METHODS, TREATMENT, AND COMPOSITIONS FOR CHARACTERIZING THYROID NODULE

Abstract

The current disclosure provides, inter alia, method of determining benign nodules from thyroid cancer in a subject that is found to have a thyroid nodule, method of treating thyroid cancer in a subject detected to have thyroid cancer by the method of the current disclosure, compositions for determining benign nodules from thyroid cancer in a subject, and kits including reagents and composition for determining benign nodules from thyroid cancer in a subject.

Description

INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING

The content of the text file named “48440-573001 US_ST25.TXT”, which was created on Jul. 22, 2016, and is 328.827 bytes in size, is hereby incorporated by reference in its entirety.

BACKGROUND OF THE DISCLOSURE

Palpable thyroid nodules are typically detected in 2-6% of the population, and this increases to 19-35% with ultrasound detection (Dean D S and Gharib H. Best Pract Res Clin Endocrinol Metab 2008; 22:901-11). Approximately 5-15% of thyroid nodules are found to be thyroid cancer, making the existence of a nodule clinically relevant. Fine needle aspiration (FNA) with cytology is currently the standard diagnostic procedure used to evaluate thyroid nodules. However, in as many as 30% of cases, the cytological diagnosis is indeterminate because of cytological features that overlap between benign and malignant nodules. For most indeterminate cases half or the entire thyroid is resected, yet as many as 80% of these cases are found to be benign.

Most thyroid nodules do not cause symptoms. Often, thyroid nodules are discovered incidentally during a routine physical examination or on imaging tests like CT scans or neck ultrasound done for completely unrelated reasons. Occasionally, patients themselves find thyroid nodules by noticing a lump in their neck while looking in a mirror, buttoning their collar, or fastening a necklace. Abnormal thyroid function tests may occasionally be the reason a thyroid nodule is found. Thyroid nodules may produce excess amounts of thyroid hormone causing hyperthyroidism. However, most thyroid nodules, including those that cancerous, are actually non-functioning, meaning current diagnostic test readouts such as the level of Thyroid-Stimulating Hormone (TSH) are normal. Rarely, patients with thyroid nodules may complain of pain in the neck, jaw, or ear. If a nodule is large enough to compress the windpipe or esophagus, it may cause difficulty with breathing, swallowing, or cause a “tickle in the throat”. Even less commonly, hoarseness can be caused if the nodule invades the nerve that controls the vocal cords but this is usually related to thyroid cancer.

Molecular testing is a potential alternative to cytopathological examination. However, FNA molecular testing based on DNA mutations frequently fails. There are two major reasons for this failure: (i) not all papillary thyroid carcinoma (PTC) specimens are characterized by a common set of cancer associated mutations, and (ii) cancer associated mutations like KRAS are frequently found in benign thyroid nodule (BTN) specimens. At the same time commercial diagnostic tests for FNA based on transcriptional activity and currently implemented in clinical practice is complicated due to RNA instability and associated with only an approximately 50% positive predictive value. Thus, there is an urgent need for highly sensitive, low cost biomarker panels that can accurately diagnose thyroid nodules from FNA biopsies.

BRIEF SUMMARY OF THE DISCLOSURE

The present subject matter provides, inter alia, a method of determining benign nodules from thyroid cancer in a subject that is found to have a thyroid nodule, a method of treating thyroid cancer in a subject detected to have thyroid cancer, compositions for determining benign nodules from thyroid cancer in a subject, and kits including reagents and compositions for determining benign nodules from thyroid cancer in a subject.

In embodiments, aspects of the present subject matter provide a method of detecting methylation or unmethylation of a thyroid nodule DNA of a subject, the method including: (i) isolating DNA from a thyroid nodule of the subject thereby forming isolated thyroid nodule DNA, (ii) contacting the isolated thyroid nodule DNA with a bisulfite salt (such as sodium bisulfite) thereby forming a reacted thyroid nodule DNA, (iii) detecting the presence or absence of uracil in the reacted thyroid nodule DNA at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of the thyroid nodule DNA of the subject.

Also provided is a method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof. The method includes isolating DNA from a thyroid nodule of the subject thereby forming isolated thyroid nodule DNA. The isolated thyroid nodule DNA is contacted with sodium bisulfite thereby forming a reacted thyroid nodule DNA. The presence or absence of uracil is detected in the reacted thyroid nodule DNA at a methylation site set forth in Table 1 thereby determining thyroid cancer in the subject.

In embodiments, provided herein is a method of treating thyroid cancer in a subject by administering to the subject an active agent for treating thyroid cancer. The method includes identifying the subject for treatment by a method including isolating DNA from a thyroid nodule of the subject thereby forming isolated thyroid nodule DNA. The isolated thyroid nodule DNA is contacted with sodium bisulfite thereby forming a reacted thyroid nodule DNA. The presence or absence of uracil in the reacted thyroid nodule DNA is detected at a methylation site set forth in Table 1 thereby determining thyroid cancer in the subject.

Also included herein is a deoxyribonucleic acid 5 to 100, 5 to 200, 5 to 300, or at least about 5, 50, 100, 150, 200, 250, 300, or more nucleotides in length including a uracil-containing sequence identical to at least a 5 contiguous nucleotides within a sequence including SEQ ID NO: 1 to SEQ ID NO:550.

In embodiments, provided herein is an oligonucleotide 5 to 100, 5 to 200, 5 to 300, or at least about 5, 50, 100, 150, 200, 250, 300, or more nucleotides in length including identical or complementary to at least 5, 10, 20, 25, 50, 100, 150, 200, 250, or 300 contiguous nucleotides within a sequence including SEQ ID NO: 1 to SEQ ID NO:550.

Aspects of the present subject matter also include a deoxyribonucleic acid including SEQ ID NO: 551 to SEQ ID NO: 782, in which the nucleic acid is hybridized to a complementary DNA sequence having uridine or cytosine.

Also provided is a kit including a plurality (e.g., at least about 10, 20, 40, 50, 100, 150, 200, 225, or 232) nucleic acids each independently comprising SEQ ID NO: 551 to SEQ ID NO: 782, in which the nucleic acids do not simultaneously include the same sequence of SEQ ID NO: 551 to SEQ ID NO: 782.

Aspects of the present subject matter also provide a system for detecting methylation or unmethylation of a thyroid nodule deoxyribonucleic acid (DNA) of a subject. The system can include at least one processor; and at least one memory including program code which when executed by the at least one memory provides operations. The operations can include: isolating DNA from a thyroid nodule of the subject thereby forming isolated thyroid nodule DNA; contacting the isolated thyroid nodule DNA with bisulfite salt thereby forming a reacted thyroid nodule DNA; detecting a presence or absence of uracil in the reacted thyroid nodule DNA at a plurality of methylation sites set forth in Table 1, thereby detecting methylation or unmethylation of the thyroid nodule DNA of the subject; and generating a diagnosis for the subject based at least in part on the presence or absence of uracil in the reacted thyroid nodule DNA at the plurality of methylation sites set forth in Table 1; and providing, via a user interface, the diagnosis for the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B show a drawing defining a threshold for thyroid adenoma specific signature for individual cytosine regions. FIG. 1A: Adenoma specific hypomethylation signature. FIG. 1B: Adenoma specific hypermethylation signature.

FIGS. 2A and 2B show 364 cytosines associated with BTN or PTC specific DNA methylation changes. Legend (FIG. 2A): Cancer specific signature (gray); benign specific signature (black). FIG. 2B: 364 CpG sites associated with benign- and thyroid cancer-specific DNA methylation changes. Each row represents a single cytosine. Each column represents tissue specimen. Dark gray, light gray and black indicate high, low and medium levels of DNA methylation, respectively. Abbreviation “A” is for thyroid benign nodule and “T” is for thyroid cancer.

FIGS. 3A-3C depict exemplary thyroid cancer diagnostics based on DNA methylation signatures. FIG. 3A: Thyroid cancer diganostics based on benign DNA methylation signature, cancer DNA methylation signature and cancer risk scores. FIG. 3B: DNA methylation signatures for malignant and benign thyroid nodules according to leave one-out-cross-validation technique. Specimens with indeterminate epigenetic signature are underlined. Abbreviation “A” is for thyroid benign nodule and “T” is for thyroid cancer. FIG. 3C: Algorithm for the diagnosis prediction based on BTN. PTC and cancer risk scores.

FIG. 4 depicts a block diagram illustrating an exemplary thyroid cancer diagnostics system.

FIG. 5 depicts a flowchart illustrating an exemplary process for diagnosing thyroid cancer.

FIG. 6 depicts a flowchart illustrating an exemplary process for diagnosing thyroid cancer.

DETAILED DESCRIPTION OF THE DISCLOSURE

Provided herein are, inter alia, compositions, methods, kits, and systems for detecting unmethylated DNA. In embodiments, compositions, methods, kits, and systems for detecting unmethylated DNA from thyroid nodule are included herein.

The following definitions are included for the purpose of understanding the present subject matter and for constructing the appended patent claims. Abbreviations used herein have their conventional meaning within the chemical and biological arts.

DEFINITIONS

The term “thyroid nodule” is used according to its plain ordinary meaning and refers to an abnormal growth of thyroid cells. The abnormal growth may form, for example, a mass or lump within or on the thyroid gland. The mass or lump may be fluid-filled or solid. The thyroid nodules may be benign (noncancerous) or cancerous.

Thyroid fine needle aspiration biopsy (FNA or FNAB): For a fine needle biopsy, a needle is used to withdraw cells from a thyroid nodule. In embodiments, several samples are taken from different parts of the nodule, e.g., to increase the chance of finding cancerous cells if they are present. In embodiments, a sample is taken from one part of the nodule. In embodiments, examination of the cells under a microscope is not necessary. In non-limiting examples, the needle used for FNA is a 20-35 gauge needle (such as a 23, 24 or 25 gauge needle).

The term “disease” refers to any deviation from the normal health of a mammal and includes a state when disease symptoms are present, as well as conditions in which a deviation (e.g., infection, gene mutation, genetic defect, etc.) has occurred, but symptoms are not yet manifested. According to the present disclosure, the methods disclosed herein are suitable for use in a patient that is a member of the Vertebrate class. Mammalia, including, without limitation, primates, livestock and domestic pets (e.g., a companion animal). Typically, a patient will be a human patient. As used herein, a “symptom” of a disease includes and clinical or laboratory manifestation associated with the disease, and is not limited to what a subject can feel or observe.

The terms “subject,” “patient,” “individual,” and the like as used herein are not intended to be limiting and can be generally interchanged. That is, an individual described as a “patient” does not necessarily have a given disease, but may be merely seeking medical advice.

The term “subject” as used herein includes all members of the animal kingdom that may suffer from the indicated disorder. In some aspects, the subject is a mammal, and in some aspects, the subject is a human.

It must be noted that as used herein and in the appended embodiments, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a disease,” “a disease state”, “a nucleic acid” or “a CpG site” is a reference to one or more such embodiments, and includes equivalents thereof known to those skilled in the art and so forth.

Throughout the description and claims of this specification the word “comprise” and other forms of the word, such as “comprising” and “comprises.” means including but not limited to, and is not intended to exclude, for example, other components.

A “control” sample or value refers to a sample that serves as a reference, usually a known reference, for comparison to a test sample. For example, a test sample can be taken from a patient suspected or at risk of having thyroid cancer and compared to samples from a known thyroid cancer patient, or a known normal (non-disease) individual. A control can also represent an average value gathered from a population of similar individuals, e.g., thyroid cancer patients or healthy individuals with a similar medical background, same age, weight, etc. A control value can also be obtained from the same individual, e.g., from an earlier-obtained sample, prior to disease, or prior to treatment. One of skill will recognize that controls can be designed for assessment of any number of parameters.

One of skill in the art will understand which controls are valuable in a given situation and be able to analyze data based on comparisons to control values. Controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in controls, variation in test samples will not be considered as significant.

The term “diagnosis” refers to a relative probability that a disease is present in the subject. Similarly, the term “prognosis” refers to a relative probability that a certain future outcome may occur in the subject. For example, in the context of the present disclosure, prognosis can refer to the likelihood that an individual will develop a disease, or the likely severity of the disease (e.g., severity of symptoms, rate of functional decline, survival, etc.). The terms are not intended to be absolute, as will be appreciated by any one of skill in the field of medical diagnostics.

“Nucleic acid” or “oligonucleotide” or “polynucleotide” or grammatical equivalents used herein means at least two nucleotides covalently linked together. Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100 nucleotides in length. Nucleic acids, including ribonucleic acids (RNA) and deoxyribonucleic acids (DNA), and polynucleotides are a polymers of any length, including longer lengths. e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc. A nucleic acid of the present invention will generally contain phosphodiester bonds, although in some cases, nucleic acid analogs are included that may have alternate backbones, comprising, e.g., phosphoramidate, phosphorothioate, phosphorodithioate, or O-methylphophoroamidite linkages (see Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press); and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, and non-ribose backbones, including those described in U.S. Pat. Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580. Carbohydrate Modifications in Antisense Research, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made.

The term “bp” and the like refer, in the usual and customary sense, to the indicated number of base pairs.

The terms “identical” or percent “identity,” in the context of two or more nucleic acids (e.g., genomic sequences or subsequences or coding sequences) or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identity over a specified region), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. Such sequences are then said to be “substantially identical.” This definition also refers to the compliment of a test sequence. Optionally, the identity exists over a region that is at least about 10 to about 100, about 20 to about 75, about 30 to about 50 amino acids or nucleotides in length.

An example of algorithms suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215:403-410 (1990), respectively. As will be appreciated by one of skill in the art, the software for performing BLAST analyses is publicly available through the website of the National Center for Biotechnology Information.

A “label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means. For example, useful labels include ³²P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.

The term “associated” or “associated with” in the context of a substance (e.g., level of uracil or methylation level in a thyroid nodule) does not necessarily mean that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function (i.e., level of uracil in the regions of chromosomes assayed).

The term “unmethylated DNA” or “demethylated DNA” means DNA that lacks a methyl group conjugated to cytosine in a segment of the DNA. DNA methylation typically occurs in a CpG dinucleotide context. DNA methylation at the 5′ position of cytosine may have the specific effect on gene expression in vivo. DNA methylation may also form the basis of epigenetic structure, which typically enables a single cell to grow into multiple organs or perform multiple functions.

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide occurs next to a guanine nucleotide in the linear sequence of bases along its length. “CpG” is shorthand for “-C-phosphate-G-”, that is, cytosine and guanine separated by only one phosphate; phosphate links any two nucleosides together in DNA. The “CpG” notation is used to distinguish this linear sequence from the CG base-pairing of cytosine and guanine. The CpG notation can also be interpreted as the cytosine being 5′ prime to the guanine base.

In embodiments, methylation is detected based on a chemical reaction of sodium bisulfite with DNA that converts unmethylated cytosines of CpG dinucleotides to uracil or UpG. However, methylated cytosine is not converted in this process, the methods described herein allow determination of methylation status as methylated or unmethylated.

Evaluation of Thyroid Fine Needle Biopsies by Visual Examination

Cells in a thyroid vine needle biopsy sample may be examined under a microscope by, e.g., a pathologist. The report of a thyroid fine needle biopsy followed by examination under a microscope will usually indicate one of the following findings:

1. The nodule is benign (noncancerous). This result is obtained in up to 80% of biopsies. The risk of overlooking a cancer when the biopsy is benign is generally less than 3 in 100 tests or 3%. This is even lower when the biopsy is reviewed by an experienced pathologist at a major medical center. Generally, benign thyroid nodules do not need to be removed unless they are causing symptoms like choking or difficulty swallowing. Follow up ultrasound exams are important. Occasionally, another biopsy may be required in the future, especially if the nodule grows over time.

2. The nodule is malignant (cancerous) or suspicious for malignancy. A malignant result is obtained in about 5% of biopsies and is most often due to papillary cancer, which is the most common type of thyroid cancer. A malignant diagnosis has a >99% risk of cancer in the nodule. A suspicious biopsy has a 50-75% risk of cancer in the nodule. These diagnoses require surgical removal of the thyroid after consultation with the endocrinologist and surgeon.

3. The nodule is indeterminate. This is actually a group of several diagnoses that may occur in up to 30% of cases. An indeterminate finding means that even though an adequate number of cells was removed during the fine needle biopsy, examination with a microscope cannot reliably classify the result as benign or cancer. The biopsy may be indeterminate because the nodule is described as a Follicular Lesion. These nodules are cancerous 20-30% of the time. However, under the current state of the art, the diagnosis can only be made by surgery. Because the odds that the nodule is not a cancer are much better by surgery (70-80%), only the side of the thyroid with the nodule is usually removed. If a cancer is found, the remaining thyroid gland is usually removed as well. If the surgery confirms that no cancer is present, no additional surgery to “complete” the thyroidectomy is necessary.

The biopsy may also be indeterminate because the cells from the nodule have features that cannot be placed in one of the other diagnostic categories. This diagnosis is called atypia, or a follicular lesion of undetermined significance. Diagnoses in this category will contain cancer rarely, so repeat evaluation with FNA or surgical biopsy to remove half of the thyroid containing the nodule is usually recommended.

4. The biopsy may also be non-diagnostic or inadequate. This result indicates that not enough cells were obtained to make a diagnosis but is a common result if the nodule is a cyst. These nodules may require reevaluation with second fine needle biopsy, or may need to be removed surgically depending on the clinical judgment of the doctor.

Methods, compositions, kits, and systems provided herein provide significant advantages over the visual examination of biopsies.

Method of Detection Methylation Status of a Thyroid Nodule DNA

In an aspect, provided herein is a method of detecting methylation or unmethylation of a thyroid nodule DNA of a subject. The method includes: (i) isolating a thyroid nodule DNA molecule from a thyroid nodule of the subject thereby forming an isolated thyroid nodule DNA molecule, (ii) contacting the isolated thyroid nodule DNA molecule with a bisulfite salt (such as sodium bisulfite) thereby forming a reacted thyroid nodule DNA molecule, (iii) detecting the presence or absence of uracil in the reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of the thyroid nodule DNA molecule of the subject. In embodiments, contacting the isolated thyroid nodule DNA with a bisulfite salt comprises adding a solution comprising the bisulfite salt to a solution comprising the isolated single stranded DNA.

In an aspect, provided herein is a method of detecting methylation or unmethylation of a thyroid nodule DNA molecule of a subject comprising (i) isolating a plurality of thyroid nodule DNA molecules from the thyroid nodule of the subject thereby forming a plurality of isolated thyroid nodule DNA molecules, (ii) contacting the plurality of isolated thyroid nodule DNA molecules with the bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, (iii) detecting the level of reacted thyroid nodule DNA molecules in the plurality of reacted thyroid nodule DNA molecules having a uracil at a methylation site set forth in Table 1, thereby detecting the level of methylation or unmethylation in the plurality of thyroid nodule DNA molecules of the subject.

In an aspect, provided herein is a method of detecting methylation or unmethylation of a thyroid nodule DNA molecule of a subject comprising (i) isolating a plurality of thyroid nodule DNA molecules from the thyroid nodule of the subject thereby forming a plurality of isolated thyroid nodule DNA molecules, (ii) contacting the plurality of isolated thyroid nodule DNA molecules with the bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, (iii) detecting the presence or absence of uracil in a reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of the thyroid nodule DNA molecule of the subject.

In an aspect, provided herein is a method of detecting methylation or unmethylation of a thyroid nodule DNA of a subject. The method includes: (i) isolating a thyroid nodule DNA molecule from a thyroid nodule of the subject thereby forming an isolated thyroid nodule DNA molecule, (ii) contacting the isolated thyroid nodule DNA molecule with a bisulfite salt (such as sodium bisulfite) thereby forming a reacted thyroid nodule DNA molecule, (iii) amplifying the reacted thyroid nodule DNA molecule thereby forming a reacted thyroid nodule DNA amplicon molecule, (iv) detecting the presence or absence of thymidine in a reacted thyroid nodule DNA amplicon molecule at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of the thyroid nodule DNA molecule of the subject. In embodiments, contacting the isolated thyroid nodule DNA with a bisulfite salt comprises adding a solution comprising the bisulfite salt to a solution comprising the isolated single stranded DNA.

In an aspect, provided herein is a method of detecting methylation or unmethylation of a thyroid nodule DNA molecule of a subject comprising (i) isolating a plurality of thyroid nodule DNA molecules from the thyroid nodule of the subject thereby forming a plurality of isolated thyroid nodule DNA molecules, (ii) contacting the plurality of isolated thyroid nodule DNA molecules with the bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, (iii) amplifying the plurality of reacted thyroid nodule DNA molecules thereby forming a plurality of reacted thyroid nodule DNA amplicon molecules, (iv) detecting one or more thyroid nodule DNA amplicon molecules within the plurality of reacted thyroid nodule DNA amplicon molecules having a thymidine at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of the thyroid nodule DNA molecule of the subject.

In embodiments, detecting one or more thyroid nodule DNA amplicon molecules comprises detecting the level of one or more one or more thyroid nodule DNA amplicon molecules. In embodiments, detecting one or more thyroid nodule DNA amplicon molecules comprises detecting the level of reacted thyroid nodule DNA amplicon molecules in the plurality of reacted thyroid nodule DNA amplicon molecules having a thymidine at a methylation site set forth in Table 1, thereby detecting the level of methylation or unmethylation in the plurality of thyroid nodule DNA molecules of the subject.

In embodiments, detecting a level includes determining the number (e.g. quantitating) or molecules having, e.g., a thymidine or a uracil. In embodiments, detecting a level includes detecting the portion or proportion of a population or plurality of molecules having, e.g., a thymidine or a uracil.

In embodiments, the isolated thyroid nodule DNA sample is treated with a bisulfite reagent, e.g., a bisulfite salt (i.e., a process called DNA bisulfite conversion). Non-limiting examples of bisulfite salts include sodium bisulfite, potassium bisulfite, ammonium bisulfite, magnesium bisulfite, sodium metabisulfite, potassium metabisulfite, ammonium metabisulfite and magnesium metabisulfite. Bisulfite salts such as sodium bisulfite or ammonium bisulfite can convert cytosine to uracil and leave 5-methylcytosine (5-mC) the same. Thus after bisulfite treatment methylated cytosine in the DNA remains the same and unmodified cytosines will be changed to uracil. The bisulfite treatment can be performed by using the methods disclosed herein or in the art, and/or with commercial kits such as the Bisulflash DNA Modification Kit (Epigentek) and Imprint DNA Modification Kit (Sigma). For achieving the optimal bisulfite conversion, the bisulfite reaction should be carried out in an appropriate concentration of bisulfite reagents, appropriate temperature and appropriate reaction time period. A reagent such as potassium chloride that reduces thermophilic DNA degradation could also be used in bisulfite treatment so that the DNA bisulfite process can be much shorter without interrupting a completed conversion of unmethylated cytosine to uracil and without a significant thermodegradation of DNA resulted from depurination. In embodiments, a commercially available bisulfite treatment kit is used. A non-limiting example of such a kit is EZ DNA Methylation-Gold™ Kit (Zymo Research. Irvine, Calif., USA).

In embodiments, once DNA bisulfite conversion is complete, DNA is captured, desulphonated and washed. In embodiments, the bisulfite-treated DNA can be captured by, e.g., a solid matrix selected from silica salt, silica dioxide, silica polymers, magnetic beads, glass fiber, celite diatoms and nitrocellulose in the presence of high concentrations of chaotropic or non-chaotropic salts. In embodiments, the bisulfite-treated DNA is further desulphonated with an alkalized solution, preferably sodium hydroxide at concentrations from 10 mM to 300 mM. In embodiments, the DNA is then eluted and collected into a capped microcentrifuge tube. Non-limiting examples of elution solutions include DEPC-treated water and TE buffer (10 mM Tris-HCL, pH 8.0, and 1 mM EDTA).

In embodiments, the reacted thyroid nodule DNA resulting from bisulfite treatment is amplified. In embodiments, detecting the presence or absence of uracil in reacted thyroid nodule DNA molecule at a methylation site comprises amplifying the reacted thyroid nodule DNA molecule thereby forming a reacted thyroid nodule DNA amplicon molecule, and detecting the presence or absence of thymidine in a reacted thyroid nodule DNA amplicon molecule at the methylation site. In embodiments, a polymerase chain reaction (PCR) method is used for amplifying the reacted thyroid nodule DNA. PCR methods are known to those of ordinary skill in the art. In general, the PCR reactions can be set up by adding sample, dNTPs, and appropriate polymerase such as Taq polymerase, primers, and a buffer.

In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA of a subject, includes detecting methylation or unmethylation at a plurality of methylation sites set forth in Table 1. In embodiments, the plurality of methylation sites comprises at least about 2, 3, 4, 5, 10, 25, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550, or 5-550 methylation sites. In embodiments, the plurality of methylation sites comprises less than about 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 85, 80, 75, 50, 25, or 10 methylation sites. In embodiments, the plurality of methylation sites is about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50.75, 80, 85.90, 100, 150, 200.250, 300.350, 400, 450, 500, or 550, or 5-550 methylation sites. In embodiments, the plurality of methylation sites includes two or more methylation sites set forth in Table 1 and no other methylation sites.

In embodiments, the method includes detecting methylation or unmethylation of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 50, 100, 200, 300, 400, or 500 of the following sites: Chromosome 1 (Chr1) position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chromosome 2 (Chr2) position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chromosome 3 (Chr3) position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chromosome 4 (Chr4) position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chromosome 5 (Chr5) position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chromosome 6 (Chr6) position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chromosome 7 (Chr7) position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chromosome 8 (Chr8) position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chromosome 9 (Chr9) position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chromosome 10 (Chr10) position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chromosome 11 (Chr11) position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chromosome 12 (Chr12) position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chromosome 13 (Chr13) position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chromosome 14 (Chr14) position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chromosome 15 (Chr15) position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chromosome 16 (Chr16) position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chromosome 17 (Chr17) position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chromosome 18 (Chr18) position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chromosome 19 (Chr19) position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chromosome 20 (Chr20) position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chromosome 22 (Chr22) position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 1 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 2 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 3 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 4 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 5 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 6 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 7 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 8 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 9 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 10 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 50 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 100 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 200 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 300 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 400 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, the method includes detecting methylation or unmethylation of at least 500 of the following sites: Chr1 position 2996653, Chr1 position 11979164, Chr1 position 12655938, Chr1 position 16450525, Chr1 position 16450542, Chr1 position 16450545, Chr1 position 16469987, Chr1 position 17494491, Chr1 position 25473203, Chr1 position 27640460, Chr1 position 29565080, Chr1 position 38493013, Chr1 position 38493030, Chr1 position 38493074, Chr1 position 46713777, Chr1 position 46914121, Chr1 position 46955744, Chr1 position 55008344, Chr1 position 109816092, Chr1 position 109816111, Chr1 position 110074669, Chr1 position 110074681, Chr1 position 110074685, Chr1 position 150949856, Chr1 position 150949857, Chr1 position 153540282, Chr1 position 155162704, Chr1 position 155162714, Chr1 position 156676611, Chr1 position 157611881, Chr1 position 182205324, Chr1 position 204118999, Chr1 position 206741875, Chr1 position 206741989, Chr1 position 212587673, Chr1 position 212841198, Chr1 position 223403952, Chr1 position 233430972, Chr1 position 234342767, Chr2 position 3454277, Chr2 position 8793724, Chr2 position 20412441, Chr2 position 42329402, Chr2 position 42329494, Chr2 position 55289272, Chr2 position 65064865, Chr2 position 70823641, Chr2 position 73143689, Chr2 position 74454110, Chr2 position 122014529, Chr2 position 128158884, Chr2 position 128158910, Chr2 position 203114171, Chr2 position 218221671, Chr2 position 219745335, Chr2 position 238341465, Chr2 position 238341542, Chr2 position 238341546, Chr2 position 238774763, Chr3 position 13323642, Chr3 position 14180153, Chr3 position 45209073, Chr3 position 45209207, Chr3 position 52525100, Chr3 position 62589658, Chr3 position 65388317, Chr3 position 65388388, Chr3 position 73599302, Chr3 position 195636893, Chr3 position 197093846, Chr4 position 3743223, Chr4 position 5755716, Chr4 position 5755717, Chr4 position 5755728, Chr4 position 5755729, Chr4 position 5755734, Chr4 position 8372861, Chr4 position 57548289, Chr5 position 1118280, Chr5 position 34564389, Chr5 position 73871907, Chr5 position 78013596, Chr5 position 78013643, Chr5 position 137802650, Chr5 position 139051189, Chr5 position 167838221, Chr5 position 177541401, Chr5 position 180018672, Chr5 position 180101026, Chr6 position 3394325, Chr6 position 3887581, Chr6 position 7236568, Chr6 position 7728692, Chr6 position 34203617, Chr6 position 37751320, Chr6 position 41410682, Chr6 position 41438516, Chr6 position 41438575, Chr6 position 43464150, Chr6 position 158734279, Chr7 position 989235, Chr7 position 2673543, Chr7 position 73508602, Chr7 position 105079565, Chr7 position 105079631, Chr7 position 151425103, Chr7 position 151425104, Chr8 position 11764017, Chr8 position 21647308, Chr8 position 22548399, Chr8 position 22548483, Chr8 position 133570537, Chr8 position 141320393, Chr8 position 141320410, Chr9 position 6566568, Chr9 position 16197862, Chr9 position 34591313, Chr9 position 98225096, Chr9 position 126126741, Chr9 position 132083428, Chr9 position 136077410, Chr9 position 139655018, Chr9 position 140205985, Chr9 position 140205985, Chr9 position 140205997, Chr10 position 3929071, Chr10 position 30047012, Chr10 position 79702989, Chr10 position 87984905, Chr10 position 94838789, Chr10 position 102131187, Chr10 position 104196489, Chr10 position 111766879, Chr10 position 112258886, Chr10 position 112258984, Chr10 position 112259015, Chr10 position 116391763, Chr10 position 120011530, Chr10 position 126172714, Chr10 position 126172747, Chr11 position 556355, Chr11 position 821282, Chr11 position 12188937, Chr11 position 12188948, Chr11 position 12188995, Chr11 position 36057726, Chr11 position 48070143, Chr11 position 48070163, Chr11 position 48070166, Chr11 position 48070174, Chr11 position 65158294, Chr11 position 65158342, Chr11 position 65297089, Chr11 position 66104481, Chr11 position 66104485, Chr11 position 66104578, Chr11 position 68608767, Chr11 position 70236292, Chr11 position 70236320, Chr11 position 70236331, Chr11 position 115530032, Chr11 position 117950310, Chr11 position 117950329, Chr11 position 117950361, Chr11 position 117950362, Chr11 position 119293593, Chr12 position 679803, Chr12 position 26039132, Chr12 position 31004558, Chr12 position 45610695, Chr12 position 45610701, Chr12 position 45610702, Chr12 position 45610706, Chr12 position 50286016, Chr12 position 52243258, Chr12 position 52243286, Chr12 position 54145732, Chr12 position 54145741, Chr12 position 54145825, Chr12 position 56115043, Chr12 position 66262229, Chr12 position 66262230, Chr12 position 66262233, Chr12 position 66262234, Chr12 position 77266621, Chr12 position 117580102, Chr12 position 123435962, Chr12 position 123436011, Chr12 position 123436065, Chr12 position 123540893, Chr13 position 20735797, Chr13 position 23500419, Chr13 position 46771519, Chr13 position 46771520, Chr13 position 53313426, Chr13 position 113807393, Chr14 position 38599118, Chr14 position 69170010, Chr14 position 75701632, Chr14 position 75701643, Chr14 position 90850454, Chr14 position 97524282, Chr14 position 103541602, Chr14 position 103768055, Chr14 position 104209000, Chr14 position 104209068, Chr14 position 104354645, Chr14 position 104360487, Chr15 position 41068807, Chr15 position 61152225, Chr15 position 61152253, Chr15 position 61152313, Chr15 position 65186440, Chr15 position 68851629, Chr15 position 70667596, Chr15 position 70767206, Chr15 position 75251486, Chr15 position 77984014, Chr15 position 77989064, Chr15 position 83952081, Chr15 position 85402496, Chr15 position 85402497, Chr15 position 99417337, Chr16 position 1231873, Chr16 position 1458639, Chr16 position 3023231, Chr16 position 23135832, Chr16 position 29616265, Chr16 position 31009547, Chr16 position 31009548, Chr16 position 31009590, Chr16 position 57793674, Chr16 position 57793715, Chr16 position 57793727, Chr16 position 70771056, Chr16 position 70771079, Chr16 position 70771141, Chr16 position 77332010, Chr16 position 78540378, Chr16 position 79333435, Chr16 position 84262419, Chr16 position 88701114, Chr16 position 89988308, Chr16 position 89988644, Chr17 position 1509928, Chr17 position 1509945, Chr17 position 1509952, Chr17 position 1509953, Chr17 position 7644013, Chr17 position 16323460, Chr17 position 16323473, Chr17 position 16924561, Chr17 position 16924562, Chr17 position 16924594, Chr17 position 17717918, Chr17 position 17718591, Chr17 position 18139506, Chr17 position 35278031, Chr17 position 39677570, Chr17 position 40826257, Chr17 position 43037426, Chr17 position 43200096, Chr17 position 43200239, Chr17 position 43510142, Chr17 position 47987828, Chr17 position 48178379, Chr17 position 48596391, Chr17 position 48764165, Chr17 position 55701962, Chr17 position 73584599, Chr17 position 73993165, Chr17 position 75827716, Chr17 position 76882243, Chr17 position 78765910, Chr17 position 79544478, Chr17 position 80696474, Chr18 position 19751759, Chr18 position 21440760, Chr18 position 45555437, Chr18 position 45555438, Chr18 position 46547891, Chr18 position 55888885, Chr18 position 56452096, Chr18 position 56452476, Chr18 position 56887181, Chr18 position 76002973, Chr18 position 77331090, Chr19 position 677895, Chr19 position 884044, Chr19 position 884059, Chr19 position 884105, Chr19 position 884115, Chr19 position 1136511, Chr19 position 1177605, Chr19 position 1177612, Chr19 position 1177640, Chr19 position 1860601, Chr19 position 1860607, Chr19 position 2503954, Chr19 position 3434917, Chr19 position 3434921, Chr19 position 3434930, Chr19 position 3434939, Chr19 position 3434952, Chr19 position 3434954, Chr19 position 3434962, Chr19 position 3434964, Chr19 position 3434979, Chr19 position 3434985, Chr19 position 4052713, Chr19 position 4052714, Chr19 position 4052749, Chr19 position 4374591, Chr19 position 5013982, Chr19 position 5048836, Chr19 position 5048867, Chr19 position 5048877, Chr19 position 8367279, Chr19 position 8428573, Chr19 position 10254577, Chr19 position 10254578, Chr19 position 10463956, Chr19 position 10464137, Chr19 position 13203671, Chr19 position 13266925, Chr19 position 13266934, Chr19 position 13266970, Chr19 position 13842142, Chr19 position 14248494, Chr19 position 15375465, Chr19 position 17218912, Chr19 position 17346702, Chr19 position 17346702, Chr19 position 18157161, Chr19 position 18157221, Chr19 position 18157258, Chr19 position 18415877, Chr19 position 18415890, Chr19 position 30606642, Chr19 position 35531842, Chr19 position 44303112, Chr19 position 47173037, Chr19 position 47316268, Chr19 position 47778278, Chr19 position 47778298, Chr20 position 34206950, Chr20 position 36771969, Chr20 position 48993661, Chr20 position 58406398, Chr20 position 61976049, Chr20 position 61976073, Chr20 position 62588571, Chr20 position 62588579, Chr22 position 19738127, Chr22 position 35965176, Chr22 position 36549809, Chr22 position 36973375, Chr22 position 37447953, Chr22 position 37914998, Chr22 position 38307317, Chr22 position 39662794, and Chr22 position 45622980.

In embodiments, a method provided herein is practiced for a subject more than once over time. In embodiments, methylation or unmethylation of thyroid nodule DNA from a subject is assessed using a method provided herein at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. In embodiments, the method is repeated at least once every 4, 6, 8, 12 or 18 months, or at least once every 2, 3, 4, or 5 more years.

In embodiments, the method includes: (i) isolating DNA from multiple cells of a thyroid nodule of the subject thereby forming a plurality of isolated thyroid nodule DNA molecules, (ii) contacting the plurality of isolated thyroid nodule DNA molecules with a bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, (iii) detecting the proportion of DNA molecules in the plurality of reacted thyroid nodule DNA molecules having a uracil at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of said thyroid nodule DNA of the subject.

The methylation of a CpG site of interest may vary between individual cells (and even between chromosome pairs of individual cells) in a biological sample. When DNA is obtained from a biological sample and treated with a bisulfite salt to convert unmethylated cytosines to uracils, the bisulfite-treated DNA will typically contain (i) a proportion of DNA molecules with a cytosine at the site of interest (indicating that the site was methylated); and (ii) a proportion of DNA molecules with a uracil at the site of interest (indicating that the site was unmethylated). Since a uracil at a site of interest in bisulfite-treated DNA indicates that the site was unmethylated in the untreated DNA, a thymidine at the corresponding site in an amplicon of the bisulfite-treated DNA (e.g., an amplicon obtained by PCR) also indicates that the site was unmethylated in the untreated DNA.

In embodiments, the level of methylation at a site of interest is the proportion of bisulfite-treated DNA molecules having a cytosine rather than a uracil at that site of interest. In embodiments, the level of methylation at a site of interest is the proportion of amplicons of bisulfite-treated DNA molecules having a cytosine rather than a thymidine at that site of interest.

In embodiments, the level of unmethylation at a site of interest is the proportion of bisulfite-treated DNA molecules having a uracil rather than a cytosine at that site of interest. In embodiments, the level of unmethylation at a site of interest is the proportion of amplicons of bisulfite-treated DNA molecules having a thymidine rather than a cytosine at that site of interest. In Table 1, an indicated level of uracil is the proportion of bisulfite-treated DNA molecules having a uracil rather than a cytosine at the specified methylation site. The same levels listed in Table 1 also apply to the thymidine levels at a site of interest in an amplicon, i.e., the proportion of amplicons (derived from the PCR amplification of bisulfite-treated DNA molecules) having a thymidine rather than a cytosine at the specified methylation site.

