaagactgc 1560

ataacctatc ctgagaatca agtggttttt agtcagatct gtgtcaagct aagaaatcta 1620

cactgcaacc ttcatttcca ctcactgtct tcccctccaa tcttagctac tccatttgat 1680

taaactgcaa acacaacatc attcaatcag atactgttga atcaatgtcc aataaagtac 1740

ttacattggt ccagctggtt catcatctac atggtgttca gttttttaaa aatccatgag 1800

agataagaga agaaaggaga aaactgttag attctgcata aggattaaca gaatagcaaa 1860

ctgcaagtgg caatcatggc tactcacagc atttattaaa ggccattcca tctggaggtg 1920

caaaacactc atggagttat tatttctaga ttcaagttta aatggcaggt atgttgtttc 1980

aatggtttta gttaacactt tgaatgcttg tcatgaaaaa ctgcaactgt agcggacaga 2040

taggctgcaa cattgttata ctcatcttgt ccccaagttc cagtggttca ctcttaaata 2100

gatgagaaga caaaccaaca tttcagttgt aaaatcctgc tgtttgtttt cttgtggtga 2160

atgcatgcag ttttggctca atcctgcaat gtgaatggat gtgtaccatc tgtacattta 2220

gccacacatc ctcacttccc caaagggcac tctgtttttc ttgctgtttt gtaatcttta 2280

gaagagtctt tagtctggag aatgagattg agaagaggca atcacaatag ttcaacctaa 2340

attgggtcag ccatgctggg ctatgccagc aacaagtgta tgtataccag aggatgttct 2400

gtgacacacc gaggaaagct gaacagtggt gacatccctc tagaaaagac ttcagaaaga 2460

caggctcact cctgtgccct ggccaaaacc agaagccaaa cccaggggag ccatgagata 2520

acttttttaa aatcaaaaag ctgacattat atgagtttaa gccttcttaa attgatactt 2580

tatgattctg atttataagt ctttcgtgtt tcaactaagt gcaacttgat cccctttaag 2640

cagagataca cattcacaga gagagaatgt tttaaaaaga cccacaaggg gaagggaaca 2700

agtaagtgct cttagtttgt ttttattata caaaagtcag gtaaactaaa tgattcagaa 2760

cagtttgatt tcactgaagg cttctagaaa aattctcagc aggattccac aagggggctt 2820

ggtgcacatg aagcagttat ggagattaca gtctcagtgt aggcatctgc aggagcacat 2880

gtcgggagta atgtctgtca gagggagaca ttgctccacc tgttccttcg aggcaacgga 2940

gaggcaaagc caccgccagc acacacagtg actggagcaa aaaaggattt caaaaaaaag 3000

aactaaccac aaaccaatga ctcatcagcc aaaacaatag gctagcgaca cactagtgtc 3060

cacaggagtc cactactaac aacagtatac actatcaaac gggtacagag aacaaactaa 3120

gacttaagga cacccaagac atctgtgtgc tgtgtatgca gtggagagat acaaagacat 3180

accaggtact aagacacaaa agcccagcct aaattctccc ctcacaacat cctaatgctc 3240

agcatcccgg ccaagccagc tcagctacat gctaggaact aagcactttg gggatttaaa 3300

tgaaaagaca taggagcaaa cttggaatac ttttagtgct ctggctgtgc actcgaaaat 3360

acaaaattct aatgcaagag agccgaatca agaatacacc aatctactcc caaatttaaa 3420

ataaaaagca ggggagggag aatcgcaata gccaggctaa tcttttcaaa gcatgacact 3480

gtaggcacca acccaagcac ctcacaccac gggctgtttt tccttttgga gtgtgggtat 3540

tccctggtgt ctgattagta atgtcacttt ccagcccaac aagctggtaa catgcaaagg 3600

gttgcatgga ggtgttttag cgacagtgcc tccggcatag ctgccatgcc tgcaagtggg 3660

agcagttgag attcacaagg gggcaaaatc ccaggagccc tcttcatctg tctccccaaa 3720

tccactttca cactgacaaa caaaagagcc tcatgtctcc ccactctcct ggactgaatc 3780

actatctgca gcaccactct cccctacagg tcagacaaaa aaacgacttg acccctaaca 3840

gggaagtcag gggagaggga aagaacagaa ttacagaaaa aagatacaga aaccaaagta 3900

aatgaggatt aaacagcaaa ctgaaatcca aattagttgt gaaagtgaat gaagtaaact 3960

tgaagaaaag tgttaacatt atgaactgtg catcgtatag a 4001

<210> 17

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 17

tttgtaactt tggaatttca tatctctact tatttccacc ttcttcccaa ttaggctatg 60

tgtgggagaa aaccaattgt aatgatttcc tctgtgagca ggaacttgtg atgaaactgt 120

ggttccctcc cccaaccagt taggcaacct attaacaaaa aagagaagtt tggatatgtc 180

acaccacagc ctgcttctgt gaatgatttc ttttaagaat cctcatattc taggaattgt 240

tttttaaaca cagtatccaa tgaaaaggtt gaagatttat ttcctccatg gagggaatag 300

aaagattatt cttattattt taaaaaacca tattgaggct gggcatggtg gctcatgcct 360

gtaatcccag cattatggga ggccgaggcg ggcggatcac gaggtcagga gatcgagacc 420

atcctggcta acacggtgaa acgctgtctc tactaaaaat acaaaaaatt agccgggtgt 480

ggtggcagat gcctgtagtc ccagctactc gggaggctga ggcaggagaa tggcgtgaac 540

ccgggaggcg gagcttgcag tgagccgaga tcttgccact gcactccagc ctgggtgaca 600

gagcgagact ccgtctcaaa caaacaaaaa agccatattg aaagtaggaa gagaactaat 660

tcttgacatt taaacaaagc tgtctctcta tctagtaagt aagaagtaag taaatgtctt 720

gctctgttgc ccaggctgga gtgcagtggc acaatcacag ctccctatag cctgaaagtc 780

ctgggctcaa gtgatcctcc tgcctcagcc tcccaggtgg gtgggactgc aggtgcagtg 840

caggtgccat cacgcccagc tatttttttt tcttgtgtag aaatgggggt ctcattatgt 900

tgttcatgct ggtcttgaac tcctgagctc aagtgatcct ctcaccttgg cccccaaagt 960

gctgggatta caggcatgaa ccaccacgcc cagcccaaag ctttattata ttagatttca 1020

aatttctaac atatcaaagt agcgaagtag tacagtcaac cccctgccat cacatggctt 1080

cgacccaatc ttgtttcttt tctcctccca cctactccct cactcccata ttattttaga 1140

gcaaatccca gccattttat ctgcatcttt cagaatatat ctctaaaaga caggaattct 1200

tctttaaaat aatgctaatt aaaatagtct atgaaagtaa tatatactta ttagcaaaaa 1260

acaggttatt aaaagtagaa gcaaaaagtc acccatagtc cttttgcctg aaataactcc 1320

cattaacatt ttgatatatt tcttcacaga tgagaaaaaa ttaagaactt tccccccttc 1380

cctgccctat aatccaaatt gtgtgggcaa atctgagatt actagatgta ttggaaatcc 1440

tttctctttc atagataaaa aaacagaagt agacagaatt ttaaaaatag atatactatg 1500

ggatggctat tggagtcatg gcagtttttt ttttcttaaa tgaaaagtac ttttatagaa 1560

attgttcttt gaaaatattc agcaaataat catttattgc tttctatgtg cagatcaagt 1620

ttgtatgata attaaattat tgataactta tacctacgat tttaagaata ttttcaaccc 1680

tttggtcaga ttgtctccaa ttagcataat agcaaagaga cttttcaagg ttaatatgaa 1740

actttttctc agctattttt ttattgtcta tttctcaggg gaaaaaggaa acttatcctc 1800

ttaggcagtt ttcataatgt tatacattta aaaattaatc tgaaggagct taaaatataa 1860

atgcattagg tgaaaaatag cagttgattt aaataaaatg aaggaggaga agaaaaagaa 1920

ccttaccgac acaaaataga atgagattgg tttgcagatg gcgagcgatg ttgcttctgc 1980

tcgcagtccc catttctgtg tatgccgggg cgggttgggg tgtgtatttg aaaggaaagt 2040

tggctttctt ttttcagaag ggaagaagag ctgaagagag gaacctctta tgaaggaacc 2100

ataatcagga actttttgaa attgtgcaag gatggcttca ccatttaaca ttgagatttt 2160

ggcctggagc acatttagaa atgtgcatat cttttttttt tccatggatt ttacagttgt 2220

cataggtgtt agatgtttct gggtgagatt ttgatttaca cctagcacat atttccagga 2280

aggagtattg tttgacaaat aattcgtact tggatttttc agaacagttc agtcactgtc 2340

tagggtacct gctctgggtg ccactctggg ccagtaactg ctgggaacaa agaacagcag 2400

aaggagaagt ggctttgtgt agagatgaga aaagttagta aacaacacat tctaatgcag 2460

cgaataaata aattgtctgt tattaacttt ttgtactcca gttttgaatc caaagacacc 2520

tgccttcccc ccttttttga cagggtctct atcacccagg ctggaatgca gtggcaagat 2580

tgcaggtcat tgcagcctca gcttcctgag tagctgggac tacaggcatg caccaccacc 2640

cctggctaat tttttttttt ttttgtagat tctgtgttgt ctaggctagt cctgccctca 2700

agcgatcccc ctgccttggc ctcccaaagt gttaggatta caggtgtgag ccaccatgcc 2760

tggcccaaag accccctttt aatgtgttga gaaacaaata tgtgggccct ctgtcctctg 2820

tgtcctctcc cccagcactt agtggtgatt cagtaagggt cttctttgta aagcagcaga 2880

aacagactca ggctgactta aaaggaaatt tatgcaaaca tttgaaggta gatcctagag 2940

tcactgggag ggctagtgaa tcttgtgtgg ggtccacagc caggaagaat gcctcaaatc 3000

acaccataaa caggtctgaa gaggatgcta ctgccactgc caaacactag gtgccatcag 3060

ccctgttgtc agcatcgctc aaccactgcc ccagcccctt ggtctcactg ccattgctcc 3120

acccccagag aaggagaagc tcacatcccc actactctgg gtcactggct ctccattcca 3180

gggcatgggc aagtgtgcct ggcttaggct gcgtgccagt gcctcagctg cacggcaggc 3240

caggaaagcg gctcccaggc cttgtgtctc tcccagactc tgggcaggca attccccaga 3300

catgggaaga gcgtcatctg caccactgaa aattatgaaa aatctcccca ccatgatatg 3360

atgtctgtgc ccttggcatc tgctcatgat atattttctc attaacagaa agttattctc 3420

agtctgtttt gttttttttt tttttttttt ttttgagaca gagtctcgct ctgtcgccca 3480

ggctggagtg cagtggcacg atcttggctc gctgcaagct ccgcctcccg ggttcacacc 3540

attctcctgc ctcagcctcc caagtagctg ggactacagg tgcatgttgc catgcccagc 3600

taattttttt gtattttttt tagtagagac ggggtttcac tgtgttagtc aggatggtct 3660

tgatctcctg acctcgtgat ccgcccacct cggcctccca aagtgctggg attacaggca 3720

tgtgccacca cgcccggcct caatctggtt ttaacacttc aacagatgta tgtagttttt 3780

gtatcaccat agcacctaaa aagtaccccc aaagttaaat atactgtcat ctctgtgtgt 3840

gtgtctgtag tcagtgccag gtttgtatgt gaatttgagg accttcccta gtccccttgt 3900

cccccaggca tctcctgctc ataggtttgg aaatgactga tagaggcttc atctctagtc 3960

caagaaatgc tggacggtgt atccatccta ctgttccatc t 4001

<210> 18

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 18

tgtaactttg gaatttcata tctctactta tttccacctt cttcccaatt aggctatgtg 60

tgggagaaaa ccaattgtaa tgatttcctc tgtgagcagg aacttgtgat gaaactgtgg 120

ttccctcccc caaccagtta ggcaacctat taacaaaaaa gagaagtttg gatatgtcac 180

accacagcct gcttctgtga atgatttctt ttaagaatcc tcatattcta ggaattgttt 240

tttaaacaca gtatccaatg aaaaggttga agatttattt cctccatgga gggaatagaa 300

agattattct tattatttta aaaaaccata ttgaggctgg gcatggtggc tcatgcctgt 360

aatcccagca ttatgggagg ccgaggcggg cggatcacga ggtcaggaga tcgagaccat 420

cctggctaac acggtgaaac gctgtctcta ctaaaaatac aaaaaattag ccgggtgtgg 480

tggcagatgc ctgtagtccc agctactcgg gaggctgagg caggagaatg gcgtgaaccc 540

gggaggcgga gcttgcagtg agccgagatc ttgccactgc actccagcct gggtgacaga 600

gcgagactcc gtctcaaaca aacaaaaaag ccatattgaa agtaggaaga gaactaattc 660

ttgacattta aacaaagctg tctctctatc tagtaagtaa gaagtaagta aatgtcttgc 720

tctgttgccc aggctggagt gcagtggcac aatcacagct ccctatagcc tgaaagtcct 780

gggctcaagt gatcctcctg cctcagcctc ccaggtgggt gggactgcag gtgcagtgca 840

ggtgccatca cgcccagcta tttttttttc ttgtgtagaa atgggggtct cattatgttg 900

ttcatgctgg tcttgaactc ctgagctcaa gtgatcctct caccttggcc cccaaagtgc 960

tgggattaca ggcatgaacc accacgccca gcccaaagct ttattatatt agatttcaaa 1020

tttctaacat atcaaagtag cgaagtagta cagtcaaccc cctgccatca catggcttcg 1080

acccaatctt gtttcttttc tcctcccacc tactccctca ctcccatatt attttagagc 1140

aaatcccagc cattttatct gcatctttca gaatatatct ctaaaagaca ggaattcttc 1200

tttaaaataa tgctaattaa aatagtctat gaaagtaata tatacttatt agcaaaaaac 1260

aggttattaa aagtagaagc aaaaagtcac ccatagtcct tttgcctgaa ataactccca 1320

ttaacatttt gatatatttc ttcacagatg agaaaaaatt aagaactttc cccccttccc 1380

tgccctataa tccaaattgt gtgggcaaat ctgagattac tagatgtatt ggaaatcctt 1440

tctctttcat agataaaaaa acagaagtag acagaatttt aaaaatagat atactatggg 1500

atggctattg gagtcatggc agtttttttt ttcttaaatg aaaagtactt ttatagaaat 1560

tgttctttga aaatattcag caaataatca tttattgctt tctatgtgca gatcaagttt 1620

gtatgataat taaattattg ataacttata cctacgattt taagaatatt ttcaaccctt 1680

tggtcagatt gtctccaatt agcataatag caaagagact tttcaaggtt aatatgaaac 1740

tttttctcag ctattttttt attgtctatt tctcagggga aaaaggaaac ttatcctctt 1800

aggcagtttt cataatgtta tacatttaaa aattaatctg aaggagctta aaatataaat 1860

gcattaggtg aaaaatagca gttgatttaa ataaaatgaa ggaggagaag aaaaagaacc 1920

ttaccgacac aaaatagaat gagattggtt tgcagatggc gagcgatgtt gcttctgctc 1980

gcagtcccca tttctgtgta tgccggggcg ggttggggtg tgtatttgaa aggaaagttg 2040

gctttctttt ttcagaaggg aagaagagct gaagagagga acctcttatg aaggaaccat 2100

aatcaggaac tttttgaaat tgtgcaagga tggcttcacc atttaacatt gagattttgg 2160

cctggagcac atttagaaat gtgcatatct tttttttttc catggatttt acagttgtca 2220

taggtgttag atgtttctgg gtgagatttt gatttacacc tagcacatat ttccaggaag 2280

gagtattgtt tgacaaataa ttcgtacttg gatttttcag aacagttcag tcactgtcta 2340

gggtacctgc tctgggtgcc actctgggcc agtaactgct gggaacaaag aacagcagaa 2400

ggagaagtgg ctttgtgtag agatgagaaa agttagtaaa caacacattc taatgcagcg 2460

aataaataaa ttgtctgtta ttaacttttt gtactccagt tttgaatcca aagacacctg 2520

ccttcccccc ttttttgaca gggtctctat cacccaggct ggaatgcagt ggcaagattg 2580

caggtcattg cagcctcagc ttcctgagta gctgggacta caggcatgca ccaccacccc 2640

tggctaattt tttttttttt ttgtagattc tgtgttgtct aggctagtcc tgccctcaag 2700

cgatccccct gccttggcct cccaaagtgt taggattaca ggtgtgagcc accatgcctg 2760

gcccaaagac ccccttttaa tgtgttgaga aacaaatatg tgggccctct gtcctctgtg 2820

tcctctcccc cagcacttag tggtgattca gtaagggtct tctttgtaaa gcagcagaaa 2880

cagactcagg ctgacttaaa aggaaattta tgcaaacatt tgaaggtaga tcctagagtc 2940

actgggaggg ctagtgaatc ttgtgtgggg tccacagcca ggaagaatgc ctcaaatcac 3000

accataaaca ggtctgaaga ggatgctact gccactgcca aacactaggt gccatcagcc 3060