The level of DNA methylation at a site of interest (e.g., a methylation site listed in Table 1) may be determined using sequencing technology. Sequencing technology can reveal nucleotide sequence variations in a plurality of DNA molecules at a single nucleotide base resolution. For example, the proportions of corresponding DNA molecules having a uracil, a thymidine, and/or a cytosine at a site may be determined. A non-limiting example of a sequencing-based method for determining the methylation level at a site of interest is described in Masser et al. (2015) Targeted DNA Methylation Analysis by Next-generation Sequencing. J Vis Exp. (96): 52488, the entire content of which is incorporated herein by reference.

The chromosomal positions listed in Tables 1-4 relate to the human genome that is publically accessible in the University of California Santa Cruz (UCSC) genome browser database under accession number HG19, the entire content of which is incorporated herein by reference in its entirety. Non-limiting information regarding the UCSC Genome Browser is provided in Kent W J, Sugnet C W, Furey T S, Roskin K M, Pringle T H, Zahler A M, Haussler D. The human genome browser at UCSC. Genome Res. 2002 June; 12(6):996-1006, the entire content of which is incorporated herein by reference. Each methylation site of interest listed in Table 1 may be located in other human genomes (e.g., within the genome of a specific subject or group of subjects) by replacing every U and R in the corresponding sequence with a C and then searching for the location of the X within a reference genome by aligning the sequence against the reference genome. For example, the methylation site of interest “X” in SEQ ID NO: 1 may be located within a genome by replacing each U and R in SEQ ID NO: 1 with a C (to obtain the pre-bisulfite-modified sequence having an X at the site of interest) and then aligning the sequence against the genome using a BLAST algorithm. Also expressly provided, disclosed, and incorporated herein is the non-bisulfite-modified sequence corresponding to each of SEQ ID NOS: 1-550. The non-bisulfite-modified sequence corresponding to each of SEQ ID NOS:1-550 is each respective sequence in which each U and R is replaced with a C, where X is the methylation site of interest. For example, the non-bisulfite-modified sequence corresponding to SEQ ID NO: 1 provided herein is a modified version of SEQ ID NO: 1 in which each U and R in SEQ ID NO: 1 is replaced with a C, where X is the methylation site of interest; the non-bisulfite-modified sequence corresponding to SEQ ID NO:2 provided herein is a modified version of SEQ ID NO:2 in which each U and R in SEQ ID NO:2 is replaced with a C, where X is the methylation site of interest; the non-bisulfite-modified sequence corresponding to SEQ ID NO:3 provided herein is a modified version of SEQ ID NO:3 in which each U and R in SEQ ID NO:3 is replaced with a C, where X is the methylation site of interest, and so on.

TABLE 1
		Uracil level in	Uracil level in	Uracil level in
		reacted thyroid	reacted thyroid	reacted thyroid
		nodule DNA	nodule DNA	nodule DNA	SEQ	SEQ
		from cancer	from benign	from benign	ID NO:	ID NO:
Chromosome	Chr	tissues is above	tissues is above	tissues is below	Forward	Reverse
(chr)	Position	indicated level*	indicated level*	indicated level*	Strand	Strand
chr1	2996653	N/A	88.84	N/A	1	2
chr1	11979164	89.29	N/A	N/A	3	4
chr1	12655938	N/A	N/A	69.23	5	6
chr1	16450525	70.00	N/A	N/A	7	8
chr1	16450542	72.00	N/A	N/A	7	8
chr1	16450545	73.33	N/A	N/A	7	8
chr1	16469987	80.00	N/A	N/A	9	10
chr1	17494491	86.00	N/A	N/A	11	12
chr1	25473203	88.89	N/A	N/A	13	14
chr1	27640460	N/A	80.56	N/A	15	16
chr1	29565080	N/A	N/A	60.00	17	18
chr1	38493013	86.36	N/A	N/A	19	20
chr1	38493030	79.17	N/A	N/A	19	20
chr1	38493074	80.95	N/A	N/A	19	20
chr1	46713777	N/A	N/A	73.33	21	22
chr1	46914121	N/A	N/A	60.00	23	24
chr1	46955744	N/A	N/A	77.78	25	26
chr1	55008344	N/A	N/A	60.00	27	28
chr1	109816092	80.77	N/A	N/A	29	30
chr1	109816111	80.77	N/A	N/A	29	30
chr1	110074669	75.00	N/A	N/A	31	32
chr1	110074681	71.43	N/A	N/A	31	32
chr1	110074685	63.16	N/A	N/A	31	32
chr1	150949856	89.29	N/A	N/A	33	34
chr1	150949857	88.46	N/A	N/A	33	34
chr1	153540282	78.26	N/A	N/A	35	36
chr1	155162704	84.21	N/A	N/A	37	38
chr1	155162714	88.64	N/A	N/A	37	38
chr1	156676611	N/A	N/A	84.62	39	40
chr1	157611881	83.05	N/A	N/A	41	42
chr1	182205324	77.50	N/A	N/A	43	44
chr1	204118999	59.09	N/A	N/A	45	46
chr1	206741875	83.33	N/A	N/A	47	48
chr1	206741989	66.67	N/A	N/A	49	50
chr1	212587673	N/A	N/A	80.00	51	52
chr1	212841198	85.29	N/A	N/A	53	54
chr1	223403952	79.17	N/A	N/A	55	56
chr1	233430972	N/A	N/A	86.67	57	58
chr1	234342767	76.67	N/A	N/A	59	60
chr10	3929071	88.68	N/A	N/A	61	62
chr10	30047012	86.84	N/A	N/A	63	64
chr10	79702989	83.33	N/A	N/A	65	66
chr10	87984905	86.36	N/A	N/A	67	68
chr10	94838789	63.33	N/A	N/A	69	70
chr10	102131187	90.00	N/A	N/A	71	72
chr10	104196489	75.00	N/A	N/A	73	74
chr10	111766879	89.47	N/A	N/A	75	76
chr10	112258886	81.82	N/A	N/A	77	78
chr10	112258984	83.33	N/A	N/A	79	80
chr10	112259015	82.61	N/A	N/A	79	80
chr10	116391763	N/A	N/A	75.00	81	82
chr10	120011530	79.55	N/A	N/A	83	84
chr10	126172714	N/A	80.00	N/A	85	86
chr10	126172747	N/A	84.62	N/A	85	86
chr11	556355	N/A	N/A	75.00	87	88
chr11	821282	89.13	N/A	N/A	89	90
chr11	12188937	83.33	N/A	N/A	91	92
chr11	12188948	77.78	N/A	N/A	91	92
chr11	12188995	78.57	N/A	N/A	93	94
chr11	36057726	N/A	79.63	N/A	95	96
chr11	48070143	N/A	84.38	N/A	97	98
chr11	48070163	N/A	87.50	N/A	97	98
chr11	48070166	N/A	84.38	N/A	97	98
chr11	48070174	N/A	84.48	N/A	97	98
chr11	65158294	78.00	N/A	N/A	99	100
chr11	65158342	85.00	N/A	N/A	99	100
chr11	65297089	75.00	N/A	N/A	101	102
chr11	66104481	81.58	N/A	N/A	103	104
chr11	66104485	83.33	N/A	N/A	103	104
chr11	66104578	81.82	N/A	N/A	105	106
chr11	68608767	N/A	N/A	73.33	107	108
chr11	70236292	89.29	N/A	N/A	109	110
chr11	70236320	85.71	N/A	N/A	109	110
chr11	70236331	70.83	N/A	N/A	109	110
chr11	115530032	N/A	N/A	79.49	111	112
chr11	117950310	79.55	N/A	N/A	113	114
chr11	117950329	79.55	N/A	N/A	113	114
chr11	117950361	80.00	N/A	N/A	115	116
chr11	117950362	81.82	N/A	N/A	115	116
chr11	119293593	N/A	N/A	60.00	117	118
chr12	679803	86.84	N/A	N/A	119	120
chr12	26039132	73.91	N/A	N/A	121	122
chr12	31004558	N/A	N/A	81.82	123	124
chr12	45610695	N/A	N/A	83.33	125	126
chr12	45610701	N/A	N/A	86.67	125	126
chr12	45610702	N/A	N/A	89.47	125	126
chr12	45610706	N/A	N/A	80.00	125	126
chr12	50286016	82.14	N/A	N/A	127	128
chr12	52243258	82.00	N/A	N/A	129	130
chr12	52243286	82.50	N/A	N/A	129	130
chr12	54145732	N/A	N/A	82.35	131	132
chr12	54145741	N/A	N/A	76.47	131	132
chr12	54145825	N/A	N/A	70.59	131	132
chr12	56115043	89.29	N/A	N/A	133	134
chr12	66262229	72.22	N/A	N/A	135	136
chr12	66262230	71.74	N/A	N/A	135	136
chr12	66262233	68.27	N/A	N/A	135	136
chr12	66262234	71.74	N/A	N/A	135	136
chr12	77266621	N/A	73.53	N/A	137	138
chr12	117580102	84.62	N/A	N/A	139	140
chr12	123435962	63.89	N/A	N/A	141	142
chr12	123436011	71.88	N/A	N/A	143	144
chr12	123436065	69.44	N/A	N/A	143	144
chr12	123540893	77.27	N/A	N/A	145	146
chr13	20735797	N/A	N/A	82.35	147	148
chr13	23500419	N/A	N/A	68.42	149	150
chr13	46771519	67.65	N/A	N/A	151	152
chr13	46771520	73.91	N/A	N/A	151	152
chr13	53313426	N/A	N/A	60.00	153	154
chr13	113807393	N/A	N/A	27.27	155	156
chr14	38599118	65.91	N/A	N/A	157	158
chr14	69170010	86.36	N/A	N/A	159	160
chr14	75701632	68.42	N/A	N/A	161	162
chr14	75701643	68.75	N/A	N/A	161	162
chr14	90850454	N/A	N/A	54.55	163	164
chr14	97524282	N/A	88.89	N/A	165	166
chr14	103541602	N/A	N/A	52.00	167	168
chr14	103768055	76.09	N/A	N/A	169	170
chr14	104209000	N/A	80.77	N/A	171	172
chr14	104209068	N/A	83.33	N/A	171	172
chr14	104354645	72.92	N/A	N/A	173	174
chr14	104360487	83.33	N/A	N/A	175	176
chr15	41068807	69.12	N/A	N/A	177	178
chr15	61152225	83.33	N/A	N/A	179	180
chr15	61152253	86.67	N/A	N/A	181	182
chr15	61152313	86.67	N/A	N/A	183	184
chr15	65186440	N/A	N/A	55.56	185	186
chr15	68851629	N/A	N/A	63.64	187	188
chr15	70667596	83.33	N/A	N/A	189	190
chr15	70767206	90.00	N/A	N/A	191	192
chr15	75251486	N/A	N/A	60.00	193	194
chr15	77984014	N/A	88.89	N/A	195	196
chr15	77989064	73.53	N/A	N/A	197	198
chr15	83952081	N/A	N/A	72.73	199	200
chr15	85402496	82.10	N/A	N/A	201	202
chr15	85402497	79.49	N/A	N/A	201	202
chr15	99417337	88.89	N/A	N/A	203	204
chr16	1231873	86.36	N/A	N/A	205	206
chr16	1458639	N/A	N/A	75.00	207	208
chr16	3023231	N/A	84.00	N/A	209	210
chr16	23135832	87.50	N/A	N/A	211	212
chr16	29616265	85.71	N/A	N/A	213	214
chr16	31009547	84.00	N/A	N/A	215	216
chr16	31009548	85.00	N/A	N/A	215	216
chr16	31009590	85.00	N/A	N/A	215	216
chr16	57793674	80.95	N/A	N/A	217	218
chr16	57793715	85.71	N/A	N/A	217	218
chr16	57793727	80.95	N/A	N/A	217	218
chr16	70771056	68.75	N/A	N/A	219	220
chr16	70771079	63.33	N/A	N/A	219	220
chr16	70771141	65.79	N/A	N/A	219	220
chr16	77332010	72.58	N/A	N/A	221	222
chr16	78540378	75.76	N/A	N/A	223	224
chr16	79333435	N/A	89.61	N/A	225	226
chr16	84262419	87.23	N/A	N/A	227	228
chr16	88701114	N/A	N/A	66.67	229	230
chr16	89988308	N/A	N/A	83.33	231	232
chr16	89988644	N/A	N/A	47.37	233	234
chr17	1509928	N/A	88.46	N/A	235	236
chr17	1509945	N/A	88.46	N/A	235	236
chr17	1509952	N/A	83.93	N/A	235	236
chr17	1509953	N/A	85.00	N/A	235	236
chr17	7644013	N/A	85.42	N/A	237	238
chr17	16323460	85.00	N/A	N/A	239	240
chr17	16323473	84.21	N/A	N/A	239	240
chr17	16924561	80.36	N/A	N/A	241	242
chr17	16924562	75.71	N/A	N/A	241	242
chr17	16924594	75.71	N/A	N/A	241	242
chr17	17717918	72.73	N/A	N/A	243	244
chr17	17718591	84.38	N/A	N/A	245	246
chr17	18139506	82.81	N/A	N/A	247	248
chr17	35278031	N/A	N/A	28.42	249	250
chr17	39677570	71.88	N/A	N/A	251	252
chr17	40826257	N/A	N/A	23.81	253	254
chr17	43037426	N/A	N/A	33.33	255	256
chr17	43200096	77.78	N/A	N/A	257	258
chr17	43200239	85.00	N/A	N/A	259	260
chr17	43510142	N/A	N/A	81.82	261	262
chr17	47987828	N/A	N/A	69.23	263	264
chr17	48178379	83.33	N/A	N/A	265	266
chr17	48596391	N/A	88.64	N/A	267	268
chr17	48764165	88.89	N/A	N/A	269	270
chr17	55701962	68.75	N/A	N/A	271	272
chr17	73584599	N/A	N/A	60.00	273	274
chr17	73993165	90.00	N/A	N/A	275	276
chr17	75827716	78.57	N/A	N/A	277	278
chr17	76882243	61.54	N/A	N/A	279	280
chr17	78765910	88.71	N/A	N/A	281	282
chr17	79544478	83.15	N/A	N/A	283	284
chr17	80696474	60.00	N/A	N/A	285	286
chr18	19751759	N/A	N/A	33.33	287	288
chr18	21440760	67.86	N/A	N/A	289	290
chr18	45555437	66.18	N/A	N/A	291	292
chr18	45555438	73.68	N/A	N/A	291	292
chr18	46547891	76.09	N/A	N/A	293	294
chr18	55888885	75.47	N/A	N/A	295	296
chr18	56452096	90.00	N/A	N/A	297	298
chr18	56452476	81.82	N/A	N/A	299	300
chr18	56887181	N/A	N/A	60.00	301	302
chr18	76002973	81.58	N/A	N/A	303	304
chr18	77331090	81.03	N/A	N/A	305	306
chr19	677895	85.29	N/A	N/A	307	308
chr19	884044	76.92	N/A	N/A	309	310
chr19	884059	76.92	N/A	N/A	309	310
chr19	884105	84.62	N/A	N/A	311	312
chr19	884115	84.62	N/A	N/A	311	312
chr19	1136511	86.96	N/A	N/A	313	314
chr19	1177605	73.68	N/A	N/A	315	316
chr19	1177612	72.73	N/A	N/A	315	316
chr19	1177640	81.82	N/A	N/A	315	316
chr19	1860601	88.46	N/A	N/A	317	318
chr19	1860607	82.81	N/A	N/A	317	318
chr19	2503954	90.00	N/A	N/A	319	320
chr19	3434917	N/A	N/A	40.00	321	322
chr19	3434921	N/A	N/A	42.86	321	322
chr19	3434930	N/A	N/A	57.14	321	322
chr19	3434939	N/A	N/A	71.43	321	322
chr19	3434952	N/A	N/A	71.43	321	322
chr19	3434954	N/A	N/A	60.00	321	322
chr19	3434962	N/A	N/A	71.43	321	322
chr19	3434964	N/A	N/A	71.43	321	322
chr19	3434979	N/A	N/A	66.67	321	322
chr19	3434985	N/A	N/A	55.56	321	322
chr19	4052713	85.56	N/A	N/A	323	324
chr19	4052714	85.14	N/A	N/A	323	324
chr19	4052749	84.62	N/A	N/A	323	324
chr19	4374591	82.14	N/A	N/A	325	326
chr19	5013982	N/A	83.33	N/A	327	328
chr19	5048836	11.21	N/A	N/A	329	330
chr19	5048867	70.59	N/A	N/A	329	330
chr19	5048877	73.53	N/A	N/A	329	330
chr19	8367279	75.00	N/A	N/A	331	332
chr19	8428573	N/A	N/A	75.00	333	334
chr19	10254577	76.25	N/A	N/A	335	336
chr19	10254578	79.17	N/A	N/A	335	336
chr19	10463956	N/A	86.73	N/A	337	338
chr19	10464137	N/A	89.29	N/A	339	340
chr19	13203671	75.86	N/A	N/A	341	342
chr19	13266925	N/A	N/A	66.67	343	344
chr19	13266934	N/A	N/A	66.67	343	344
chr19	13266970	N/A	N/A	63.64	343	344
chr19	13842142	N/A	N/A	76.47	345	346
chr19	14248494	N/A	N/A	73.91	347	348
chr19	15375465	72.22	N/A	N/A	349	350
chr19	17218912	81.25	N/A	N/A	351	352
chr19	17346702	N/A	N/A	85.71	353	354
chr19	17346702	N/A	N/A	78.95	353	354
chr19	18157161	88.24	N/A	N/A	355	356
chr19	18157221	86.76	N/A	N/A	357	358
chr19	18157258	65.22	N/A	N/A	359	360
chr19	18415877	N/A	N/A	47.83	361	362
chr19	18415890	N/A	N/A	47.83	361	362
chr19	30606642	80.56	N/A	N/A	363	364
chr19	35531842	N/A	N/A	83.33	365	366
chr19	44303112	N/A	N/A	77.78	367	368
chr19	47173037	N/A	88.64	N/A	369	370
chr19	47316268	76.67	N/A	N/A	371	372
chr19	47778278	N/A	N/A	66.67	373	374
chr19	47778298	N/A	N/A	83.33	373	374
chr2	3454277	N/A	84.78	N/A	375	376
chr2	8793724	N/A	78.57	N/A	377	378
chr2	20412441	85.71	N/A	N/A	379	380
chr2	42329402	N/A	N/A	78.95	381	382
chr2	42329494	N/A	N/A	60.00	381	382
chr2	55289272	N/A	75.00	N/A	383	384
chr2	65064865	64.71	N/A	N/A	385	386
chr2	70823641	79.03	N/A	N/A	387	388
chr2	73143689	N/A	N/A	77.78	389	390
chr2	74454110	70.00	N/A	N/A	391	392
chr2	122014529	N/A	86.36	N/A	393	394
chr2	128158884	85.00	N/A	N/A	395	396
chr2	128158910	77.50	N/A	N/A	395	396
chr2	203114171	79.63	N/A	N/A	397	398
chr2	218221671	N/A	85.19	N/A	399	400
chr2	219745335	N/A	N/A	81.82	401	402
chr2	238341465	86.36	N/A	N/A	403	404
chr2	238341542	90.00	N/A	N/A	405	406
chr2	238341546	87.50	N/A	N/A	405	406
chr2	238774763	67.57	N/A	N/A	407	408
chr20	31126186	87.50	N/A	N/A	409	410
chr20	31126189	84.21	N/A	N/A	409	410
chr20	34206950	N/A	N/A	76.47	411	412
chr20	36771969	79.31	N/A	N/A	413	414
chr20	48993661	80.00	N/A	N/A	415	416
chr20	58406398	89.66	N/A	N/A	417	418
chr20	61976049	87.93	N/A	N/A	419	420
chr20	61976073	89.66	N/A	N/A	419	420
chr20	62588571	N/A	N/A	50.00	421	422
chr20	62588579	N/A	N/A	38.46	421	422
chr22	19738127	70.59	N/A	N/A	423	424
chr22	35965176	76.32	N/A	N/A	425	426
chr22	36549809	83.33	N/A	N/A	427	428
chr22	36973375	80.43	N/A	N/A	429	430
chr22	37447953	N/A	N/A	73.33	431	432
chr22	37914998	N/A	N/A	69.23	433	434
chr22	38307317	N/A	89.66	N/A	435	436
chr22	39662794	84.62	N/A	N/A	437	438
chr22	45622980	85.00	N/A	N/A	439	440
chr3	13323642	N/A	N/A	72.73	441	442
chr3	14180153	57.89	N/A	N/A	443	444
chr3	45209073	N/A	N/A	60.00	445	446
chr3	45209207	N/A	N/A	83.33	447	448
chr3	52525100	79.41	N/A	N/A	449	450
chr3	62589658	87.50	N/A	N/A	451	452
chr3	65388317	71.43	N/A	N/A	453	454
chr3	65388388	79.31	N/A	N/A	455	456
chr3	73599302	85.11	N/A	N/A	457	458
chr3	195636893	N/A	N/A	84.62	459	460
chr3	197093846	80.00	N/A	N/A	461	462
chr4	3743223	68.18	N/A	N/A	463	464
chr4	5755716	85.48	N/A	N/A	465	466
chr4	5755717	80.00	N/A	N/A	465	466
chr4	5755728	82.26	N/A	N/A	465	466
chr4	5755729	79.17	N/A	N/A	465	466
chr4	5755734	79.17	N/A	N/A	465	466
chr4	8372861	N/A	85.71	N/A	467	468
chr4	57548289	80.23	N/A	N/A	469	470
chr5	1118280	73.08	N/A	N/A	471	472
chr5	34564389	89.29	N/A	N/A	473	474
chr5	73871907	89.47	N/A	N/A	475	476
chr5	78013596	70.00	N/A	N/A	477	478
chr5	78013643	80.00	N/A	N/A	479	480
chr5	137802650	72.73	N/A	N/A	481	482
chr5	139051189	84.09	N/A	N/A	483	484
chr5	167838221	68.18	N/A	N/A	485	486
chr5	177541401	N/A	N/A	69.23	487	488
chr5	180018672	N/A	N/A	72.73	489	490
chr5	180101026	N/A	N/A	64.71	491	492
chr6	3394325	N/A	87.84	N/A	493	494
chr6	3887581	N/A	85.71	N/A	495	496
chr6	7236568	84.43	N/A	N/A	497	498
chr6	7728692	N/A	N/A	73.33	499	500
chr6	34203617	N/A	N/A	45.45	501	502
chr6	37751320	N/A	N/A	78.57	503	504
chr6	41410682	N/A	N/A	77.78	505	506
chr6	41438516	N/A	N/A	39.13	507	508
chr6	41438575	89.66	N/A	N/A	507	508
chr6	43464150	75.76	N/A	N/A	509	510
chr6	158734279	N/A	86.84	N/A	511	512
chr7	989235	76.67	N/A	N/A	513	514
chr7	2673543	82.14	N/A	N/A	515	516
chr7	73508602	N/A	N/A	85.71	517	518
chr7	105079565	78.75	N/A	N/A	519	520
chr7	105079631	71.25	N/A	N/A	519	520
chr7	151425103	86.96	N/A	N/A	521	522
chr7	151425104	76.19	N/A	N/A	521	522
chr8	11764017	80.77	N/A	N/A	523	524
chr8	21647308	N/A	N/A	71.43	525	526
chr8	22548399	N/A	88.16	N/A	527	528
chr8	22548483	N/A	87.50	N/A	527	528
chr8	133570537	N/A	80.00	N/A	529	530
chr8	141320393	75.00	N/A	N/A	531	532
chr8	141320410	85.00	N/A	N/A	531	532
chr9	6566568	86.84	N/A	N/A	533	534
chr9	16197862	N/A	86.36	N/A	535	536
chr9	34591313	N/A	N/A	80.00	537	538
chr9	98225096	N/A	N/A	22.22	539	540
chr9	126126741	86.11	N/A	N/A	541	542
chr9	132083428	N/A	N/A	70.59	543	544
chr9	136077410	73.91	N/A	N/A	545	546
chr9	139655018	83.33	N/A	N/A	547	548
chr9	140205985	75.00	N/A	N/A	549	550
chr9	140205985	83.33	N/A	N/A	549	550
chr9	140205997	79.17	N/A	N/A	549	550
*Level values provided are the proportion (percentage) of reacted thyroid nodule DNA molecules having a uracil at the methylation site of interest. When amplicons generated from reacted thyroid nodule DNA molecules (e.g., by PCR) are used to assess the level of methylation, the values provided correspond to the proportion of amplicons having a thymidine at the nucleotide position that corresponds to the methylation site of interest.

In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA of a subject detects an alteration in methylation including increase or loss of uracil level at plurality of methylation sites. In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA of a subject detects an alteration in methylation including increase or loss of thymidine level at plurality of methylation sites. The indicated levels in Tables 1, 2, 3, and 4, are approximate indicated levels, and include values that are within about 15%, about 10%, or about 5% above and below the indicated levels.

In embodiments, the method detects the uracil level above about a threshold as set forth in Table 2 in subjects with a cancerous thyroid nodule. In embodiments, the method detects the thymidine level above about a threshold as set forth in Table 2 in subjects with a cancerous thyroid nodule.

TABLE 2
Methylation Threshold for Cancerous Thyroid Nodule
		Uracil level in reacted
		thyroid nodule DNA from
	Chromosomal	cancer tissues is about
Chromosome	Position	above indicated level*
chr1	11979164	89.29
chr1	16450525	70.00
chr1	16450542	72.00
chr1	16450545	73.33
chr1	16469987	80.00
chr1	17494491	86.00
chr1	25473203	88.89
chr1	38493013	86.36
chr1	38493030	79.17
chr1	38493074	80.95
chr1	109816092	80.77
chr1	109816111	80.77
chr1	110074669	75.00
chr1	110074681	71.43
chr1	110074685	63.16
chr1	150949856	89.29
chr1	150949857	88.46
chr1	153540282	78.26
chr1	155162704	84.21
chr1	155162714	88.64
chr1	157611881	83.05
chr1	182205324	77.50
chr1	204118999	59.09
chr1	206741875	83.33
chr1	206741989	66.67
chr1	212841198	85.29
chr1	223403952	79.17
chr1	234342767	76.67
chr10	3929071	88.68
chr10	30047012	86.84
chr10	79702989	83.33
chr10	87984905	86.36
chr10	94838789	63.33
chr10	102131187	90.00
chr10	104196489	75.00
chr10	111766879	89.47
chr10	112258886	81.82
chr10	112258984	83.33
chr10	112259015	82.61
chr10	120011530	79.55
chr11	821282	89.13
chr11	12188937	83.33
chr11	12188948	77.78
chr11	12188995	78.57
chr11	65158294	78.00
chr11	65158342	85.00
chr11	65297089	75.00
chr11	66104481	81.58
chr11	66104485	83.33
chr11	66104578	81.82
chr11	70236292	89.29
chr11	70236320	85.71
chr11	70236331	70.83
chr11	117950310	79.55
chr11	117950329	79.55
chr11	117950361	80.00
chr11	117950362	81.82
chr12	679803	86.84
chr12	26039132	73.91
chr12	50286016	82.14
chr12	52243258	82.00
chr12	52243286	82.50
chr12	56115043	89.29
chr12	66262229	72.22
chr12	66262230	71.74
chr12	66262233	68.27
chr12	66262234	71.74
chr12	117580102	84.62
chr12	123435962	63.89
chr12	123436011	71.88
chr12	123436065	69.44
chr12	123540893	77.27
chr13	46771519	67.65
chr13	46771520	73.91
chr14	38599118	65.91
chr14	69170010	86.36
chr14	75701632	68.42
chr14	75701643	68.75
chr14	103768055	76.09
chr14	104354645	72.92
chr14	104360487	83.33
chr15	41068807	69.12
chr15	61152225	83.33
chr15	61152253	86.67
chr15	61152313	86.67
chr15	70667596	83.33
chr15	70767206	90.00
chr15	77989064	73.53
chr15	85402496	82.10
chr15	85402497	79.49
chr15	99417337	88.89
chr16	1231873	86.36
chr16	23135832	87.50
chr16	29616265	85.71
chr16	31009547	84.00
chr16	31009548	85.00
chr16	31009590	85.00
chr16	57793674	80.95
chr16	57793715	85.71
chr16	57793727	80.95
chr16	70771056	68.75
chr16	70771079	63.33
chr16	70771141	65.79
chr16	77332010	72.58
chr16	78540378	75.76
chr16	84262419	87.23
chr17	16323460	85.00
chr17	16323473	84.21
chr17	16924561	80.36
chr17	16924562	75.71
chr17	16924594	75.71
chr17	17717918	72.73
chr17	17718591	84.38
chr17	18139506	82.81
chr17	39677570	71.88
chr17	43200096	77.78
chr17	43200239	85.00
chr17	48178379	83.33
chr17	48764165	88.89
chr17	55701962	68.75
chr17	73993165	90.00
chr17	75827716	78.57
chr17	76882243	61.54
chr17	78765910	88.71
chr17	79544478	83.15
chr17	80696474	60.00
chr18	21440760	67.86
chr18	45555437	66.18
chr18	45555438	73.68
chr18	46547891	76.09
chr18	55888885	75.47
chr18	56452096	90.00
chr18	56452476	81.82
chr18	76002973	81.58
chr18	77331090	81.03
chr19	677895	85.29
chr19	884044	76.92
chr19	884059	76.92
chr19	884105	84.62
chr19	884115	84.62
chr19	1136511	86.96
chr19	1177605	73.68
chr19	1177612	72.73
chr19	1177640	81.82
chr19	1860601	88.46
chr19	1860607	82.81
chr19	2503954	90.00
chr19	4052713	85.56
chr19	4052714	85.14
chr19	4052749	84.62
chr19	4374591	82.14
chr19	5048836	77.27
chr19	5048867	70.59
chr19	5048877	73.53
chr19	8367279	75.00
chr19	10254577	76.25
chr19	10254578	79.17
chr19	13203671	75.86
chr19	15375465	72.22
chr19	17218912	81.25
chr19	18157161	88.24
chr19	18157221	86.76
chr19	18157258	65.22
chr19	30606642	80.56
chr19	47316268	76.67
chr2	20412441	85.71
chr2	65064865	64.71
chr2	70823641	79.03
chr2	74454110	70.00
chr2	128158884	85.00
chr2	128158910	77.50
chr2	203114171	79.63
chr2	238341465	86.36
chr2	238341542	90.00
chr2	238341546	87.50
chr2	238774763	67.57
chr20	31126186	87.50
chr20	31126189	84.21
chr20	36771969	79.31
chr20	48993661	80.00
chr20	58406398	89.66
chr20	61976049	87.93
chr20	61976073	89.66
chr22	19738127	70.59
chr22	35965176	76.32
chr22	36549809	83.33
chr22	36973375	80.43
chr22	39662794	84.62
chr22	45622980	85.00
chr3	14180153	57.89
chr3	52525100	79.41
chr3	62589658	87.50
chr3	65388317	71.43
chr3	65388388	79.31
chr3	73599302	85.11
chr3	197093846	80.00
chr4	3743223	68.18
chr4	5755716	85.48
chr4	5755717	80.00
chr4	5755728	82.26
chr4	5755729	79.17
chr4	5755734	79.17
chr4	57548289	80.23
chr5	1118280	73.08
chr5	34564389	89.29
chr5	73871907	89.47
chr5	78013596	70.00
chr5	78013643	80.00
chr5	137802650	72.73
chr5	139051189	84.09
chr5	167838221	68.18
chr6	7236568	84.43
chr6	41438575	89.66
chr6	43464150	75.76
chr7	989235	76.67
chr7	2673543	82.14
chr7	105079565	78.75
chr7	105079631	71.25
chr7	151425103	86.96
chr7	151425104	76.19
chr8	11764017	80.77
chr8	141320393	75.00
chr8	141320410	85.00
chr9	6566568	86.84
chr9	126126741	86.11
chr9	136077410	73.91
chr9	139655018	83.33
chr9	140205985	75.00
chr9	140205989	83.33
chr9	140205997	79.17
*Level values provided are the proportion (percentage) of reacted thyroid nodule DNA molecules having a uracil at the methylation site of interest. When amplicons generated from reacted thyroid nodule DNA molecules (e.g., by PCR) are used to assess the level of methylation, the values provided correspond to the proportion of amplicons having a thymidine at the nucleotide position that corresponds to the methylation site of interest.

In embodiments, the uracil level is above a threshold as set forth in Table 3 in subjects with benign thyroid nodules. In embodiments, the thymidine level is above a threshold as set forth in Table 3 in subjects with benign thyroid nodules.

TABLE 3
Threshold for Benign Thyroid Nodule
			Uracil level in
			reacted thyroid
			nodule DNA from
			benign tissues is
		Chromosomal	about above
	Chromosome	Position	indicated level*
	chr1	2996653	88.84
	chr1	27640460	80.56
	chr10	126172714	80.00
	chr10	126172747	84.62
	chr11	36057726	79.63
	chr11	48070143	84.38
	chr11	48070163	87.50
	chr11	48070166	84.38
	chr11	48070174	84.48
	chr12	77266621	73.53
	chr14	97524282	88.89
	chr14	104209000	80.77
	chr14	104209068	83.33
	chr15	77984014	88.89
	chr16	3023231	84.00
	chr16	79333435	89.61
	chr17	1509928	88.46
	chr17	1509945	88.46
	chr17	1509952	83.93
	chr17	1509953	85.00
	chr17	7644013	85.42
	chr17	48596391	88.64
	chr19	5013982	83.33
	chr19	10463956	86.73
	chr19	10464137	89.29
	chr19	47173037	88.64
	chr2	3454277	84.78
	chr2	8793724	78.57
	chr2	55289272	75.00
	chr2	122014529	86.36
	chr2	218221671	85.19
	chr22	38307317	89.66
	chr4	8372861	85.71
	chr6	3394325	87.84
	chr6	3887581	85.71
	chr6	1.59E+08	86.84
	chr8	22548399	88.16
	chr8	22548483	87.50
	chr8	1.34E+08	80.00
	chr9	16197862	86.36
	*Level values provided are the proportion (percentage) of reacted thyroid nodule DNA molecules having a uracil at the methylation site of interest. When amplicons generated from reacted thyroid nodule DNA molecules (e.g., by PCR) are used to assess the level of methylation, the values provided correspond to the proportion of amplicons having a thymidine at the nucleotide position that corresponds to the methylation site of interest.

In embodiments, the uracil level is below a threshold as set forth in Table 4 in subjects with benign thyroid nodule. In embodiments, the thymidine level is below a threshold as set forth in Table 4 in subjects with benign thyroid nodule.

TABLE 4
Methylation Threshold for Benign Thyroid Nodule
		Uracil level in reacted
		thyroid nodule DNA from
	Chromosomal	benign tissues is about
Chromosome	Position	below indicated level*
chr1	12655938	69.23
chr1	29565080	60.00
chr1	46713777	73.33
chr1	46914121	60.00
chr1	46955744	77.78
chr1	55008344	60.00
chr1	156676611	84.62
chr1	212587673	80.00
chr1	233430972	86.67
chr10	116391763	75.00
chr11	556355	75.00
chr11	68608767	73.33
chr11	115530032	79.49
chr11	119293593	60.00
chr12	31004558	81.82
chr12	45610695	83.33
chr12	45610701	86.67
chr12	45610702	89.47
chr12	45610706	80.00
chr12	54145732	82.35
chr12	54145741	76.47
chr12	54145825	70.59
chr13	20735797	82.35
chr13	23500419	68.42
chr13	53313426	60.00
chr13	113807393	27.27
chr14	90850454	54.55
chr14	103541602	52.00
chr15	65186440	55.56
chr15	68851629	63.64
chr15	75251486	60.00
chr15	83952081	72.73
chr16	1458639	75.00
chr16	88701114	66.67
chr16	89988308	83.33
chr16	89988644	47.37
chr17	35278031	28.42
chr17	40826257	23.81
chr17	43037426	33.33
chr17	43510142	81.82
chr17	47987828	69.23
chr17	73584599	60.00
chr18	19751759	33.33
chr18	56887181	60.00
chr19	3434917	40.00
chr19	3434921	42.86
chr19	3434930	57.14
chr19	3434939	71.43
chr19	3434952	71.43
chr19	3434954	60.00
chr19	3434962	71.43
chr19	3434964	71.43
chr19	3434979	66.67
chr19	3434985	55.56
chr19	8428573	75.00
chr19	13266925	66.67
chr19	13266934	66.67
chr19	13266970	63.64
chr19	13842142	76.47
chr19	14248494	73.91
chr19	17346702	85.71
chr19	17346735	78.95
chr19	18415877	47.83
chr19	18415890	47.83
chr19	35531842	83.33
chr19	44303112	77.78
chr19	47778278	66.67
chr19	47778298	83.33
chr2	42329402	78.95
chr2	42329494	60.00
chr2	73143689	77.78
chr2	219745335	81.82
chr20	34206950	76.47
chr20	62588571	50.00
chr20	62588579	38.46
chr22	37447953	73.33
chr22	37914998	69.23
chr3	13323642	72.73
chr3	45209073	60.00
chr3	45209207	83.33
chr3	195636893	84.62
chr5	177541401	69.23
chr5	180018672	72.73
chr5	180101026	64.71
chr6	7728692	73.33
chr6	34203617	45.45
chr6	37751320	78.57
chr6	41410682	77.78
chr6	41438516	39.13
chr7	73508602	85.71
chr8	21647308	71.43
chr9	34591313	80.00
chr9	98225096	22.22
chr9	132083428	70.59
*Level values provided are the proportion (percentage) of reacted thyroid nodule DNA molecules having a uracil at the methylation site of interest. When amplicons generated from reacted thyroid nodule DNA molecules (e.g., by PCR) are used to assess the level of methylation, the values provided correspond to the proportion of amplicons having a thymidine at the nucleotide position that corresponds to the methylation site of interest.

In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA is of a candidate thyroid cancer patient. In embodiments, the subject is suspected of having thyroid cancer. In embodiments, the subject has thyroid cancer.

In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA is based on the level of uracil as set forth Table 2, in which the uracil level above the threshold identifies the thyroid nodule as a cancerous thyroid nodule. In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA is based on a level of thymidine indicated in Table 2, in which the thymidine level above the threshold identifies the thyroid nodule as a cancerous thyroid nodule. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method. Non-limiting examples of quantitation methods include sequencing and microarray methods.