ctgttgtcag catcgctcaa ccactgcccc agccccttgg tctcactgcc attgctccac 3120

ccccagagaa ggagaagctc acatccccac tactctgggt cactggctct ccattccagg 3180

gcatgggcaa gtgtgcctgg cttaggctgc gtgccagtgc ctcagctgca cggcaggcca 3240

ggaaagcggc tcccaggcct tgtgtctctc ccagactctg ggcaggcaat tccccagaca 3300

tgggaagagc gtcatctgca ccactgaaaa ttatgaaaaa tctccccacc atgatatgat 3360

gtctgtgccc ttggcatctg ctcatgatat attttctcat taacagaaag ttattctcag 3420

tctgttttgt tttttttttt tttttttttt ttgagacaga gtctcgctct gtcgcccagg 3480

ctggagtgca gtggcacgat cttggctcgc tgcaagctcc gcctcccggg ttcacaccat 3540

tctcctgcct cagcctccca agtagctggg actacaggtg catgttgcca tgcccagcta 3600

atttttttgt atttttttta gtagagacgg ggtttcactg tgttagtcag gatggtcttg 3660

atctcctgac ctcgtgatcc gcccacctcg gcctcccaaa gtgctgggat tacaggcatg 3720

tgccaccacg cccggcctca atctggtttt aacacttcaa cagatgtatg tagtttttgt 3780

atcaccatag cacctaaaaa gtacccccaa agttaaatat actgtcatct ctgtgtgtgt 3840

gtctgtagtc agtgccaggt ttgtatgtga atttgaggac cttccctagt ccccttgtcc 3900

cccaggcatc tcctgctcat aggtttggaa atgactgata gaggcttcat ctctagtcca 3960

agaaatgctg gacggtgtat ccatcctact gttccatctc t 4001

<210> 19

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 19

gcatggccca tggcggcctc ggaggaagct gaaagggtcc tgggtacagt gcaggtggga 60

aggagggggc aggaatccca gcctgcccac cccagatggg agaagccagc attccggcgc 120

ctcacgccag actcaaagcc attcatttct gccctgggat gttggataag ggcagcagac 180

gctcaaggtc agggctgcct ccccatgtct gtttgaagcc cagctccggg gcaccgttgc 240

tagtgggact ctgctaggcc ggcagccatc ctgttgaggg tgacaggacc acccaagggg 300

cttgtggtgc ccaggacggg gaccacacag ggccaccttc ctgctcagga atacagagcc 360

gctgcgagcc ccctcaggga gccaggctgg tcccgagggc ccagctttcc caagacgcac 420

ctgtggtcta ttcggagcct ctgtcccctt taaaatgagc tgtcttttta ttatcaggct 480

atgtgtgctc tttatccatt ctagatgtta gaccttgtcc gaggcctgat ctgcaagtgt 540

tccctcccgt tctgtgggtt ctttctcttt cttgatggtg ttctttgtag cgcaacagct 600

taacttctga ggaagttggg cttgtctatt ctttcttctg ttggcgtcac atccaagaga 660

ccactgcctg aggcaagtgc gtggagatgc tgtttggctc cggtactctg aagaggcgcc 720

tgctgtccca ggcccactac ccccgctcat gtcttttcct ttccttcctc cagattgttt 780

cctatcttct caccttctcc tttgcagtct ctgaacctgg aaatctgggg acaagctggc 840

agcggttggg gctgtggagg caccgccccc tccagcgagg tggtcccccc gcatctgggc 900

caacgtcagg gagggaggat gctggggcac agggctcggg gaggacacgg ggacccatct 960

ccagaaatca gccagcaggg acagctggct ggggaccagt ccaaccgctc agccataagc 1020

catggagcca gaagagggag ctaacggctc agagctggag acccagtcca cgcggcgctt 1080

acctgatgga caccgcgagg gacagcacct ccagcagcag ggctgcactg aagaccgcca 1140

gggcggcggg cgggggaggc acggtggccg cctcgtactt caggaagcag gtggtggaca 1200

gcgtcagaaa cactgtggtc gacagaaaca catccaggag ggagctgaag gtgggactag 1260

caaacgtctt cacgggggag ttctttatga cctgtgtgga gcaggagtgg agcagaatga 1320

ctgggaggcc atgggcggcc aggagcgcag ttcagatgga gaaacaggca acacgtgcgg 1380

agcactgctg ctctgggcca ggcacagggc aggaaggctc tcggagggct gtctccctct 1440

actaccccat ttaacactgg ggagtccaag gcacagagaa gttaaacttg cccagggggc 1500

tgggcacggt ggctcacgcc tgtaatcccg acactttggg aggctgacgt aggagggtcg 1560

ctggagccca ggagttcccg gccagcgtaa cacagtgaga ctccatctct acaaaaaact 1620

ttaaaattag ccaggcatgg cagtgcgtga gtgtggtccc agctactcag gaggatgacg 1680

caggaggatt gtgtgagccc aggagtttca ggccgcagtg agctataatc atgccactgc 1740

actccagcct gggcaacata gcgagacccc gtctaccaaa aaataaaata attagctggg 1800

catagtggtt tgtgcctgta gtcccaggta cttgggatct gaggtgggag gattgcttga 1860

gcccaggagt ttgaagccgc agtgaactat gatcacacca ctgcagaatt ataccgtttc 1920

cgaaaacaaa aaaacacaaa aaaaaccctg ccagggtcac agagcaactg attatgaccc 1980

agcacattct catagacaca ttatatattt agctgcaaga tgagttactg actggcgcag 2040

gtgaggtccc tgcatctgta aggcagttgg acgagagcaa tgtgcagggc ggtcctgctg 2100

catggcggag tcctaggttc agcaggtgcg aaagcggggc ttcgtggcgg aagtggccga 2160

cggggattta agtggcacat catcgcctgg gaacctacgg ggcctggctc tgtgctgggg 2220

gccagtacac tagagaggca cacactagtg ttcggcaatt gagggggaga aataacgatg 2280

ctgacacgtc caagaggtga ccaggcccag gccctgcaag gctctgggga ggtgcgatct 2340

ccattgacgc tcacggcacc ccacaggcag gaactaccac ccatctcggt gtacagattg 2400

ggaggccaag gccaggggct acccctaggg cacacagcga acaaggagcc aggccaggac 2460

ttggcatgga ccggttgact cctgagtgtg tccctaacct agaggaaggt gtaggatcca 2520

aaggcagagg ctgtggttgg gagaggaagg gatgtagcca gttcagctgc tttccatttg 2580

gccttgcaac cttctggcaa cccctgagag gccatgggtg tccactcagc atcccggcca 2640

ggctcggggc tgagggcagg agctggagac gcacggagcg gaaaggtctc ctggcagccc 2700

tgggtgcggt gtgcgttctt tgggacaaac cagctccggg tgcctcgacc actcccagga 2760

actaggtggg agggcaggag gggcacttgg acggtgggag caaggctgcc agtcagccct 2820

gatgccaggc tggaccctgc cagggcaacc tgggggttag ggtttggttc caaattctct 2880

ccaaggaagc tggaggctct gtagtgccca aaagggcaag tcaggtccca gccctggaat 2940

cccctcagaa ggtgtgggaa tttctttttt ttcatttttc ttttcttttc cttttttttt 3000

tttttttttt tgagatggga tctggctgtc gccaggctgg agtgcagtgg cgcgatcttg 3060

gctcactgca acctccgcct cccaggttca agcaattctc ctgcctcagc ctctggagta 3120

gctgggagga caggcacccg ccaccacgcc cagctaattt ttgtatgatt agtagagatg 3180

ggatttcacc aagttggcta ggatggtctc tatctcgacc tcgtgatctg cctgcctcgg 3240

cctcccaaag tgctgggatt acaggcctga gccactgtac ccggccaggt gtaggaattt 3300

caggggcgac actgcccatg cccactcacc ttggcagagg cccacgcacg tcccctttct 3360

gtggggctcc atctagtgcc cgtcaggggt tcgagtcagg gccgggtgca tgcatgtgat 3420

gtccctgaga catcactgcc ttgcccacat gtgaggccgg aaggtttcca cgtgggctgc 3480

cgtccttctg agagcccaca cctcccacct tccaagccaa gggctcgggt acagggcctt 3540

tcctgattgg ggctgccatc tcctctgtag aactgcccca tccatggacg ctgccagagg 3600

ccccgctcct ccctccacct cccttgcagt ctctcctgcc tgccctgcta cttgccagag 3660

acacctgtcc ctgccacagc ctccccctct gggccacccc tggccctgat gccagaggct 3720

cccaggccca tctgccccac ccctgtgcat cccgggagtg ccacctgtcc cagtcccact 3780

gagaacgacg ctcccccaca tcatgacact ctttcgccct ctctccccat gggcgaaacc 3840

cagggacagt gccactggct gccagggcac cgtgggccag gctccgccct gctcactacc 3900

cacatcccag ggcctccggg tgcggccgtc ccaccatcat cagagcacag gctctgcagc 3960

cgggctgtct gggctcaagg ccactccacc atgattagct a 4001

<210> 20

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 20

agtgtaggat tggaatttct gtctttattc caattttata ctttgaagac aatatctgga 60

gctgataaat cctttatctt ttttcattat aaaagagaat atcaccaaac ttagtgataa 120

ttctctttta taatgcatct ttattgatat tttaagttag aggtcagcaa actttttatg 180

ttaagggcca gataataaat atttgaggcc ttgtgggcca tatggtctct gtcacaacta 240

cgcaggtctg ctcttgctgg gcaagagcag ccataggcaa tacattaaca attaagcatg 300

tgttccaata aaactttatt tgcaaaagca ggtggtaggc ctgctggccc atttgaagat 360

aaagtatagc ataatcaaat tttttcctca tgactaaaaa taatagttac aaataaacac 420

tttacaaagc agaacataga gatcatataa aaatccttcc tggtatttat aatatacttt 480

ttacatggta gacttagctt ctgattatag tttgagttcc tttttatttg tgaatacctg 540

gctgactgac atagctattt tcgagtaact ttttgttcat attgtttacc tttttggata 600

ttaggtgctc tgtttctctt tttctttttc tttctttctt tctttttttt tttttttctt 660

gagacagtgt cttcctctgt tgctcaggct ggagtgtagt ggcgcgatct ctgctcacta 720

ttgcaacctc tgcctcctgt gttcaagcag tcctcctgcc tcagcctccc aagtagctgg 780

gactacaggc gcaagctacc acgctagact aatttttgta atttttttag agatggggtt 840

tcaccatgtt attcatttga tcttaaactc ctgagctcaa gcgatccacc cacctcagcc 900

tcccaaagtg ctgggattac tggtgtgaac cacggcacct ggcctgctct gtttttctat 960

aaaacaattt catttttctc aaaaggagaa caggtcagac tctcctacag ataatgcgga 1020

actgcatagg agtattggtt ggagcaacag tagtctatga ccaaacaaaa atgttatgtg 1080

tataaaactt ggaattggta ccaactttgt aaccatctta gaaataacat tttactgtgt 1140

acagcttatt ataacagtat tcaaaattgc ataatacgtc atattaagaa aattatctct 1200

gtaatgcgtt aatgcactgg gagctgccta ttctctgacc aaactgttag tttgttaatc 1260

tcacttaaca aaactagaat atgttcatta ataatgtgtg aaagactgtt acaccatttt 1320

taactcagtt gctgcagttg tctagttgta agcagcactg cttgcatggt gcagagggat 1380

atttcaaaat attatgcagc agcagttttg ggtttaattg tctgcagatg gtagatgatc 1440

tattttcctt actcgctgcc acatttctaa tagtacccag gctgttccat gtaaattagt 1500

aatctttcat gtaagcctgt ccttaatttt ccaatatttt tttgcatcat tttccagctg 1560

tatcatgtta gaactgatgt tttaattttc tatttttttt aaatatctgt gtgtcattaa 1620

tgttaaccac ttaaacacaa ctgctgagct gtgcaggcaa actaagaagc cagcctggtc 1680

tgcttcaaga ctcttaatca tttctttgtt cacatgttaa ccatgataac tatagcaaag 1740

gcaattcgta gtttctattc ttttccaacc aatacttgga gatgcatttt ttattctctt 1800

aaagtgaaaa aataaagttc ctgaatggaa agctgcatga aatttagata tcagagaaat 1860

ttttctacat aaaaacgttt ttagtgaaag agtgtaatat tcttctttac aaaagggatt 1920

tagtaagaag agaaaacatt gtgatttcaa caatagaatg ttgaaaaacc taatacgttc 1980

taaaagccta aagtttggat caccagaatt aacaatgaat ctttcagcac cacactcaat 2040

ttcaattgga aacactgctc agtcttcacc tttatttagg atgaatgttt ttggttttgt 2100

tttccttttt ttcttcttca gttgatctat ccaagatctc agccaaacct tgcaactgtg 2160

tcatagttag aaatccaact gcctgactag agcttgttta agggaaaaga attcagaata 2220

ttcagcacct tgctatgttt tttttttctt tttttccttt tctttttgtt gttgttagaa 2280

caaagttgag acaatttgat atactgatgg ggattcttct tgctagccta gcttcagtct 2340

ggcttttttt tccctcatgc atgctgacct ggaaatcctc ctttgcctta gctgcgataa 2400

tcgtgactca gcttacaaca ccttacattc gcatcgcccc cgctgcaggc gacggccaac 2460

taacaggtca gatgttcaag tatagacgag tcatcttgcc catttcccac tcatttttct 2520

cagctctgtt tcccctctac atttcctcct ttgcttaagg cctgtttaca atgtttcaga 2580

cccttggtac agacctttgc tcgtattaaa ttaagtgaca tgcttggcct cttctgtgtg 2640

cacatttata tccatgcatt aagtacaact ccactgcatg ttttcattgt gtgtttggtc 2700

tgttggtatg tttctttcta gactaatgtt atatagaaat gaaatttgct ggacttgaaa 2760

tagcaataac atcaaacagg gtttccaaca aaatacataa agatatattc ctagttttcc 2820

aaattagtct aaaatggtat tcagatttga gggtgcaaga gatttatttt ttaccttgcc 2880

tggtctagtt tgcacataca tttagctata cacaatcttg gctgccagta gtattaaacg 2940

aagcccccca aaggtgttta gggtggcagt gttctaacag ctttgtgtgt atgtacaata 3000

gttgcagagc tgattgcatt ccttatagat ccttgtttca aagcatagtg tttatataaa 3060

tcatgcagtg gcatatctgc aagtcaaatg ctttgaataa tttaggaaag tttagaaaaa 3120

ttgaatggct tagagtcatg gagttgaact gtgcttcctt ataccaagag aagtgagctt 3180

gttcactctt ccctctaaag ccttatagac atctctatac attcatatag gaaaagagtc 3240

cagtaaatta cttcagattg aaggtgagta gttagtgaac tccaaaagac aaactttttt 3300

gcttcagcaa aggcaagtca ttgtcaagat ttctaacatg attacctggg caggactcaa 3360

aattctggtt tcagaagcac ctgcttacag tctaggcctg atgaaagcca agtaagaagc 3420

agaaactact ttctatatga ttttcactcc agcaattgtt ttttgtgtgt gaaactaggc 3480

aatgtcccct aacatttaag aaaatggtaa agcttaactc atggtagtaa attacaaatg 3540

tttaagttgt tctgtgaact tattattttg gacagtaaag aaaactaagc ctcaggaaaa 3600

ttgtagactg atgttataag gtaaagaaat gtaaaataat tctatttcct tctccactgg 3660

aattctgtac atattttcag ttttaaagct atcaatttat tgacagttct gttgcccttg 3720

cctgcaagtt tcttttaaga gtatttcttt tcctgattga agttctactt gttacagact 3780

cttcctgctc ctgaacttct gaagtgttct tcccacaagt aaaagtattt gagggacagt 3840

gcctttctta ataagtcctc ccctctaaaa ccttgacctt tcaggactgg cctgtggcac 3900

tctgtgtagg gttaggagtc catcttgaag gttattggga tccttcagca actctgacca 3960

cccattgtgt ctgagctggc cccagactca tcagtacatt g 4001

<210> 21

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 21

ttctcaccag tatggatcct ttgatgcaga gtaagttctg agccacgact aaaggccctc 60

ccacattcct tacattcata gggtttctct ccagtatgag ttctcagatg ttcagtaagg 120

tgtgagccac gaataaaagc cttcccacac tgtttacatt cataaggttt ttcacctctg 180

tgaattctct gatgttcact aagttgtgag ccataaataa aggccttgtc acattcctta 240

catttgtagg gcttttcacc tgtatgaatt ctttgatgat atgtaagttg tgtagcacgt 300

acaaaggtct tcccacattc cttacattca taatgtttct caccatgaat tttctcatgt 360

tgagtaagat atgcaacacg aataaaggcc tttccacatt ccttacattc aaagggtttc 420

tcacctgtat gaattctctg atgttcacta agttgtttgc cacaaataaa ggcctttcca 480

cattccttac atttgtaggg cttctctccg gtatgaattc tttgatgttg aataagatta 540