In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA is based on the level of uracil as set forth Table 3, in which the uracil level above the threshold identifies the thyroid nodule as a benign thyroid nodule. In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA is based on a level of thymidine indicated in Table 3, in which the thymidine level above the threshold identifies the thyroid nodule as a benign thyroid nodule. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA is based on the level of uracil as set forth Table 4, in which the uracil level below the threshold identifies the thyroid nodule as a benign thyroid nodule. In embodiments, the method of detecting methylation or unmethylation of a thyroid nodule DNA is based on a level of thymidine indicated in Table 4, in which the thymidine level below the threshold identifies the thyroid nodule as a benign thyroid nodule. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the thyroid nodule is a specimen obtained by biopsy or by surgical resection of a subject.

In embodiments, the subject has undergone thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and administration of an active agent before the subject undergoes the method of detecting methylation or unmethylation of a thyroid nodule DNA.

In embodiments, the method includes a determination of prognosis for local recurrence in thyroid cancer. In embodiments, the method includes determination of prognosis of distant recurrence of thyroid cancer.

In embodiments, the method of detecting DNA methylation level in DNA of thyroid nodule may lead to changes in therapeutic regimen for treating the subject. In embodiments a subject identified as having thyroid cancer may be treated with tyrosine kinase inhibitors.

In embodiments, the active agent administered to a subject before or after detecting the level of methylation or unmethylation is: Cabozantinib-S-Malate, Caprelsa® (Vandetanib). Cometriq® (Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate, Lenvima® (Lenvatinib Mesylate), Nexavar® (Sorafenib Tosylate), Sorafenib Tosylate, and/or Vandetanib.

Method of Determining Thyroid Cancer or Risk of Developing Thyroid Cancer

In an aspect, provided herein is a method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof. The method involves:

• • (i) isolating a thyroid nodule DNA molecule from a thyroid nodule of the subject thereby forming an isolated thyroid nodule DNA molecule;
  • (ii) contacting the isolated thyroid nodule DNA molecule with a bisulfite salt (such as sodium bisulfite) thereby forming a reacted thyroid nodule DNA molecule; and
  • (iii) detecting the presence or absence of uracil in the reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1; thereby detecting the thyroid cancer in the subject.

In an aspect, provided herein is a method of detecting a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof, comprising (i) isolating a plurality of thyroid nodule DNA molecules from the thyroid nodule of the subject thereby forming a plurality of isolated thyroid nodule DNA molecules, (ii) contacting the plurality of isolated thyroid nodule DNA molecules with the bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, (iii) detecting the level of reacted thyroid nodule DNA molecules in the plurality of reacted thyroid nodule DNA molecules having a uracil at a methylation site set forth in Table 1; thereby detecting the thyroid cancer in the subject.

In an aspect, provided herein is a method of detecting a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof, comprising (i) isolating a plurality of thyroid nodule DNA molecules from the thyroid nodule of the subject thereby forming a plurality of isolated thyroid nodule DNA molecules, (ii) contacting the plurality of isolated thyroid nodule DNA molecules with the bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, (iii) detecting the presence or absence of uracil in a reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of the thyroid nodule DNA molecule of the subject.

In an aspect, provided herein is a method of detecting a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof. The method includes: (i) isolating a thyroid nodule DNA molecule from a thyroid nodule of the subject thereby forming an isolated thyroid nodule DNA molecule, (ii) contacting the isolated thyroid nodule DNA molecule with a bisulfite salt (such as sodium bisulfite) thereby forming a reacted thyroid nodule DNA molecule, (iii) amplifying the reacted thyroid nodule DNA molecule thereby forming a reacted thyroid nodule DNA amplicon molecule, (iv) detecting the presence or absence of thymidine in a reacted thyroid nodule DNA amplicon molecule at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of the thyroid nodule DNA molecule of the subject. In embodiments, contacting the isolated thyroid nodule DNA with a bisulfite salt comprises adding a solution comprising the bisulfite salt to a solution comprising the isolated single stranded DNA.

In an aspect, provided herein is a method of detecting a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof, comprising (i) isolating a plurality of thyroid nodule DNA molecules from the thyroid nodule of the subject thereby forming a plurality of isolated thyroid nodule DNA molecules, (ii) contacting the plurality of isolated thyroid nodule DNA molecules with the bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, (iii) amplifying the plurality of reacted thyroid nodule DNA molecules thereby forming a plurality of reacted thyroid nodule DNA amplicon molecules, (iv) detecting one or more thyroid nodule DNA amplicon molecules within the plurality of reacted thyroid nodule DNA amplicon molecules having a thymidine at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of the thyroid nodule DNA molecule of the subject.

In embodiments, detecting one or more thyroid nodule DNA amplicon molecules comprises detecting the level of one or more one or more thyroid nodule DNA amplicon molecules. In embodiments, detecting one or more thyroid nodule DNA amplicon molecules comprises detecting the level of reacted thyroid nodule DNA amplicon molecules in the plurality of reacted thyroid nodule DNA amplicon molecules having a thymidine at a methylation site set forth in Table 1, thereby detecting the level of methylation or unmethylation in the plurality of thyroid nodule DNA molecules of the subject.

In embodiments, detecting a level includes determining the number (e.g. quantitating) or molecules having, e.g., a thymidine or a uracil. In embodiments, detecting a level includes detecting the portion or proportion of a population or plurality of molecules having, e.g., a thymidine or a uracil.

In embodiments, contacting the isolated thyroid nodule DNA with a bisulfite salt comprises adding a solution comprising the bisulfite salt to a solution comprising the isolated thyroid nodule DNA.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes selecting a subject that has or is at risk for developing thyroid cancer. In embodiments, the subject (a) is a woman; (b) is about 20 to about 55 years old; (c) has a mutated Ret Proto-Oncogene; (d) has a grandparent, parent, or sibling who has been diagnosed with thyroid cancer, (e) self-identifies as being Caucasian or Asian; and/or (f) has or has had breast cancer.

In embodiments, the method includes detecting methylation or unmethylation at a plurality of methylation sites set forth in Table 1. In embodiments, the plurality of methylation sites comprises at least about 2, 3, 4, 5, 10, 25, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550, or 5-550 methylation sites. In embodiments, the plurality of methylation sites comprises less than about 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 85, 80, 75, 50, 25, or 10 methylation sites. In embodiments, the plurality of methylation sites is about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550, or 5-550 methylation sites. In embodiments, the plurality of methylation sites includes two or more methylation sites set forth in Table 1 and no other methylation sites.

In embodiments, a method provided herein is practiced for a subject more than once over time. In embodiments, methylation or unmethylation of thyroid nodule DNA from a subject is assessed using a method provided herein at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. In embodiments, the method is repeated at least once every 4, 6, 8, 12 or 18 months, or at least once every 2, 3, 4, or 5 more years.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining alteration in methylation at a plurality of methylation sites set forth in Table 1. In embodiments, the method comprises: (i) isolating DNA from multiple cells of a thyroid nodule of the subject thereby forming a plurality of isolated thyroid nodule DNA molecules, (ii) contacting the plurality of isolated thyroid nodule DNA molecules with a bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, (iii) detecting the proportion of DNA molecules in the plurality of reacted thyroid nodule DNA molecules having a uracil at a methylation site set forth in Table 1.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes alteration. i.e., increase or loss of uracil level at plurality of methylation sites. In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes alteration, i.e., increase or loss of thymidine level at plurality of methylation sites.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a uracil level which is above a threshold as set forth in Table 2. In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a thymidine level which is above a threshold indicated in Table 2. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a uracil level which is above a threshold as set forth in Table 3. In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a thymidine level which is above a threshold indicated in Table 3. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a uracil level which is below a threshold as set forth in Table 4. In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a thymidine level which is below a threshold indicated in Table 4. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer involves a candidate thyroid cancer patient. In embodiments, the subject is suspected of having thyroid cancer. In embodiments, the subject has thyroid cancer.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a uracil level in which a threshold above the threshold set forth in Table 2 identifies the thyroid nodule as a cancerous thyroid nodule. In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a thymidine level in which a threshold above the threshold indicated in Table 2 identifies the thyroid nodule as a cancerous thyroid nodule. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a uracil level in which a threshold above the threshold set forth in Table 3 identifies the thyroid nodule as a benign thyroid nodule. In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a thymidine level in which a threshold above the threshold indicated in Table 3 identifies the thyroid nodule as a benign thyroid nodule. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a uracil level in which a threshold below the threshold set forth in Table 4 identifies the thyroid nodule as a benign thyroid nodule. In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a thymidine level in which a threshold below the threshold indicated in Table 4 identifies the thyroid nodule as a benign thyroid nodule. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a uracil level in DNA of a thyroid nodule specimen obtained by biopsy or by surgical resection of a subject. In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof includes determining a thymidine level in DNA of a thyroid nodule specimen obtained by biopsy or by surgical resection of a subject.

In embodiments, the method of determining a thyroid cancer or risk of developing thyroid cancer is of a subject who has previously undergone thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and/or administration of an active agent, before the determination.

In embodiments, a subject having thyroid cancer or at risk of developing thyroid cancer was administered an active agent: Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate). Sorafenib Tosylate, and/or Vandetanib.

In embodiments, the method of determining a thyroid cancer may lead to changes in therapeutic regimen for treating the subject. In embodiments a subject identified as having thyroid cancer may be treated with tyrosine kinase inhibitors. In embodiments, a subject identified as having thyroid cancer or being at risk of developing thyroid cancer according to a method disclosed herein is advised and/or directed to receive additional screening and/or treatment for thyroid cancer.

In embodiments, the active agent administered to a subject after determining thyroid cancer is: Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), Doxorubicin Hydrochloride. Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate). Sorafenib Tosylate, and/or Vandetanib.

Method of Treating Thyroid Cancer

Also provided herein is a method of treating thyroid cancer in a subject by administering to the subject an active agent for treating thyroid cancer, in which the subject is identified for treatment by a method including isolating a thyroid nodule DNA molecule from a thyroid nodule of the subject thereby forming an isolated thyroid nodule DNA molecule; contacting the isolated thyroid nodule DNA molecule with a bisulfite salt (such as sodium bisulfite) thereby forming a reacted thyroid nodule DNA molecule; and detecting the presence or absence of uracil in the reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1; thereby detecting the thyroid cancer in the subject. In embodiments, contacting the isolated thyroid nodule DNA with a bisulfite salt comprises adding a solution comprising the bisulfite salt to a solution comprising the isolated thyroid nodule DNA.

In embodiments, the method includes detecting methylation or unmethylation at a plurality of methylation sites set forth in Table 1. In embodiments, the plurality of methylation sites comprises at least about 2, 3, 4, 5, 10, 25, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550, or 5-550 methylation sites. In embodiments, the plurality of methylation sites comprises less than about 550, 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 85, 80, 75, 50, 25, or 10 methylation sites. In embodiments, the plurality of methylation sites is about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550, or 5-550 methylation sites. In embodiments, the plurality of methylation sites includes two or more methylation sites set forth in Table 1 and no other methylation sites.

In embodiments, a method provided herein is practiced for a subject more than once over time. In embodiments, methylation or unmethylation of thyroid nodule DNA from a subject is assessed using a method provided herein at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times. In embodiments, the method is repeated at least once every 4, 6, 8, 12 or 18 months, or at least once every 2, 3, 4, or 5 more years.

In embodiments, the method of treating a thyroid cancer in a subject in need thereof includes determining alteration in methylation at a plurality of methylation sites set forth in Table 1.

In embodiments, the method of treating a thyroid cancer in a subject in need thereof includes alteration which includes increase or loss of uracil level at plurality of methylation sites.

In embodiments, the method of treating a thyroid cancer in a subject in need thereof includes determining a uracil level which is above a threshold as set forth in Table 2. In embodiments, the method of treating a thyroid cancer in a subject in need thereof includes determining a thymidine level which is above a threshold indicated in Table 2. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of treating a thyroid cancer in a subject in need thereof includes determining a uracil level which is above a threshold as set forth in Table 3. In embodiments, the method of treating a thyroid cancer in a subject in need thereof includes determining a thymidine level which is above a threshold indicated in Table 3. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of treating a thyroid cancer in a subject in need thereof includes determining a uracil level which is below a threshold as set forth in Table 4. In embodiments, the method of treating a thyroid cancer in a subject in need thereof includes determining a thymidine level which is below a threshold indicated in Table 4. In embodiments, the level is the proportion of molecules (e.g., in a plurality of reacted thyroid nodule DNA molecules or a plurality of reacted thyroid nodule DNA amplicons) having a uracil or thymidine as determined by a quantitation method.

In embodiments, the method of treating a thyroid cancer is in a subject who has undergone surgery, radiation therapy, radioactive iodine therapy, chemotherapy, or thyroid hormone therapy, before the detecting thyroid cancer.

In embodiments, an active agent administered to a subject for treating thyroid cancer: Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate). Doxorubicin Hydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate). Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and/or Vandetanib.

In embodiments, the subject has or is at risk of papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

In embodiments, the method includes determining a papillary thyroid carcinoma (PTC) methylation alteration score for the subject, wherein the PTC methylation alteration score is equal to the number of methylation sites in Table 1 having a uracil level equal to or greater than the corresponding threshold level set forth in Table 2.

In embodiments, the method includes determining a PTC methylation alteration score for the subject, wherein the PTC methylation alteration score is equal to the number of methylation sites in Table 1 having a thymidine level equal to or greater than the corresponding threshold level set forth in Table 2.

In embodiments, the method includes determining a benign thyroid nodule (BTN) methylation alteration score for said subject, wherein the BTN methylation alteration score is equal to: (a) the number of methylation sites in Table 1 having a uracil level equal to or greater than the corresponding threshold level set forth in Table 3; (b) the number of methylation sites in Table 1 having a uracil level equal to or less than the corresponding threshold level set forth in Table 4; or (c) the number of methylation sites in Table 1 having a uracil level equal to or greater than the corresponding threshold level set forth in Table 3 plus the number of methylation sites in Table 1 having a uracil level equal to or less than the corresponding threshold level set forth in Table 4.

In embodiments, the method includes determining a benign thyroid nodule (BTN) methylation alteration score for said subject, wherein the BTN methylation alteration score is equal to: (a) the number of methylation sites in Table 1 having a thymidine level equal to or greater than the corresponding threshold level set forth in Table 3; (b) the number of methylation sites in Table 1 having a thymidine level equal to or less than the corresponding threshold level set forth in Table 4; or (c) the number of methylation sites in Table 1 having a thymidine level equal to or greater than the corresponding threshold level set forth in Table 3 plus the number of methylation sites in Table 1 having a thymidine level equal to or less than the corresponding threshold level set forth in Table 4.

In embodiments, the method comprises calculating a Composite Cancer Risk Score for the subject. In embodiments, the Composite Cancer Risk Score for the subject equals: [the PTC methylation alteration score for said subject]/[BTN methylation alteration score for said subject]. In embodiments, the Composite Cancer Risk Score for the subject equals: [(the PTC methylation alteration score for said subject)+1]/[(BTN methylation alteration score for said subject)+1].

In embodiments, the subject is identified as being at risk of developing thyroid cancer or diagnosed as having thyroid cancer if (a) the PTC methylation alteration score for the subject is at least 5, 6, 7, 8, 9, or 10; (b) the BTN methylation alteration score for the subject is at least 5, 6, 7, 8, 9, or 10; and/or (c) the Composite Cancer Risk Score for the subject is at least about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0.

In embodiments, the subject receives treatment (e.g., is directed or advised to receive treatment) for thyroid cancer or is directed to receive additional screening for thyroid cancer if (a) the PTC methylation alteration score for the subject is at least 5, 6, 7, 8, 9, or 10; (b) the BTN methylation alteration score for the subject is at least 5, 6, 7, 8, 9, or 10; and/or (c) the Composite Cancer Risk Score for the subject is at least about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0.

Target Sites for Methylation Level of Thyroid Nodule

In another aspect, provided herein is a deoxyribonucleic acid 5 to 100, 5 to 300, 5 to 300, or at least about 5, 50, 100, 150, 200, 250, 300, or more nucleotides in length including a uracil-containing sequence identical to the sequence of at least 5 contiguous nucleotides within a sequence including SEQ ID NO: 1 to SEQ ID NO:550.

SEQ ID NO: 1 to SEQ ID NO:500 are 300 bp length sequences that include the target sites (i.e., methylation sites of interest). The sequences provided are as modified after bisulfite conversion. Therefore “C” in the non-CpG context becomes “U”, and C in the CpG context is designated as R or X (either “U” either “C”), where X is the target site. The DNA strands (sense and antisense) are no longer complementary after bisulfite conversion. Therefore, each DNA strand is identified with its unique sequence, and is designated as “forward” and “reverse” respectively, in Table 1.

The sequences listed in Table 1 are provided below with their respective sequence identification number.