gaattagaaa taaaggcttt cccacattct ttgcatttat aaggtctctc acctgaatga 600

actctcaggt ggtaagtaag ttgtgagcca cgaaaaaagg tcttcccgca ttctttacat 660

tcatagggtt tctctcctgt atgaattctc tgatgttcat tcagttggga ggcacataaa 720

aaggctttcc cacattcttt acatatgtaa ggcttttcac cagtatgaac tctctgatgg 780

tatgtaaggt gtgaaccaag aataaaggcc tttccacatt ccttacactc ataaggtttc 840

tcaccactat gaattctctg atggtaagta agttgagagc caagaataaa ggccttccca 900

caatccttac attcataggg tttttcacca ctatgaattc tctgatgaag agtatattgt 960

gaacaataac taaaggcttt tccacatttc ttacattcat atggtttctc tcctgtatga 1020

actctctgat gttcagtgag ctgtgaacca cgaataaaag ctttcccaca tgcgttacac 1080

tgataaggtt tttcattagt atgaattttc tgatgttgaa tgagatcaga agtacgacca 1140

aaggcctttc cacattccat acactcataa ggtttctcac cagtctgaat tctctgatgt 1200

tgaatatagc ttggcttttt gctaaaggta ttcctgtgtt tcttaacttc agagcatttt 1260

tctatattat gattttcctc atgttgaata aggcatgaca ggtagctgaa accttgtctg 1320

cattccttac atttgtacaa tttttccttg gtaggaatta tccgatgaaa agtagaagag 1380

gttgaatgac tttcagtggc cttttcttca caggtaattt tgacacacat gtaaagccct 1440

tcctgacttg cttcttgacc ctctaagttg cctttgcact ccatattgtc tccaagacca 1500

ttgtattgaa ggtgatggtt gatacgtttc cccatattct cccactggag tgattccatt 1560

tcataaattt ccttttctgg agataacttt ttggtcacac aactggattc caagtctgta 1620

gaataaaaag aaagcaaatt cctgcttttg tttacaagga gaaataaaaa ttctatggta 1680

aaaatgatag atgaaaataa ttctcattaa gaatagaatg gcttaaacag tacagaaata 1740

ttttctgcca tttttcttta aaggcacaag gagagaataa agaaaaagga gagcttatag 1800

gaaagaaggt aattagaaaa ataggttaag tcagtggttc tcaaactttg gaatggctta 1860

gagacaccca ggaggcttat aaaatagtaa taaaaacacc ctcttgaaaa caaacagatg 1920

tgtagctgga catacaatct atcaacaaat cctatcagct ctcctgtcaa cattaagaat 1980

ctgaccacct ctactaccac catcctaggc caagtcaccc ctctctcatt gtcataacct 2040

cttagctggt ttctctgctt tcatccttgc ttctatgatc tattcttcat acagcagcca 2100

gaggaattct tttaaaatgt ggtttatata acatgatttc ccctgctaaa aatcttccct 2160

attaatggtc tgccatctca ggataaaatc caaagtcctt aatatggctc acaagaccct 2220

acacaagctt gcctgtggcc acttttctta tgtcatctcc cactttggcc acttttctga 2280

tatcatcact taccactccc ctaattattc atttggctgt ggtcataatg gcctccttgg 2340

tgttaaaaaa gtgtcaagca tatgcctaca gttttgtctt tagaatgccc ttcctctaga 2400

tacctgcatg gcttgttccc tcatttcagt tttctgctca gctgtcacat tatcaaaaca 2460

tccaacacat aattgtacct atattgcatt tttcactaat ggatatacca tttctaaagt 2520

ttgactattg tctgtctgtc ccatgcttaa tcaaagcaag ggctttgttt catatactgc 2580

tttatctcta gtgcctaaca tcattactta cacattgctg gcattcaata tttgtcaaca 2640

atttctaaaa tatatatgtt ccttcattca taaatctcct tagatgcttc tcataaaaca 2700

caaagtttga gaatagagct aataatcttt caatggttta cccttgtatt tagaataaaa 2760

tccaaactcc tattcatggc ctacaagccc ctttacgatc cagttctttc ttaaatttct 2820

ccaatttctt caacgtacct tttaagcctc aaattgagcc actactatct tcagaacaat 2880

gctctaatct tattggcctg atttaagttc caagaacatg tcaaattctt tcccatttta 2940

gattttccat atgctgttcc atctgccaag aatgctctca aagtggccac ctcctttgcg 3000

tgtgaaatgt cctagcttaa atgtcagctg ctcagaaaga ctatcctgga tcactttaat 3060

taggtccatg ccaggtattt tctatacctg taatttattc ctaattcttg tttgaatttt 3120

tgcaattcta aaatttcatt tatttatctg ttgatctttc tgctcctcaa gctctacatg 3180

tgtaggggga aaatgcctgt tttattatat agctagtccc cagaacacag tatacatata 3240

atgttttatt cctttaatat agtttttcat gtcttacttt ccaatattta ttacttaagg 3300

ccaaatgttc ttatatttcc caaagaagta cctcaaaatc tcctagaaat agtgacaagt 3360

ttacacaata aagatcttat attattccga agaaagaagt tgagaaacaa gtgtactttt 3420

caaatgcaga gaaacctatc tgatgtaact ggatcagcag gcacagggtc tctgaccact 3480

gtatataggc tgtagaataa caaagactgg tcatgggaag aaaaataaat acacatcagt 3540

aagctcaaat ttaaacagtc ttttagaaat aagcctccaa aacttgagaa aacacacttt 3600

tgctgaaaag caaaaagaaa tgataaaaac aaaagcaact accccccccc acttgccata 3660

tacacaccac agctcagttt aacaccaatt catgtcagca acacatccta gaacaagata 3720

gaccctgctt ttgtttcttt catagaagaa caatatggtt tataaaacac tgaaagaaat 3780

caatgggctt atggtgatta agggaacact ataaggaatc aaataaattc agttgggacc 3840

caaaatagct acctatgtgc tagtgcccta ataaaaatgg gaagaaatat taatctaata 3900

tgattctggg gtaggaggca ctatgagaac acaggatggt gctaaacaga aatctagagg 3960

aatatagaaa aagttaagat tagaatacca aagtctcaga a 4001

<210> 22

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 22

aaaacatgtc tgtctccatg tgtctctctc tccccacccc aatctatacc tcccctggcc 60

accaccccac ttctacacct ctttcacaac ccctactttc ctccccctcc tccagtcacc 120

acccctatct ctgaagttat tcgtaaaggt accattgtct cacctccttc ccccactctt 180

cccagccttc ttcccctacc accccggccc ccgccaccac aagcctgccc tctgaaaatt 240

aattcgccat cgagatatac atgcttcggt tctattttgc atttctgcac tcaatgaggt 300

ttttgcagcc agattccctt cccacagtcg aagcaagtat ccctccgtga aaaattcaca 360

gcgttacacc aagggcagtc ccagtcccct ggcctgcgat atactggagg tctttgctga 420

tgaggttcgg agtatctcct gtctcttggg tgctcctgat ggtctattct gtggggcccc 480

ccatcagacc acaggctagt atcaaaggcc tcccagtcgg aaggcagctg aggcggaact 540

ggtgctgtga ctgttgcttg tggaggggat atagtgggta tgtctgagaa ggaggaaaaa 600

gggcttgagt atgagtatga gtatgaggca gggagctgga caggaagagg ttctgatgag 660

gctctggacc aggggttcgt ggttccagag aaataagatg tggctgtttc gaccgaccgg 720

agatctccct ccttctgccc ccaataggtg tacttttcct gatcagcatc tccaaggagc 780

tgcaggagga ttctctccag cttctctgtg gtctccatgg aggcagccct ggcctccacg 840

tgggggaact gggtctccat gggggcagcc ccagcctcca cagggggagc catggcctcc 900

acaggggcag ccacaacctc cacatccctc tgctcttctt ctgctccttt tcctccagca 960

gcaccagcag cagccaccgc cgcctcttct tcctcctcag ctgctccttc tgtgcaaacc 1020

cctccggcag tggccaggcc tggccaccct gccccctgct cccactcatg gggagacacc 1080

agctcctgga gagaagtggg cagggctgag gtgtgttctg ggggcaaggc gggagcacta 1140

agcagggtag gacggagcta ccaggtggga agggcggggc agggcgaagc catggagcag 1200

ggtggagagg ggtgggaatg gggcagggca gtggtactgg gcagggacca gttgagggat 1260

cttactgcat ggagcggctt ccaactcacc ttgtctctct ctttctgcac ctccacgagg 1320

ctggtctggg ccattcttag ccgggaggcc gcctccttgc gttccgtctc ctgctgctcc 1380

ctgagcttct tcaggtctga tgccaaggcc tgtgcggctg atttgtgcag tttggcgaag 1440

ccgtgcagcc accgcaccct gtgcctttgt agctgtgcct gcctgtgggc aaagcgcact 1500

cccaaggcca ggctgcccca ggtgcaggcc tctttgacct cactgggcac ctcgctgtcc 1560

tccagtatgg ccctcagctt gtcttccacc ttctcccagg ataaggatat attctcaaga 1620

tagaactcgg ggcctttcgt gtgcctggcc attttctcgt tgatgaaggc caccacgttg 1680

ctatgccgga acccgctact ggggtcctca ggtctcaagg ccatgatcgc ctaggggttt 1740

aacggtttca ctagccctgt gtggatggag cagccaatag gttcctttcc tcccccttag 1800

cccctcccct catccatctt ctcccgccct cttgtccccg ccctacccgc tctgacaaga 1860

ccgtcctaat gaccccctga ccggcttgtc ctaccctagg acacctccca ccaggcctca 1920

cctcttcagc cagggccaga ggaagtacag gccaaccccg ctgtcttaac acgcccgaag 1980

agagaggaag atctctctcc ctcctaaggt tccagggaaa ggaagactca gggccaacgt 2040

cggcttttac tctgggactg ttccaatttc cagagatacc aggagtggaa gggagtgagt 2100

gaggaaggcc cctgccactc cattgggatt taagggaacc tgtcacatgg ttgggagccc 2160

ttaaaggtcg gaagaaacag gagtggtcag aaaagactta gaaccaagaa aattaagccc 2220

ttataatcaa gtcaaaaaag tcccatgtat ccctccctct tgacaatggt ttgtcccatg 2280

ccaacggcta gtagggaccc ccctagaggt tgaaggggga ataatgggta tgttctagaa 2340

cacgaaaaag cccccaaccc atgaaaattc tgcagttcat tttccagact cctaaatcct 2400

agtatacagg ttagtgacct ttttctgaaa cgggcaagat agcaggcatt tgaggctttg 2460

tgggcaaaag attatcccaa ctacttgtag cacaaaagca gccataaata atacctgaag 2520

aaatgaccat ggccatgttc taataaaagt tcatttataa aaccaggcag ttggcatgat 2580

ttggcctgta gatgtcaaac tcccaatcta gattcacatt tcatacatgt cctacagaca 2640

catacaatca gaatgttcat gatatgactc ccccttttcc ctgttaaaag aaaaacgtta 2700

gacaacgtta acagtttgtt tacacataaa caacaaccaa aaaaaaaaaa aaagaaaaac 2760

gagtcatgaa tttgtcagta ctcagaacca gaagagtttc agagagctat tcccagcaac 2820

atgagaagtg aatttttata ggctgagttt ggacacaaaa gagaaaaatc acctgattgg 2880

ctacagcaag gcatttgcct tatttggaca tggtcttgtc acttgactgc ctgtaattag 2940

ctggagcctg gctagttgtg tttggctgaa attaggctgt cttttataca gcttatgtta 3000

agtttcagtc tgtttacatg ctaagttagt ttgcggtttg ttagatagga actcaaagta 3060

tggaaacagc ttcaaactaa tggcctcttg cttattttaa tatatgcagg agatgattcc 3120

cctcctaaat tcctatgttg tccaatacag aaacctcaaa atcaaatttt taagttacct 3180

acccttcata ccgaccctta aaaacaagtc aactaagaga caaaatcttg ttgctgtgac 3240

ctcagaaact tctaagacat ccatgcccac ttagggaatg tccatgtttc ttctcaaata 3300

atcttcctgt ctttaatttc ttcataatcc ctaatcactt cctaatcttt cctatgatca 3360

tgtttctctt aagcttaaaa tcatttgatg gatccttgtg gcacactcct tgtcctgaca 3420

ttagaatctc accccaggat accattctaa tttaactctc tccacaatgt tatccaccat 3480

catttatgta cctaagggac taagccatac agggatacac tgattttggc gttttaagtt 3540

attttccctt ctgaaaaatc agagcattca ttttttatta tatgggcatt atgttctatt 3600

ctatgaacta catttaaaaa gacaatattt cttctctaag ggtcctatgt cagataatta 3660

gagaggaaaa agacaataaa tcaagcatta aaatattacc taagaaggta gttaaacccc 3720

agaggcataa agtcccacca tttaaatgct gtttttagat gctgttttgt gatttctttc 3780

cttctcagct tgtatatttt atttatcagc catcagtgga aagggttcat gttttggctt 3840

attctagagt gacttctaca gaaagagcat ccagaagata atgtagaaaa gagaatggtg 3900

aggaaagggg gagagactgg agtcaggaag acccattagg gagatgctaa agcaattcaa 3960

gaagtaaact aaagcagtgg aaatagggat ggagagaaga g 4001

<210> 23

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 23

gtgtctctct ctccccaccc caatctatac ctcccctggc caccacccca cttctacacc 60

tctttcacaa cccctacttt cctccccctc ctccagtcac cacccctatc tctgaagtta 120

ttcgtaaagg taccattgtc tcacctcctt cccccactct tcccagcctt cttcccctac 180

caccccggcc cccgccacca caagcctgcc ctctgaaaat taattcgcca tcgagatata 240

catgcttcgg ttctattttg catttctgca ctcaatgagg tttttgcagc cagattccct 300

tcccacagtc gaagcaagta tccctccgtg aaaaattcac agcgttacac caagggcagt 360

cccagtcccc tggcctgcga tatactggag gtctttgctg atgaggttcg gagtatctcc 420

tgtctcttgg gtgctcctga tggtctattc tgtggggccc cccatcagac cacaggctag 480

tatcaaaggc ctcccagtcg gaaggcagct gaggcggaac tggtgctgtg actgttgctt 540

gtggagggga tatagtgggt atgtctgaga aggaggaaaa agggcttgag tatgagtatg 600

agtatgaggc agggagctgg acaggaagag gttctgatga ggctctggac caggggttcg 660

tggttccaga gaaataagat gtggctgttt cgaccgaccg gagatctccc tccttctgcc 720

cccaataggt gtacttttcc tgatcagcat ctccaaggag ctgcaggagg attctctcca 780

gcttctctgt ggtctccatg gaggcagccc tggcctccac gtgggggaac tgggtctcca 840

tgggggcagc cccagcctcc acagggggag ccatggcctc cacaggggca gccacaacct 900

ccacatccct ctgctcttct tctgctcctt ttcctccagc agcaccagca gcagccaccg 960

ccgcctcttc ttcctcctca gctgctcctt ctgtgcaaac ccctccggca gtggccaggc 1020

ctggccaccc tgccccctgc tcccactcat ggggagacac cagctcctgg agagaagtgg 1080

gcagggctga ggtgtgttct gggggcaagg cgggagcact aagcagggta ggacggagct 1140

accaggtggg aagggcgggg cagggcgaag ccatggagca gggtggagag gggtgggaat 1200

ggggcagggc agtggtactg ggcagggacc agttgaggga tcttactgca tggagcggct 1260

tccaactcac cttgtctctc tctttctgca cctccacgag gctggtctgg gccattctta 1320

gccgggaggc cgcctccttg cgttccgtct cctgctgctc cctgagcttc ttcaggtctg 1380

atgccaaggc ctgtgcggct gatttgtgca gtttggcgaa gccgtgcagc caccgcaccc 1440

tgtgcctttg tagctgtgcc tgcctgtggg caaagcgcac tcccaaggcc aggctgcccc 1500

aggtgcaggc ctctttgacc tcactgggca cctcgctgtc ctccagtatg gccctcagct 1560

tgtcttccac cttctcccag gataaggata tattctcaag atagaactcg gggcctttcg 1620

tgtgcctggc cattttctcg ttgatgaagg ccaccacgtt gctatgccgg aacccgctac 1680

tggggtcctc aggtctcaag gccatgatcg cctaggggtt taacggtttc actagccctg 1740

tgtggatgga gcagccaata ggttcctttc ctccccctta gcccctcccc tcatccatct 1800

tctcccgccc tcttgtcccc gccctacccg ctctgacaag accgtcctaa tgaccccctg 1860

accggcttgt cctaccctag gacacctccc accaggcctc acctcttcag ccagggccag 1920

aggaagtaca ggccaacccc gctgtcttaa cacgcccgaa gagagaggaa gatctctctc 1980

cctcctaagg ttccagggaa aggaagactc agggccaacg tcggctttta ctctgggact 2040

gttccaattt ccagagatac caggagtgga agggagtgag tgaggaaggc ccctgccact 2100