SEQ
ID
NO: Sequence
1   TUUTTAGUUUTURGTGGRGUUAGAGTTGGTTGUUTUAGTAGRGRGTGUUUAUURGG
    UUUAAAGUTGTTUTGUAGUTGGTUAUTGTGGGAGAAGAGAUTGGAAAAGTTUAAAG
    GTGGAGAGGRGGUAGRGATUTGGAGUAUTTTTURGUAXGUTGTAAUUUUTGAGAAG
    AAAUAAAGAGGAAARGAGGUTGTTTAGATAATUURGGGUUUTGGTGUTTGUATTTA
    GAAAAATTAGGUUUTUTGAAAAATTAUAGAATTATGUTGUUAGTGTUAGGTTUUU
2   AGATAATGATGTGTUTGTGT
    UAUAGAUAUATUATTATUTGGGAAUUTGAUAUTGGUAGUATAATTUTGTAATTTTT
    UAAGAGGGUUTAATTTTTUTAAATGUAAGUAUUAGGGUURGGGATTATUTAAAUAG
    UUTRGTTTUUTUTTTGTTTUTTUTUAGGGGTTAUAGXGTGRGGAAAAGTGUTUUAGA
    TRGUTGURGUUTUTUUAUUTTTGAAUTTTTUUAGTUTUTTUTUUUAUAGTGAUUAGU
    TGUAGAAUAGUTTTGGGURGGGTGGGUARGRGUTAUTGAGGUAAUUAAUTUTGGRG
3   UUARGGAGGGUTAAGGAU
    GGGTGAUUAGTGUUAUTAAAAGUAGAGUTTGAGTTTAUTUTUATAAUUATRGGUTG
    TGGGUUAGAUATTTGGUTGUTTTGUAGGUAGAUUAGGUTTUURGGTGAGTUATGUT
    GUTTAAAATGUTGTUTGGGAARGUAGAGAAAGTUTAAAXGUUAAGARGUTGAGGA
    UAGUUURGUAGGTGGAUTGUUATGUURGGUTRGGUUUUTTTTTGGTUUUUAGAGTG
    GAUUUTTUTUUTUUUUAUAGAGGGGAGGUATUTGATGGTGGUTTUAGUAGAUAAU
4   UTGGAGAAGAAUUAUTUAGGGT
    AUUUTGAGTGGTTUTTUTUUAGGTTGTUTGUTGAAGUAUUATUAGATGUUTUUUU
    TUTGTGGGGAGGAGAAGGGTUUAUTUTGGGGAUUAAAAAGGGGURGAGURGGGUA
    TGGUAGTUUAUUTGRGGGGUTGTUUTUAGRGTUTTGGXGTTTAGAUTTTUTUTGRGT
    TUUUAGAUAGUATTTAAGUAGUATGAUTUAURGGGAAGUUTGGTUTGUUTGUAAA
    GUAGUUAAATGTUTGGUUUAUAGURGATGGTTATGAGAGTAAAUTUAAGUTUTGUT
5   TTTAGTGGUAUTGGTUAUUU
    CAGUTGGGGAGGGGAUAGGGTAGGTGGUTGUAGAAGGGGGUTGGGTTGAGGTUTU
    AGGTGUAGARGAGGAGGGGUTGGGRGGAGGGGGTGAGGAGGGGAGURGGGUTGGG
    GGURGGGRGRGUTGUTGGGGTUUUUUTUURGUUURGGGAUXGTURGUTUTTGUUUA
    GAUURGTRGGTAAAUAGARGURGTGATGTUARGGGRGURGUTGAUUTGTGGUTGAA
    UURGGAGUTGTAAATGAGATGUAAGGTGUUAGUAGUUTURGGURGUAGGGUUTAR
6   GAGUUAUARGRGUTUUTURGURGG
    URGGRGGAGGAGRGRGTGTGGUTRGTAGGUUUTGRGGURGGAGGUTGUTGGUAUUT
    TGUATUTUATTTAUAGUTURGGGTTUAGUUAUAGGTUAGRGGRGUURGTGAUATUA
    RGGRGTUTGTTTAURGARGGGTUTGGGUAAGAGRGGAXGGTUURGGGGRGGGAGGG
    GGAUUUUAGUAGRGUUURGGUUUUUAGUURGGUTUUUUTUUTUAUUUUUTURGUU
    UAGUUUUTUUTRGTUTGUAUUTGAGAUUTUAAUUUAGUUUUUTTUTGUAGUUAUU
    TAUUUTGTUUUUTUUUUAGUTG
7   TTTTUTGTAAAATGGGGURGUUUAUAAAAUTUATAAUAAAGTGTTGAGGTTURGAU
    AAGURGAAAUUTGTGAAAAGUTTGTGTAAAUUTUAGAGUTGTAUATGGATGGTTGA
    AGGATUTATTTRGAUAGUTURGGGGAGUXGTGGGAGGGAAGUTGAXGGXGGUTUTT
    GUTGTTUTUUTAUUTUUUAGUUUTUURGAAGAUTUTGAGUAGUUTGGAGATUAAAG
    GTGATTGGGGUUTGUTGGUATGGAGGURGGGUTRGGUAGAAUUTGUTTUURGGUUU
    UUTGUUUAUUTUUUAUUUAU
8   GTGGGTGGGAGGTGGGUAGGGGGURGGGAAGUAGGTTUTGURGAGUURGGUUTUU
    ATGUUAGUAGGUUUUAATUAUUTTTGATUTUUAGGUTGUTUAGAGTUTTRGGGAGG
    GUTGGGAGGTAGGAGAAUAGUAAGAGUXGUXGTUAGUTTUUUTUUUAXGGUTUUU
    RGGAGUTGTRGAAATAGATUUTTUAAUUATUUATGTAUAGUTUTGAGGTTTAUAUA
    AGUTTTTUAUAGGTTTRGGUTTGTRGGAAUUTUAAUAUTTGTTATGAGTTTTGTGG
    GRGGUUUUATTTTAUAGAAAA
9   TGAGUAGTGTTTUAGRGUUUAGAGAGAUAUTGTGGAGAAGGTUUAUUAGGATGUU
    TAUUTGUUTTAUAUAAGAGUUTAAUTTTGGUAUAUUTGTGGUAUAUUTGTGGAGAG
    UTGTTUTGGUUURGGTTGTUTGGUAGGUUTGGGUTAUTUXGAGUAGGGGAAUTGGG
    GUAUAGTGGUTGUAUUTURGGUTATAUUUTGGTTTTTUUAGTTUUTGATGUURGUU
    UUTUAGGTGGUAGUATGAGGTGAUTUAGGGAUAGARGUUUTTATRGTGARGUAAGT
    UUAGUUUUUAGTGGAGUUUUT
10  AGGGGUTUUAUTGGGGGUTGGAUTTGRGTUARGATAAGGGRGTUTGTUUUTGAGTU
    AUUTUATGUTGUUAUUTGAGGGGRGGGUATUAGGAAUTGGAAAAAUUAGGGTATA
    GURGGAGGTGUAGUUAUTGTGUUUUAGTTUUUUTGUTXGGAGTAGUUUAGGUUTG
    UUAGAUAAURGGGGUUAGAAUAGUTUTUUAUAGGTGTGUUAUAGGTGTGUUAAAG
    TTAGGUTUTTGTGTAAGGUAGGTAGGUATUUTGGTGGAUUTTUTUUAUAGTGTUTUT
    UTGGGRGUTGAAAUAUTGUTUA
11  TUTTGTAAAATTUUAGAGUUAGGTATAUUUAATrUTGUAARGTGGTAGUTGUATGA
    UTGTAUAAGTUUUTTAAUAGUAURGGGUUTUAGTGAUATUATUTGTTAAATGGGTT
    GGTGATGATAATGGTUAGUATTTATGGAGGAGUUUAUAXGGTGUTAAGTGUTTrAU
    AUATATUAGUTAAUTGAATUUTUAUTGUTGUUAATGAGAUAGGTAUTATTGAATUA
    GAGGUURGGAGAGAGUTUUARGRGGTTGGTUATAUTGGTGAAGAGUTTGGTTUAAT
    GUUTGGTGAAUTUTRGGUAU
12  GTGURGAGAGTTUAUUAGGUATTGAAUUAAGUTUTTUAUUAGTATGAUUAAURGRG
    TGGAGUTUTUTURGGGUUTUTGATTUAATAGTAUUTGTUTUATTGGUAGUAGTGAG
    GATTUAGTTAGUTGATATGTGTAAAGUAUTTAGUAUXGTGTGGGUTUUTUUATAAA
    TGUTGAUUATTATUATUAUUAAUUUATTTAAUAGATGATGTUAUTGAGGUURGGTG
    UTGTTAAGGGAUTTGTAUAGTUATGUAGUTAUUARGTTGUAGAATTGGGTATAUUT
    GGUTUTGGAATTTTAUAAGA
13  TURGGAGUUAGTGAAUTTGTGATURGGAGUUAGTTAAUTTUAUAGUTAATGTGUTG
    AGUAGUATTUUAGUUAGRGTUTGAAGUUAGAGUAGGGAGGRGGARGGGUUUUAGG
    AGTTRGAGGTURGGGAAGURGAAGUAUUAUUAAAUTGAGXGAGGTTUUAAUTUTU
    UUTUUUAGGAGGTURGGUTGUUTUUUAUUAGUAGUUUAAUUAUAGGGTUUTGUTU
    UAGARGTTAUTATTTTUTUTTTTTUAGTGTGTUUAGUAGUAAUUTRGAUTGUUAAUA
    AUAARGTGAAAAATAAUTGUAG
14  UTGUAGTTATTTTTUARGTTGTTGTTGGUAGTRGAGGTTGUTGUTGGAUAUAUTGAA
    AAAGAGAAAATAGTAARGTUTGGAGUAGGAUUUTGTGGTTGGGUTGUTGGTGGGAG
    GUAGURGGAUUTUUTGGGAGGGAGAGTTGGAAUUTXGUTUAGTTTGGTGGTGUTTR
    GGUTTUURGGAUUTRGAAUTUUTGGGGUURGTURGUUTUUTGUTUTGGUTTUAGA
    RGUTGGUTGGAATGUTGUTUAGUAUATTAGUTGTGAAGTTAAUTGGUTURGGATUA
    UAAGTTUAUTGGUTURGGA
15  TTGUUAAAAUTGGAAGUAAUUAAGATGUUUUTUAAAAGGTGAATGGAGGUUAGGT
    GRGGTGGUTUARGURGATAATUUUAGUAUTTTGGGAGGUTGAGGUAGGTGGATUAU
    TTGAGATUARGAGTTTGAGAUUAGUURGGUUAAUATGGXGAAAUUURGTUTUTAUT
    AAAAATAUTAAGATTAAURGGGRGTGGTGGUARGTGUUTGTTATUUUAGUTAUTTG
    GGAAGUTGAGGUAGGUAAATTGUTTGAAUUTGGGAGGTGGAGGTUAUAGTGAGUU
    AAGATTGTGUUAUTGUAUTUUA
16  TGGAGTGUAGTGGUAUAATUTTGGUTUAUTGTGAUUTUUAUUTUUUAGGTTUAAGU
    AATTTGUUTGUUTUAGUTTUUUAAGTAGUTGGGATAAUAGGUARGTGUUAUUARGU
    URGGTTAATUTTAGTATTTTTAGTAGAGARGGGGTTTXGUUATGTTGGURGGGUTGG
    TUTUAAAUTRGTGATUTUAAGTGATUUAUUTGUUTUAGUUTUUUAAAGTGUTGGGA
    TTATRGGRGTGAGUUAURGUAUUTGGUUTUUATTUAUUTTTTGAGGGGUATUTTGGT
    TGUTTUUAGTTTTGGUAA
17  GGRGGGATURGAGURGAGAUARGTGUTGGAGRGGAGURGUTTUUTUARGGTRGUUA
    GURGUAGAUAAUTGAUUTUUURGGUATRGRGTTRGRGGUUUTGUTGUTGGUTURGG
    TGTUTRGGGURGGAAUTUUTGTGGUTUUAGRGTTRGXGURGGUUAUTGGUUAGRGU
    TTGGGUUTRGUUUTGUAGUTURGGGGUUATAGGGUAUAGUTTTAGUTTTGAUUTUU
    URGTTUURGAAAGGARGUUUAAGGRGAUUTUUUAUUUUATUUTUUUUAAUTTUTU
    UUUUATGTUUTGRGGUAAUTT
18  AGTTGURGUAGGAUATGGGGGAGAAGTTGGGGAGGATGGGGTGGGAGGTRGUUTTG
    GGRGTUUTTTRGGGAARGGGGAGGTUAAAGUTAAAGUTGTGUUUTATGGUUURGGA
    GUTGUAGGGRGAGGUUUAAGRGUTGGUUAGTGGURGGXGRGAARGUTGGAGUUAU
    AGGAGTTURGGUURGAGAUAURGGAGUUAGUAGUAGGGURGRGAARGRGATGURG
    GGGAGGTUAGTTGTUTGRGGUTGGRGAURGTGAGGAAGRGGUTURGUTUUAGUARG
    TGTUTRGGUTRGGATUURGUUU
19  UUAGUAGGGAAGGUAGUUAAUAGATGUAGAUTRGUTUTGUUTAUUTGTGGAGGUR
    GGTGAGGUUAGGGUUTGTTGGGAUTTGAAAUAGTGAGGUAAGTGGGTGTGTGGTGU
    TGGGUTUUUXGUTUAAGTTUTUUUAGXGTGUUAGTTUURGGAGUUTTATGTGUAGG
    GTGTTGGGGAAGGGXGGGUTGAATRGTGGGTGGGAGTUTTGGUTUAAAGUUUUAGG
    TGAGTGGAGGAATTGGGGGRGGAUUTGAAGTAUTGTUTTGAAGTGGAUUTGGUAGG
    UUTUTTGGGUTTGTGUAGUTG
20  UAGUTGUAUAAGUUUAAGAGGUUTGUUAGGTLTUAUTTUAAGAUAGTAUTTUAGGT
    URGUUUUUAATTUUTUUAUTUAUUTGGGGUTTTGAGUUAAGAUTUITUAUUUARGAT
    TUAGUUXGUUUTTUUUUAAUAUUUTGUAUATAAGGUTURGGGAAUTGGUAXGUTG
    GGAGAAUTTGAGXGGGGAGUUUAGUAUUAUAUAUUUAUTTGUUTUAUTGTTTUAA
    GTUUUAAUAGGUUUTGGUUTUAURGGUUTUUAUAGGTAGGUAGAGRGAGTUTGUA
    TUTGTTGGUTGUUTTUUUTGUTGG
21  UUAGAUTRGUUUTUUUUAUURGGGUUTRGGAUTTTUAUUUUAGUTTUTUTUTUUTG
    GUUAGTGATTAUUUAUUUUUAATUUUAUUURGUUURGURGRGUAAUTAUUTUUTU
    UUTTUAUURGGAUTGGGAUUATUATUUUUAUTUUAUTUXGUUUAGTUTGGGAUTU
    UAUUTGUUTUUTUUUUAATUUUAUAUTAATUTUTGUTTGGTUTUTTUUTUTTTGGUU
    TAATUTUTRGTUTRGGUTTATTGGGGARGGUUAUTUTUAUAGTTTGGTTUUAAAUAU
    UAGTTUUTGGATGGATTUUU
22  GGGAATUUATUUAGGAAUTGGTGTTTGGAAUUAAAUTGTGAGAGTGGURGTUUUUA
    ATAAGURGAGARGAGAGATTAGGUUAAAGAGGAAGAGAUUAAGUAGAGATTAGTG
    TGGGATTGGGGAGGAGGUAGGTGGAGTUUUAGAUTGGGXGGAGTGGAGTGGGGAT
    GATGGTUUUAGTURGGGTGAAGGGAGGAGGTAGTTGRGRGGRGGGGRGGGGTGGG
    ATTGGGGGTGGGTAATUAUTGGUUAGGAGAGAGAAGUTGGGGTGAAAGTURGAGG
    UURGGGTGGGGAGGGRGAGTUTGG
23  RGUAGGUURGRGUUURGUTUURGUUURGUUTGURGRGUUTUURGGGGRGUURGUA
    TTAAAGRGUATATGUAAGUUATGAATTATUAAUTGAAAGGAGTUAATTAURGGUTU
    TAAAAARGAGTGTUTGRGUTRGUAGRGUUURGGGUUATUXGUUTATTTARGGAGRG
    ATUTAUUURGUURGGUTGGGGAGGGGGUUTRGGGAGGGAGAGAGARGGAGAAARG
    GAGUURGAGAURGGGAGAGAGURGGAGAGGUAGGGAUTGGAGAGTUTGGGAUARG
    AAGGAGAGGRGGGGAGAGAURGA
24  TRGGTUTUTUUURGUUTUTUUTTRGTGTUUUAGAUTUTUUAGTUUUTGUUTUTURGG
    UTUTUTUURGGTUTRGGGUTURGTTTUTURGTUTUTUTUUUTUURGAGGUUUUUTUU
    UUAGURGGGRGGGGTAGATRGUTURGTAAATAGGXGGATGGUURGGGGRGUTGRG
    AGRGUAGAUAUTRGTTTTTAGAGURGGTAATTGAUTUUTTTUAGTTGATAATTUATG
    GUTTGUATATGRGUTTTAATGRGGGRGUUURGGGAGGRGRGGUAGGRGGGGRGGGA
    GRGGGGRGRGGGUUTGRG
25  AUAGTRGUTGUAGGGAGGARGRGGGURGTGAGAAUURGGGGAUAGUUTUUUUTUT
    TGRGGTUUTGUAGTUURGGAUUUAUTGGGRGGATUAGAAAGTTTGUAGGGAGUUA
    GGGAUTAGGAGAUAGAUAGAUAGRGUAGGGAUAGAGAAAGXGGAGGGATGUUAG
    AAAGAURGAGTRGGGGAUAGAUAGAGAGAUUUAGGGTGAGAUAGAGGAAGAGAT
    AUURGGGGUTGAAAARGGTGGUAGAAAGTGAGUAAUTTAGGGAGAUAGAAAGAGR
    GUAGAAUTRGAAATTURGAGGUAGAGA
26  TUTUTGUUTRGGAATTTRGAGTTUTGRGUTUTTTUTGTUTUUUTAAGTTGUTUAUTTT
    UTGUUAURGTTTTUAGUUURGGGTATUTUTTUUTUTGTUTUAUUUTGGGTUTUTUTG
    TUTGTUUURGAUTRGGTUTTTUTGGUATUUUTUXGUTTTUTUTGTUUUTGRGUTGTU
    TGTUTGTUTUUTAGTUUUTGGUTUUUTGUAAAUTTTUTGATURGUUUAGTGGGTURG
    GGAUTGUAGGAURGUAAGAGGGGAGGUTGTUUURGGGTTUTUARGGUURGRGTUU
    TUUUTGUAGRGAUTGT
27  TUAGUUTGTAUUURGGRGUTGGUUTUUAGAUAGUUAGGTGUTGUUTRGUARGGTUT
    TGUTTGUAGGUTGGGGUATGAAGUAUUUTGGTATTTARGUTGGGATTGGTUTUTUA
    UTAGGGTTGGGGRGGGUTGTGGTUAUUTGGUURGGRGXGURGUAGAGGUTGGUTUR
    GGAGAAGAUUTGGGGGRGUAAGAUTUAGAGGUUAGAGGGTGUAGURGUTGUTGAU
    TUATTTGRGGARGGGGRGGUTGGGAGGAGRGUTAGUUUUTGTTGTGAGRGATTTGA
    GAGUUAGGGUUAAATUTGGGT
28  AUUUAGATTTGGUUUTGGUTUTUAAATRGUTUAUAAUAGGGGUTAGRGUTUUTUUU
    AGURGUUURGTURGUAAATGAGTUAGUAGRGGUTGUAUUUTUTGGUTUTUTGAGTUT
    TGRGUUUUUAGGTUTTUTURGGAGUUAGUUTUTGRGGXGRGURGGGUUAGGTGAU
    UAUAGUURGUUUUAAUUUTAGTGAGAGAUUAATUUUAGRGTAAATAUUAGGGTGU
    TTUATGUUUUAGUUTGUAAGUAAGAURGTGRGAGGUAGUAUUTGGUTGTUTGGAG
    GUUAGRGURGGGGTAUAGGUTGA
29  GUUUAGUUTUAUAAAGGTGAGTGGGGUAUUUUUAGUTGURGAGUTUUUUTAGTUA
    GUAGUUTUATAUUTUAUATTUTUUTGTGGURGUAUUTUAUAGUUURGUUURGGUU
    UAUAGGUATUUTTAAGAAGAAGTGTUTGUUUAUUATUAGXGAGAAGAGUAGUUTU
    UTGXGGUTUUUUUTGGAGUAATGUAUAGGGTUTTUURGGGGUTUUTURGUTAGTGA
    GGGUAGURGGGGAGGUUUUUUTUUURGUUUAURGUUURGGUAGAGUUTUUAGGA
    GUAGUTGAARGGGGTUATGUUUATRG
30  RGATGGGUATGAUUURGTTUAGUTGUTUUTGGAGGUTUTGURGGGGRGGTGGGRGG
    GGAGGGGGGUUTUUURGGUTGUUUTUAUTAGRGGAGGAGUUURGGGAAGAUUUTG
    TGUATTGUTUUAGGGGGAGUXGUAGGAGGUTGUTUTTUTXGUTGATGGTGGGUAGA
    UAUTTUTTUTTAAGGATGUUTGTGGGURGGGGRGGGGUTGTGAGGTGRGGUUAUAG
    GAGAATGTGAGGTATGAGGUTGUTGAUTAGGGGAGUTRGGUAGUTGGGGGTGUUU
    UAUTUAUUTTTGTGAGGUTGGGU
31  TUAGAATAATGGUTGGTTTGTAGAGATUAGAAATGUUUAUTGUTGTTTUUTGTAT
    UUUTUUAUUUAUUUAGAUTGAGUUTUTGAAGUTGTURGGGGUUTGGAGAGAGAAG
    UUAUTUAAGGAUAGUAGUTGUTGAUTUAGAXGUTUAAATTUTXGGGXGGAAAAGG
    AUUTTAGAGAATGUUTAAAATRGTGGUUUAATUUUTUATTGGAAGUTGGGGUTURG
    AAAAGURGGGGUTURGAAAAGUTGGGAGAGUAGUUUAAAGRGTAUTGUUUAUTAA
    ATGTGGATGUARGUTGGAURGU
32  GRGGTUUAGRGTGUATUUAUATTTAGTGGGUAGTARGUTTTGGGUTGUTUTUUUAG
    UTTTTRGGAGUUURGGUTTTTRGGAGUUUUAGUTTUUAATGAGGGATTGGGUUARG
    ATTTTAGGUATTUTUTAAGGTUUTTTTUXGUUXGAGAATTTGAGXGTUTGAGTUAGU
    AGUTGUTGTUUTTGAGTGGUTTUTUTUTUUAGGUUURGGAUAGUTTUAGAGGUTUA
    GTUTGGGTGGGTGGAGGGATAUAGGAAAUAGUAGTGGGUATTTUTGATUTUTAUAA
    AUUAGGUUATTATTUTGGA
33  AAGTTUTGGGGUAGAAGTTGGATAAUUAGGGUUTGAGAAATAAAGATAAGAGGGT
    ATATTUUTUUUUUAGGAGAUAAAAGAGAAGGTGGATGGAGAAGGGGAAAUTGGGU
    UTUAGUUAGUAURGGGATGATGRGAUUAGUTTTGTUAGUAXGUTTGGGGAGUATAU
    AUAURGUTTGUUTTGGUTGGAURGGAGAUTGTGATUAUUAUUUTTUUAAUUUATUU
    UUUAAUARGUAGGUTGGUATGGUUARGUUUAUAGTGUUUUAAGTGUTGUUTGUUT
    TGUAGTGAUTUAUTTUUTUTGTA
34  TAUAGAGGAAGTGAGTUAUTGUAAGGUAGGUAGUAUTTGGGGUAUTGTGGGRGTG
    GUUATGUUAGUUTGRGTGTTGGGGGATGGGTTGGAAGGGTGGTGATUAUAGTUTUR
    GGTUUAGUUAAGGUAAGRGGTGTGTATGUTUUUUAAGXGTGUTGAUAAAGUTGGTR
    GUATUATUURGGTGUTGGUTGAGGUUUAGTTTUUUUTTUTUUATUUAUUTTUTUTTT
    TGTUTUUTGGGGGAGGAATATAUUUTUTTATUTTTATTTUTUAGGUUUTGGTTATUU
    AAUTTUTGUUUUAGAAUTT
35  TUAGAARGTGUUUAUAUATGUUUATGUUUTUTATUUTGUTGAAATUUAAUUUUUU
    UTTUAAAGGUUAUTGUAGGGAGUUTTUUUAGGGUUUAAURGGATTUAGTGTUTAU
    UTGTTUTGTUUTGTAUAAAGRGUUUUTTTTGUUUTTTTXGTGTGTAUTTAGAGAATT
    UTGATTTTGAUTGAATUAUUTGTGTAUTTGTTTTUTUTUAGUUTUAUUUUUAUATGG
    TGAGUTUAURGGTUTTAUTUATTTUTGUATGAGGTAAGGGTUTRGUUUAUAUUAGG
    TGUUAAUUAGTGUTTARGGU
36  URGTAAGUAUTGGTTGGUAUUTGGTGTGGGRGAGAUUUTTAUUTUATGUAGAAATG
    AGTAAGAURGGTGAGUTUAUUATGTGGGGGTGAGGUTGAGAGAAAAUAAGTAUAU
    AGGTGATTUAGTUAAAATUAGAATTUTUTAAGTAUAUAXGAAAAGGGUAAAAGGG
    GRGUTTTGTAUAGGAUAGAAUAGGTAGAUAUTGAATURGGTTGGGUUUTGGGAAGG
    UTUUUTGUAGTGGUUTTTGAAGGGGGGGTTGGATTTUAGUAGGATAGAGGGUATGG
    GUATGTGTGGGUARGTTUTGAA
37  UAUUTRGTGUUUUTUAUUTGTAAGUAUTGTGAGGAGUAGUAGUAGGAAGAAAGGA
    GAUTGGGTGUURGGTGTUATGGTGGTGGTGAAATGGGTGGGGAGGGGGUAGAAUA
    GATTUAGGUAGGRGUTGGUTGUTTGAGAGGTGGAGXGGGUAUAGGXGUUTAURGU
    TTTATAURGGTUUUUUUAUTUUURGUURGUURGUUUTAGGUAUAGURGGAGUAGG
    TGAUAGGTGAUAAAAUUURGUUUUUTUUUUTAUUTUUTAUUTUTTUUTUUTUUTUU
    UUAAUUATTUUTGGGTAGGGTAUA
38  TGTAUUUTAUUUAGGAATGGTTGGGGAGGAGGAGGAAGAGGTAGGAGGTAGGGGA
    GGGGGRGGGGTTTTGTUAUUTGTUAUUTGUTURGGUTGTGUUTAGGGRGGGRGGGR
    GGGGAGTGGGGGGAURGGTATAAAGRGGTAGGXGUUTGTGUUXGUTUUAUUTUTU
    AAGUAGUUAGRGUUTGUUTGAATUTGTTUTGUUUUUTUUUUAUUUATTTUAUUAUU
    AUUATGAUAURGGGUAUUUAGTUTUUTTTUTTUUTGUTGUTGUTAUTUAUAGTGUT
    TAUAGGTGAGGGGUARGAGGTG
39  AGARGGAGAAAUAGAAARGGAGGTUAGGRGGGGAGUUTRGGGGAUAGGUUTGGGA
    UURGAGGURGGAAAURGUAGAGGAGRGAAGUUTGGRGGGATGUAGTGATTGGAGU
    UAAAGGAAURGTUURGGUUTGTUUAARGRGGGGGGGUUTTXGGUURGGTGGUUUT
    GAGRGAAURGATGUARGTGGUUURGURGUATUUUATUUUUUAUUUTUUUUAGAUT
    UTUUUTUUUAGUTUUTTUTGAGGRGGAAAGAAAAAUUUTAUATUTGGTUUUAGUU
    UTGGGTUUUTGUUUTGGUUUUTUUT
40  AGGAGGGGUUAGGGUAGGGAUUUAGGGUTGGGAUUAGATGTAGGGTTTTTUTTTUR
    GUUTUAGAAGGAGUTGGGAGGGAGAGTUTGGGGAGGGTGGGGGATGGGATGRGGR
    GGGGUUARGTGUATRGGTTRGUTUAGGGUUAURGGGUXGAAGGUUUUUURGRGTT
    GGAUAGGURGGGARGGTTUUTTTGGUTUUAATUAUTGUATUURGUUAGGUTTRGUT
    UUTUTGRGGTTTURGGUUTRGGGTUUUAGGUUTGTUUURGAGGUTUUURGUUTGAU
    UTURGTTTUTGTTTUTURGTUT
41  TUAAAUUUAGGTATTUTGGGTUTAGTRGGTGTTUTTUTGUUAAAGAGTAUTTTGTGG
    UTAAATTUAUTGGATGTGAUTUAGTTTTTATUTTTRGTUATUTUTTAGUTTTGUUTTA
    TUUAAAURGGATUAUTUTUTTUTGUTTAGAAUTXGTTUTGUTUTTGGTGAUAGTGGT
    AUATAUTUTUATAUTGUUTUTTUUUTTGUUUAGAGTUUTTUUTTUTUATGTTUUAUU
    TUUTUTAUTGGGAURGGUUTGGGTGTGUTGTUUAATRGGAUAUTATTTTGTTGGGUU
    UTUTUUTTUAUTUU
42  GAGTGAAGGAGAGGGUUUAAUAAAATAGTGTURGATTGGAUAGUAUAUUUAGGUR
    GGTUUUAGTAGAGGAGGTGGAAUATGAGAAGGAAGGAUTUTGGGUAAGGGAAGAG
    GUAGTATGAGAGTATGTAUUAUTGTUAUUAAGAGUAGAAXGAGTTUTAAGUAGAA
    GAGAGTGATURGGTTTGGATAAGGUAAAGUTAAGAGATGARGAAAGATAAAAAUTG
    AGTUAUATUUAGTGAATTTAGUUAUAAAGTAUTUTTTGGUAGAAGAAUAURGAUTA
    GAUUUAGAATAUUTGGGTTTGAU
43  AAGTGTUTTTAUUTUUTGAGTGRGAUUUAAGTUAGGAGGUAGGAGGUTGAUTGAGG
    GAUARGGAGGAGGTATGUAUAUTUAUAGUATGAGGUAGAGUTGTGTGUAUAUATU
    AAGUAAGGAAATGGGGURGGAATATGGGGUAAAGGUUTAXGGATTGAATGGTGGA
    TTTGGATGTGGGUUAUTTUTTUUAGUUUUTGAAAGAGGAUUAGGUAATGTGGUTAT
    GAATGGGUUTAATGAGAATTGATTGATTRGUTRGAGATGTTTTUTTTTTUTTUUTAAA
    ATAGAAAATGAUATAUUUUA
44  TGGGGTATGTUATTTTUTATTTTAGGAAGAAAAAGAAAAUATUTRGAGRGAATUAAT
    UAATTUTUATTAGGUUUATTUATAGUUAUATTGUUTGGTUUTUTTTUAGGGGUTGG
    AAGAAGTGGUUUAUATUUAAATUUAUUATTUAATUXGTAGGUUTTTGUUUUATATT
    URGGUUUUATTTUUTTGUTTGATGTGTGUAUAUAGUTUTGUUTUATGUTGTGAGTGT
    GUATAUUTUUTURGTGTUUUTUAGTUAGUUTUUTGUUTUUTGAUTTGGGTRGUAUT
    UAGGAGGTAAAGAUAUTT
45  GGATGTGUTUAGGUTUUAGGGUUAUAUUUTGUATGTAUTUATAGUAUAGUUUATTU
    TGGAAGGTGUAGTAGAGTTTGGGGGUAUAGUTGTGTGUTRGUAGUAGUTGGAAGTT
    TUTGAUUTUATTUTUURGGTUUAUUAGUAGUTURGTUXGUTUUUUATAUAUURGGA
    UUAGUARGUAGTUUTGUATGTUUTUUTUUAUATAGUAGGUUAUUAGUTTGTTGGTG
    ATGUUATURGTGAAGRGUTAGUATGGGGAGAGGAUAGTGRGTGGGTGGGTGGGTGG
    GGUAGGATUTUTUTGGTUTU
46  GAGAUUAGAGAGATUUTGUUUUAUUUAUUUAUUUARGUAUTGTUUTUTUUUUATG
    UTAGRGUTTUARGGATGGUATUAUUAAUAAGUTGGTGGUUTGUTATGTGGAGGAGG
    AUATGUAGGAUTGRGTGUTGGTURGGGTGTATGGGGAGXGGARGGAGUTGUTGGTG
    GAURGGGAGAATGAGGTUAGAAAUTTUUAGUTGUTGRGAGUAUAUAGUTGTGUUU
    UUAAAUTUTAUTGUAUUTTUUAGAATGGGUTGTGUTATGAGTAUATGUAGGGTGTG
    GUUUTGGAGUUTGAGUAUATUU
47  AGUUAGGAAGGGUTGUAUTTUUUUAGTGGTUAGRGUAGGUTGGRGTUUTGGUTGUT
    GGRGUAAGTUTUAAGUTGUUUUTUUUUTTUTAGUAAGUATGGGRGGTGTGGGTATG
    RGGGGTGUTGGGTAUTGAUTUAUUTURGGAGAUUAUTXGGUTUUUAUAUAUUAUU
    TUTGAATGATUTGAATUATTTATGAGGUTGAATGUUUTGTUUTUUAGGGAGUTUUA
    GUTGGAGUTGGAGUUAGUATATGGAGGTGGAGAGAGUTUUXGUAGTUAUURGGGU
    UUTGTAUAGUUTGUAGGUAGAAU
48  GTTUTGUUTGUAGGUTGTAUAGGGUURGGGTGAUTGXGGGAGUTUTUTUUAUUTUU
    ATATGUTGGUTUUAGUTUUAGUTGGAGUTUUUTGGAGGAUAGGGUATTUAGUUTUA
    TAAATGATTUAGATUATTUAGAGGTGGTGTGTGGGAGUXGAGTGGTUTURGGAGGT
    GAGTUAGTAUUUAGUAUUURGUATAUUUAUAURGUUUATGUTTGUTAGAAGGGGA
    GGGGUAGUTTGAGAUTTGRGUUAGUAGUUAGGARGUUAGUUTGRGUTGAUUAUTG
    GGGAAGTGUAGUUUTTUUTGGUT
49  GGGTGUTGGGTAUTGAUTUAUUTURGGAGAUUAUTXGGUTUUUAUAUAUUAUUTU
    TGAATGATUTGAATUATTTATGAGGUTGAATGUUUTGTUUTUUAGGGAGUTUUAGU
    TGGAGUTGGAGUUAGUATATGGAGGTGGAGAGAGUTUUXGUAGTUAUURGGGUUU
    TGTAUAGUUTGUAGGUAGAAUUTATAAAUTGGAUTUUTAAAGUUAUTUUTUTUAAG
    GUUTGGAGATTUTGUTGAGTTTUAUTUTITGGUTUTUAGAGUATUTGGAAUTUTAUA
    TAAAGUTGAGGAAUUUTTTGT
50  AUAAAGGGTTUUTUAGUTTTATGTAGAGTTUUAGATGUTUTGAGAGUUAAAGAGTG
    AAAUTUAGUAGAATUTUUAGGUUTTGAGAGGAGTGGUTTTAGGAGTUUAGTTTATA
    GGTTUTGUUTGUAGGUTGTAUAGGGUURGGGTGAUTGXGGGAGUTUTUTUUAUUTU
    UATATGUTGGUTUUAGUTUUAGUTGGAGUTUUUTGGAGGAUAGGGUATTUAGUUTU
    ATAAATGATTUAGATUATTUAGAGGTGGTGTGTGGGAGUXGAGTGGTUTURGGAGG
    TGAGTUAGTAUUUAGUAUUU
51  AGTUUATGAAGGUAUTTTTTUAAAGTTAGGTGGTUAUUAAAAAAUAGGTAATUAAT
    UUTGTUAUUAGURGRGGGGAUAGRGAGGUUTTGGGUTTGGAGGGGGAGGATGURG
    ARGATGURGAURGRGUATUAGATUTRGURGGGAGGAGGGXGRGGGRGUTUUAUTTG
    TTGUAAAGAARGURGGGTTUUTUTGGGUUATTGGGUTGURGUTURGGRGGGGAGRG
    RGGAAGGUTGGGUUTUAGGTAGUTTUAATUATTUAUUTGUTGGTTARGGGTRGRGG
    RGURGGGGAUUUTAUTURGGA
52  TURGGAGTAGGGTUUURGGRGURGRGAUURGTAAUUAGUAGGTGAATGATTGAAGU
    TAUUTGAGGUUUAGUUTTURGRGUTUUURGURGGAGRGGUAGUUUAATGGUUUAG
    AGGAAUURGGRGTTUTTTGUAAUAAGTGGAGRGUURGXGUUUTUUTUURGGRGAGA
    TUTGATGRGRGGTRGGUATRGTRGGUATUUTUUUUUTUUAAGUUUAAGGUUTRGUT
    GTUUURGRGGUTGGTGAUAGGATTGATTAUUTGTTTTTTGGTGAUUAUUTAAUTTTG
    AAAAAGTGUUTTUATGGAUT
53  GTUTGUAGUTGGGAATGAATGGAATGAAGGTUAAGGATGAAGTAATAAUUAAATAT
    TGGGTTTTGGGTGUUUTGGTAAUTGTURGGTTTUUAGTTAGGGTTUUTGGGTGAUAT
    UTTUUTTUTGGGGGAAGAUAGAGTUAAATGAGAAAXGTGAGTTGAGUUUAGGGGA
    AAGGATUATURGGGAGATGUUTGAGGGGUTUUAGGGUATRGTAATUTUTTGUTUAG
    UTGGUAGAGTGGGGUTGAUARGGUUAGUTGUTUTUTGGAGTUUTRGGUUTTUUTGT
    TTUUUUUTGAGGAUTTTGAG
54  TUAAAGTUUTUAGGGGGAAAUAGGAAGGURGAGGAUTUUAGAGAGUAGUTGGURG
    TGTUAGUUUUAUTUTGUUAGUTGAGUAAGAGATTARGATGUUUTGGAGUUUUTUA
    GGUATUTUURGGATGATUUTTTUUUUTGGGUTUAAUTUAXGTTTUTUATTTGAUTUT
    GTUTTUUUUUAGAAGGAAGATGTUAUUUAGGAAUUUTAAUTGGAAAURGGAUAGT
    TAUUAGGGUAUUUAAAAUUUAATATTTGGTTATTAUTTUATUUTTGAUUTTUATTUU
    ATTUATTUUUAGUTGUAGAUA
55  UUAGTGUAGAAUAGGUAUTGUUUAUUATAUAGGUUAGAAGAGGTGUUUTUTUUAU
    AUTGGUUAUTGAAAUTAUTUAUTGGUAGUAGTGGGTGUUAUTTGGAAAAUAAGAT
    GGUUUTUUUTGUAGAGUAGGUUAUUUTGURGGAGGTGTUUXGATGRGTGTGAAGU
    AGGGTTGGAGGUAUAUTAUAGGUAUTUTUTAGTUUTTUAAAUAAUAUTGTAGTGTA
    GATUTTGTTGGTTUTTTUAGAGAAGGGGAAARGGAAAUTUAUAGAAGUAAUTAGAG
    GAGTGAGTAGAAGUUUAGGTATG
56  UATAUUTGGGUTTUTAUTUAUTUUTUTAGTTGUTTUTGTGAGTTTURGTTTU
    UTUTGAAAGAAUUAAUAAGATUTAUAUTAUAGTGTTGTTTGAAGGAUTAGAGAGTG
    UUTGTAGTGTGUUTUUAAUUUTGUTTUAUARGUATXGGGAUAUUTURGGUAGGGTG
    GUUTGmWGUAGGGAGGGUUATUTTGTTTTUUAAGTGGUAUUUAUTGUTGUUAGT
    GAGTAGTTTUAGTGGUUAGTGTGGAGAGGGUAUUTUTTUTGGUUTGTATGGTGGGU
    AGTGUUTGTTUTGUAUTGG
57  TURGGUATUAATTUTTAATGAGTUUURGAGUUUURGUAGTUUGTUTAUTTUTTTTU
    TTTTUUAGTGAATUUTUAUAGTUUUUTTTUUUTGUATGTTUTUTGTUUUAAATTTUT
    GAAGUUUUTUUUTTTURGTUTUTTAAGAATUTUTAXGAAUURGAAAGUURGTGAGG
    UTGATGGUARGTUTGTGGTTUUTTTUTUUTTUTTUUUTUUATAUUUAUAGUTUUURG
    GGAURGGAUUUTUUUUAUTUAUUAGGTGUAGGGUUAGGGGUAGUAGUAGGAGGA
    AUAGUUAUAGGTAGAGGTG
58  UAUUTUTAUUTGTGGUTGTTUUTUUTGUTGUTGUUUUTGGUUUTGUAUUTGGTGAG
    TGGGGAGGGTURGGTUURGGGGAGUTGTGGGTATGGAGGGAAGAAGGAGAAAGGA
    AUUAUAGARGTGUUATUAGUUTUARGGGUTTTRGGGTTXGTAGAGATTUTTAAGAG
    ARGGAAAGGGAGGGGUTTUAGAAATTTGGGAUAGAGAAUATGUAGGGAAAGGGGA
    UTGTGAGGATTUAUTGGAAAAGAAAAGAAGTAGAUAGGAUTGRGGGGGUTRGGGG
    AUTUATTAAGAATTGATGURGGA
59  AGUUTGTGUTUAGGAATAAUTAAGGAGTGGAGURGUATUAAUUTUUTTUUUAAATU
    RGGARGTUTTUUTURGAUTUAAGUUUAGUUTGAGGGUUATTUTUUTTGATTUAUUU
    TTGGAAAUAGAUAUUAGUUAAGGGAGUTGTUTUUTGGXGTTGARGAGGATURGATT
    TAGGTUAGTATTUTAGTTUUUAUTUUAUAGAGGAATUTGAUTGGAGGUUAGUTGTG
    GTRGATGAGTUATURGGAAUAUAAGUAGGUAGUTATTTURGAAUTAAATGGUATUT
    GATUTUUUTUUTUAUUTTGA
60  TUAAGGTGAGGAGGGAGATUAGATGUUATTTAGTTRGGAAATAGUTGUUTGUTTGT
    GTTURGGATGAUTUATRGAUUAUAGUTGGUUTUUAGTUAGATTUUTUTGTGGAGTG
    GGAAUTAGAATAUTGAUUTAAATRGGATUUTRGTUAAXGUUAGGAGAUAGUTUUUT
    TGGUTGGTGTUTGTTTUUAAGGGTGAATUAAGGAGAATGGUUUTUAGGUTGGGUTT
    GAGTRGGAGGAAGARGTURGGATTTGGGAAGGAGGTTGATGRGGUTUUAUTUUTTA
    GTTATTUUTGAGUAUAGGUT
61  GAUUTUAGGATUTGAATGGTTUTTGGAGTTUTTTGUAGATGAGGTAATGTTTTGGTT
    AAUTUATAGGTUAGAUUTGUTGTUUTTAGUTAAUTTGUURGGGAGGTTTTTAARGG
    AAGGUUTGTGTTAGUAUAAATUATATTTUUTGATGAXGAGUAGAGAUITITGATUTG
    GTUTTAAAGAARGRGTTTTUUAAUTTAUUUTGGGAUTTTTTTGAATTAGURGGUUAU
    ATATAUUAGGGTTUTUAGAGGATTTTTTUTUUUUTTTUTUTUTGTUTUTTTUTGGG
    TTTUUTATTAUTAATT
62  ATTAGTAATAGGAAAAAUUUAGAAAGAGAUAGAGAGAAAGGGGGGAAAAAATUUT
    UTGAGAAUUUTGGTATATGTGGURGGUTAATTUAAAAAAGTUUUAGGGTAAGTTGG
    AAAARGRGTTUTTTAAGAUUAGATUAAGGTUTUTGUTXGTUATUAGGAAATATGAT
    TTGTGUTAAUAUAGGUUTTURGTTAAAAAUUTUURGGGUAAGTTAGUTAAGGAUAG
    UAGGTUTGAUUTATGAGTTAAUUAAAAUATTAUUTUATUTGUAAAGAAUTUUAAGA
    AUUATTUAGATUUTGAGGTUU
63  GUUTGGAAUUURGGRGATUTUTTGTTTUTUUAUUAAGGGAAUTUTGUTTGTAAUAU
    TTTAAGUUTUAGUTGAAAAGTGGTUTUUTGGGTGAAGTUTUAUUTGTGUAUUUAUU
    TGAGGGTGAGTUAGUTUTGUTUUUUTGGUTUTUAURGXGGUTGTTATAGUATTTAU
    RGGAGTUUUAUAGTGAUTUATTTGTUUATUAUUUTUURGAUAAAUUTTUUAGUTTU
    TGAAGGGUAGAGAUAGUATUATAATUATUTTTTATAAUTUURGTGUUTAGTGUTAU
    TUUUAATUUUTAGTAAGUAT
64  ATGUTTAUTAGGGATTGGGAGTAGUAUTAGGUARGGGAGTTATAAAAGATGATTAT
    GATGUTGTUTUTGUUUTTUAGAAGUTGGAAGGTTTGTRGGGAGGGTGATGGAUAAA
    TGAGTUAUTGTGGGAUTURGGTAAATGUTATAAUAGUXGRGGTGAGAGUUAGGGGA
    GUAGAGUTGAUTUAUUUTUAGGTGGGTGUAUAGGTGAGAUTTUAUUUAGGAGAUU
    AUTTTTUAGUTGAGGUTTAAAGTGTTAUAAGUAGAGTTUUUTTGGTGGAGAAAUAA
    GAGATRGURGGGGTTUUAGGU
65  AATUUUTTUUURGGGATAGTUAARGAGGUTTTUAATTTAAAUTTGUATTTGAAGUTT
    GUAGAGAUTUAUAUTGAUTTAUUUAGGUUUTAAUAUAUAGUAGUTGTUTUUATGG
    TTGRGUUAGGTAGTGAAGGATAUAGGGUAGUAGGAAAXGAGTUURGGTTUTUAGGT
    GGATUURGTGUTTUUAUUTUTGTTAGAGUUUAGGUUUTGAGGGUATAGGGUUAAAT
    TGUUAUAGAGUTUUAGAGAAATUTGTUTUTUURGTUUUUUAUUUTAAGAUTGAGUT
    GUTGGAGGAAAGAGGUUAGG
66  UUTGGUUTUTTTUUTUUAGUAGUTUAGTUTTAGGGTGGGGGARGGGAGAGAUAGAT
    TTUTUTGGAGUTUTGTGGUAATTTGGUUUTATGUUUTUAGGGUUTGGGUTUTAAUA
    GAGGTGGAAGUARGGGATUUAUUTGAGAAURGGGAUTXGTTTUUTGUTGUUUTGTA
    TUUTTUAUTAUUTGGRGUAAUUATGGAGAUAGUTGUTGTGTGTTAGGGUUTGGGTA
    AGTUAGTGTGAGTUTUTGUAAGUTTUAAATGUAAGTTTAAATTGAAAGUUTRGTTGA
    UTATUURGGGGAAGGGATT
67  AGGAATGTTTAUTGAAGGAGTGAATGAAAUTATTGUATTAGATUAAGUUUAGGTGU
    AGAGGAUTGGTTTUAUATAGAAAGUATRGATTTTGUUUTAUAGAAUUUTGAUTUUA
    GTTTTUUAGUAGAUAAUUUTGGTGTGAAGAUAGAGGGGXGGGGAGGAAGGTAGGG
    GUTGAUATTTUUUAGUUUUTUUUAGGURGGTGGGGAGUTGAATAGUTUAGTGAUTT
    GTUUAGGAGUURGAGGTAAAUUAUAGAUTAAGAGUUAAGAGTUATGATTUAUTAU
    TTGUATTTUTUUAGUUATGAUA
68  TGTUATGGUTGGAGAAATGUAAGTAGTGAATUATGAUTUTTGGUTUTTAGTUTGTGG
    TTTAUUTRGGGUTUUTGGAUAAGTUAUTGAGUTATTUAGUTUUUUAURGGUUTGGG
    AGGGGUTGGGAAATGTUAGUUUUTAUUTTUUTUUUXGUUUUTUTGTUTTUAUAUUA
    GGGTTGTUTGUTGGAAAAUTGGAGTUAGGGTTUTGTAGGGUAAAATRGATGUTTTUT
    ATGTGAAAUUAGTUUTUTGUAUUTGGGUTTGATUTAATGUAATAGTTTUATTUAUTU
    UTTUAGTAAAUATTUUT
69  GUTGGGATTATATATGUAUAUUAUUATGUURGGUTAATTTTTATATTTTTGGTAGAG
    ATAGGGGTTUUAUUATGTTGGUUAGGGTGGTUTTGAAUUUUTGAUUTUAGGTGATU
    UAUUUAUUTTGGUUTUUUAGAGTGUTGGGATTAUAGGXGTGAGUUAUTGUAUURG
    GUAUAAAGUUATTTTAAAAUAGUTTTTTTTTTTTTTTTGAAAUAGUUTTGUUUTGTA
    GUUUAGGUTGGAGTGTAGTGGTAUAATUTUAGUTUAUTGUAAUUTUUAUUTTURGG
    GTTUAAGTGATTUTTGTGU
70  GUAUAAGAATUAUTTGAAUURGGAAGGTGGAGGTTGUAGTGAGUTGAGATTGTAUU
    AUTAUAUTUUAGUUTGGGUTAUAGGGUAAGGUTGTTTUAAAAAAAAAAAAAAAGU
    TGTTTTAAAATGGUTTTGTGURGGGTGUAGTGGUTUAXGUUTGTAATUUUAGUAUTU
    TGGGAGGUUAAGGTGGGTGGATUAUUTGAGGTUAGGGGTTUAAGAUUAUUUTGGU
    UAAUATGGTGGAAUUUUTATUTUTAUUAAAAATATAAAAATTAGURGGGUATGGTG
    GTGTGUATATATAATUUUAGU
71  AAUAAATGUUAUAGGUUUTAATTGUAGGUTUUAAGGAGTTGAGATTUUATAUTGGG
    GTTGUTGGAGGUAGAAGUUTTUUUAUTTTUAGGAUURGGAUUTGUUUTTUUUUUAR
    GRGGTUURGUUUAGUUAGUTAUAUUUTGGUUAUAGAGXGUTUAUAAAGGUTUAGT
    GTGTGTATGURGGGUTGAUTUAUAGTGGTTUTGGGUUUAGGRGAGGAUUTTUTUAG
    AGGGGRGGAAGGGGUUUTUTUUUTUUTGGUUATTTTUUATGGGGAGUAGTUAGTAA
    UUAGGAUUATGUUAGAUTTUA
72  TGAAGTUTGGUATGGTUUTGGTTAUTGAUTGUTUUUUATGGAAAATGGUUAGGAGG
    GAGAGGGUUUUTTURGUUUUTUTGAGAAGGTUUTRGUUTGGGUUUAGAAUUAUTG
    TGAGTUAGUURGGUATAUAUAUAUTGAGUUTTTGTGAGXGUTUTGTGGUUAGGGTG
    TAGUTGGUTGGGRGGGAURGRGTGGGGGAAGGGUAGGTURGGGTUUTGAAAGTGG
    GAAGGUTTUTGUUTUUAGUAAUUUUAGTATGGAATUTUAAUTUUTTGGAGUUTGUA
    ATTAGGGUUTGTGGUATTTGTT
73  GUAGTGUTAUAAUATUAATGUUAAGGURGTGGGGUAGUTGATGGTTTGGGUTUUUA
    AUTTUUUAGUUAGGTGUTTUTGUAGGUUUAUATUTTGUUUAUTGGUUAAAUUTTTA
    AATAAUTTTGAUTRGGGUTAUTUTTATGUTUAAAGAXGTUAGGGGUTUTUUUAAAT
    UTUTTTAUUUTGUUAGAAAGTUTTUTATAGTARGGUUTUUAUTTAGUTTTUARGUUT
    GATUTTUUATRGUATUUTGUTUATAAUUTGUUAUTAGTGAAUUUUTGUTGUTURGG
    UTUUAUAUTTUTUATGUTG
74  AGUATGAGAAGTGTGGAGURGGAGUAGUAGGGGTTUAUTAGTGGUAGGTTATGAG
    UAGGATGRGATGGAAGATUAGGRGTGAAAGUTAAGTGGAGGURGTAUTATAGAAG
    AUTTTUTGGUAGGGTAAAGAGATTTGGGAGAGUUUUTGAXGTUTTTGAGUATAAGA
    GTAGUURGAGTUAAAGTTATTTAAAGGTTTGGUUAGTGGGUAAGATGTGGGUUTGU
    AGAAGUAUUTGGUTGGGAAGTTGGGAGUUUAAAUUATUAGUTGUUUUARGGUUTT
    GGUATTGATGTTGTAGUAUTGUU
75  AGGAGGGARGTGGAAGTRGTGGGTGGUAGAGAAAAGTGTGUAURGUTGGGAGGTU
    TATTTUAAGAATAGGTTGGGATGAGAAAUATGTUTGGGRGAGGGGGGTGGGAGGUU
    RGGTGTUAUUTGTGGATGGATUUAUAGUUUTGUAATTGXGTGTTGUAAAGTTTGUU
    RGGUUURGUATTUATTTTGAAGGTTUTTGGRGATGUUTRGAUTTTTRGUUTUAAAGA
    AGTGAGUTUTUATAAGGTTUAGAGGURGGGAGUUAAAGRGGGAGTGAAGAUTUTR
    GAGGGGTUUAAATGAAGUAGA
76  TUTGUTTUATTTGGAUUUUTRGAGAGTUTTUAUTUURGUTTTGGUTUURGGUUTUTG
    AAUUTTATGAGAGUTUAUTTUTTTGAGGRGAAAAGTRGAGGUATRGUUAAGAAUUT
    TUAAAATGAATGRGGGGURGGGUAAAUTTTGUAAUAXGUAATTGUAGGGUTGTGGA
    TUUATUUAUAGGTGAUAURGGGUUTUUUAUUUUUUTRGUUUAGAUATGTTTUTUAT
    UUUAAUUTATTUTTGAAATAGAUUTUUUAGRGGTGUAUAUTTTTUTUTGUUAUUUA
    RGAUTTUUARGTUUUTUUT
77  UUTTTTTGAUUTGGRGAGTUUUTTUUUTTTUUATTTUATTTTATTGUTTTTTATTGTTT
    UUUTURGGUUTUTTUTUUUUTUUTAGGTUTTTTUTUTAGUTUAGTTTGGAGUTUAUA
    TUUTTTUUAUUUTTTTUAUUTUUTUUTTUUTUXGUUUUAGGATTATUUUTGGGAUU
    UATUUTGAGUTGAGUUTAUAGUUAGUUAGUUARGAAATAGAGGTGRGRGGGGGUA
    GGGTGGTATGGAGATTUTGXGGUUTTTGATTTGAUAUUTUURGGAGUTAURGUUAU
    AGGUUTGUUUATTTUAU
78  TGAAATGGGUAGGUUTGTGGRGGTAGUTURGGGAGGTGTUAAATUAAAGGUXGUA
    GAATUTUUATAUUAUUUTGUUUURGRGUAUUTUTATTTRGTGGUTGGUTGGUTGTA
    GGUTUAGUTUAGGATGGGTUUUAGGGATAATUUTGGGGXGGAGGAAGGAGGAGGT
    GAAAAGGGTGGAAAGGATGTGAGUTUUAAAUTGAGUTAGAGAAAAGAUUTAGGAG
    GGGAGAAGAGGURGGAGGGAAAUAATAAAAAGUAATAAAATGAAATGGAAAGGGA
    AGGGAUTRGUUAGGTUAAAAAGGU
79  GUTUAGTTTGGAGUTUAUATUUTTTUUAUUUTTTTUAUUTUUTUUTTUUTUXGUUUU
    AGGATTATUUUTGGGAUUUATUUTGAGUTGAGUUTAUAGUUAGUUAGUUARGAAA
    TAGAGGTGRGRGGGGGUAGGGTGGTATGGAGATTUTGXGGUUTTTGATTTGAUAUU
    TUURGGAGUTAUXGUUAUAGGUUTGUUUATTTUAUUTGURGGGAAGATAAUTTTGG
    UTTUTGGTGGTGGGTGGGTGATTGAUTUTUAAAATUUAAAGUATTGGTTTITTUTGG
    GTTAUTTUUTATGAUTGUT
80  AGUAGTUATAGGAAGTAAUUUAGAAAAAAUUAATGUTTTGGATTTTGAGAGTUAAT
    UAUUUAUUUAUUAUUAGAAGUUAAAGTTATUTTUURGGUAGGTGAAATGGGUAGU
    UUTGTGGXGGTAGUTURGGGAGGTGTUAAATUAAAGGUXGUAGAATUTUUATAUU
    AUUUTGUUUURGRGUAUUTUTATTTRGTGGUTGGUTGGUTGTAGGUTUAGUTUAGG
    ATGGGTUUUAGGGATAATUUTGGGGXGGAGGAAGGAGGAGGTGAAAAGGGTGGAA
    AGGATGTGAGUTUUAAAUTGAGU
81  UATTUUAAUTTUTGUAAUUATGUAUAGTGATRGATATTTATAATTAUUTTTTTUUTT
    UAUUATGGUAAURGGGTUUTURGARGAGUAGGAUTGAAGAAGGAARGAGGAATAA
    AUTUTGGGAGTGGAAGRGRGUUTRGGUAGAUAGATURGXGGGRGUTGGGGUAGUU
    AGGAGAAGUUURGGUATURGUTTGTGAGGTURGGGGUTGTGGTUTRGAGTUURGUU
    URGUUTRGGRGGGUUURGUTUUUATGUURGUUURGUTATRGUUUURGRGUTUTTUT
    URGUURGUURGURGAGUTGUA
82  TGUAGUTRGGRGGGRGGGRGGAGAAGAGRGRGGGGGRGATAGRGGGGRGGGUATG
    GGAGRGGGGUURGURGAGGRGGGGRGGGAUTRGAGAUUAUAGUUURGGAUUTUAU
    AAGRGGATGURGGGGUTTUTUUTGGUTGUUUUAGRGUUXGRGGATUTGTUTGURGA
    GGRGRGUTTUUAUTUUUAGAGTTTATTUUTRGTTUUTTUTTUAGTUUTGUTRGTRGG
    AGGAUURGGTTGUUATGGTGAAGGAAAAAGGTAATTATAAATATRGATUAUTGTGU
    ATGGTTGUAGAAGTTGGAATG
83  TATGATGUUAGTGGTTGAATAUUTTAGTAGAGAAAAATUTTGAATAATUAAUKUUA
    GGTTUAGGAGAUAGUTGGGTATTTGAGAGUUTATGAGTUAUATAAGUAAUUTTGGA
    GUUAAGTTGTATTUTUTGTTTGGUUTUAGAGUUAGTUTXGAGUAUATGUAGUUAGA
    UTGURGGUAGAGAAGATGTGGAGUTGGUATTUTGGUTTAGGUUTGAGUAAGGTRGT
    GGAAGUUUUAGGTTUUTGAUUATGGUURGUAUAGAGUUATGUTUUAGUUUTGGGT
    UTUAGUAGGUAGUUAGGTGAG
84  UTUAUUTGGUTGUUTGUTGAGAUUUAGGGUTGGAGUATGGUTUTGTGRGGGUUATG
    GTUAGGAAUUTGGGGUTTUUARGAUUTTGUTUAGGUUTAAGUUAGAATGUUAGUT
    UUAUATUTTUTUTGURGGUAGTLTTGGUTGUATGTGUTXGAGAUTGGUTUTGAGGUU
    AAAUAGAGAATAUAAUTTGGUTUUAAGGTTGUTTATGTGAUTUATAGGUTUTUAAA
    TAUUUAGUTGTUTUUTGAAUUTURGGTTGATTATTUAAGATTTTTUTUTAUTAAGGT
    ATTUAAUUAUTGGUATUATA
85  GGGGUTRGUAGTGGUUTAGTUTGUTUTGGGUTTTGUTGGATGUUUTTRGAGAATUA
    URGRGUAAUUTUUTTUAGAGGUUUAAUAUTUUARGTGUTGAUTTUURGGGUUTGTG
    TUTUUUUTGURGUAGAUTGAAGXGTTUURGGUTGAAGGTGAGGTTUTGUAUUAAXG
    AGTRGUAGAAGTUURGGGUAGAGUTGGTGGGGUAGUTTUAGAGGUTGGGATTTGAU
    ATUTUTGAGUAGGAGGTGAURGUUURGGUAUUAGUTGUUTGUUAGATUUTGAAGG
    AGUAAGGUUTGRGAUUATAUU
86  GGTATGGTRGUAGGUUTTGUTUUTTUAGGATUTGGUAGUUAGUTUUUUKUUUUKU
    GTUAUUTUUTGUTUAGAGATGTUAAATUUUAGUUTUTGAAGUTGUUUUAUUAGUTU
    TGUURGGGAUTTUTGRGAUTXGTTGGTGUAGAAUUTUAUUTTUAGURGGGAAXGUT
    TUAGTUTGRGGUAGGGGAGAUAUAGGUURGGGAAGTUAGUARGTGGAGTGTTGGG
    UUTUTGAAGGAGGTTGRGRGGTGATTUTRGAAGGGUATUUAGUAAAGUUUAGAGU
    AGAUTAGGUUAUTGRGAGUUUU
87  GRGGGGUUAGUAGRGTGUURGGRGGGAAGRGGTAUAGGRGUTURGGGAAGURGRG
    UAUUAGUTGUTTUAGUAUUATGURGUTUAGGTRGGURGTGUTUTUUTGRGARGGGT
    TGAAGATGRGGARGAAUTTUTUURGGUAGUTUAUAGUUAXGATUTTUAGGUUTGTR
    GGGUTGGGAAGAGAGGAGARGUTGTGAGGAGATGRGGURGGTUUAUURGUAUAGU
    TGRGRGUUURGUURGGAAAUUAGUTUUAGTURGGRGURGGAGGUTTGGGTUAUTRC
    UUUUTTAUUTUTGUAGGAGTTU
88  GAAUTUUTGUAGAGGTAAGGGGRGAGTGAUUUAAGUUTURGGRGURGGAUTGGAG
    UTGGTTTURGGGRGGGGRGRGUAGUTGTGRGGGTGGAURGGURGUATUTUUTUAUA
    GRGTUTUUTUTUTTUUUAGUURGAUAGGUUTGAAGATXGTGGUTGTGAGUTGURGG
    GAGAAGTTRGTURGUATUTTUAAUURGTRGUAGGAGAGUARGGURGAUUTGAGRGG
    UATGGTGUTGAAGUAGUTGGTGRGRGGUTTUURGGAGRGUUTGTAURGUTTUURGU
    RGGGUARGUTGUTGGUUURGU
89  AGGAGTGTTTGGGGTGUTTUUTUTTGGUTGUAGTGGGAUAUAGGTGTGUUTTUUTA
    GGAAUTGGGUUUTGAUTAUTTUUAGUUUAAUAUTUURGGGUUTGTGAAUTGTGAU
    UTGTGTGURGGGATGGGTTTTGTGGGTUTGUUUUATUUUXGUAUTGUTGGATUTGG
    UUAAGTGGGTGAAGGUTAAGGURGGTUAGAGTTGAGTTTUTGUUTTGTUUUUTUTU
    UTGGGUTAGATGUUAUAUUAGGUUUAGTGAUTUATAGGGUAGGUAGTTGGGAAAT
    AUUAGGUAGAGGGUAGGTUUTG
90  UAGGAUUTGUUUTUTGUUTGGTATTTUUUAAUTGUUTGUUUTATGAGTUAUTGGGU
    UTGGTGTGGUATUTAGUUUAGGAGAGGGGAUAAGGUAGAAAUTUAAUTUTGAURG
    GUUTTAGUUTTUAUUUAUTTGGUUAGATUUAGUAGTGXGGGGATGGGGUAGAUUU
    AUAAAAUUUATUURGGUAUAUAGGTUAUAGTTUAUAGGUURGGGAGTGTTGGGUT
    GGAAGTAGTUAGGGUUUAGTTUUTAGGAAGGUAUAUUTGTGTUUUAUTGUAGUUA
    AGAGGAAGUAUUUUAAAUAUTUUT
91  GUAGGAATUAGGUUAGRGTATGTAATGAAAAUTUTTGRGTTATUTTTTTAGAAGGAT
    GTGAUTGTATTTTATGAGTATGUAGUAGGGTUAUUAUAUAUUTTTTGUTUUTGGGU
    UUUTUUUUTGTGTGTAGUUUAGGUUURGGTTTGTGUTXGAGGGUUAGAXGGUUUTA
    TGGTUUUUAGTTTUUTURGTAGATUAUAUAGGGAGGUAGRGAGGUAGGGTGUAAG
    GATGTTAGGGGTGGAAGGGGTGAUAURGGGAGUAAAGAUTGUTAUUUUTTGGUUT
    GGATAAAUUTGTUTGAUATTU
92  GAATGTUAGAUAGGTTTATUUAGGUUAAGGGGTAGUAGTUTTTGUTUURGGTGTUA
    UUUUTTUUAUUUUTAAUATUUTTGUAUUUTGUUTRGUTGUUTUUUTGTGTGATUTA
    RGGAGGAAAUTGGGGAUUATAGGGURGTUTGGUUUTXGAGUAUAAAUXGGGGUUT
    GGGUTAUAUAUAGGGGAGGGGUUUAGGAGUAAAAGGTGTGTGGTGAUUUTGUTGU
    ATAUTUATAAAATAUAGTUAUATUUTTUTAAAAAGATAARGUAAGAGTTTTUATTA
    UATARGUTGGUUTGATTUUTGU
93  TGAUTGTATTTTATGAGTATGUAGUAGGGTUAUUAUAUAUUTTTTGUTUUTGGGUU
    UUTUUUUTGTGTGTAGUUUAGGUUURGGTTTGTGUTRGAGGGUUAGARGGUUUTAT
    GGTUUUUAGTTTUUTURGTAGATUAUAUAGGGAGGUAGXGAGGUAGGGTGUAAGG
    ATGTTAGGGGTGGAAGGGGTGAUAURGGGAGUAAAGAUTGUTAUUUUTTGGUUTG
    GATAAAUUTGTUTGAUATTUURGAUUTUTGAAGTUATUUATUATGGUTGRGUTGGU
    TUAGAUAUTTUAAGGGUUAUTTT
94  AAAGTGGUUUTTGAAGTGTUTGAGUUAGRGUAGUUATGATGGATGAUTTUAGAGGT
    RGGGAATGTUAGAUAGGTTTATUUAGGUUAAGGGGTAGUAGTUTTTGUTUURGGTG
    TUAUUUUTTUUAUUUUTAAUATUUTTGUAUUUTGUUTXGUTGUUTUUUTGTGTGAT
    UTARGGAGGAAAUTGGGGAUUATAGGGURGTUTGGUUUTRGAGUAUAAAURGGGG
    UUTGGGUTAUAUAUAGGGGAGGGGUUUAGGAGUAAAAGGTGTGTGGTGAUUUTGU
    TGUATAUTUATAAAATAUAGTUA
95  UAUAUAUUTTTUAGTTGAGGGGRGUTGAGGTUUUTGUTGTTGUTGTGURGTUTGAU
    UTGTUUUUTUTUTUTGAUAGAGAGUUAGUTGUTUUURGGGAAUAAUTTUAUUAATG
    AGTGUAAUATAUUAGGUAAUTTUATGTGUAGUAATGGAXGGTGUATUURGGGRGU
    UTGGUAGTGTGARGGGUTGUUTGAUTGUTTRGAUAAGAGTGATGAGAAGGAGTGUR
    GTGAGTGGUUTGGUUUTTTGUTGGGGTGGGGTGGUAGUUATUUTGGGGUAGAGGGG
    AGUAGGTUUTGAGUAGGUTTA
96  TAAGUUTGUTUAGGAUUTGUTUUUUTUTGUUUUAGGATGGUTGUUAUUUUAUUUU
    AGUAAAGGGUUAGGUUAUTUARGGUAUTUUTTUTUATUAUTUTTGTRGAAGUAGTU
    AGGUAGUURGTUAUAUTGUUAGGRGUURGGGATGUAUXGTUUATTGUTGUAUATG
    AAGTTUUTGGTATGTTGUAUTUATTGGTGAAGTTGTTUURGGGGAGUAGUTGGUTU
    TUTGTUAGAGAGAGGGGAUAGGTUAGARGGUAUAGUAAUAGUAGGGAUUTUAGRG
    UUUUTUAAUTGAAAGGTGTGTG
97  UATGUATTTTGTGTTTGTAGTGTGUTGGUUARGGGAGUAUTUTAAAUAUATTATGGG
    URGGGRGUAGTGGUTURGGUUTGTAATUTUAGUAUTTTGGGAGGUTGAGGRGGGUA
    GATUAUTTGAGUUUAGGAGTTXGAUAUUAGUUTGGUUAAUAXGGXGAAAUUUXGT
    UTUTAUTAAAAATAUAAAAATTAAURGGGTGTGATGGRGRGTGUUTGTATTUUUAG
    UTAUTAGGGAGGUTGAGGUAGGAGAATUTUUTGAAUUTGGGAGGUAGGGAUTGUA
    GTGAGUUAAGATTGTGUUAUT
98  AGTGGUAUAATUTTGGTUAUTGUAGTUUUTGUUTUUUAGGTUAGGAGATTUTUU
    TGUUTUAGUUTUUUTAGTAGUTGGGAATAUAGGUARGRGUUATUAUAUURGGTTAA
    TTTTTGTATTTTTAGTAGAGAXGGGTTTXGUXGTGTTGGUUAGGUTGGTGTXGAAU
    TUUTGGGUTUAAGTGATUTGUURGUUTUAGUUTUUUAAAGTGUTGAGATTAUAGGU
    RGGAGUUAUTGRGUURGGUUUATAATGTGTTTAGAGTGUTUURGTGGUUAGUAUAU
    TAUAAAUAUAAAATGUATG
99  GGAUTGTGGGUUUUTTGGTTTGTGTUTGAAAGUTGGGGGTAUAGTTUTGUATGGGTT
    GGUUUUTGUUTTAUUTRGGGAAGUTUUUAGAGUUTGUTGGGUAGUUTGUUTUUTU
    UTUTUAUUTUUTUXGTUTUUAUTUUUTUUTUAUUAUATTURGGUTUTUUUARGGUR
    GGAGGUXGTGAATGGGUTGUTTTGTTGUURGGUUUAUAUAGGAGGATGGTGGUAG
    AAGAUUURGGUAUAAAGTUAGUAUUUAUTUTGTTUUUAGGUTGGGTTUAGGGAGG
    UTGAAAAGUUAUTTUAGUTGTG
100 UAUAGUTGAAGTGGUTTTTUAGUUTUUUTGAAUUUAGUUTGGGAAUAGAGTGGGTG
    UTGAUTTTGTGURGGGGTUTTUTGUUAUUATUUTUUTGTGTGGGURGGGUAAUAAA
    GUAGUUUATTUARGGUUTURGGURGTGGGAGAGURGGAATGTGGTGAGGAGGGAG
    TGGAGARGGAGGAGGTGAGAGGAGGAGGUAGGUTGUUUAGUAGGUTUTGGGAGUT
    TUURGAGGTAAGGUAGGGGUUAAUUUATGUAGAAUTGTAUUUUUAGUTTTUAGAU
    AUAAAUUAAGGGGUUUAUAGTUU
101 TAUTUTUTTGATGTATGAUUTTGGATGTGATTTAGUUTUTUTGGGUUTTGGUUUKUU
    TGAAUUATGTGATUAGAGUAUUAAGURGGUUTUUUARGUTGGTUTGAGUTGUTUAA
    GGGUUATUTAGGTUUTUTTTGTUUUAAGUUAGAGGTXGUUTUTUUURGGUUAAGUR
    GRGGUTATGGGGGTGGTGGTAUAAUAGAGAGUAUAGGGAUTTTGGAAUAUAAUAU
    TGGGTUATGAUUUUTGUUTGGUUAUTUTTGGUTGUTGAUUTTGAUUUTUTGTUTUU
    TUUTTTGTGAATGGGGGGAGT
102 AUTUUUUUUATTUAUAAAGGAGGAGAUAGAGGGTUAAGGTUAGUAGUUAAGAGTG
    GUUAGGUAGGGGTUATGAUUUAGTGTTGTGTTUUAAAGTUUUTGTGUTUTUTGTTG
    TAUUAUUAUUUUUATAGURGRGGUTTGGURGGGGAGAGGXGAUUTUTGGUTTGGG
    AUAAAGAGGAUUTAGATGGUUUTTGAGUAGUTUAGAUUAGRGTGGGAGGURGGUT
    TGGTGUTUTGATUAUATGGTTUAGRGGGGUUAAGGUUUAGAGAGGUTAAATUAUAT
    UUAAGGTUATAUATUAAGAGAGTA
103 GUUATGGAGAAAATATGUUATGTUTUUATGGAAAUUAAUUTATTTGUTTAAUTGAGGTTUTG
    GGGGTGGTTUTGAUAUTUAGTGUTAAUUAGGGGGAGTUTGGUTGTGAGGTRGTUAGUAUATG
    GRGGTGUTGURGGUTGUUTUUUAXGUAXGUAGGUTUTGUUAGUUTGUUTTGUUAATUTGUU
    AGGUAAUTGGGAUAGGTGUAGAUATGAUUUAGGUTUUAAGUAUARGUATUUAUUUTUUUR
    GURGAGGUAUTUTUURGGTGUUATATGTTGAUTUTGUUUAGRGUUAGGUAGUUUA
104 TGGGUTGUUTGGRGUTGGGUAGAGTUAAUATATGGUAURGGGAGAGTGUUTRGGRGGGGAG
    GGTGGATGRGTGTGUTTGGAGUUTGGGTUATGTUTGUAUUTGTUUUAGTTGUUTGGUAGATT
    GGUAAGGUAGGUTGGUAGAGUUTGXGTGXGTGGGAGGUAGURGGUAGUAURGUUATGTGUT
    GARGAUUTUAUAGUUAGAUTUUUUUTGGTTAGUAUTGAGTGTUAGAAUUAUUUUUAGAAUU
    TUAGTTAAGUAAATAGGTTGGTTTUUATGGAGAUATGGUATATTTTUTUUATGGU
105 GAGTUTGGUTGTGAGGTRGTUAGUAUATGGRGGTGUTGURGGUTGUUTUUUARGUA
    RGUAGGUTUTGUUAGUUTGUUTTGUUAATUTGUUAGGUAAUTGGGAUAGGTGUAG
    AUATGAUUUAGGUTUUAAGUAUARGUATUUAUUUTUUUXGURGAGGUAUTUTUUR
    GGTGUUATATGTTGAUTUTGUUUAGRGUUAGGUAGUUUAGRGUUUAUUTUUUUUT
    UUUUAGUUTGGUUUUARGUAUAGTGUTUTAGUUTUTGUTGGGTAGTGTGAGGAGTG
    GUAATUTGUAGGUAUUUTAGAAG
106 UTTUTAGGGTGUUTGUAGATTGUUAUTUUTUAUAUTAUUUAGUAGAGGUTAGAGUA
    UTGTGRGTGGGGUUAGGUTGGGGAGGGGGAGGTGGGRGUTGGGUTGUUTGGRGUT
    GGGUAGAGTUAAUATATGGUAURGGGAGAGTGUUTRGGXGGGGAGGGTGGATGRG
    TGTGUTTGGAGUUTGGGTUATGTUTGUAUUTGTUUUAGTTGUUTGGUAGATTGGUA
    AGGUAGGUTGGUAGAGUUTGRGTGRGTGGGAGGUAGURGGUAGUAURGUUATGTG
    UTGARGAUUTUAUAGUUAGAUTU
107 GURGAATUURGAGGGURGAGUAUUUUTUUUTUAGURGUAUTGUAUUTGUURGTAG
    GTGAUUAAUUUARGGGRGGAUUUUUAGAUUUAATUUTUTUUAGAGUUAGGGTGGG
    ATGGGUAGGGAUAGGAGURGGAGGUUUTAUTGGUUURGGGXGAAGGUATUUTGGA
    AAGUATUUAGAGRGTUUAGUATUUUTUURGRGGUUAUURGUAGGUTGAURGAUUU
    UTGGGUAGAUUUTUAGAUTUAATUUAGTUUAGGGRGGATTAAGGAGTGGGAGAUA
    AGGGAGURGGTGGUUURGUTGGUUU
108 GGGUUAGRGGGGUUAURGGUTUUUTTGTUTUUUAUTUUTTAATURGUUUTGGAUTG
    GATTGAGTUTGAGGGTUTGUUUAGGGGTRGGTUAGUUTGRGGGTGGURGRGGGAGG
    GATGUTGGARGUTUTGGATGUTTTUUAGGATGUUTTXGUURGGGGUUAGTAGGGUU
    TURGGUTUUTGTUUUTGUUUATUUUAUUUTGGUTUTGGAGAGGATTGGGTUTGGGG
    GTURGUURGTGGGTTGGTUAUUTARGGGUAGGTGUAGTGRGGUTGAGGGAGGGGTG
    UTRGGUUUTRGGGATTRGGU
109 TTGUTTGAUUAAAAGAATGUAGUAGAUATAAUTTTGAGAUUTGGAGUTAGGTUAUA
    AGARGATTTUUTGGGTTTTGTGGAATTUTRGTTUTGAAAGAAAUAAGUUAUUAAGT
    GGURGGGTGAGUTGGUTUAXGUUTGTAATUUUAGUAUTTTGGGAGGUXGAGURGG
    GUXGATUAUAAGGTUAGGAGATRGAGAUUATUUTGGUTAAUATGGTGAAAUUURG
    TUTUTAUTAAAAATAUAAAAAAATTAGURGGGUATAUTGGRGGGRGUUTGTAGTUU
    UAGUTAUTRGGGAGGUTGAGGU
110 GUUTUAGUUTUURGAGTAGUTGGGAUTAUAGGRGUURGUUAGTATGUURGGUTAAT
    TTTTTTGTATTTTTAGTAGAGARGGGGTTTUAUUATGTTAGUUAGGATGGTUTRGATU
    TUUTGAUUTTGTGATXGGUURGGUTXGGUUTUUUAAAGTGUTGGGATTAUAGGXGT
    GAGUUAGUTUAUURGGUUAUTTGGTGGUTTGTTTUTTTUAGAARGAGAATTUUAUA
    AAAUUUAGGAAATRGTUTTGTGAUUTAGUTUUAGGTUTUAAAGTTATGTUTGUTGU
    ATTUTTTTGGTUAAGUAA
111 AGAATUTGUUTAGUAGGRGGUTUTUUUUTGUTUUUUUAURGAGUAUAUAUKUIUU
    GAGGGGAUUUTGRGGGAGGAGGUTGUTTUAGTUTUUAGAGAUUATUTUUUATUTUT
    AUAGRGAUTUUUUTATGAURGTUUUUUAUURGGTGUTUTXGGGUUARGGGGAAGG
    GAUAUTRGGGAAAGAUAUUAGAGAURGGGAGGGTGUAGUTGGGUTUTTRGRGGGG
    AGRGGGRGGGAGGUUTTUUTGTTAUATGTRGUAGUTGGGAUAUAGARGGUAGRGUT
    UUAGGGTUUAUTTGURGGUTTRG
112 RGAAGURGGUAAGTGGAUUUTGGAGRGUTGURGTUTGTGTUUUAGUTGRGAUATGT
    AAUAGGAAGGUUTUURGUURGUTUUURGRGAAGAGUUUAGUTGUAUUUTUURGGT
    UTUTGGTGTUTTTUURGAGTGTUUUTTUUURGTGGUUXGAGAGUAURGGGTGGGGG
    ARGGTUATAGGGGAGTRGUTGTAGAGATGGGAGATGGTUTUTGGAGAUTGAAGUAG
    UUTUUTUURGUAGGGTUUUUTUUUARGGTUTGTGUTRGGTGGGGGAGUAGGGGAG
    AGURGUUTGUTAGGUAGATTUT
113 AGGUUUAGGUAGAGGTUAGAGUUUAAGUUUTGTUUURGAAGGAAATGTGTUUUAT
    GUTAAUTAUTUUATAGUTGAGGUUTGGAGGGAAGTUAGGGAUUUTGGGAUTGGTTA
    TUUTGGUUTTGAUTUATTAUTGTTURGGAGAUUTAAAXGUAUUUTGAGUUAUUAGA
    XGTGGGTGTTAAUAUUTGAGGTUAAUUUUUTGAXGUTTURGGUTGUTUTGGAGGAA
    GUTGGTUUTUUUTUUUAUUTUUTGTTTTURGTGUUAGUUTGGTAUAGAGTUAAGGG
    GUTTGGUTGGGUTTGGUTGGG
114 UUAGUUAAGUUUAGUUAAGUUUUTTGAUTUTGTAUUAGGUTGGUARGGAAAAUAG
    GAGGTGGGAGGGAGGAUUAGUTTUUTUUAGAGUAGURGGAAGXGTUAGGGGGTTG
    AUUTUAGGTGTTAAUAUUUAXGTUTGGTGGUTUAGGGTGXGTTTAGGTUTURGGAA
    UAGTAATGAGTUAAGGUUAGGATAAUUAGTUUUAGGGTUUUTGAUTTUUUTUUAG
    GUUTUAGUTATGGAGTAGTTAGUATGGGAUAUATTTUUTTRGGGGAUAGGGUTTGG
    GUTUTGAUUTUTGUUTGGGUUTG
115 UUUATGUTAAUTAUTUUATAGUTGAGGUUTGGAGGGAAGTUAGGGAUUUTGGGAU
    TGGTTATUUTGGUUTTGAUTUATTAUTGTTURGGAGAUUTAAAXGUAUUUTGAGUU
    AUUAGAXGTGGGTGTTAAUAUUTGAGGTUAAUUUUUTGAXGUTTURGGUTGUTUTG
    GAGGAAGUTGGTUUTUUUTUUUAUUTUUTGTTTTURGTGUUAGUUTGGTAUAGAGT
    UAAGGGGUTTGGUTGGGUTTGGUTGGGUTUAGAAARGTGGUAGTUAGGAGUUAGU
    UTGRGGGUAGRGGGGTGUTGGG
116 UUUAGUAUUURGUTGUURGUAGGUTGGUTUUTUAUTGUUARGTTTUTGAGUUUAG
    UUAAGUUUAGUUAAGUUUUTTGAUTUTGTAUUAGGUTGGUARGGAAAAUAGGAGG
    TGGGAGGGAGGAUUAGUTTUUTUUAGAGUAGURGGAAGXGTUAGGGGGTTGAUUT
    UAGGTGTTAAUAUUUAXGTUTGGTGGUTUAGGGTGXGTTTAGGTUTURGGAAUAGT
    AATGAGTUAAGGUUAGGATAAUUAGTUUUAGGGTUUUTGAUTTUUUTUUAGGUUT
    UAGUTATGGAGTAGTTAGUATGGG
117 UTUTUUURGUAGTTTUATURGTUUTUUTUUURGUUTUTGRGAGUTGGGTTTGGGGAR
    GTUTGGGTGGAATGTAGAUUUAUAGGUTGTUUTTGGTGUUUTUUUTUUUTGTTUTU
    UAGRGUUUUAGUUUUAGAUAUUAGTUUUUUAGRGGGXGAAAGUURGGGAGRGUU
    TTUUURGAAAGAUATUAGGGTGUUARGRGGUUUUTGUUUTGUAGAAGUATUUUUU
    TUURGUUUUTGUUTGGAAAGUAGGUUUUTUUUTAAGUTUTGRGUUUTTUTTUUUTG
    GGRGUUUTRGGAURGTGGUURG
118 RGGGUUARGGTURGAGGGRGUUUAGGGAAGAAGGGRGUAGAGUTTAGGGAGGGGU
    UTGUTTTUUAGGUAGGGGRGGGAGGGGGATGUTTUTGUAGGGUAGGGGURGRGTG
    GUAUUUTGATGTUTTTRGGGGAAGGRGUTUURGGGUTTTXGUURGUTGGGGGAUTG
    GTGTUTGGGGUTGGGGRGUTGGAGAAUAGGGAGGAAGGGUAUUAAGGAUAGUUTG
    TGGGTUTAUATTUUAUUUAGARGTUUUUAAAUUUAGUTRGUAGAGGRGGGGAGGA
    GGARGGATGAAAUTGRGGGGAGAG