ccattgggat ttaagggaac ctgtcacatg gttgggagcc cttaaaggtc ggaagaaaca 2160

ggagtggtca gaaaagactt agaaccaaga aaattaagcc cttataatca agtcaaaaaa 2220

gtcccatgta tccctccctc ttgacaatgg tttgtcccat gccaacggct agtagggacc 2280

cccctagagg ttgaaggggg aataatgggt atgttctaga acacgaaaaa gcccccaacc 2340

catgaaaatt ctgcagttca ttttccagac tcctaaatcc tagtatacag gttagtgacc 2400

tttttctgaa acgggcaaga tagcaggcat ttgaggcttt gtgggcaaaa gattatccca 2460

actacttgta gcacaaaagc agccataaat aatacctgaa gaaatgacca tggccatgtt 2520

ctaataaaag ttcatttata aaaccaggca gttggcatga tttggcctgt agatgtcaaa 2580

ctcccaatct agattcacat ttcatacatg tcctacagac acatacaatc agaatgttca 2640

tgatatgact cccccttttc cctgttaaaa gaaaaacgtt agacaacgtt aacagtttgt 2700

ttacacataa acaacaacca aaaaaaaaaa aaaagaaaaa cgagtcatga atttgtcagt 2760

actcagaacc agaagagttt cagagagcta ttcccagcaa catgagaagt gaatttttat 2820

aggctgagtt tggacacaaa agagaaaaat cacctgattg gctacagcaa ggcatttgcc 2880

ttatttggac atggtcttgt cacttgactg cctgtaatta gctggagcct ggctagttgt 2940

gtttggctga aattaggctg tcttttatac agcttatgtt aagtttcagt ctgtttacat 3000

gctaagttag tttgcggttt gttagatagg aactcaaagt atggaaacag cttcaaacta 3060

atggcctctt gcttatttta atatatgcag gagatgattc ccctcctaaa ttcctatgtt 3120

gtccaataca gaaacctcaa aatcaaattt ttaagttacc tacccttcat accgaccctt 3180

aaaaacaagt caactaagag acaaaatctt gttgctgtga cctcagaaac ttctaagaca 3240

tccatgccca cttagggaat gtccatgttt cttctcaaat aatcttcctg tctttaattt 3300

cttcataatc cctaatcact tcctaatctt tcctatgatc atgtttctct taagcttaaa 3360

atcatttgat ggatccttgt ggcacactcc ttgtcctgac attagaatct caccccagga 3420

taccattcta atttaactct ctccacaatg ttatccacca tcatttatgt acctaaggga 3480

ctaagccata cagggataca ctgattttgg cgttttaagt tattttccct tctgaaaaat 3540

cagagcattc attttttatt atatgggcat tatgttctat tctatgaact acatttaaaa 3600

agacaatatt tcttctctaa gggtcctatg tcagataatt agagaggaaa aagacaataa 3660

atcaagcatt aaaatattac ctaagaaggt agttaaaccc cagaggcata aagtcccacc 3720

atttaaatgc tgtttttaga tgctgttttg tgatttcttt ccttctcagc ttgtatattt 3780

tatttatcag ccatcagtgg aaagggttca tgttttggct tattctagag tgacttctac 3840

agaaagagca tccagaagat aatgtagaaa agagaatggt gaggaaaggg ggagagactg 3900

gagtcaggaa gacccattag ggagatgcta aagcaattca agaagtaaac taaagcagtg 3960

gaaataggga tggagagaag agtgtagaga gccatttggt a 4001

<210> 24

<211> 4001

<212> DNA

<213> Homo sapiens

<400> 24

cattcaaatg attctccagc cagagaagtt ataggcagag gcagtgacaa aggtcaaagc 60

acataataag tgtactttct gagagggagt tttttttccc cattttaaca tttttgtctt 120

gaatttcaat tacttaaatc caaaatcact gccttttcct atgtctcaaa taatggaagc 180

tgctttgaga ttcacatcaa aagccaacat ggcactataa tggctctcca gcgcttgaat 240

aaagcccagt agtacttata acagtatcag ctcaaaaatg ggaagcgtta caatagctac 300

cacttaatga gcactatgtg gatgatacta ttcgaaagct ttacaccctt cattttattt 360

aatccccaca atcatcctga gataaactct attattcata ttttacagat gactcaacta 420

aggctcaggg aggtaaggta gcatgatcaa agtgtctatc agaaagtgat agagatggaa 480

cttgaaccca ggcaatatgg ctccagaaca catactccaa cccctaggca tattttctcc 540

cttagcttgt gagagccaat gcctttccgg tgtatattgc ttgaaatcta ttatatttga 600

acccctcagg agcacaggtg tcatcagcct cgtctctgcg tccctattgt ttcctcttcc 660

cttcacttgg ttcaaaaaga actgttctgc ttttccacta agcctcttca ccatttgact 720

gctactatct ggggaagcct ctctatctgc actctgtatc tagagtgttc cttgctgctc 780

gaaatatact ccacggtcca gcagcatcag catcaccagg gaacttgtta gaaatgaagc 840

atctcaggta tcaccccaga ctactgaatc agaatctgca ttttaacaga ctctcaggtg 900

attcgtgtgc acattgaagc tcgagagcag cgctctccat cttttgcagt acttactccc 960

ttagtaattc cttgctggag tgttccgtac acagaagtct aaaatctatg gcttgaaagg 1020

gagggaatca tttaagctgt tccctgttct ctggccttta ggagctccaa aatcagtcag 1080

agaccatgct aagagtagat cttgctgtca ttagactaac aaatatgtgg acgaaatgaa 1140

aagacagcca cgttagccat gatttccttt ccatatttca ttcatgctct ccctgtatct 1200

cacactgcca caacacagat gctttctttt atatcatggg aacattttta attaaagcat 1260

tggaaccttt gagaatagac aatcctttaa aagttaagtt tatctgtatt tacaagcctc 1320

catttatttg gcagtgacaa taggaaaaaa aaactgctgc taaaggcata tagaggaatg 1380

attaagctaa tttacaataa ttgctttaat cttgacatat tgaattgtag tgtctaactc 1440

tttgagttct ctcggtctga ggtaaaggaa aaatataaca ctgtgttcga tattgtacct 1500

ctgaagcaca atggaaattt tgccctacag tgccagcctg tcacccatgg tgtccatgtg 1560

atagaagggg agagatcacc cgcaatgtct aattgccact gtactcactc ctgtgcttta 1620

agatagaaag cccatgttca gaagcaaagc cattagcagc tattaattgc ttagctctaa 1680

taaattgtcc agaccaggac ttaattaggg aagacattta ggaacaggac acaggacaag 1740

aggacataaa ggagagccag gaatgagatg aaacctgagc agccaggaag gccaggaagg 1800

ggcccaggat ggagagaggg tagttgagat atccggatgt caactttact tactttctga 1860

tcgcgtttca agacagtccg gctggttgct tcttctaaag actcctatag ttttgcatct 1920

atacctctcc aggaagcacc tggagtagga agagccgtgg tatctaaggt gatatgaatg 1980

gtttcttttt gctcttggca gctctgctca cccctgcctc ccctgaagct gtctacttct 2040

ctgcttgatg ggactggctg ggtcaggcct ggttttgctt tctgactgac tcaggtctga 2100

gtcactgatc aagaggagga agtcctaatc atgggtgcag ccctttcaag taagaaacat 2160

ggaatttcat caaaagggac tgtgagctct ccgagacatt tggctgacag ttattgtccc 2220

attatttcac ttttagagaa actacattct tcatctttgg cccttcgtga actctgctcc 2280

accagtgatt tcaatctcaa agtttcctga agggctttgg ccagatgtga ccaacagctc 2340

atcatgagct gatatctggt atacggcctc aaacaatagg aagaagatga tcattgtatt 2400

catgcaacat ttatataggt gtctctctcc agattctggc aagaaattgc aaaaaaatga 2460

actattgctt ttgaattgga aacaaagtac ttggctgcta aaaatgtggc actgcagccc 2520

acttacaaca gttgagggca ttacaacagt tggactctct tggtgtcatt cctttaaaga 2580

aaagcattat cagcaagaag caaatatggg tcattcttat taatatttcc atactctaac 2640

ttccttctga ggggcttggt gcattctaac tcaattatct cacttatctt tgagggcttt 2700

tgattatctt gggtggggtt gtgggacagg gagggtcgac acacaagcac atatccttta 2760

agagctcaca gatgctttta catctagcaa cttgtttgag cctcgtaagt ctatgaggtc 2820

tacagagatg atcatacctt atttgtgaaa gaaccatgtt tgaaagccag ggcttccagc 2880