119 AGAGGAGTGGGGAGRGUAGUAGGGTGGUUUURGUTUURGUTUAGAGGAGUTGGUU
    UTTTAAGGUUAGGUUUAGGRGGGTRGGGAAUAGAGAUURGGGAATGTGGGUTGGA
    UTGGGGAGUAGAGUUAUUUAGUATGAGTUATTUURGTTTXGURGGAUTUTTRGURG
    UTGGUTUTRGUTTGURGUUUTUUUUTGGUUUTGGUUUTGGUUTUTGRGUUUTUUUT
    GUAGAGUTGGTURGGGTGGGUTGGRGGUUTUUAUURGUUAUAAGRGUAUAGGGUT
    UTGUUUAUTUUURGUUUUTTTTU
120 GAAAAGGGGRGGGGAGTGGGUAGAGUUUTGTGRGUTTGTGGRGGGTGGAGGURGU
    UAGUUUAUURGGAUUAGUTUTGUAGGGAGGGRGUAGAGGUUAGGGUUAGGGUUA
    GGGGAGGGRGGUAAGRGAGAGUUAGRGGRGAAGAGTURGGXGAAARGGGAATGAU
    TUATGUTGGGTGGUTUTGUTUUUUAGTUUAGUUUAUATTUURGGGTUTUTGTTUUR
    GAUURGUUTGGGUUTGGUUTTAAAGGGUUAGUTUUTUTGAGRGGGAGRGGGGGUU
    AUUUTGUTGRGUTUUUUAUTUUTUT
121 GURGAGRGRGGTGGUTUATGUUTGTAATUUUAGUAUTTTGGGAGARGGAGGTGGGT
    GGATUAUUTUAGGTUAGAAGTTTGAGAUUTUTGTUTUTAUTGAAAUTATAAAAAAT
    TGGURGGGUATGGTGGTGGGTGTUTGTAGTTUUAGUTAXGTGGTAAGUTGAGGUAG
    GAGAATGAUTTGAAUURGGGAGGRGGAGGTTGUAGTGAGUUAGGATTGRGUUAUT
    GUAUTUUAGUUTGGGAGAUAGAGTUAGAUTUTGTUTUAAAAAAAAGUTATGGGUU
    TGUAGGATGUUTAATATAAAAG
122 UTTTTATATTAGGUATUUTGUAGGUUUATAGUTTTTTTTTGAGAUAGAGTUTGAUTU
    TGTUTUUUAGGUTGGAGTGUAGTGGRGUAATUUTGGUTUAUTGUAAUUTURGUUTU
    URGGGTTUAAGTUATTUTUUTGUUTUAGUTTAUUAXGTAGUTGGAAUTAUAGAUAU
    UUAUUAUUATGUURGGUUAATTTTTTATAGTTTUAGTAGAGAUAGAGGTUTUAAAU
    TTUTGAUUTGAGGTGATUUAUUUAUUTURGTUTUUUAAAGTGUTGGGATTAUAGGU
    ATGAGUUAURGRGUTRGGU
123 UARGUTUUTGTTTUAUTTTUATGTTUTGUTUTGTAUAUUTGGUTURGUUTTUTAGAT
    AGUAATAGUAGAATTAGTGAAAGTATTAAAGTUTTTGATUTTTUTGAGAAGAGUAT
    AGAAGAAATAATGARGTAAGUTGTUUTUTUTUUAGUTXGGUTAUUTAAAAGGGAAA
    GGUUUUUTGTURGGTGGAUARGTGAUTUAUATGAUUTTATTAATUAUTGGAGATGA
    UTUAUAUTUUTTAUUUTGUUUUTTTGUUTTGTAUAUAATAAATAAUAGRGRGAUUA
    GGUATTRGGGGUUAUTGUU
124 GGUAGTGGUUURGAATGUUTGGTRGRGUTGTTATTTATTGTGTAUAAGGUAAAGGG
    GUAGGGTAAGGAGTGTGAGTUATUTUUAGTGATTAATAAGGTUATGTGAGTUARGT
    GTUUAURGGAUAGGGGGUUTTTUUUTTTTAGGTAGUXGAGUTGGAGAGAGGAUAG
    UTTARGTUATTATTTUTTUTATGUTUTTUTUAGAAAGATUAAAGAUTTTAATAUTTTU
    AUTAATTUTGUTATTGUTATUTAGAAGGRGGAGUUAGGTGTAUAGAGUAGAAUATG
    AAAGTGAAAUAGGAGRGTG
125 AGUUUUUTGGGRGGGGTURGGGGAGUAGGUURGUATTTGGAGGAUAGGGTGTGAU
    UUATUTGAATUUTRGTTAAAGTAAAAGURGAURGARGGUTUTGGGAGGTTTGAGGU
    UTGGRGGGGRGGUUURGGGAAGTGATTTGTGGUXGUTAGGXGRGXGUTGGAAAUU
    UTTTUUUATUTGRGGAGUUUAURGGAGUTGTGATRGGAGGAGGAATTUUUUUAGGU
    AGGGAGGAURGUAGGGUUTTTTTUAUTRGTUUTGAGGGGUUUTGGGGUTTGGGGAG
    UAAAUUTGGGGTGAUUUATTTU
126 GAAATGGGTUAUUUUAGGTTTGUTUUUUAAGUUUUAGGGUUUUTUAGGARGAGTG
    AAAAAGGUUUTGRGGTUUTUUUTGUUGGGGGAATTUUTUUTURGATUAUAGUTUR
    GGTGGGUTURGUAGATGGGAAAGGGTTTUUAGXGRGXGUUTAGXGGUUAUAAATU
    AUTTUURGGGGURGUUURGUUAGGUUTUAAAUUTUUUAGAGURGTRGGTRGGUTTT
    TAUTTTAARGAGGATTUAGATGGGTUAUAUUUTGTUUTUUAAATGRGGGUUTGUTU
    UURGGAUUURGUUUAGGGGGUT
127 UATUUAUAAAUUTUUUAGGUUUUUTUAUTUTTUURGUAUAGTUTGUUTURGGTGUT
    UUAGAAAGAUTGGAAATGAGGTGAGUTUUUTTGGATUUUTGUUTGUUAUUTGUAA
    ATATUATGTGGTGUTAUTTGUUUTUUTGTUUUTUUTUUXGTUUUAGGUUAATUUTU
    UUAUUUUUTTAATTGUURGGGGATUTUUATTAUTTAAAUUTTTUUAUTGGTAUUTUT
    UUTUUUAUAUAAGUUTUUTUAGUTGTTTTURGTUTTTAAUUAAUAUUTTUUUTGGU
    TUUAGUTAUTGUUAUTTUAT
128 ATGAAGTGGUAGTAGUTGGAGUUAGGGAAGGTGTTGGTTAAAGARGGAAAAUAGU
    TGAGGAGGUTTGTGTGGGAGGAGAGGTAUUAGTGGAAAGGTTTAAGTAATGGAGAT
    UUURGGGUAATTAAGGGGGTGGGAGGATTGGUUTGGGAXGGGAGGAGGGAUAGGA
    GGGUAAGTAGUAUUAUATGATATTTGUAGGTGGUAGGUAGGGATUUAAGGGAGUT
    UAUUTUATTTUUAGTUTTTUTGGAGUAURGGAGGUAGAUTGTGRGGGAAGAGTGAG
    GGGGUUTGGGAGGTTTGTGGATG
129 UTTTUUUAGGAUTGUUTTGGUUUUUTGGUUUUAGTUTGGAGGAUTUTTGUTUAUTT
    UUTURGUUUUUAGGTGAGUTGAGAAUUUAUTGRGRGRGGGAUTUTGUTGRGUUTG
    UUUTUURGGGUTGUAGAGGGUAGGAXGUAURGUUAGGUAAGGURGRGGUTUTGXG
    UTGATGUUAUTURGGGAGRGGGTGGUTGRGGGGGAGGAGGGRGAGUAUTGGARGG
    GGGUAGRGGAGTGTAGGGTGTGAGATUTAAAUAGAGGGUTUUAUTGGAGGGUTTG
    UUUAGAAGGRGGUAGTUAUAUTGG
130 UUAGTGTGAUTGURGUUTTUTGGGUAAGUUUTUUAGTGGAGUUUTUTGTTTAGATU
    TUAUAUUUTAUAUTURGUTGUUUURGTUUAGTGUTRGUUUTUUTUUUURGUAGUUA
    UURGUTUURGGAGTGGUATUAGXGUAGAGURGRGGUUTTGUUTGGRGGTGXGTUUT
    GUUUTUTGUAGUURGGGAGGGUAGGRGUAGUAGAGTUURGRGRGUAGTGGGTTUT
    UAGUTUAUUTGGGGGRGGAGGAAGTGAGUAAGAGTUUTUUAGAUTGGGGUUAGGG
    GGUUAAGGUAGTUUTGGGAAAG
131 TTTAGGGTUTUTUTUURGUUTUTTTTUUTUUUURGUTUUUTUTUTUUTTGRGGUTGA
    UTUUAGUTUUUUUTRGGTGUURGTAAUUUTUUTTTUUTUTTTTGUXGUAGTUTUXG
    TUTUTUTTUUAUAGGGTUTUTUUUTUUUUUTUTUUURGTGGTTGTUAGAUTTTUTUU
    TGGAUTTTUTURGUUURGUAURGUUXGUUURGGATGURGAGRGTGGTAGAUTUTGU
    AGURGGGUTUUTRGUTGUURGUTGGRGUTGUUTAUAUUUUUTTGGGUTUUUUTUUA
    AGGTUUUUTURGUTRGU
132 GRGAGRGGAGGGGAUUTTGGAGGGGAGUUUAAGGGGGTGTAGGUAGRGUUAGRGG
    GUAGRGAGGAGUURGGUTGUAGAGTUTAUUARGUTRGGUATURGGGGXGGGRGGT
    GRGGGGRGGAGAAAGTUUAGGAGAAAGTUTGAUAAUUARGGGGAGAGGGGGAGGG
    AGAGAUUUTGTGGAAGAGAGAXGGAGAUTGXGGUAAAAAGAGGAAAGGAGGGTTA
    RGGGUAURGAGGGGGAGUTGGAGTUAGURGUAAGGAGAGAGGGAGRGGGGGAGG
    AAAAGAGGRGGGAGAGAGAUUUTAAA
133 GAGGGUUAUAGTAAAUTGGAUAAGTTTTTUTGUUUAGUUTAGGUTGUUAUUTGTAG
    GTUAUTTGGGUTUUAGUTATGTGGUTGUUTUTTUTGUTGGGTGUUTTAUTUTGGGUA
    GTGUTGTGGTTGUTUAGGGAURGGUAGAGUUTGUUXGUUAGUAATGUUTTTGTUTT
    UATUAURGGUTGTGAUTUAGGUTTTGGGRGUUTTUTGGUAUTGUAGUTGGAUUAGA
    GAGGUTTURGAGTUUTGGUUAGUTGUUTGAUUUUUTURGGGGURGAGGAUUTGUA
    GRGGGTGGUUTUUTUURGUU
134 GRGGGAGGAGGUUAUURGUTGUAGGTUUTRGGUUURGGAGGGGGTUAGGUAGUTG
    GUUAGGAUTRGGAAGUUTUTUTGGTUUAGUTGUAGTGUUAGAAGGRGUUUAAAGU
    UTGAGTUAUAGURGGTGATGAAGAUAAAGGUATTGUTGGXGGGUAGGUTUTGURG
    GTUUUTGAGUAAUUAUAGUAUTGUUUAGAGTAAGGUAUUUAGUAGAAGAGGUAG
    UUAUATAGUTGGAGUUUAAGTGAUUTAUAGGTGGUAGUUTAGGUTGGGUAGAAAA
    AUTTGTUUAGTTTAUTGTGGUUUTUA
135 GTTUTGGUTTUATTTTTTTTTTUUUAAAATGUUATTTTUATTTGTTUTTAGAGTTUAG
    AAUATGTUAAAGAGUTTUTTTAAGUAGTAGGTGGTTTTAUAGAGUUUAUAGAGAAG
    GAAAAUTAAATATUATUURGGATGUAGTUUAUTAXGATXGTGGAGGAGTUAGATTA
    UTUTURGGGUTTTGUTGTGTUTGUTTGTGAAAUAGGAAAGGGAGAAUTGAGGUAAT
    GAGTUAUUTUAUTTGGGUUUAAAGUAUUAUUTARGTTGAATATGGAGAAAATGTGA
    AGUAAGAGTTTUTTTTTA
136 TAAAAAGAAAUTUTTGUTTUAUATTTTUTUUATATTUAARGTAGGTGGTGUTTTGGG
    UUUAAGTGAGGTGAUTUATTGUUTUAGTTUTUUUTTTUUTGTTTUAUAAGUAGAUA
    UAGUAAAGUURGGAGAGTAATUTGAUTUUTUUAXGATXGTAGTGGAUTGUATURGG
    GATGATATTTAGTTTTUUTTUTUTGTGGGUTUTGTAAAAUUAUUTAUTGUTTAAAGA
    AGUTUTTTGAUATGTTUTGAAUTUTAAGAAUAAATGAAAATGGUATTTTGGGAAAA
    AAAAAATGAAGUUAGAAU
137 UUTUUTUUAGTUTTTGUATATATAUUAGGUTGGTATUUATTGUAGGTGGGGAUUTU
    UTUTTTGGGUTTTGGAGUUUUUUTUUUTGTGTUTUTGTAURGGGGAGUTTUTTUUTT
    UTGTUTTUTUUUTTUUTTUTTGUTUATTAAAUTUTUXGUTUUTTAAAAUUAUTUUAR
    GTGTGTURGTGTTGTTTTATUTAAAURGGRGGUAGGATUAAGAAUUUTTGTGT
    GUAUTUATUAGAGURGTATGATAATUAAGAGUTGAUTAUUTGGGUUATTUTUATAU
    UATTAGTGURGUATTTA
138 TAAATGRGGUAUTAATGGTATGAGAATGGUUUAGGTAGTUAGUTUTTGATTATUAT
    ARGGUTUTGATGAGTGUAGGAAUAUAAGGGTTUTTGATUUTGURGURGGTTTAGAT
    AAAAUAAUARGGAUAUARGTGGAGTGGTTTTAAGGAGXGGAGAGTTTAATGAGUAA
    GAAGGAAGGGAGAAGAUAGAAGGAAGAAGUTUUURGGTAUAGAGAUAUAGGGAG
    GGGGGUTUUAAAGUUUAAAGAGGAGGTUUUUAUUTGUAATGGATAUUAGUUTGGT
    ATATATGUAAAGAUTGGAGGAGG
139 AAGGTTAAAGTRGUTGUTAGAUUAAGGUTAAAURGTGGRGAGGTAGTTGUTTGRGU
    RGUAGAGTGTGGGTGTGAAUAGUTGGAGUTUAGTGGTTUUTGGAGAUTUAGGGAUU
    AUUTGTATTUUAUATURGGUTTUUUAUUUARGUAUAXGUAGTATGAUUTGGGTTTU
    UUUTTTATAUAGTGGAATGUTAAGTGUUTAUAUUUTAGURGGGGTUAGUUAAUTAT
    GGUUTGTGGGUAUUATUUUAUUTGUAGUUTGTTTTTGAGUTAAGAATGTTGTTGAU
    AUTTITAAAAAUAGAGAAUA
140 GTTUTUTGTTTTTAAAAGTGTUAAUAAUATTUTTAGUTUAAAAAUAGGUTGUAGGTG
    GGATGGTGUUUAUAGGUUATAGTTGGUTGAUUURGGUTAGGGTGTAGGUAUTTAGU
    ATTUUAUTGTATAAAGGGGAAAUUUAGGTUATAUTGXGTGTGRGTGGGTGGGAAGU
    RGGATGTGGAATAUAGGTGGTUUUTGAGTUTUUAGGAAUUAUTGAGUTUUAGUTGT
    TUAUAUUUAUAUTUTGRGGRGUAAGUAAUUTAUUTRGUUARGGTTTAGUUTTGGTUT
    AGUAGRGAUTTTAAUUTTG
141 GAGAUAGGGTTTUAUTUUTGTRGUUUAGGUTGGAGTGUAGUUTUAAUUTUUTGGGU
    TUAGTGGATUTTUUUAUUTUAGAUTUUTGAGTAGURGGGAUTAUAGGUAUARGUUA
    UUAGGUUTAGUTAATTTTTTGTATTTTTTTGTAGAGAXGAGGTTTRGUTAGGTrGUU
    UAGGUTGGTUTUTAAUTUUTGGGUTUAAGXGATUUAUUUAUUTUAGUTTUUUAAAG
    TGUTGGGGTTAUAGGUUTGAGTUAUAGXGTURGGUTGAAAGTGAAGTTGAATGAGA
    TGAUTRGTUUAGGUUAUAT
142 ATGTGGUUTGGARGAGTUATUTUATTUAAUTTUAUTTTUAGURGGAXGUTGTGAUT
    UAGGUUTGTAAUUUUAGUAUTTTGGGAAGUTGAGGTGGGTGGATXGUTTGAGUUUA
    GGAGTTAGAGAUUAGUUTGGGUAAUUTAGRGAAAUUTXGTUTUTAUAAAAAAATA
    UAAAAAATTAGUTAGGUUTGGTGGRGTGTGUUTGTAGTUURGGUTAUTUAGGAGTU
    TGAGGTGGGAAGATUUAUTGAGUUUAGGAGGTTGAGGUTGUAUTUUAGUUTGGGR
    GAUAGGAGTGAAAUUUTGTUTU
143 AUARGUUAUUAGGUUTAGUTAATTTTTTGTATTTTTTTGTAGAGAXGAGGTTTRGOT
    AGGTTGUUUAGGUTGGTUTUTAAUTUUTGGGUTUAAGXGATUUAUUUAUUTUAGUT
    TUUUAAAGTGUTGGGGTTAUAGGUUTGAGTUAUAGXGTURGGUTGAAAGTGAAGTT
    GAATGAGATGAUTRGTUUAGGUUAUATGGUAATUAGTGGUTGATTGARGUUAAAGT
    TGATTTUATTUTTUTUAATGGGTTUAGAGTUUAAATTUTGGAAUUTUAGAAGARGTT
    GUTATTUTGGTTUUAAGU
144 UTTGGAAUUAGAATAGUAARGTUTTUTGAGGTTUUAGAATTTGGAUTUTGAAUUUA
    TTGAGAAGAATGAAATUAAUTTTGGRGTUAATUAGUUAUTGATTGUUATGTGGUUT
    GGARGAGTUATUTUATTUAAUTTUAUTTTUAGURGGAXGUTGTGAUTUAGGUUTGT
    AAUUUUAGUAUTTTGGGAAGUTGAGGTGGGTGGATXGUTTGAGUUUAGGAGTTAGA
    GAUUAGUUTGGGUAAUUTAGRGAAAUUTXGTUTUTAUAAAAAAATAUAAAAAATT
    AGUTAGGUUTGGTGGRGTGTG
145 AGTGAUTGUAGRGTUAGGUUAAGUTTGGUUAUTTAUATGTUTGGUATGAUAGTGGU
    UTUAGAGTAUTRGTUTGAGAAGAAGAGUTATUAUUTGAGRGUTUTGGAGAAUTTAG
    URGGAGUTTTUAGGUAGTUTGGGAGUUTAUATGGAGGXGTGTAGGUTTATGTUTUA
    TGTUUARGTTGUURGGGAGAUAAAATUUTTTUTTTATTTAGAGUTGUUUUAAAATG
    UTGUAUUAGUTTUTUAUTGRGGTGGUTTUAUUTTAGUATAUAGGTATGTGGARGGU
    UAUTGTGUTGGUTUAUUTT
146 AAGGTGAGUUAGUAUAGTGGURGTUUAUATAUUTGTATGUTAAGGTGAAGUUAUR
    GUAGTGAGAAGUTGGTGUAGAAUATTTTGGGGUAGUTUTAAATAGAAAAGGATTTT
    GTUTUURGGGUAARGTGGAUATGAGAUATAAGUUTAUAXGUUTUUATGTAGGUTUU
    UAGAUTGUUTGAAAGUTURGGUTAAGTTUTUUAGAGRGUTUAGGTGATAGUTUTTU
    TTUTUAGARGAGTAUTUTGAGGUUAUTGTUATGUUAGAUATGTAAGTGGUUAAGUT
    TGGUUTGARGUTGUAGTUAUT
147 RGGGUAUUTAGGTUTRGUURGUUTGUAGURGUUTGGGGARGRGGGTTURGGARGGU
    TGGRGRGGGGRGGGGRGGGGAUUAURGAGUAGGAAGTUUURGRGGAAGRGURGUR
    GGGUAUAGRGTGGGTGUTGTRGAGGAGTGGRGUURGGGXGGGGRGGGAGGTTATA
    AATAGRGGURGUUATUUTGUTTUTUTTUAGAUAUAUTTAATTTAGURGGUAGGUAU
    ARGGATGUTTATTTTTAAAAAAAGAAUTTGTTTTATTGRGUTRGAGGTGAURGGGAA
    GGTGTUUURGRGGGTUAUTRG
148 RGAGTGAUURGRGGGGAUAUUTTUURGGTUAUUTRGAGRGUAATAAAAUAAGTTUT
    TTTTTTAAAAATAAGUATURGTGTGUUTGURGGUTAAATTAAGTGTGTUTGAAGAGA
    AGUAGGATGGRGGURGUTATTTATAAUUTUURGUTGUURGGGRGUUAUTUUTRG
    AUAGUAUUUARGUTGTGUURGGRGGRGUTTURGRGGGGAUTTUUTGUTRGGTGGTU
    UURGUUURGUUURGRGUUAGURGTURGGAAUURGRGTUUUUAGGRGGUTGUAGGR
149 GGGRGAGAUUTAGGTGUURG
    GAAGGTGRGGTGRGGTGAGGTGAGAAGAGAGAURGRGUTAGAUUAGGRGATGTUTT
    AGGGARGGGAGAGGGGTGAGGUUUARGGRGGTUUTGGGGAGRGGUUUARGAURGG
    UUUARGUAGAGUTTGTAGUUAGTGAAUAGGAAGTATTGGXGAGAGGGAUTGAGAA
    AUUUAAGAGAGTGTGGGGTGAGGAAAAGGTUAAGGAAGGUUUAGGUTTUUAGGAA
    GGGUUTGGGURGGGGRGGGGRGGGTGGTGGGAGGUAGTGGTTAGGARGGGRGGGG
    GTGGGGGTGGGGGTGGGGGTAGGG
150 UUUTAUUUUUAUUUUUAUUUUUAUUUURGUURGTUUTAAUUAUTGUUTUUUAUUA
    UURGUUURGUUURGGUUUAGGUUUTTUUTGGAAGUUTGGGUUTTUUTTGAUUTTTT
    UUTUAUUUUAUAUTUTUTTGGGTTTUTUAGTUUUTUTXGUUAATAUTTUUTGTTUAU
    TGGUTAUAAGUTUTGRGTGGGURGGTRGTGGGURGUTUUUUAGGAURGURGTGGGU
    UTUAUUUUTUTUURGTUUUTAAGAUATRGUUTGGTUTAGRGRGGTUTUTUTTUTUA
    TTTTTTTATTRUATURGUAUUTTU
151 GAGAAAUAAAATAUATTTTTTAATTTAAAAAAAAGTAUUAGAATGAATAAAAUAGG
    GGUTTTUUAAAAUTGUTTTTGGTAGATTTAGUAAAUUTAUTGAAUTTTAGAAAUTTTU
    ATTTTATAATTGTURGGAGATAGAAAGUAGTGUTTUXGAATAAGTGGATAAUTUTGU
    RGGTUUUAGTAGGTGUUATTGGTGAGUAUAUAGGGTTGUTTAAGTUTUTAAGTUAT
    TTUUUTGAUTGTGGTTTGAATUAATGTUAAATATUTAUAGGGGTUAGGUAGGTAAU
    TUAATGAAGTGAAAUAGG
152 UTGTUAUTTUATTGAGTTAUUTGUUTGAUUUUTGTAGATATTTGAUATTGATTUA
    AAUUAUAGTUAGGGAAATGAUTTAGAGAUTTAAGUAAUUUTGTGTGUTUAUUAATG
    GUAUUTAUTGGGAURGGUAGAGTTATUUAUTTATTXGGAAGUAUTGUTTTUTATUT
    URGGAUAATTATAAAATGAAAGTTTUTAAGTTUAGTAGGTTTGUTAAATUTAUUAAA
    AGUAGTTTTGGAAAGUUUUTGTTTTATTUATTUTGGTAUTTTTTTTTAAAUUAAAAAA
    TGTATTTTGTTTUTUT
153 GGAGGGUTTUAURGTUAGRGTAGRGTARGUUTGRGGGURGGGGRGGGAGAGGGAU
    RGTRGRGTTTGTGURGUUAGUAUUTGRGGUUUUUAGRGUAUURGGGUUUUARGRG
    GTAGUUUUUAGGGAGTGGGGAGTRGGGRGGGAAAUAGUTXGUURGGGUTUUTARG
    GGTGUUUUTTTRGURGRGUTUUUTUURGAGGGTUUTTTGUAGTRGGGRGTGGAAGT
    GGGATGAGUAAAUUURGUAGUAUAGGGUUTTRGUUUUAGGAUUTGUAUUUTUTAU
    RGGUUARGGGARGTUUUTURGUAU
154 GTGRGGAGGGARGTUURGTGGURGGTAGAGGGTGUAGGTUUTGGGGRGAAGGUUU
    TGTGUTGRGGGGTTTGUTUATUUUAUTTUUARGUURGAUTGUAAAGGAUUUTRGGG
    AGGGAGRGRGGRGAAAGGGGUAUURGTAGGAGUURGGGXGAGUTGTTTUURGUUR
    GAUTUUUUAUTUUUTGGGGGUTAURGRGTGGGGUURGGGTGRGUTGGGGGURGUA
    GGTGUTGGRGGUAUAAARGRGARGGTUUUTUTUURGUUURGGUURGUAGGRGTAR
    GUTARGUTGARGGTGAAGUUUTUU
155 AGAUAUAAAGAGGGRGGAGAGAUAGAUAUAGAAAGAGGGAGAUAGRGGGGUTGG
    ATGGARGTGTGGURGGGUUAGTGGGGAGGAGAGARGAGTURGUAGAUAGRGTTUA
    GAGGURGRGUTGUTTTGGGTGUTGAGURGTUURGGGGTTUAXGGTRGUAGTTTGTUU
    TTAUAAAARGUUUAGURGUUURGAUUTGTGGTGUTTAGGGAGGAUUTAUUTGGUTG
    TGURGGTUTGAGAAGGGGUUAGTGAGGUURGGTGRGGGTARGGGRGGGTGUAGAT
    GUAGUUAGGAGGARGGGRGGGAGU
156 GUTUURGUURGTUUTUUTGGUTGUATUTGUAUURGUURGTAUURGUAURGGGUUTU
    AUTGGUUUUTTUTUAGAURGGUAUAGUUAGGTAGGTUUTUUUTAAGUAUUAUAGG
    TRGGGGRGGUTGGGRGTTTTGTAAGGAUAAAUTGRGAUXGTGAAUUURGGGARGGU
    TUAGUAUUUAGGUAGRGRGGUUTUTGAARGUTGTUTGRGGAUTRGTUTUTUUTUUU
    UAUTGGUURGGUUAUARGTUUATUUAGUUIRGUTGTUTUUUTUTITUTGTGTUTGT
    UTUTURGUUUTUTTTGTGTUT
157 GUTGTUAUAUTGAGUTGTTTAAUAUTTAAGATGTTGGTGGATGGUAAAGUTAAAAG
    AGUATUGTAAUAUATGAUUTUTGGGGUTUURGGAGTUATGAGTAUUUUTTUTAGAU
    AUAGURGTGGGGUUAUAUAGAATTUTGUTUUTGUTGUXGUURGGAAGUAUTUATUT
    GGUTUUTGUAUUUAUTUAUUTGUATUUTTUUUUTUUUARGAGGTGTTAAGAGUTGT
    GGGATGAGTAAAGGAGGUUTGTGAAGGATTTUUTGTTTUAGTUTTAUATTUAGGTUT
    GAGTTUTUAGAGGAATUTT
158 AAGATTUUTUTGAGAAUTUAGAUUTGAATGTAAGAUTGAAAUAGGAAATUUTTUAU
    AGGUUTUUTTTAUTUATUUUAUAGUTUTTAAUAUUTRGTGGGAGGGGGAGGATGUA
    GGTGAGTGGGTGUAGGAGUUAGATGAGTGUTTURGGGXGGUAGUAGGAGUAGAAT
    TUTGTGTGGUUUUARGGUTGTGTUTAGAAGGGGTAUTUATGAUTURGGGAGUUUUA
    GAGGTUATGTGTTAUAGTGUUUTTTAGUTTTGUUATUUAUUAAUATUTTAAGTGTT
    AAAUAGUTUAGTGTGAUAGU
159 UAGGGUTGGGAGAATAGGATGGAUAGRGTTTTGUUAGAGUUTUATGGGAAGUTTUU
    TTTUAGGUAGUTGAAUUUATTTUAGGGGTAGGGAGUAUTGATUAGGGGTTGGGAUA
    TTGUUURGGGAGGAGGATGAGGATGTTTUUAGGUUTXGGUTGAUTUATGGTAGTGA
    GTATTAGTUAUTUUUTUAUAAGAATUAGUUUAUATUUTUTAGTAGUUTUTTGTUTU
    UUAGAGGUUUUTGUUUUATGTTTAUUTGUUTGAAGUTUUTUTUURGGURGUUUUUA
    UUUAUATURGUAUAGTTTGG
160 UAAAUTGTGRGGATGTGGGTGGGGGRGGURGGGAGAGGAGUTTUAGGUAGGTAAA
    UATGGGGUAGGGGUUTUTGGGAGAUAAGAGGUTAUTAGAGGATGTGGGUTGATTUT
    TGTGAGGGAGTGAUTAATAUTUAUTAUUATGAGTUAGUXGAGGUUTGGAAAUATUU
    TUATUUTUUTUURGGGGUAATGTUUUAAUUUUTGATUAGTGUTUUUTAUUUUTGAA
    ATGGGTTUAGUTGUUTGAAAGGAAGUTTUUUATGAGGUTUTGGUAAAARGUTGTUU
    ATUUTATTUTUUUAGUUUTGU
161 GAGGAUTAAAAGAAGUUAGAGATGUTGGTUAATTGAUAUAAAAATAAAGAGUTAA
    GGGAGAGGTTGAGAGAGGGAGAGUAATATUTATGGGTGTUTGGAATTTTTAAAGGG
    UTUAGAGGAGGAGGGGGURGGGRGTGGTGGUTUAXGUUTGTTATUXGAGUAUTTTG
    GGAGGUUAAGGTGGGUAAATUARGAGGTUAGGAGTTTGAGAGUAGUUTGAUUAAU
    ATGGTGUAAUUURGTUTUTAUTAAAAATAUAAAATTTAGURGGGTGTGGTTGTGTG
    UUTGTAATUUUAGUTAUTUAGG
162 UUTGAGTAGUTGGGATTAUAGGUAUAUAAUUAUAUURGGUTAAATTTTGTATTTTT
    AGTAGAGARGGGGTTGUAUUATGTTGGTUAGGUTGUTUTUAAAUTUUTGAUUTRGT
    GATTTGUUUAUUTTGGUUTUUUAAAGTGUTXGGATAAUAGGXGTGAGUUAUUARG
    UURGGUUUUUTUUTUUTUTGAGUUUTTTAAAAATTUUAGAUAUUUATAGATATTGU
    TUTUUUTUTUTUAAUUTUTUUUTTAGUTUTTTATTTTTGTGTUAATTGAUUAGUATUT
    UTGGUTTUTTTTAGTUUTU
163 UUAGGAGUURGUUTGGGAGRGRGUAGRGUTUTAGGAGURGAGAGURGUTGUTTGG
    UUUTRGUTGGURGGGTAAAURGAGGGGAAGUTUUTGGUUTUUTTTUUUTTAAGUUU
    UTTATTGUTTUTGTGGGGAAGGUUUTUUTAGGTAGAGGXGAAGGAURGGGGAGATA
    AUUTUTUUUATGGGUUAUATURGUTGUUATGGTUTGTGTRGTGUUAGAAGGTAUUT
    UTUAGUUUTUAGTGURGTGAAAAATUTGAUAUTUAAGAAGGTRGATTGAUARGUUT
    AARGTRGUAUAGUAATTTAGT
164 AUTAAATTGUTGTGRGARGTTAGGRGTGTUAATRGAUUTTUTTGAGTGTUAGATTTT
    TUARGGUAUTGAGGGUTGAGAGGTAUUTTUTGGUARGAUAUAGAUUATGGUAGRG
    GATGTGGUUUATGGGAGAGGTTATUTUUURGGTUUTTXGUUTUTAUUTAGGAGGGU
    UTTUUUUAUAGAAGUAATAAGGGGUTTAAGGGAAAGGAGGUUAGGAGUTTUUUUT
    RGGTTTAUURGGUUAGRGAGGGUUAAGUAGRGGUTUTRGGUTUUTAGAGRGUTGRG
    RGUTUUUAGGRGGGUTUUTGG
165 GAGGUARGAAGUTGURGGAGUTAUTUAGUTTTAUUTUTAGGAAAGATAUAGRGAAT
    UAURGUUAATAAAAUAAAGUAAAAUAAAAAGUTRGUUATGUTGAARGGAATGGGA
    AAATTGUTUTUTTGTUAUTAATTTTGATTGAATTGAGTXGGUAATUTUTGAAURGGT
    TUAUTGATAUAAUAATAGGAAAUATTTAAUTGTTTUTTGUAUUTTTAAAUATAAATA
    GTAGGTTTTTAAGUAGTUAGTAGGRGATGTGTGATUAAGGTTUAGAUAGARGUAGA
    UAAUTGATUAUUUAUTUAG
166 UTGAGTGGGTGATUAGTTGTUTGRGTUTGTUTGAAUUTTGATUAUAUATRGUUTAUT
    GAUTGUTTAAAAAUUTAUTATTTATGTTTAAAGGTGUAAGAAAUAGTTAAATGTTTU
    UTATTGTTGTATUAGTGAAURGGTTUAGAGATTGUXGAUTUAATTUAATUAAAATTA
    GTGAUAAGAGAGUAATTTTUUUATTURGTTUAGUATGGRGAGUTTTTTGTTTTGUTT
    TGTTTTATTGGRGGTGATTRGUTGTATUTTTUUTAGAGGTAAAGUTGAGTAGUTURG
    GUAGUTTRGTGUUT
167 GAUUTUAGUTURGGGTGAUAURGGTGGGRGTRGGGTGTGGUUTUAGAUAGUTUUUT
    TUUTUUURGGUTGGTTGUUAGGTUAAUAURGGGTGGGAUTAGUUTUTGGTGTRGGU
    AGTAGUUUUATGUTUURGGUUTTTGGGTTUTTGUATGXGURGTUUUUATUAUUTGG
    UTGUUUUTUTUAUTTURGTUTUUAUUTGTUURGGGTUAUUTGTUUTTUAAGUUAGA
    AATTAAGGAUAGUAUUUUUTUUUAGAURGUUTGGUTGUAGTUURGGGATGGGRGU
    TUUTAGTRGUUTAGATRGGGU
168 GUURGATUTAGGRGAUTAGGAGRGUUUATUURGGGAUTGUAGUUAGGRGGTUTGG
    GAGGGGGTGUTGTUUTTAATTTUTGGUTTGAAGGAUAGGTGAUURGGGAUAGGTGG
    AGARGGAAGTGAGAGGGGUAGUUAGGTGATGGGGARGGXGUATGUAAGAAUUUAA
    AGGURGGGAGUATGGGGUTAUTGURGAUAUUAGAGGUTAGTUUUAUURGGTGTTG
    AUUTGGUAAUUAGURGGGGAGGAAGGGAGUTGTUTGAGGUUAUAUURGARGUUUA
    URGGTGTUAUURGGAGUTGAGGTU
169 GTATUTGTGTUAAUUAGRGGTTUTUAGUUTGGUUTUATUUAGGGUUTGAAGUUTAU
    TAUAGAAUUUUUAGUAGUARGTGGGGTGUAUAGUAAAGATUAGUUUTGGAUAUAG
    URGGGTGUTUAGGGRGGGGTGAGGGGGUAGGAGGUAGGAXGUAGGAGGTGAGUTG
    TURGGGRGGGGUAGGATGAGGGAGTUUTGUATTGUAGAGUTAAGGGGGAGAATUA
    TUAGUAUUUTAATTAGUTTTTTGATGGUTTUUAAAGUUTTTTAAGTUUTTTTTTTTTTT
    TTTTTTTTTTATUUUTAUAAG
170 UTTGTAGGGATAAAAAAAAAAAAAAAAAAAAAGGAUTTAAAAGGUTTTGGAAGUU
    ATUAAGAGUTAATTAGGGTGUTGATGATTUTUUUUUTTAGUTUTGUAATGUAGGAU
    TUUUTUATUUTGUUURGUURGGAUAGUTUAUUTUUTGXGTUUTGUUTUUTGUUUUU
    TUAUUURGUUUTGAGUAUURGGUTGTGTUUAGGGUTGATUTTTGUTGTGUAUUUUA
    RGTGUTGUTGGGGGTTUTGTAGTAGGUTTUAGGUUUTGGATGAGGUUAGGUTGAGA
    AURGUTGGTTGAUAUAGATAU
171 GATTAAUTTGUUTUUTGAUAAGTUATAUUUTTTAGUTTAGTAUTAAGGUAGAAGAG
    AGUUUTGTTGAAGAGUURGUTTGTGTTUTGTGGTAAAGAUAUAGGUUTAURGGUTT
    UTUXGTGGGTUUUAGTGUTGAGAAGGGUAUAGGUTGGUTGGAGAUAGTGUUUTGU
    TTGAUAGAUUUUTUUAXGUTRGGATUUTTUUAGTUTGUAURGGUUAUUTGUAUTGG
    TTTUARGGAAGAGUTAGAATTUTGTTTTAATGTTGGUUAGTTTUUATUATTAGUTTG
    AAAAGAAUAUAGAAUTTARG
172 RGTAAGTTUTGTGTTUTTUUAAGUTAATGATGGAAAUTGGUUAAUATTAAAAUAGA
    ATTUTAGUTUTTURGTGAAAUUAGTGUAGGTGGURGGTGUAGAUTGGAAGGATURG
    AGXGTGGAGGGGTUTGTUAAGUAGGGUAUTGTUTUUAGUUAGUUTGTGUUUTTUTU
    AGUAUTGGGAUUUAXGGAGAAGURGGTAGGUUTGTGTUTTTAUUAUAGAAUAUAA
    GRGGGUTUTTUAAUAGGGUTUTUTTUTGUUTTAGTAUTAAGUTAAAGGGTATGAUTT
    GTUAGGAGGUAAGTTAATU
173 GAUUAUAGGTGTGTGUTATUATGUURGGGTAATTTTTATATTTTTTGGTUTUAUTAT
    GTTGUUUAGGUTGGTUTUAAAUTUUTGGGUTUAAGTGATUUTUUTGUUTUAGUUTU
    UUAAAGTGTTGGATTAGAGGUATGAGUUAUUTTGUAXGTTTGUUTUUTGAUUTUAG
    GTUUUUARGGAGTTGGTUATUTTUTGGGUUTRGUTUAGURGGTGUTGAAGGTGAGT
    UATGUTRGATGATGAUUTGAGGAGUAGAAGAAGGTGUAGGTGAGTUAUUTGAGGG
    GAAUTGGGTUATGAUUAGAG
174 UTUTGGTUATGAUUUAGTTUUUUTUAGGTGAUTUAUUTGUAUUTTUTTUTGUTUUT
    UAGGTUATUATRGAGUATGAUTUAUUTTUAGUAURGGUTGAGRGAGGUUUAGAAG
    ATGAUUAAUTURGTGGGGAUUTGAGGTUAGGAGGUAAAXGTGUAAGGTGGUTUAT
    GUUTUTAATUUAAUAUTTTGGGAGGUTGAGGUAGGAGGATUAUTTGAGUUUAGGA
    GTTTGAGAUUAGUUTGGGUAAUATAGTGAGAUUAAAAAATATAAAAATTAUURGG
    GUATGATAGUAUAUAUUTGTGGTU
175 AGGAAGTRGAGGUTTAGAAGTTGGGTGAUTTGTUAAAGGTRGUUAUUUARGGTGAG
    GGUUAGGTTUTGGGAGGGUTGAGGGGUAGGUATGGTGAGUUAGTTURGGGUATGA
    GGUAAGGRGTGGUAGGUUTGGGGGUAAAAGUUAUAGUUXGTGTGGAGGGGGTGGG
    GGGATRGAGGUUTTTGGGAAGUUTGTGGATTUTGGUTGUAGTGTGGGTGTGAUAUT
    GAGTGUTURGGGGAUTURGAGTTATUAUUUAGGUAUTGGUUAGUUUUARGUTUUU
    TUUTUUAGGTAUTTGGUTUUUTG
176 AGGGAGUUAAGTAUUTGGAGGAGGGAGRGTGGGGUTGGUUAGTGUUTGGGTGATA
    AUTRGGAGTUUURGGAGUAUTUAGTGTUAUAUUUAUAUTGUAGUUAGAATUUAUA
    GGUTTUUUAAAGGUUTRGATUUUUUUAUUUUUTUUAUAXGGGUTGTGGUTTTTGUU
    UUUAGGUUTGUUARGUUTTGUUTUATGUURGGAAUTGGUTUAUUATGUUTGUUUUT
    UAGUUUTUUUAGAAUUTGGUUUTUAURGTGGGTGGRGAUUTTTGAUAAGTUAUUU
    AAUTTUTAAGUUTRGAUTTUUTU
177 AGUUARGGRGAUUAUUAUUTUUATUUTUUUUUAUUTUUTUUTUUTGUAGGTGGUU
    TTTTTGGUUAGTGTGTUTGAGTGUTUAUUTUTTGUTUTAGTGTUUTGGTGUTURGGUT
    UTUUTUTTUUTUUTUAUTUTUUTGGGUUTGGGUUTGUXGUTUURGGGUUTUUAGGT
    UTAGAUAUAAGGGTTGAATGAUUAGAUTGUTGGTUTGTTUAGTTTUUATGTGGUUT
    RGGUUUAUUUUAGUTUTGGUTGUUTUUUUAAAGTUTUAATUARGARGAGATUATA
    UAGTAAUTUTGUUUUUTUUUT
178 AGGGAGGGGGUAGAGTTAUTGTATGATUTRGTRGTGATTGAGAUTTTGGGGAGGUA
    GUUAGAGUTGGGGTGGGURGAGGUUAUATGGAAAUTGAAUAGAUUAGUAGTUTGG
    TUATTUAAUUUTTGTGTUTAGAUUTGGAGGUURGGGAGXGGUAGGUUUAGGUUUA
    GGAGAGTGAGGAGGAAGAGGAGAGURGGAGUAUUAGGAUAUTAGAGUAAGAGGT
    GAGUAUTUAGGUAUAUTGGUUAGAAGGUUAUUTGUAGGAGGAGGAGGTGGGGGA
    GGATGGAUUTGGTGGTRGURGTGGUT
179 AAGGTGAATGUTGUAAUUUTUTUTUUTUAGUUUTGUAGURGATUUUTGAUATAAAU
    TUUTTGAAGTTUAGTGGUUTUTTTUUATGUAUUTAUUAUUTAUAUUTGUTGU
    AAGAAAUUAUAAUUTGGAURGGGAAUAGAAUTGGAXGTGUUAAAATGUUTGAGGA
    UAUTTUATXGAATGTGGUTGGUTTGATGGGAAGUTGGUATGAUTAGAAATGTUAGG
    AGTUTTUUUTUTXGAGGTTTUAAGUTTTGTGTTTUTGAUTUAATGGTURGGATTGAG
    ATUAGATGAGTUAAGTTUA
180 GAAUTTGAUTUATUTGATUTUAATURGGAUUATTGAGTUAGAAAUAUAAAGUTTGA
    AAUUTXGAGAGGGAAGAUTUUTGAUATTTUTAGTUATGUUAGUTTUUUATUAAGUU
    AGUUAUATTXGATGAAGTGTUUTUAGGUATTTTGGUAXGTUUAGTTUTGTTUURGGT
    UUAGGTTGTGGTTTUTTTGAAAGUAGUAGGTGTAGGTGGTAGGTGUATGGAAAGAG
    GUUAUTGAAUTTUAAGGAGTTTATGTUAGGGATRGGUTGUAGGGUTGAGGAGAGAG
    GGTTGUAGUATTUAUUTTU
181 UAGUUUTGUAGURGATUUUTGAUATAAAUTUUTTGAAGTTUAGTGGUUTUTTTUUA
    TGUAUUTAUUAUUTAUAUUTGUTGUTTTUAAAGAAAUUAUAAUUTGGAURGGGAA
    UAGAAUTGGAXGTGUUAAAATGUUTGAGGAUAUTTUATXGAATGTGGUTGGUTTGA
    TGGGAAGUTGGUATGAUTAGAAATGTUAGGAGTUTTUUUTUTXGAGGTTTUAAGUT
    TTGTGTTTUTGAUTUAATGGTURGGATTGAGATUAGATGAGTUAAGTTUAGATGAUU
    ATGUAAAUUTTTAGATGGGG
182 UUUUATUTAAAGGTTTGUATGGTUATUTGAAUTTGAUTUATUTGATUTUAATURGGA
    UUATTGAGTUAGAAAUAUAAAGUTTGAAAUUTXGAGAGGGAAGAUTUUTGAUATTT
    UTAGTUATGUUAGUTTUUUATUAAGUUAGUUAUATTXGATGAAGTGTUUTUAGGUA
    TTTTGGUAXGTUUAGTTUTGTTUURGGTUUAGGTTGTGGTTTUTTTGAAAGUAGUAG
    GTGTAGGTGGTAGGTGUATGGAAAGAGGUUAUTGAAUTTUAAGGAGTTTATGTUAG
    GGATRGGUTGUAGGGUTG
183 UUTAUUAUUTAUAUUTGUTGUTTTUAAAGAAAUUAUAAUUTGGAURGGGAAUAGAAUTGGA
    XGTGUUAAAATGUUTGAGGAUAUTTUATXGAATGTGGUTGGUTTGATGGGAAGUTGGUATG
    AUTAGAAATGTUAGGAGTUTTUUUTUTXGAGGTTTUAAGUTTTGTGTTTUTGAUTUAATGGTU
    RGGATTGAGATUAGATGAGTUAAGTTUAGATGAUUATGUAAAUUTTTAGATGGGGUUTAAAA
    UUAAATUTGTGTTUTTAAAUUATTUUAAATGTGTTUATUAUUAGTTATAGTTT
184 AAAUTATAAUTGGTGATGAAUAUATTTGGAATGGTTTGAGAAUAUAGATTTGGTTTTAGGUU
    UUATUTAAAGGTTTGUATGGTUATUTGAAUTTGAUTUATUTGATUTUAATURGGAUUATTGA
    GTUAGAAAUAUAAAGUTTGAAAUUTXGAGAGGGAAGAUTUUTGAUATTTUTAGTUATGUUA
    GUTTUUUATUAAGUUAGUUAUATTXGATGAAGTGTUUTUAGGUATTTTGGUAXGTUUAGTTU
    TGTTUURGGTUUAGGTTGTGGTTTUTTTGAAAGUAGUAGGTGTAGGTGGTAGG
185 GAGAGGGGAAGGGGURGAUUAUUTGUTUURGAGUUATTUTRGGGUTRGGUUAGUU
    ATTGGGUTGGGAAUUTGTUAATUUTGGTTGATUTTUUAATGAGUTGTGAAUTGGTUT
    TURGGGAGGAUTTAUAGGAGGUTGGAAARGGGGUUTGGXGRGRGUTTUUUTUTUAG
    TGRGAGGUTGAUTGGTTGGAUTRGURGGGUTUTAUTGTGGGUUUUARGUTATGTTT
    AGARGUURGARGTGTUUUATTTTATTGAAUTRGTUUTGUUUUUUAAGTAGGGARGA
    TTTAUUTUUATTTTUTAGAT
186 ATUTAGAAAATGGAGGTAAATRGTUUUTAUTTGGGGGGUAGGARGAGTTUAATAAA
    ATGGGAUARGTRGGGRGTUTAAAUATAGRGTGGGGUUUAUAGTAGAGUURGGRGA
    GTUUAAUUAGTUAGUUTRGUAUTGAGAGGGAAGRGRGXGUUAGGUUURGTTTUUA
    GUUTUUTGTAAGTUUTUURGGAAGAUUAGTTUAUAGUTUATTGGAAGATUAAUUAG
    GATTGAUAGGTTUUUAGUUUAATGGUTGGURGAGUURGAGAATGGUTRGGGAGUA
    GGTGGTRGGUUUUTTUUUUTUTU
187 RGGGGGUAGGGAGUAGAUUTGAUTUAGTGGRGTUAGTGUTAUTTUAAAGRGGUAG
    RGUATTTUATTAAAAATUTGATGTAGAAATTAUUUTGGGUTTTGTTTTGUAAAGAGU
    ATTTGUATAAGAAAAAATAATUAGURGGTTAATTUUUUXGTUUAUTGGUAGGAAGA
    GAGAUAGUUTTUAGAGAGTTTGGGAUTUTUTUATTUURGGAGAATTAAAAGUUTUR
    GAGAUATUUATTTTAGAAGTTUTGGTUAATRGTTUTTAAAGTGRGGTUAGAAGAUU
    UUTTGRGTUTGAATGGTTTG
188 UAAAUUATTUAGARGUAAGGGGTUTTUTGAURGUAUTTTAAGAARGATTGAUUAGA
    AUTTUTAAAATGGATGTUTRGGAGGUTTTTAATTUTURGGGAATGAGAGAGTUUUA
    AAUTUTUTGAAGGUTGTUTUTUTTUUTGUUAGTGGAXGGGGGAATTAAURGGUTGA
    TTATTTTTTUTTATGUAAATGUTUTTTGUAAAAUAAAGUUUAGGGTAATTTUTAUAT
    UAGATTTTTAATGAAATGRGUTGURGUTTTGAAGTAGUAUTGARGUUAUTGAGTUA
    GGTUTGUTUUUTGUUUURG
189 UAGTGTTGTAGAUUTATTAATTATUAGGATAATTARGGARGGGGAAATUUAGAUAU
    AGATAUAATUAGTGUUUTUUTUUAUUTUUURGUAUARGUUUUTUURGGTUTUUUTG
    AUATUUTGGTGTGUAUTGTGTTUUUUTGUUATUTUUAXGUTGRGGUTUUTAUTAGA
    UUUAUUUUTGURGGTGUUAAAATGUUUAAAGGAAGGUTGAGTUATGUTUTGGUUT
    GUUUAGURGUAATAGTUATGUTGUAAUTUUUARGGAAAAUUTUUTTTUAUUUAUTU
    UAGAGGTUTGAGAUAUUUTAA
190 TTAGGGTGTUTUAGAUUTUTGGAGTGGGTGAAAGGAGGTTTTURGTGGGAGTTGUA
    GUATGAUTATTGRGGUTGGGUAGGUUAGAGUATGAUTUAGUUTTUUTTTGGGUATT
    TTGGUAURGGUAGGGGTGGGTUTAGTAGGAGURGUAGXGTGGAGATGGUAGGGGA
    AUAUAGTGUAUAUUAGGATGTUAGGGAGAURGGGAGGGGRGTGTGRGGGGAGGTG
    GAGGAGGGUAUTGATTGTATUTGTGTUTGGATTTUUURGTURGTAATTATUUTGATA
    ATTAATAGGTUTAUAAUAUTG
191 GGAAGGAGRGAGUTTUTTTTTATAGGAGUTUUAGTTUUTRGTTTTGTTUTUTTRG
    TTATTUTUUAAAGAAAGURGGUTUTTGAGTUAGUTGGUAGGAGAGRGAGGRGAATG
    RGUTGGTGUTGGURGUAATGGUUURGGTTUAARGUTXGUTUUAGUTGGTUARGTUU
    TUAURGGGGRGGURGGRGGUUTGUUTGUUUARGUTUTGUUAGGAGUUUAGGTUAG
    UUUrrGUUTRGURGGGGURGGAGUURGTUUAAAATUAAUAAGTUTTTTGTGUUTUT
    UUTTTGGARGUTGTATAATT
192 AATTATAUAGRGTUUAAAGGAGAGGUAUAAAAGAUTTGTTGATTTTGGARGGGUTU
    RGGUUURGGRGAGGUAAGGGUTGAUUTGGGUTUUTGGUAGAGRGTGGGUAGGUAG
    GURGURGGURGUUURGGTGAGGARGTGAUUAGUTGGAGXGAGRGTTGAAURGGGG
    UUATTGRGGUUAGUAUUAGRGUATTRGUUTRGUTUTUUTGUUAGUTGAUTUAAGAG
    URGGUTTTUTTTGGAGAATAAUURGAAGAGAAUAAAARGAGGAAUTGGAGUTUUTA
    TAAAAAGAAGUTRGUTUUTTUU
193 UTGGTTGTGGAAGGAGRGAGUTUTURGTUUURGGGAGTATGUAAGTTTUUUUTUUA
    RGATUAUTTGGAAGGGATTGGGRGGAGTTUTGTUATTTGGAGAAAGGGTUUTGGGA
    GUTTUAGGTTTGTGTAGGGRGAGGARGGGGRGGTTUTGXGTURGGUUAGGTTGGUU
    UTRGAGGAUUUAGURGTUUUUAAUUTUUTAAAUTGUTGTRGGATGTAGAAGAUTRG
    UATTUAUTGUTUTUUAUAGTRGGTGAAGGGAGAARGURGAAAAGGGURGUATTUUU
    TUUTGURGGTUUUUTUUUUT
194 AGGGGAGGGGAURGGUAGGAGGGAATGRGGUUUTTTTRGGRGTTUTUUUTTUAURG
    AUTGTGGAGAGUAGTGAATGRGAGTUTTUTAUATURGAUAGUAGTTTAGGAGGTTG
    GGGARGGUTGGGTUUTRGAGGGUUAAUUTGGURGGAXGUAGAAURGUUURGTUUT
    RGUUUTAUAUAAAUUTGAAGUTUUUAGGAUUUTTTUTUUAAATGAUAGAAUTURG
    UUUAATUUUTTUUAAGTGATRGTGUAGUUUAAAUTTGUATAUTUURGGGGARGGAG
    AGUTRGUTUUTTUUAUAAUUAG
195 GGGTGTUAGGUTAUUUTTGAAGGGAUUTAUUTUUTUUAGUUAUTGUUAUTGGAUU
    UTUUUTUAGUUUUTUTAGUAAAGUAGUUUUAATGUATGTUUTGAGATTGTUURGGA
    AAAUTGTUAUTUAGAGGGGAAGAUTUTTGGGUAUAGAGUXGTTATTTATAAUAGUA
    AGAUAUTGUAGGUTGUUTAAAUAUTUUARGAUAGAGATGARGGAGUAATTUARGG
    UAUUUUTGUUAAGAGAGTATTAUAUAGUUATTAAAAATGATUAAGUAGAGAURGG
    TAGTGARGUTGAGTAATGTTTTU
196 GAAAAUATTAUTUAGRGTUAUTAURGGTUTUTGUTTGATUATTTTTAATGGUTGTGT
    AATAUTUTUTTGGUAGGGGTGURGTGAATTGUTURGTUATUTUTGTRGTGGAGTGTT
    TAGGUAGUUTGUAGTGTUTTGUTGTTATAAATAAXGGUTUTGTGUUUAAGAGTUTT
    UUUUTUTGAGTGAUAGTTTTURGGGAUAATUTUAGGAUATGUATTGGGGUTGUTTT
    GUTAGAGGGGUTGAGGGAGGGTUUAGTGGUAGTGGUTGGAGGAGGTAGGTUUUTT
    UAAGGGTAGUUTGAUAUUU
197 GUUUAURGRGGAGGGUUUUUUTATUUTUUTUATUUTUAUTGGUTUAUUUAGGGUA
    UUAUUAUUTUUTUUAGGAAAUUUTUUUTGUUUUUTATUTUTGGGTGTUTUAUAUUU
    TGGGUAUUTAUAGUUAGAAUUUUAUUTURGGGUUUTUXGTTTUUAGTGGUTGAGT
    AGGAGUTTUAGTTTTAGGAGAUTUUUUTGAGUAGAAURGAUUUUTUTTUATUTTUU
    UAAUUUUUAUUUAUAUAUTUAGGAUTGGGTAURGGGGUUTGUUUUAATTTGUAGG
    UTTAGAGTUAGGGGTTAGGGTGG
198 UAUUUTAAUUUUTGAUTUTAAGUUTGUAAATTGGGGUAGGUUURGGTAUUUAGTU
    UTGAGTGTGTGGGTGGGGGTTGGGAAGATGAAGAGGGGTRGGTTUTGUTUAGGGGA
    GTUTUUTAAAAUTGAAGUTUUTAUTUAGUUAUTGGAAAXGGAGGGUURGGAGGTG
    GGGTTUTGGUTGTAGGTGUUUAGGGTGTGAGAUAUUUAGAGATAGGGGGUAGGGA
    GGGTTTUUTGGAGGAGGTGGTGGTGUUUTGGGTGAGUUAGTGAGGATGAGGAGGAT
    AGGGGGGUUUTURGRGGTGGGUA
199 UTTAAATGAGAAGAAUATGTTTUTAUAURGUATTTGTGAAAGTTTGGUTRGGAGUTA
    RGRGUTGATTAATATUAGATUTUUTTUAUTRGUUTRGUUAUAATUTTGTUAUATUTG
    GUTGAUAAATUURGAGGAAUTURGGUAAAGUUAGGXGGRGGRGGGGUTURGGGTU
    TGGGRGGRGGUTURGGAGGAGUAGRGGGAGAUUURGUAGRGGUUTUUTUUTTUTU
    RGUURGRGGUUUUUAGUUTRGURGURGURGUURGGUTUUUAGUARGGAAURGARG
    GGGRGUTUURGAGARGGGRGA
200 TRGUURGTUTRGGGAGRGUUURGTRGGTTURGTGUTGGGAGURGGGRGGRGGRGGR
    GAGGUTGGGGGURGRGGGRGGAGAAGGAGGAGGURGUTGRGGGGTUTUURGUTGU
    TUUTURGGAGURGURGUUUAGAUURGGAGUUURGURGUXGUUTGGUTTTGURGGA
    GTTUUTRGGGATTTGTUAGUUAGATGTGAUAAGATTGTGGRGAGGRGAGTGAAGGA
    GATUTGATATTAATUAGRGRGTAGUTURGAGUUAAAUTTTUAUAAATGRGGTGTAG
    AAAUATGTTUTTUTUATTTAAG
201 GTGGTAGGTUTGTGTGGAGAUTTGAATUUTGTTTTUTUUUAGUUTTTTUUAUUAAGG
    AUAUUUAGGAGAGUAAGGATATGGUUAGAGGAGAGGTGGTGTTUUUUTUTTGAUT
    GGGUUUTGUTUTUAGUUUUAUAGGTGATURGGAAGATTXGGGTGGAGUAGTTTUUT
    GATGUUTURGGTAGUUTGAAGUTGTGGTGUUAGTTTTTUAAUATTUTTAGTGAUTUA
    GTUTTGAUATGGGUUAAGGATUAGRGUUUAGTGGGRGAGGTGGGUAGGAGGTAAG
    UUAARGAUAUUAUTGUUAUU
202 GGTGGUAGTGGTGTRGTTGGUTTAUUTUUTGUUUAUUTRGUUUAUTGGGRGUTGAT
    UUTTGGUUUATGTUAAGAUTGAGTUAUTAAGAATGTTGAAAAAUTGGUAUUAUAGU
    TTUAGGUTAURGGAGGUATUAGGAAAUTGUTUUAUUXGAATUTTURGGATUAUUTG
    TGGGGUTGAGAGUAGGGUUUAGTUAAGAGGGGAAUAUUAUUTUTUUTUTGGUUAT
    ATUUTTGUTUTUUTGGGTGTUUTTGGTGGAAAAGGUTGGGAGAAAAUAGGATTUAA
    GTUTUUAUAUAGAUUTAUUAU
203 TGUUTAUUAUAUUTRGTGGGTGAAAUAGATATTTRGAGUATGAUTGAGUTTATTAA
    GAGUUUTGRGGRGUTTUUTUTGURGGGGGTTTAGAAATTTUAAAGGATGGGGGTTG
    AGGGAGGGAGGAGTTATGGGUATGTGATGTGGAUAGGGXGGGUAGGAGGATGGAA
    GTAAUAGGTUUAAAATGTATUTTTGGTGGUURGGUAGAGUTUTTGUATGGGGTGAG
    AATGGTAATTTAGGAAGAGUAAGTUTTUUUATUTGTGAAGUAGAAGAAAAAAGTGG
    AUTTAAGGAGAAGTTRGGGTG
204 UAUURGAAUTTUTUUTTAAGTUUAUTTTTTTUTTUTGUTTUAUAGATGGGAAGAUTT
    GUTUTTUUTAAATTAUUATTUTUAUUUUATGUAAGAGUTUTGURGGGUUAUUAAAG
    ATAUATTTTGGAUUTGTTAUTTUUATUUTUUTGUUXGUUUTGTUUAUATUAUATGU
    UUATAAUTUUTUUUTUUUTUAAUUUUUATUUTTGAAATTTUTAAAUUUURGGUAG
    AGGAAGRGURGUAGGGUTUTTAATAAGUTUAGTUATGUTRGAAATATUTGTTTUAU
    UUARGAGGTGTGGTAGGUA
205 GAGUUAAUUTUTUUTTTUATTUUTGGAGGTGGGGGAUURGUUUTUATUTUAGGUUT
    GAAGAGGGUTGTGTGTGAGTTUTUUAUTTGTGTGTGGGGTGAGUURGGUUUATGUA
    UAUAGUTAUAUAUAUATUAUAUAUUUAUAUURGGAUAXGRGUUTUAGGTUUUUAU
    AUTGUUUTTAUAUAUATGRGUUUUTUAUAUATGUATGTUUUUTTTGUAUAUARGUU
    UUUTRGUAUARGUATGUUUUUTRGUAUARGUATGUAUAUAGGUTUAUTUTGUTGU
    UTGTUUUTGGUTGUTGTGTGUT
206 AGUAUAUAGUAGUUAGGGAUAGGUAGUAGAGTGAGUUTGTGTGUATGRGTGTGRG
    AGGGGGUATGRGTGTGRGAGGGGGRGTGTGTGUAAAGGGGAUATGUATGTGTGAGG
    GGRGUATGTGTGTAAGGGUAGTGTGGGGAUUTGAGGRGXGTGTURGGGTGTGGGTG
    TGTGATGTGTGTGTAGUTGTGTGUATGGGURGGGUTUAUUUUAUAUAUAAGTGGAG
    AAUTUAUAUAUAGUUUTUTTUAGGUUTGAGATGAGGGRGGGTUUUUUAUUTUUAG
    GAATGAAAGGAGAGGTTGGUTU
207 UUUARGGGGGUAGGUAURGGAGGGGGTGUUUAUAGAGGATAGAGGARGURGAGA
    AGTGAUUTGGGGAGUUATAGGATGAGGAAGAGAGAAGAGATGAUAGUAGGGGUTG
    TAGGAGGTUAUUUTUUARGGAGGGAGGGGTGARGGUAGAGGXGTURGUAGGAGUT
    GGTAURGGTGGGGUTGUUUUUAGGGGGGGUTGAUAGAGGUAGUAAUTGAGUAGGU
    AGGGGTGGAGRGAGGTGUUAGUUTGURGTGGAAAGGAGARGUUAGUAGRGGGGGG
    UUUTUUTGGGGTUUUAGTUUTGUTUT
208 AGAGUAGGAUTGGGAUUUUAGGAGGGUUUUURGUTGUTGGRGTUTUUTTTUUARG
    GUAGGUTGGUAUUTRGUTUUAUUUUTGUUTGUTUAGTTGUTGUUTUTGTUAGUUUU
    UUUTGGGGGUAGUUUUAURGGTAUUAGUTUUTGRGGAXGUUTUTGURGTUAUUUU
    TUUUTURGTGGAGGGTGAUUTUUTAUAGUUUUTGUTGTUATUTUTTUTUTUTTUUTU
    ATUUTATGGUTUUUUAGGTUAUTTUTRGGRGTUUTUTATUUTUTGTGGGUAUUUUU
    TURGGTGUUTGUUUURGTGGG
209 TGAUAUTUAGGATUUAAAAGUTAGUUUTGUUUAUUUUAGUUUUTUUAUUTUUTTA
    UUTGGGTGTGUAUUTGUTURGGGGGGTGGAGGTGUTUUUUAUAGTURGGGUUAGG
    AUAGUUTUAGGGGAGAGTGAAGGUUTGUAGGAGGGUAGGXGAGAUAAGGAGGGT
    GTUUAGGGUTAGGGAGTGURGGATGAAAUUAGUTUTGTUUUTGTGUAGGUTUUAG
    GUTUURGUUTGAUAAAUAGGUAGGGAGUUAUAGTUAGGGAUAATAAAAAUTTGGT
    GUAUTUTGAAAGUAGUAUTTGGAUAG
210 TGTUUAAGTGUTGUTTTUAGAGTGUAUUAAGTTTTTATTGTUUUTGAUTGTGGUT
    UTGUUTGTTTGTUAGGRGGGAGUUTGGAGUUTGUAUAGGGAUAGAGUTGGTTTUAT
    URGGUAUTUUUTAGUUUTGGAUAUUUTUUTTGTUTXGUUTGUUUTUUTGUAGGUUT
    TUAUTUTUUUUTGAGGUTGTUUTGGUURGGAUTGTGGGGAGUAUUTUUAUUUUURG
    GAGUAGGTGUAUAUUUAGGTAAGUAGGTUUAGGGGUTGGGGTGGGUAGGGUTAGU
    TTTTGGATUUTGAGTGTUAU
211 UAAATAAGTAGTTAUUTUAGAAGTUAUTTARGTAAAAGAUTUATTUUUUAAAARGU
    UAGGUAUATGGATTATUAUTGTGTTATTUAARGARGATAUAATGGUAUAGAATGTA
    TUATAUTGAGAAGTGAGTGUUUTUTURGGGAUATAUTXGTUAGTGAGTUATUUAGU
    AUTAGAAUAUTGGAGATATAAATAAATAUUAUUTUTTUTAAAAUAGTUTGAAATTU
    AAGTGGTUATAAUUTAGAGUATUATGGURGGGUATGGTGGUTUATGUUTGTAAUUU
    UAGUATGAGGUTGAGATGGG
212 UUATUTUAGUUTUATGUTGGGGTTAUAGGUATGAGUUAUUATGUURGGUUATGATG
    UTUTAGGTTATGAUUAUTTGAATTTUAGAUTGTTTTAGAAGAGGTGGTATTTATTTAT
    ATUTUUAGTGTTUTAGTGUTGGATGAUTUAUTGAXGAGTATGTUURGGAGAGGGUA
    UTUAUTTUTUAGTATGATAUA1TUTGTGUUATTGTATRGTRGTTGAATAAUAUAGTG
    ATAATUUATGTGUUTGGRGTTTTGGGGAATGAGTUTTTTARGTAAGTGAUTTUTGAG
    GTAAUTAUTTATTTGA
213 GTUUTUAUATTTGAUTURGGATAAAUUTUTTUAAATATTTTAUAGAUTUTGGUTTTU
    TRGTTAAUAAGUAGUTUAUAUATATAGTGTUTUAGUAGTGAUAGATGUTGGUUUAU
    UURGAGGTUAGGATGAUTUAGUAGGGATTGAGTTTGXGGGRGTUATGUTUUAAGGU
    URGGAATAGGAGUTTGGTGUTUATTUUTUAUATAGTGGGUAAATUUTAGGGUAGGG
    GAGGGGGGGUAATGUUAGAGAATGGTUUUUAUUTGGGGRGGTUTGARGGUUAGAG
    ATGUAGAGAAAGAGARGUUT
214 AGGRGTUTUTTTUTUTGUATUTUTGGURGTUAGAURGUUUUAGGTGGGGAUUATTU
    TUTGGUATTGUUUUUUUTUUUUTGUUUTAGGATTTGUUUAUTATGTGAGGAATGAG
    UAUUAAUUTUUTATTURGGGUUTTGGAGUATGARGUUXGUAAAUTUAATUUUTGUT
    GAGTUATUUTGAUUTRGGGGTGGGUUAGUATUTGTUAUTGUTGAGAUAUTATATGT
    GTGAGUTGUTTGTTAARGAGAAAGUUAGAGTUTGTAAAATATTTGAAGAGGTTTATU
    RGGAGTUAAATGTGAGGAU
215 GAAAGUAGUUUTUTUUUTGUUUTGTAAGGTGATUUURGATURGGGAATTUUUAUTT
    UTGAAGGARGTTUTGGAAAAGTGUAUAGATTAAUTGAGATTUUTGUTTUTGGATUA
    AGUAUTUUTGAUAUTATXGTTURGATTTTUTAAAAAAGAGATTGTGGUAAAATUTA
    UUTXGTGAGATUAGAAAATGUAGUAGGGATGAATUAURGGUUUTUTUAGAUUTUA
    UUAGUUTUUAGGUUATTUUTAAGAGUUTUAUTUUTURGTTUTGTTGGUAGTGGGGG
    AGGTARGGGGURGGATGGUA
216 TGUUATURGGUUURGTAUUTUUUUUAUTGUUAAUAGAARGGAGGAGTGAGGUTUT
    TAGGAATGGUUTGGAGGUTGGTGAGGTUTGAGAGGGURGGTGATTUATUUUTGUTG
    UATTTTUTGATUTUAUXGAGGTAGATTTTGUUAUAATUTUTTTTTTAGAAAATRGGA
    AXGATAGTGTUAGGAGTGUTrGATUUAGAAGUAGGAATUTUAGTTAATUTGTGUAU
    TTTTUUAGAARGTUUTTUAGAAGTGGGAATTUURGGATRGGGGATUAUUTTAUAGG
    GUAGGGAGAGGGUTGUTTTU
217 AAGAAAAGAGAAAGUUUATUUAGGTAAGGGUAGUUTGGTGAUTATTAUUUTGGGGAGAUTU
    UUUAUUUAUAUTGUUAUTUUAGGUTUAUURGAGGGUTGUAGUTTUUTURGGATGGATUUAG
    GGXGGUTAUTGGTUUUAGAGUTGGGGGUTGAGTGGGUURGTGUXGAGGGUTGTGGXGTUTG
    AUAAGURGGUTUUUAUTGTGAGUAGGGAAGGGRGGATGGGRGGGGGUUARGGUTGUUUTGG
    UTUUUUAUUUTGUTGTGUTTUTUTUTAUTUUUUTGUUUTGUUTUUTAAUAUUUAGT
218 AUTGGGTGTTAGGAGGUAGGGUAGGGGAGTAGAGAGAAGUAUAGUAGGGTGGGGAGUUAG
    GGUAGURGTGGUUUURGUUUATURGUUUTTUUUTGUTUAUAGTGGGAGURGGUTTGTUAGA
    XGUUAUAGUUUTXGGUARGGGUUUAUTUAGUUUUUAGUTUTGGGAUUAGTAGUXGUUUTG
    GATUUATURGGAGGAAGUTGUAGUUUTRGGGTGAGUUTGGAGTGGUAGTGTGGGTGGGGAG
    TUTUUUUAGGGTAATAGTUAUUAGGUTGUUUTTAUUTGGATGGGUTTTUTUTTTTTTIT
219 UTGAGGUAGGGUTGUAGGUTUAGGAGGAGGAGATGGGTGGAGAGAGAAUAAGUTTT
    AUUURGGGAGGGTGAUTAUAGGAGAAATGGGUUUUTUAAGTATGUTGATTTUXGU
    UTUAUTGUTGUUTGTUUTUXGUUUAUUTURGGUTUTGGUTUATUTGUTUTTGTAAG
    UAGGGTUUTGGGUTGGGTGUTGUAGGXGUATGAGGAAAGTGGGAGURGGGARGGG
    GUAGUTUAGGGUARGUUUTUUAAUAUTGRGUTURGAGGAUUTUAGRGGTTTTAUTU
    AGGGGTGUUAUTGAGGUAUAGU
220 GUTGTGUUTUAGTGGUAUUUUTGAGTAAAAURGUTGAGGTUUTRGGAGRGUAGTGT
    TGGAGGGRGTGUUUTGAGUTGUUURGTUURGGUTUUUAUTTTUUTUATGXGUUTGU
    AGUAUUUAGUUUAGGAUUUTGUTTAUAAGAGUAGATGAGUUAGAGURGGAGGTGG
    GXGGAAGAGUAGGUAGUAGTGAGGXGGAAATUAGUATAUTTGAGGGGUUUATTTU
    TUUTGTAGTUAUUUTUURGGGGTGAGUTTGTTUTUTUTUUAUUUATUTUUTUUTUUT
    GAGUUTGUAGUUUTGUUTUAG
221 GUUUAGGUTGGAGTGUAGTGGRGTGATUTTGGUTUAUTGUAAUUTUTGUUTUURGG
    GTTUAAGRGATTUTULTTGUUTUAGUUTUUUAGATAUUTGGGATTAUAGGTGTGTGA
    UAUUATAUUUAGUTAATTTTTGTATTTTTAGTAGAGAXGGUUATGTTAGTUAGGUTG
    GTUTTGAAUTUUTGAUUTUAGTGATTUAURGGUUTUAGUUUUUAAAGTGUTGGTAT
    TATAGTUATGAGUUAUTGUAUURGGUUTUTGUTTTTGUTTUUTTAGTGGUATUUUAU
    TGUUTTGUTTTUAAUATT
222 AATGTTGAAAGUAAGGUAGTGGGATGUUAUTAAGGAAGUAAAAGUAGAGGURGGG
    TGUAGTGGUTUATGAUTATAATAUUAGUAUTTTGGGGGUTGAGGURGGTGAATUAU
    TGAGGTUAGGAGTTUAAGAUUAGUUTGAUTAAUATGGUXGTUTUTAUTAAAAATAU
    AAAAATTAGUTGGGTATGGTGTUAUAUAUUTGTAATUUUAGGTATUTGGGAGGUTG
    AGGUAGGAGAATRGUTTGAAUURGGGAGGUAGAGGTTGUAGTGAGUUAAGATUAR
    GUUAUTGUAUTUUAGUUTGGGU
223 GUUAUTUTATAAAAATGAAGAGUAGAGUTRGAGTGUTTATAAUARGTUATTTTTAU
    UUAAGAUAGAGAAGAAAAARGAAAGAGAGUUTGAGUATTUUTTTGAUTUUUTUUA
    UUUURGGAAGGTATATTUAGAGTUTUUAAGAUTGUUTUXGUUUAUTUAUATGTTrA
    TGGUURGGTGAGAURGUATUUTUUUTTTUTATATUTGTUUUTTTTUTGGATGUAGGG
    AUAUAGAATUUUUTAAGTGGGAAGAGUTTTGGAGTGGAGGUTGTTUAAAGTTUTGT
    GGTGATTAATTATTAUUTAU
224 TAGGTAATAATTAATUAUUAUAGAAUTTTGAAUAGUUTUUAUTUUAAAGUTUTTUU
    UAUTTAGGGGATTUTGTGTUUUTGUATUUAGAAAAGGGAUAGATATAGAAAGGGAG
    GATGRGGTUTUAURGGGUUATAAAUATGTGAGTGGGXGGAGGUAGTUTTGGAGAUT
    UTGAATATAUUTTURGGGGGTGGAGGGAGTUAAAGGAATGUTUAGGUTUTUTTTRG
    TTTTTUTTUTUTGTUTTGGGTAAAAATGARGTGTTATAAGUAUTRGAGUTUTGUTUTT
    UATTTTTATAGAGTGGUT
225 ATTAAAAUAGUAAAUTUUAGGUUUAAAGTAGGTTTUAGTUTUTATTAAGATAAUAA
    AAGGTUUTAAATGUUAGGUUTGGGRGUAAAUTGTGUAGAUAAGRGGGTGGURGGA
    GAAGGAGGGGGGTUAAGGAAGAGAGGGAAAUTUAATTGAXGGTTAUTTTTTTTTUA
    GAGTTATTTURGGTGGGTUTGUUUUUAUUUUTUAAUAAATTTTGTTGUTUTGA
    TUUAGGUATAAAAAGTGAGGUUUTGGAGGGUUUUTGAGAUUAGRGTUUTGUAUAG
    TGAUATGGUAUAGTGAUATGG
226 UUATGTUAUTGTGUUATGTUAUTGTGUAGGARGUTGGTUTUAGGGGUUUTUUAUUG
    UUTUAUTTTTTATGUUTGGAATGUUUAGAGUAAUAAAATTrGTTGAGGGGTGGGGG
    UAGAUUUAURGGAAATAAUTUTGAAAAAAAAGTAAUXGTUAATTGAGTTTUUUTUT
    UTTUUTTGAUUUUUUTUUTTUTURGGUUAUURGUTTGTUTGUAUAGTTTGRG
    GGUUTGGUATTTAGGAUUTTTTGTTAUTTTAATAGAGAUUGAAAUUTAUTTTGGGUU
    TGGAGTTTGUTGTTTTAAT
227 GGUTUTGAGAGTGUTGGAAUUAAURGGARGGGGTUAGUUUUAUUATGGGAUUTGG
    URGATGAGTUATUTUTUTGAAGGRGTUTTUUUTTUTGTGAAGTGGGGAAGGTAAUT
    GTUATUUUAUAGGGRGATTGTGGGUAUURGGGAGAUUXGUTGAGGGATGUTGUAG
    TGTAGAAGUTTUUUAAATUTARGUTGUTTUTUTTUUTUUTUAGTUUTUTUURGUTGU
    TGUUUTURGGTTUATGUUUTGTGGUTGATUUATUAURGGUTUTUUARGGUUTTUAU
    UTTGGGRGGGTTGGATGGUTG
228 AGUUATUUAAUURGUUUAAGGTGAAGGURGTGGAGAGURGGTGATGGATUAGUUA
    UAGGGUATGAAURGGAGGGUAGUAGRGGGAGAGGAUTGAGGAGGAAGAGAAGUA
    GRGTAGATTTGGGAAGUTTUTAUAUTGUAGUATUUUTUAGXGGGTUTUURGGGTGU
    UUAUAATRGUUUTGTGGGATGAUAGTTAUUTTUUUUAUTTUAUAGAAGGGAAGARG
    UUTUAGAGAGATGAUTUATRGGUUAGGTUUUATGGTGGGGUTGAUUURGTURGGT
    TGGTTUUAGUAUTUTUAGAGUUU
229 GURGURGUTTTTUUAGTUTTGUUUAAUURGGTATTTUTGRGUTTGUUTUAGUUAUUR
    GUAGGAGRGUAGGURGUUUTTRGTUUTUURGTUUTUTGRGUUUAUAGGAUUURGG
    GUUURGUUUAGTURGUAGGTUURGUAGGTUUUUURGGGXGTGTUTTUUTGGUUUTG
    RGAUUUURGGGAUAGRGUTGAGAAUARGRGGAAGGTGGGGAGARGRGRGGRGUTG
    GURGGGTUUUTGGRGURGTTUTRGRGGTGUAGUUTGTGUUTGGGAGTURGGURGTU
    UUAUUTUAGAAUUAGAGUAAA
230 TTTGUTUTGGTTUTGAGGTGGGARGGURGGAUTUUUAGGUAUAGGUTGUAURGRGA
    GAARGGRGUUAGGGAUURGGUUAGRGURGRGRGTUTUUUUAUUTTURGRGTGTTUT
    UAGRGUTGTUURGGGGGTRGUAGGGUUAGGAAGAUAXGUURGGGGGGAUUTGRGG
    GAUUTGRGGAUTGGGRGGGGUURGGGGTUUTGTGGGRGUAGAGGARGGGAGGARG
    AAGGGRGGUUTGRGUTUUTGRGGGTGGUTGAGGUAAGRGUAGAAATAURGGGTTG
    GGUAAGAUTGGAAAAGRGGRGGU
231 UUTGGGAUAGGUTUAATGGAGGUTGUAGGGUUATUAGURGAUTUUTARGUAGGUT
    UAGTUAGUAGUUUUUTGGUUAGUUUUAUUUUTGAUTGURGGUUTUAGAAUTGGGA
    GUTGUTTUUTGGUAGGGUURGUUTUTGUTGGGAGAURGGAXGGTGAGTUAGUUTTA
    AGUURGGUAUUAGAUUUUTUTGAGGATGGAGUAUUAGUTGGUTGUUUTGAGGUTG
    UAAAAUTTUTTUUUTRGTGGAGAUAGGGAGGUAUUTUAGAUAUTUAUUURGGAUT
    UUUTTGAAUAGGGAUAGGGAGGAA
232 TTUUTUUUTGTUUTTTGTTUAAGGGAGTURGGGGTGAGTGTUTGAGGTGUUTUUUTGT
    UTUUARGAGGGAAGAAGTTTTGUAGUUTUAGGGUAGUUAGUTUUTGUTUUATUUTU
    AGAGGGGTUTGGTGURGGGUTTAAGGUTGAUTUAUXGTURGGTUTUUUAGUAGAGG
    RGGGUUUTGUUAGGAAGUAGUTUUUAGTTUTGAGGURGGUAGTUAGGGGTGGGGU
    TGGUUAGGGGGUTGUTGAUTGAGUUTGRGTAGGAGTRGGUTGATGGUUUTGUAGUU
    TUUATTGAGUUTGTUUUAGG
233 AUAUTGTGGGGUAGGGAGGGGUATUTUTTGAGAAUAAAAGATUUATTTUTRGAUTT
    TUUAAAUTGGAGAGUTTUTTGAGAGAAAAGAGAGAGAUAGGTAUAGGTUUARGUU
    AUUUAUAUAUAGUUUTGTGUAUAUAGAURGGAUAUAGGXGTUUAUAGGUAAGTTR
    GUAGUTGUTUATTTTGTGAAGTGAATGUTGATTTGGGGGURGGGTGGGGTTRGTUTG
    TAUATRGTGUAUTGTUAGAUUUTTUUTGAAGGATTTTTGTTAUTGAAGTATUAGAAG
    GUUUTTGTTUTAAGGTGGTG
234 AUUAUUTTAGAAUAAGGGUUTTUTGATAUTTUAGTAAUAAAAATUUTTUAGGAAGG
    GTUTGAUAGTGUARGATGTAUAGARGAAUUUUAUURGGUUUUUAAATUAGUAUUU
    AUTTUAUAAAATGAGUAGUTGRGAAUTTGUUTGTGGAXGUUTGTGTURGGTUTGTG
    TGUAUAGGGUTGTGTGTGGGTGGRGTGGAUUTGTAUUTGTUTUTUTUTTTTUTUTUA
    AGAAGUTUTUUAGTTTGGAAAGTRGAGAAATGGATUTTTTGTTUTUAAGAGATGUU
    UUTUUUTGUUUUAUAGTGTG
235 AUUUARGGGGAUAGGGGTUAGAGTAATGGAGTGGAAATGGUAGGTTUAUAATTTTG
    GUTAUAGUTGUTUUUATUTUTAAGUAAUUUAGGUTURGGGTTGGAGGGTGGRGAUU
    UUAAGATGRGGUUTUAGURGURGGUXGTGTTTGTGUTUUAGUXGATGAAGXGAGTG
    UAAAGGGUTGTAUAAARGRGAGGUAUTGAAUAAAUAUTGAGRGTGURGTUUAGAT
    GTUURGGGGGAGGUTGAGGATUUAUAURGTGGGGAGTGUTUTGUUUUUATGGAGT
    GAUUTGGRGTURGUUUTUUARG
236 RGTGGAGGGRGGARGUUAGGTUAUTUUATGGGGGUAGAGUAUTUUUUARGGTGTG
    GATUUTUAGUUTUUUURGGGAUATUTGGARGGUARGUTUAGTGTTTGTTUAGTGUU
    TRGRGTTTGTAUAGUUUTTTGUAUTXGUTTUATXGGUTGGAGUAUAAAUAXGGURG
    GRGGUTGAGGURGUATUTTGGGGTRGUUAUUUTUUAAUURGGAGUUTGGGTTGUTT
    AGAGATGGGAGUAGUTGTAGUUAAAATTGTGAAUUTGUUATTTUUAUTUUATTAUT
    UTGAUUUUTGTUUURGTGGGT
237 RGAGGTGRGGUTGUUURGRGGUTTUUTRGGUTTUURGTUURGRGTGUTTTUUTGGA