actacatccc aaataccccg agagctgtgg ctctcagcac cactgttgct gtagacagca 2940

ttcactgttc tttaacttcc aaggatgtca gggtagccgt gcgcttgcaa agagggggca 3000

ccagggcttt tttcttcccc tgcttcattt gctctttatt tcttacactc tgactcctta 3060

ttgaaggttt gtggccctaa atgcagtttc tttagctgtc tctttccctc caaccccagg 3120

tagtatttta gcctggatag ttcccatagg tatttcttta tacctaaatt caaaagtgtt 3180

tcttgacttc cttaaaccta tgccctttta tgatcaacat cttgcatgtc ctaccatttc 3240

tccccctccc ctgacccttg caaagacact ggaatggaca ttcatcccca gtggagagtt 3300

caggctcctg gtttccatag ccttcatctt atccctacca gcagccacat ttttacgaat 3360

ctttatttcc tgttttaaga aagcaatatg cctatttttt ctctgcgata taaggtagca 3420

taatattgat aggatctttc aaactatttc tctctggccc tggttctgaa acatatagcc 3480

ccttgagaaa catggctcta ttattaccta tcaagtttta ttatatttaa aactgtttcc 3540

acatctgttc ccctaaaccg tgacctcctt gaggatgggg atataatctg gttaatcttt 3600

gtatctgcaa atgccaagca gagtgccagg tacataaatt gttgaacgaa cgaacgaatg 3660

aatgaatgaa tgaataaata gtgccagaag aagacaatgc tactccatca tttcccccat 3720

gtcttgctct gtttttagcc aaagtacaaa ctggaagtgt ctaagatatt ttaacaccca 3780

actatgaata gtgtcaatga aaatgacaat agttcccttc tctgttcccc cattctgtct 3840

attttcccat agaatcttta ctgctcaggt tctatatgct tctgcttgac taattataca 3900

cttctttctt tcttcttgaa tgtttaaact gacagtaatt gcccagaact gaatgcatga 3960

cctctaagaa tctaatacta ctaaaaaggg actggtttca c 4001

Claims (10)

1. A system for predicting the prognostic survival of a patient with intrahepatic cholangiocellular carcinoma, comprising:

the acquisition module is used for acquiring variables related to the prognosis survival period of the intrahepatic cholangiocellular carcinoma patient; and

the prediction module is used for predicting a prognosis parameter of the intrahepatic cholangiocellular carcinoma patient according to the at least one variable obtained by the acquisition module and outputting the prognosis parameter;

wherein the variables comprise promoter methylation scores that are based on methylation levels of at least 24 promoter regions; the 24 promoter regions are a set of polynucleotide sequences shown in SEQ ID No.1 to SEQ ID No.24 or a set of polynucleotide sequences complementary to SEQ ID No.1 to SEQ ID No. 24;

the acquisition module and the prediction module are connected in a wireless and/or wired mode.

2. The prediction system of claim 1, wherein the obtaining module is configured to obtain a promoter methylation score, and wherein the obtaining module comprises:

an analysis unit at least for analyzing the methylation level of the 24 promoter regions in an ex vivo sample of a patient with intrahepatic cholangiocellular carcinoma; and

a scoring unit for calculating a promoter methylation score based on at least the methylation levels of the 24 promoter regions;

wherein, the analysis unit is connected with the scoring unit in a wired and/or wireless mode.

3. The prediction system of claim 2, wherein the acquisition module further comprises: an output unit for transmitting the promoter methylation score to the prediction module; the output unit is connected with the scoring unit in a wired and/or wireless mode.

4. The prediction system of any one of claims 1 to 3, wherein the promoter methylation score is calculated according to formula (1):

promoter methylation score = (-1.778426) × M (SEQ ID No. 1) + (-0.5188023) × M (SEQ ID No. 2) + (-0.007917956) × M (SEQ ID No. 3) + (-4.853461) × M (SEQ ID No. 4) + (0.442986) × M (SEQ ID No. 5) + (-1.512141) × M (SEQ ID No. 6) + (-0.503913) × M (SEQ ID No. 7) + (-2.622882) × M (SEQ ID No. 8) + (-5.796018E-14) × M (SEQ ID No. 9) + (-2.918528) × M (SEQ ID No. 10) + (-1.456336) × M (SEQ ID No. 11) + (-0.02070397) × M (SEQ ID No. 12) + (-0.4516687) × M (SEQ ID No. 13) + (-0.5262961) × M (SEQ ID No. 14) + (-0.01533871) (-3615) (-3985) × M (SEQ ID No. 3) (-0.3580827) (-3615) × M (SEQ ID No. 3) (-18) SEQ ID NO. 17) + (-0.03428591) × M (SEQ ID NO. 18) + (-0.183213) × M (SEQ ID NO. 19) + (-0.6439997) × M (SEQ ID NO. 20) + (-0.9643823) × M (SEQ ID NO. 21) + (-0.4090321) × M (SEQ ID NO. 22) + (-1.727257E-14) × M (SEQ ID NO. 23) + (-0.1818805) × M (SEQ ID NO. 24) (1)

Wherein "x" refers to a multiple, and M refers to the average methylation level of all CpG dinucleotides contained in the corresponding polynucleotide sequence.

5. The prediction system of claim 1, wherein the variables further comprise: ascites status, tumor size, macrovascular invasion status, lymph node metastasis status, degree of tumor differentiation, and CA19-9 saccharide antigen concentration.

6. The prediction system of claim 1, wherein the prognostic parameter includes: a prognostic survival risk grouping, and/or a survival probability value for a specified age.

7. The prediction system according to claim 6, wherein the prognostic risk grouping is based on a preset threshold to obtain a prognostic classification for patients with intrahepatic cholangiocellular carcinoma.

8. The prediction system of claim 6, wherein the probability-to-live value for the specified age comprises: the prognostic survival is a probability value of three years and the prognostic survival is a probability value of five years.

9. The prediction system of claim 1, wherein the prediction module predicts and outputs the prognostic parameter by: and importing the acquired variables into a pre-established Cox regression model, calculating the prognosis parameters through the Cox regression model, and visually presenting a prediction result.

10. The prediction system of claim 1, wherein the obtaining module and the prediction module are respectively a processor, a server or a computer host; or, the obtaining module and the predicting module are integrated in the same processor, the same server or the same computer host.

Images