    GTUUUTUUTTURGGAGGUUUTUUTGUUTUUARGTGTGUUUTTUTUUATGTUUAGUA
    TTRGGGRGUUTUTTGTUTTTUTTUTGTTUUUTGGUTTXGGRGTUUURGGGAGTGTGA
    UTUURGUAGRGGGGTGUAGUTTTUUTUTGGGATGAGTGAURGGAGGGAAUURGUUT
    TUURGGGUARGTRGUUAGUUTUTTUUTUTTUTTUUUTAGGUTATUAAGRGGAUTTAT
    GAUAAGAAGGRGGTGGAT
238 ATUUAURGUUTTUTTGTUATAAGTURGUTTGATAGUUTAGGGAAGAAGAGGAAGAG
    GUTGGRGARGTGUURGGGAAGGRGGGTTUUUTURGGTUAUTUATUUUAGAGGAAA
    GUTGUAUUURGUTGRGGGAGTUAUAUTUURGGGGARGUXGAAGUUAGGGAAUAGA
    AGAAAGAUAAGAGGRGUURGAATGUTGGAUATGGAGAAGGGUAUARGTGGAGGUA
    GGAGGGUUTURGGAAGGAGGGAUTUUAGGAAAGUARGRGGGARGGGAAGURGAGG
    AAGURGRGGGGUAGURGUAUUTRG
239 TGUAGTGTGTAUAGGAUTUUUTGAAAGGGUTUUUTGGGATGGAGGGTTTTTTGGGGG
    GGUUTGTGGTTUTTUTUUAGUATGAGTUAUAAAUUAUATUUTUUAUAGTUAGURGG
    ATUUAAAURGATTTGAURGAGATXGGUTUTTUAATGXGGTUTUURGGGGTGTUUUR
    GAGGATUTGGUTGGAUTTUUAGAGTAUUTGAGUAAGAUUAGUAAGTAUUTUAURG
    AUTRGGAATAUAUAGGTAGAUUUTGUUUTGTGGATUUAAGGUTAGGUATUUTGTGA
    GUTGATAGTTAGGTGGGUTGT
240 UAGUUUAUUTAAUTATUAGUTUAUAGGATGUUTAGUUTTGGATUUAUAGGGUAGG
    GTUTAUUTGTGTATTURGAGTRGGTGAGGTAUTTGUTGGTUTTGUTUAGGTAUTUTG
    GAAGTUUAGUUAGATUUTRGGGGAUAUUURGGGAGAUXGUATTGAAGAGUXGATU
    TRGGTUAAATRGGTTTGGATURGGUTGAUTGTGGAGGATGTGGTTTGTGAUTUATGU
    TGGAGAAGAAUUAUAGGUUUUUUUAAAAGUUUTUUATUUUAGGGAGUUUTTTUAG
    GGAGTUUTGTAUAUAUTGUAU
241 AGGAGUUTGTGAUUUAGAAATGGTAAGTAAGGTURGATTUTUAUUAAUAAAGUAG
    GUATGAUUTUAGAUAAGTUUUTAUUUTGUTUTGGGUUTUAGTTTUTUUTTTAGTGA
    GGAGGTGGGTGAGGGTUUTGTUUTUUTURGGGAAUTGGXGATTTGGGAAGGUAGAG
    AUATTUUUAGAATUXGURGGAGTUUTGAAAAUAUUUARGUUUTTTGTUUUAGUAAT
    UUTGAGAAAGGUUAUAUTGATAAAGUTGTGGGTGGUUAGATGAUAGUATTUTTGGG
    UUTUAGARGAAGTGGGAGGGG
242 UUUTUUUAUTTRGTUTGAGGUUUAAGAATGUTGTUATUTGGUUAUUUAUAGUTTTA
    TUAGTGTGGUUTTTUTUAGGATTGUTGGGAUAAAGGGRGTGGGTGTTTTUAGGAUTU
    RGGXGGATTUTGGGAATGTUTUTGUUTTUUUAAATXGUUAGTTUURGGAGGAGGAU
    AGGAUUUTUAUUUAUUTUUTUAUTAAAGGAGAAAUTGAGGUUUAGAGUAGGGTAG
    GGAUTTGTUTGAGGTUATGUUTGUTTTGTTGGTGAGAATRGGAUUTTAUTTAUUATT
    TUTGGGTUAUAGGUTUUTT
243 AGUUUTGGUTGAGTGUUUUUUAUTTUUUTGGUTRGAGTTUUUTUAUGAAAAAAUUT
    GGTGAUTUUTUUTGUAUAGAAUAAAGGUTGAGTGAGGUAUAGTGUUUAGGGGATG
    AGGAAGGUTGAGUURGGGAUUAGGUAGGAGGAAUUTGUXGTGUAUTUAUTUAGAU
    TUUTGUAGUAUURGGGGUAGGTGUTUUAUUAGRGGGUAUAGURGUTUAGURGUUT
    UUTUATUURGURGUAGUUAGTGGATUAUUAUAGUTGTUAGAGAGGUUUAUUAUTT
    GGUUAURGGGTUTARGUUTGUAGA
244 TUTGUAGGRGTAGAUURGGTGGUUAAGTGGTGGGUUTUTUTGAUAGUTGTGGTGAT
    UUAUTGGUTGRGGRGGGATGAGGAGGRGGUTGAGRGGUTGTGUURGUTGGTGGAG
    UAUUTGUUURGGGTGUTGUAGGAGTUTGAGTGAGTGUAXGGUAGGTTUUTUUTGUU
    TGGTUURGGGUTUAGUUTTUUTUATUUUUTGGGUAUTGTGUUTUAUTUAGUUTTTG
    TTUTGTGUAGGAGGAGTUAUUAUUTTTTTTUUTUAGGGAAUTRGAGUUAGGGAAGT
    GGGGGGUAUTUAGUUAGGGUT
245 UTUTGGGUTUTUTUUAUAGGGTTGAGGUUAGAGUTATTUTUAGAATUURGURGGAG
    GGGUUTTGUUTGGAGGAGGGUAUAARGAUAUTTAUTTGTUUUUATUAGUUGAUTG
    AGGGUTGGGGTTGGGUTGGGTUAUAUAGTTUAGTGUTXGUTUTAAGAGATGTTUUR
    GGAATAGUTGAGTUAUUTGGGUUAGGGGGTUUAUTGTGGAGAGGAGGAGGTGAGT
    GGGGTGGGGAGUAGGGUUUUAUUUTUUTUTUUAAGUTAAGGGUTTTTTUUTGGGTG
    GGUTGGGGUUAUAUUTAGGGUU
246 GUUUTAGGTGTGGUUUUAGUUUAUUUAGGAAAAAGUUUTTAGUTTGGAGAGGAGG
    GTGGGGUUUTGUTUUUUAUUUUAUTUAUUTUUTUUTUTUUAUAGTGGAUUUUUTG
    GUUUAGGTGAUTUAGUTATTURGGGAAUATUTUTTAGAGXGAGUAUTGAAUTGTGT
    GAUUUAGUUUAAUUUUAGUUUTGGGTUAGUTGATGGGGAUAAGTAAGTGTRGTTG
    TGUUUTUUTUUAGGUAAGGUUUTURGGRGGGATTUTGAGAATAGUTUTGGUUTUA
    AUUUTGTGGAGAGAGUUUAGAGU
247 RGUUUTGGUTUTGGGUTTTUAUUAURGUUTGGGGUUUTGUTTGGAUTUTGUAGUTG
    TGTUUUAAGGUTGRGUUUTAGATTTGTUTAUTUUTTUUUUTGUUUUUTUUUTGUTTT
    UTUURGGUUTUTGTAGTUTTUUTGUTUUTUUAUUTAXGTGGUTGUUTTGGGUUUUA
    TGUAGUTUUTUUUURGGGATGUUUUATGUTUTGTTUTGTGAUTGUUTTAUTUTTGAT
    UAUUTUTGATGGUTGUTUUAGTGUAGGUAGAAUUUUUAAAGTUUTUTGTTUTUTAU
    ATGTUUUUUTTTGUUAUU
248 GGTGGUAAAGGGGGAUATGTAGAGAAUAGAGGAUTTTGGGGGTTUTGUUTGUAUTG
    GAGUAGUUATUAGAGGTGATUAAGAGTAAGGUAGTUAUAGAAUAGAGUATGGGGU
    ATUURGGGGGAGGAGUTGUATGGGGUUUAAGGUAGUUAXGTAGGTGGAGGAGUAG
    GAAGAUTAUAGAGGURGGGAGAAAGUAGGGAGGGGGUAGGGGAAGGAGTAGAUA
    AATUTAGGGRGUAGUUTTGGGAUAUAGUTGUAGAGTUUAAGUAGGGUUUUAGGRG
    GTGGTGAAAGUUUAGAGUUAGGGRG
249 TTTUUTUUTUTUTTTUUTTUUTTUTUUAGTTUUTUUUTTTTUUTUUTTUAUTGTTTGA
    TTTTTAGUUUTUTGATTTTTTUTTUUTUTTUTUUAUTUTTTATTTUTTTTUATUUTUT
    UURGGTUUTTTTTTUTGUTTTGTUAUUTUUTTXGTTTTUTTUTUTUTUTGGUTGAUTU
    AGGGGAURGGAGGTGGGUUTATUTGGAGTGAGTGAGTAAGTGTGTTGGGAGGTGAG
    GGTGGAGGGUTGGAGGGGGGUAGTGATUTGGUUTGAGUUUUTUUAGTATTGUTUUA
    GUUUUAGURGUAG
250 UTGRGGUTGGGGUTGGAGUAATAUTGGAGGGGUTUAGGUUAGATUAUTGUUUUUU
    TUUAGUUUTUUAUUUTUAUUTUUUAAUAUAUTTAUTUAUTUAUTUUAGATAGGUU
    UAUUTURGGTUUUUTGAGTUAGUUAGAGAGAGAAGAAAAXGAAGGAGGTGAUAAA
    GUAGAAAAAAGGAURGGGAGGAGGATGAAAAGAAATAAAGAGTGGAGAAGAGGA
    AGAAAAAATUAGAGGGUTAAAAATUAAAUAGTGAAGGAGGAAAAGGGAGGAAUTG
    GAGAAGGAAGGAAAGAGAGGAGGAAA
251 UTATAUTUTUAGGUUUAGGUUAGGGGRGGUAGUTGUUUUUUTUAUTGUUUUARGU
    AUAAATUUUTGGTTTUAGTUUAAAURGUTAUTGTGAGUTUUAGATUTGGGTGGGGU
    URGGAGUUTUUTUATTAGUAUUAGGTGGGATGGUUTTGXGAAGATAAAGUTUTGTU
    TGGUUUUAGUUUAGGUTGTAGUUURGGGUUUTGUUUUAGGUAGUUTGUUUAGGAT
    GUTGTGUUAGTTTUTGAUUTTTGUUUAUTGUAGUUAGATGGGGUUATUTGTGGAGU
    TGGUUTTTTUTUUTTAGAATGA
252 TUATTUTAAGGAGAAAAGGUUAGUTUUAUAGATGGUUUUATUTGGUTGUAGTGGG
    UAAAGGTUAGAAAUTGGUAUAGUATUUTGGGUAGGUTGUUTGGGGUAGGGUURGG
    GGUTAUAGUUTGGGUTGGGGUUAGAUAGAGUTTTATUTTXGUAAGGUUATUUUAU
    UTGGTGUTAATGAGGAGGUTURGGGUUUUAUUUAGATUTGGAGUTUAUAGTAGRG
    GTTTGGAUTGAAAUUAGGGATTTGTGRGTGGGGUAGTGAGGGGGGUAGUTGURGUU
    UUTGGUUTGGGUUTGAGAGTATAG
253 ARGGGTGTUTGUTUUUAAGUTGGGUAUUUUTUUUUUAGGUTGTGGGAAURGUTGG
    GUUATTUTGAUUTRGAAUUAGAAATAGUUURGAUUUUUUTUTTTUTUUURGRGUUU
    UUAGURGGAURGUUUUURGGGAUUUUAGUUAAAUUAUAGXGTURGGUATAGGGU
    UTUTUUUTTATTGUAUAAURGUTAGGGGAGAUAGAGAGGATGGGGGTUURGGGAA
    UATGUTGGGGTRGUUAGAUTATGGGARGTAGGGGRGTAGUTUAUUTGTTGGAGAUA
    GGUURGUTUUTUAUTGGUTGAGTU
254 GAUTUAGUUAGTGAGGAGRGGGUUTGTUTUUAAUAGGTGAGUTARGUUUUTARGT
    UUUATAGTUTGGRGAUUUUAGUATGTTUURGGGAUUUUUATUUTUTUTGTUTUUUU
    TAGRGGTTGTGUAATAAGGGAGAGGUUUTATGURGGAXGUTGTGGTTTGGUTGGGG
    TUURGGGGGGRGGTURGGUTGGGGGRGRGGGGAGAAAGAGGGGGGTRGGGGUTAT
    TTUTGGTTRGAGGTUAGAATGGUUUAGRGGTTUUUAUAGUUTGGGGGAGGGGTGUU
    UAGUTTGGGAGUAGAUAUURGT
255 GUAGTAAAUAGTUUTATTGTAUAAATATATAGRGRGGGUTGGGRGGGGGRGGTUAA
    UUURGGTTUUUTGGUARGGGGAUAGGGRGRGUTGGGUURGGUTUTGUAGRGAGUR
    GGTGGGAGGGUUTAGUTGTGGUUUAGGRGGTGTTGAGUAXGGGURGGGGGRGTUA
    TAGURGGGGAGGGURGGGUAGRGAGRGGGTGGGRGAGGGGRGAGTUATRGTUTGU
    UURGUURGGAGGGGAUUURGGRGGGTGAGGGARGTGGGTGGAGGGAGARGTGGGG
    AGUTUAGTRGGAGTAGATGATGAA
256 TTUATUATUTAITTURGAUTGAGUTUUUUARGTUTUUUTUUAUUUARGTUUUTUAUU
    RGURGGGGTUUUUTURGGGRGGGGUAGARGATGAUTRGUUUUTRGUUUAUURGUT
    RGUTGUURGGUUUTUUURGGUTATGARGUUUURGGUUXGTGUTUAAUAURGUUTG
    GGUUAUAGUTAGGUUUTUUUAURGGUTRGUTGUAGAGURGGGUUUAGRGRGUUUT
    GTUUURGTGUUAGGGAAURGGGGTTGAURGUUUURGUUUAGUURGRGUTATATATT
    TGTAUAATAGGAUTGTTTAUTGU
257 AGTTATTTAATAUATGGUUUUAGTGGUAUTAALUTGTUAUTAAGUUTUATGTTUTU
    UATUUATAAAATGGAGAUUAUAATUATAUUTGUTGUAAAATUUAAAATTUAGAGGT
    TTUTAUAGRGTGAURGAUAUTGTGUUURGGAGAGTTTXGGUUUTUTUUTGGUTUTG
    GUUUUUTGGAAUARGTGATGUUUAGUUUAAAUAGTGUUAUAUUUTGUTUTAUAAT
    GUUTUAARGAGAGTUAUAAUUAAAGATTTTTGAGTUAGAGGAUAATAGAGGAGGT
    GGGAAUTGGGTAAAXGGAGAGT
258 UTUTUXGTTTAUUUAGTTUUUAUUTUUTUTATTGTUUTUTGAUTUAAAAATUTTTGG
    TTGTGAUTUTRGTTGAGGUATTGTAGAGUAGGGTGTGGUAUTGTTTGGGUTGGGUAT
    UARGTGTTUUAGGGGGUUAGAGUUAGGAGAGGGUXGAAAUTUTURGGGGUAUAGT
    GTRGGTUARGUTGTAGAAAUUTUTGAATTTTGGATTTTGUAGUAGGTATGATTGTGG
    TUTUUATTTTATGGATGGAGAAUATGAGGUTTAGTGAUAGGTTAGTGUUAUTGGGG
    UUATGTATTAAATAAUTG
259 GAGTTTXGGUUUTUTUUTGGUTUTGGUUUUUTGGAAUARGTGATGUUUAGUUUAAA
    UAGTGUUAUAUUUTGUTUTAUAATGUUTUAARGAGAGTUAUAAUUAAAGATTTTTG
    AGTUAGAGGAUAATAGAGGAGGTGGGAAUTGGGTAAAXGGAGAGTUUATGGUUTT
    TGGAGGTGGGGUAUAGUURGGAGTGAATGAGGGUUUAGAGTTTUUAGAGAAURGA
    ATATAGATUTGTGTGTGAAGUUTUUAGATATTUTAATGTTGAUAARGAAATUAAATT
    GAAAAAAAATAAAAATUAATA
260 ATTGATTTTTATTTTTTTTUAATTTGATTTRGTTGTUAAUATTAGAATATUTGGAGGUT
    TUAUAUAUAGATUTATATTRGGTTUTUTGGAAAUTUTGGGUUUTUATTUAUTURGG
    GUTGTGUUUUAUUTUUAAAGGUUATGGAUTUTUXGTTTAUUUAGTTUUUAUUTUUT
    UTATTGTUUTUTGAUTUAAAAATUTTTGGTTGTGAUTUTRGTTGAGGUATTGTAGAG
    UAGGGTGTGGUAUTGTTTGGGUTGGGUATUARGTGTTUUAGGGGGUUAGAGUUAGG
    AGAGGGUXGAAAUTUT
261 RGGGTGRGGAUURGUUAUUTGURGUAUUUTTUUUTTUUUAAUUUTGUUUTTTUUUU
    AUUUUUAUUUUAUTTUUUAUUUUUAAUUUURGUTRGGRGUUUUAUTUURGAUUUT
    GUUTGUURGGGUAUUTRGGGGRGTURGUTRGURGGUTTXGUUTUUAUTTGUUURGG
    UAGGRGRGRGTGGGUTRGGRGTUURGRGUTUUUTUUTRGAUTGTGRGGUTUURGRG
    UTGURGGGTTTUUTGTTUAAUAATATAAUUAGGGAGGUAURGGRGGAGAGRGURGG
    GUAGAAUTTUUTUURGGAUTG
262 UAGTURGGGAGGAAGTTUTGUURGGRGUTUTURGURGGTGUUTUUUTGGTTATATT
    GTTGAAUAGGAAAUURGGUAGRGRGGGAGURGUAUAGTRGAGGAGGGAGRGRGGG
    ARGURGAGUUUARGRGRGUUTGURGGGGUAAGTGGAGGXGAAGURGGRGAGRGGA
    RGUUURGAGGTGUURGGGUAGGUAGGGTRGGGAGTGGGGRGURGAGRGGGGGTTG
    GGGGTGGGAAGTGGGGTGGGGGTGGGGAAAGGGUAGGGTTGGGAAGGGAAGGGTG
    RGGUAGGTGGRGGGTURGUAUURG
263 GGUAAGGUAGTUTGGGRGURGTUTURGGTUTRGGGGUUTGRGGTRGGGGUAURGRG
    GTGURGRGTTTGAGURGGTUAGUTUUUTGRGGAAATTAUAGGGGRGUTRGGRGUTG
    RGGTRGRGUUUUURGGGGUAGRGUURGUTGGTTGGAGGXGTTTAAATTGAAAGUAG
    UTTTGGGGAGAGGGGGRGGARGRGGGURGURGAGUAAGGGGAGGGGGRGGUURGG
    UAUAGRGAUUUUATTGTUTGTGUURGURGAGGGGTGGAAUUTTGRGGTGAGUTRGG
    RGRGGRGUUUUUTUUURGAGU
264 GUTRGGGGAGGGGGRGURGRGURGAGUTUAURGUAAGGTTUUAUUUUTRGGRGGG
    UAUAGAUAATGGGGTRGUTGTGURGGGURGUUUUUTUUUUTTGUTRGGRGGUURGR
    GTURGUUUUUTUTUUUUAAAGUTGUTTTUAATTTAAAXGUUTUUAAUUAGRGGGRG
    UTGUUURGGGGGGRGRGAURGUAGRGURGAGRGUUUUTGTAATTTURGUAGGGAG
    UTGAURGGUTUAAARGRGGUAURGRGGTGUUURGAURGUAGGUUURGAGAURGGA
    GARGGRGUUUAGAUTGUUTTGUU
265 GGAGGGAGUUTGUAUTUTGGGUAGTGATGTGGAGTUAGAGATTTUUAAGTTUATGG
    TGUAAGTUTGTGGGAGAGUAGAAUTUAUTTTAUAAAATTGTTGAUAGURGGTGTTG
    TTAGAGARGGAAAGGGAUAAUUURGGUTUUTUTUUAGGXGTGGAGTUTGTGGGGAT
    GTGUTTUUAGAAAATGUAGGGTTAAGUAGGAGUTGUAGAGTAGAATUAAATGAUA
    ATGAUTUAUTGUTGTUAUTAAUAGGUTUTTTGTGGGGGUTGTAGGTGGGAGGRGAT
    ATGGURGGUAUUTTRGUAUAA
266 TTGTGRGAAGGTGURGGUUATATRGUUTUUUAUUTAUAGUUUUUAUAAAGAGUUT
    GTTAGTGAUAGUAGTGAGTUATTGTUATTTGATTUTAUTUTGUAGUTUUTGUTTAAU
    UUTGUATTTTUTGGAAGUAUATUUUUAUAGAUTUUAXGUUTGGAGAGGAGURGGG
    GTTGTUUUTTTURGTUTUTAAUAAUAURGGUTGTUAAUAATTTTGTAAAGTGAGTTU
    TGUTUTUUUAUAGAUTTGUAUUATGAAUTTGGAAATUTUTGAUTUUAUATUAUTGU
    UUAGAGTGUAGGUTUUUTUU
267 GTTUTGGTTRGGUAGAGTGGRGGUAATUTTGUUTUTUTUTUTAGAAUAUUTAAAGA
    AGUUAGTGAGTGAGUTGUTUATGUAUAURGGGGAGAUUTAUAGARGGATUUAGGA
    GGAGRGGGAGUTUATTGAUTGUAUAUTTUUAAUURGGXGTGATAGGAAAGTGAGG
    UUAUUTGTUUTAAGTGUURGGGGGUAGGGGGGTUUATGGAGGAGGGGGRGGGGGU
    AGGTGTUTGGAUAUAGGGATGUTGGTUTUAGGTGGUAUAGUTGGGGAGAAAAAAU
    UTATUUATTGUAAAAUATUATTAG
268 TAATGATGTTTTGUAATGGATAGGTTTTTTUTUUUUAGUTGTGUUAUUTGAGAUUAG
    UATUUUTGTGTUUAGAUAUUTGUUUURGUUUUUTUUTUUATGGAUUUUUUTGUUU
    URGGGUAUTTAGGAUAGGTGGUUTUAUTTTUUTATUAXGURGGGTTGGAAGTGTGU
    AGTUAATGAGUTUURGUTUUTUUTGGATURGTUTGTAGGTUTUUURGGTGTGUATG
    AGUAGUTUAUTUAUTGGUTTUTTTAGGTGTTUTAGAGAGAGAGGUAAGATTGURGU
    UAUTUTGURGAAUUAGAAUA
269 RGTGATUAGAGAUAGAAATUAGUTUUUUTUUTUUUTUAUTGAGUTTGTAGUUAUTT
    TAAGTATAAUUTGTGTUUTGTGUUAGTTUUAUUATAAATUAGUUUTGAGTTTTTATUR
    GGRGGUTTATTUTGUTGUUAAAAUUTTUAUAGTTGXGGGAATGGGUUAGGGAGAG
    AGUURGGAUTTTAUTURGGUTGTGGTGAUTUARGUUTTTGGGAAGGGUTGAGGTAT
    TTGTUUTTGGATGTGGGGATGUTGTGGUUTUTGGTTGGGAAUAUAGUUTRGTTTTGT
    UTGUTGGUTUTGGUTTUU
270 GGAAGUUAGAGUUAGUAGAUAAAARGAGGUTGTGTTUUUAAUUAGAGGUUAUAGU
    ATUUUUAUATUUAAGGAUAAATAUUTUAGUUUTTUUUAAAGGRGTGAGTUAUUAU
    AGURGGAGTAAAGTURGGGUTUTUTUUUTGGUUUATTUUXGUAAUTAATGAAGGTT
    TTGGUAGUAGAATAAGURGURGGATAGAAUTUAGGGUTGATTTATGGTGGAAUTGG
    UAUAGGAUAUAGGTTATAUTTAAAGTGGUTAUAAGUTUAGTGAGGGAGGAGGGGA
    GUTGATTTUTGTUTUTGATUARG
271 UAGTATGUATGTGTUUATTTAAGGUATUTGAGUUUTGGUUTTTGUTGTTUTTUUTTU
    UTTUTTimURGTRGGGTTGUTGAGUTUAAUATUUUAURGGGUTUUTGUTUUTTAGU
    TAGUAGTUAGTGUAGAGUTGUTGGGTUUTTUUGUUTXGUTTGGGUAGGUTTUTGTU
    AATGAGTUAUUAAGUAURGGGAAATAAGTGUAUAGGAAGGAGUAGGTGGUAAGAU
    UUTGTGGAGGTAGAGAUAGTTUUATTUAGTGAGTGAGUTGTGAUTGUAAATTTGGG
    AAGGTTUTGGGGGAAGUAA
272 TTGUTTUUUUUAGAAUUTTUUUAAATTTGUAGTUAUAGUTUAUTUAUTGAATGGAA
    UTGTUTUTAUUTUUAUAGGGTUTTGUUAUUTGUTUUUUUTGTGUAUTTATTTUURG
    GTGUTTGGTGAUTUATTGAUAGAAGUUTGUUUAAGXGAGGUAGAAGGAUUUAGUA
    GUTUTGUAUTGAUTGUTAGUTAAGGAGUAGGAGUURGGTGGGATGTTGAGUTUAGU
    AAUURGARGGAGAAAGAAGGAAGGAAGAAUAGUAAAGGUUAGGGUTUAGATGUU
    TTAAATGGAUAUATGUATAUTG
273 RGGURGRGGGGGGRGUUTGGAGGAGGGAAGUUTUTURGGAGGAGAAGAGUTGGGR
    GGURGURGTAGGAGGAAGRGGAAAGATAAGGGGUUUTRGGUTRGGRGGGGURGUR
    GGARGUUUAGGAGUUTUAATGGGGAUARGTRGGGTGGGGAXGGAGGUAGUTUUTG
    TURGGAUAGRGAAAUURGRGAGGUUUAGGAGAGRGGUAGUUAGRGRGGUAUAGUU
    RGGGAGUTGRGGUUUARGURGGAGUUTARGGAUATGGGUTRGGAAGGGAUAAAAA
    URGGGURGGAGTUAGRGUTGGAGUU
274 GGUTUUAGRGUTGAUTURGGUURGGTTTTTGTUUUTTURGAGUUUATGTURGTAGG
    UTURGGRGTGGGURGUAGUTUURGGGUTGTGURGRGUTGGUTGURGUTUTUUTGGG
    UUTRGRGGGTTTRGUTGTURGGAUAGGAGUTGUUTUXGTUUUUAUURGARGTGTUU
    UUATTGAGGUTUUTGGGRGTURGGRGGUUURGURGAGURGAGGGUUUUTTATUTTT
    URGUTTUUTUUTARGGRGGURGUUUAGUTUTTUTUUTURGGAGAGGUTTUUUTUUT
    UUAGGRGUUUUURGRGGURG
275 GUATUAUAUATUUUTUUUTGTUTUUUTGUTGUUAAUUAGTTUUAUUAUTGTUUAUU
    TUTGUUUUAATTUUAUUTUUUARGUUTGUTGUTGUAUUTTGGAUTTGTTTTUUTGAA
    ATTGUATGUUATUUAUTUTUUUTTUTAUTTUTGUTGXGTUUUTUTTGUUUTATUAGG
    AUUTGTGGAUTUAGGAUTUURGGGUTTTUTUUUUUATUTUTUTTUUURGTTGGGUU
    TUAUTAUUATTTUAGUUAUTTTUUTGGUAGUTTUAUTUUTGUUUUAAGAUUUUAGU
    UTTTUAUUUTUUTGGTTUT
276 AGAAUUAGGAGGGTGGAGGUTGGGGTUTTGGGGUAGGAGTGAAGUTGUUAGGAAA
    GTGGUTGAAATGGTAGTGAGGUUUAARGGGGAAGAGAGATGGGGGAGAAAGUURG
    GGAGTUUTGAGTUUAUAGGTUUTGATAGGGUAAGAGGGAXGUAGUAGAAGTAGAA
    GGGAGAGTGGATGGUATGUAATTTUAGGAAAAUAAGTUUAAGGTGUAGUAGUAGG
    RGTGGGAGGTGGAATTGGGGUAGAGGTGUAUAGTGGTGGAAUTGGTTGGUAGUAG
    GGAGAUAGGGAGGGATGTGTGATGU
277 GGTGGRGATGUTUTAGUUAUUTGUTTUTUTGTUUTUTTTUAUAUAAATGTATUUTGU
    TTUTTTUUAGATGTURGGUTTAATGGGAUTGGATTTATUTTUAAAAGTUUTGGTTTG
    UUTUTGATTGAAAAUUAGTGTGUTUUUUATGGTTAXGGARGGUTGTGUAGGTTTTTG
    TTTTGTTGAAGGGAATTGGUTUAUTUTGAGTUAGURGTGUAUURGGGUTGUTGATGT
    AGTUTUAGTGTGATGGTTAAAUTTTAAGTGTUAATTTGAUTGGGUTAAGGAATGUUA
    GAUATTATTTURGGG
278 UURGGAAATAATGTUTGGUATTUUTTAGUUUAGTUAAATTGAUAUTTAAAGTTTAA
    UUATUAUAUTGAGAUTAUATUAGUAGUURGGGTGUARGGUTGAUTUAGAGTGAGU
    UAATTUUUTTUAAUAAAAUAAAAAUUTGUAUAGURGTUXGTAAUUATGGGGAGUA
    UAUTGGTTTTUAATUAGAGGUAAAUUAGGAUTTTTGAAGATAAATUUAGTUUUATT
    AAGURGGAUATUTGGAAAGAAGUAGGATAUATTTGTGTGAAAGAGGAUAGAGAAG
    UAGGTGGUTAGAGUATRGUUAUU
279 GGTTTTGGGTGTGGAUATUUUTGGAGGGUTGTTTTAGTGUUUAUAUUAATGUUUTAG
    TTAAAGAAUUAUUUTGTUUUUTTAGUUTTUTGUAGGAUAGGTGGGAAAGGGURGG
    GTGTUTGGTUUTGUTGUUAGGGGAUAGTGUAGGTGTGAUXGTURGGGUAGAGATGA
    GTUAUUUTUUAUAUTGTUTTGUTGUURGTUTUUARGUUTAGTTTTAGUTRGTGTGGT
    UAAGAAGGGGRGATTUUTUAUUTAGAAUAUATGGGTUAUAAATGUTAUUTTTGAAA
    ATGGAAAUAAAAATAAUUUA
280 TGGGTTATTTTTGTTTUUATTTTUAAAGGTAGUAUUAAATGGATTGGTGTGAUUU
    AGGAATRGUUUUTTUTTGAUUAUARGAGUTAAAAUTAGGRGTGGAGARGGGUAGU
    AAGAUAGTGTGGAGGGTGAUTUATUTUTGUURGGAXGGTUAUAUUTGUAUTGTUUU
    UTGGUAGUAGGAUUAGAUAUURGGUUUTTTUUUAUUTGTUUTGUAGAAGGUTAAG
    GGGAUAGGGTGGTTUTTTAAUTAGGGUATTGGTGTGGGUAUTAAAAUAGUUUTUUA
    GGATGTUUAUAUUUAAAAUU
281 UAGAAUUTGAGRGATGAAGTGARGGGATTTAGTUAGGUUTATGAAGAGTUAATGGU
    AUTTGUUTUUUATAATUUTTUUAGTUUUATTGGUUAAUURGTUTGTUUUTRGRGTG
    ATUTTTTGGATUTGAAGTGGTGTTTUAGGAUURGGAGXGTGGUUTGUAUTGUUTTG
    TTUTGTTTGTTTGTGUAURGGATTUATRGTGAUTUATUUTGAGTUATUUAGGUAGTA
    TGGAAGAAUTTTGGAGTTATTTTAAAUUUTTTGGUTUAGAAUUUUATTTGGAGGAT
    ATTAAUATGUAAGATAA
282 TTATUTTGUATGTTAATTUTAGAAGAAATGGGGTTUTGAGUUAAAGGGTTTAAAATA
    AUTUUAAAGTTUTTUUATAUTGUUTGGATGAUTUAGGATGAGTUARGATGAATURG
    GTGUAUAAAUAAAUAGAAUAAGGUAGTGUAGGUUAXGUTURGGGTUUTGAAAUAU
    UAUTTUAGATUUAAAAAGATUARGRGAGGGAUAGARGGGTTGGUUAATGGGAUTG
    GAAGGATTATGGGAGGUAAGTGUUATTGAUTUTTUATAGGUUTGAUTAAATUURGT
    UAUTTUATRGUTUAGGTTUTG
283 GTUUUTTGGUAUUAGGAUATUAUUUTUUUAUUTUTUUUAGAUUUTTUTUUTTGAUU
    TUTTTAGAGUAGUUATUUTTGGAGTTGUTUAARGUUUTGRXXRGGAAGGTTGAAUR
    UUAUAGUTTGGUTUATUTAUTTURGGGTTAGUTUAAXGUUUTUTTUTTTTUUUG
    TGAAUUAUAGUTTGGUTUATUTAUTURGGGTTAGUTUAARGUAUTUTTUTUTUTU
    UUTUTGAAUUARGGUTTGGUTUATUTAUTTUTGGGTTAATTTAGGUTTTUTUUAUAG
    ATAGTUTGAAAAGGGA
284 TUUUTTTTUAGAUTATUTGTGGAGAAAGUUTAAATTAAUUUAGAAGTAGATGAGUU
    AAGURGTGGTTUAGAGGGAGAAGAGAAGAGTGRGTTGAGUTAAUURGGAAGTAGA
    TGAGUUAAGUTGTGGTTUAGAGGGAGAAAAGAAGAGGGXGTTGAGUTAAUURGGA
    AGTAGATGAGUUAAGUTGTGGTTUAGAGGGAGAAGAGAAGAGGGRGTTGAGUAAU
    TUUAAGGATGGUTGUTUTAAAGAGGTUAAGGAGAAGGGTUTGGGAGAGGTGGGAG
    GGTGATGTUUTGGTGUUAAGGGAU
285 UTGAGTUAAUAAGGUTGAUAAGGUTGTGTTUTGGATGUAGGUURGGUAGATGTTTG
    AGGGGGAGGTGGUUAGUUTGGAGGUUUTUAGGAGUARGGGUUTGGTGRGGGTGUR
    GAGGUUUATGAAGGTUATRGAUUTGURGGGAGGTGGGGUXGUUTTTGTGATGGAGU
    ATTTGAAGATGAAGAGUTTGAGUAGGTGAGTGTGTGTGAGAUUUATATGRGUAUAT
    GTGTAUAGGUAGAGAGAGAUTUAGAGAUAAAUAGAGAGAGAUAGAGAAAGGGAT
    AGAGATGGGGAGGGAGAUAGAAA
286 TTTUTGTUTUUUTUUUUATUTUTATUUUTTTUTUTGTUTUTUTUTGTTTGTUTUTGAG
    TUTUTUTUTGUUTGTAUAUATGTGRGUATATGGGTUTUAUAUAUAUTUAUUTGUTU
    AAGUTUTTUATUTTUAAATGUTUUATUAUAAAGGXGGUUUUAUUTUURGGUAGGTR
    GATGAUUTTUATGGGUUTRGGUAUURGUAUUAGGUURGTGUTUUTGAGGGUUTUU
    AGGUTGGUUAUUTUUUUUTUAAAUATUTGURGGGUUTGUATUUAGAAUAUAGUUT
    TGTUAGUUTTGTTGAUTUAG
287 TTRGTGUAUTUTGRGGURGRGGRGGUAGUAGURGRGGRGGRGGUUAGUTUUURGGT
    UTARGTGUUUAUUAUURGRGTGGGTTUUATGUTGUURGGUUTAURGTAUUAUUTGU
    AGGGGTRGGGUAGTGGGUUAGUUAAUUARGRGGGRGGXGRGGGRGRGUAUUURGG
    UTGGUUTUAGGUUTRGGURGAUAGUUUTUUATARGGUAGRGGAGGRGGRGRGGUT
    GGRGGRGGGGURGRGGGGUUTGGRGGRGUTGGUTUAGURGRGGRGUARGTUTRGGR
    GRGUTTUUUUTAUTUTUUUAGU
288 GUTGGGAGAGTAGGGGAAGRGRGURGAGARGTGRGURGRGGUTGAGUUAGRGURG
    UUAGGUUURGRGGUUURGURGUUAGURGRGURGUUTURGUTGURGTATGGAGGGU
    TGTRGGURGAGGUUTGAGGUUAGURGGGGTGRGRGUURGXGURGUURGRGTGGTTG
    GUTGGUUUAUTGUURGAUUUUTGUAGGTGGTARGGTAGGURGGGUAGUATGGAAU
    UUARGRGGGTGGTGGGUARGTAGAURGGGGAGUTGGURGURGURGRGGUTGUTGU
    RGURGRGGURGUAGAGTGUARGAA
289 TUTTTGTGTGAGTUATGTUTTATATUUAAUAAGTAUTUAAAAAAAGATTTTTTTTTTT
    TTTTTTTAAGATGGAGTGTRGUTUTGTUAUUUAGGUTGGAGTGUAGTGGUATGATUT
    TGGUTUAUTGUAAUUUTGUUTUURGGGTTUAAGXGATTUTTUTGUUTUAGGUTUU
    TGAGTAGUTGGAATTAUAGGUATGUUUUAUUAUAUURGGUTAATTTTTATATGTAA
    TAGAAAUAAGGTTTUAUUATGTTGGUUAGAUAGGTUTTGAAUTUUTGAUUTUAGGT
    GATUUAUUUAUUTRGGU
290 GURGAGGTGGGTGGATUAUUTGAGGTUAGGAGTTUAAGAUUTGTUTGGUUAAUATG
    GTGAAAUUTTGTTTUTATTAUATATAAAAATTAGURGGGTGTGGTGGGGUATGUUTG
    TAATTUUAGUTAUTUAGGAGUUTGAGGUAGAAGAATXGUTTGAAUURGGGAGGUA
    GAGGTTGUAGTGAGUUAAGATUATGUUAUTGUAUTUUAGUUTGGGTGAUAGAGRG
    AUAUTUUATUTTAAAAAAAAAAAAAAAAAATUTTTTTTTGAGTAUTTGTTGGATATA
    AGAUATGAUTUAUAUAAAGA
291 AUUAUUUUUTGAUUUUTUATGAUTUAUUUAGUTUUTAAGTGUUUUTGGGUAUUUA
    GTTUTTTGTGGUATGGGURGGTGUAAGTTTUTATATGAGAGUUAGAGAGAUAGGGA
    GGGAGGUURGGGUTUUTGGUUTTTTGGGAAAAGATGUUXGTUTUAGAUUAGUAAA
    AGGAGGUAGUTGUTTTAGGAGUURGGGAAAATGUUATUAUTGATAGTATTATTATT
    ATTTTUUUATTTTUUUTTTGTGTTTTTAAAATGAAAAGTTUAGATUUATGGGGTAGG
    GTAGAGTGGGUUTGGAGGGAG
292 TUUUTUUAGGUUUAUTUTAUUUTAUUUUATGGATUTGAAUTTTTUATTTTAAAAAU
    AUAAAGGGAAAATGGGAAAATAATAATAATAUTATUAGTGATGGUATTTTUURGGG
    UTUUTAAAGUAGUTGUUTUUTTTTGUTGGTUTGAGAXGGGUATUTTTTUUUAAAAG
    GUUAGGAGUURGGGUUUUTUUUTGTUTUTUTGGUTUTUATATAGAAAUTTGUAU
    RGGUUUATGUUAUAAAGAAUTGGGTGUUUAGGGGUAUTTAGGAGUTGGGTGAGTU
    ATGAGGGGTUAGGGGGTGGTT
293 GUAGUARGUAGUUUUUAGGGGUUUTAAUTUAUUUUUTUTTUUUTUAUAGGGUTTU
    UUTGURGTUUAGTGTTGGGTGAGAAAGGTGGAGGGGAUATGTAGUUURGGATGGAG
    GTGUAGUAUUAARGAGAGAGUTURGGUUTGTGGGAGGGAXGUTUAGGUTTAGGTU
    AAAGUUAGGAGUTURGGGAAAUUTGGGTTUAGURGUUARGUUUUARGGAGGGGAU
    AUAUUUTTUUUTGUUTGATGGUAGGGUUUATGGTAGAUAAAAUUUATGAUUTUAU
    UTUTUUTGGUTUUAGGGUTUAGUU
294 GGUTGAGUUUTGGAGUUAGGAGAGGTGAGGTUATGGGTTTTGTUTAUUATGGGUUU
    TGUUATUAGGUAGGGAAGGGTGTGTUUUUTURGTGGGGRGTGGRGGUTGAAUUUA
    GGTTTUURGGAGUTUUTGGUTTTGAUUTAAGUUTGAGXGTUUUTUUUAUAGGURGG
    AGUTUTUTRGTTGGTGUTGUAUUTUUATURGGGGUTAUATGTUUUUTUUAUUTTTUT
    UAUUUAAUAUTGGARGGUAGGGAAGUUUTGTGAGGGAAGAGGGGGTGAGTTAGGG
    UUUUTGGGGGUTGRGTGUTGU
295 ATTTUTTTUTAUUTGTUATTGAAGTGAATUATUAGTATAAGTAGRGAGUTGGGRGUA
    TTUUTTUTUAGTTGTGTTAAAAUTTGUTGGTATTUUUURGGTATUAGUAGAGGTGTG
    TARGGGUAUTGUTTTAAAAUTGGGAAGGAGGAAGAXGAGGUUAGGGAGURGGAGG
    GTUAUUAAGGTAGATTTUUAGUAGRGUTAGTUUAGUTGAAUAUTTTUUAGUUTTGT
    TTTTUAGUAGUTTTGAGGAAAAGTATAGGTAAGAAUAAAGAUAUUAUTGTATGTTT
    GUTATATGAATGUATAAUA
296 GTTATGUATTUATATAGUAAAUATAUAGTGGTGTUTTTGTTUTTAUUTATAUTTTTUU
    TUAAAGUTGUTGAAAAAUAAGGUTGGAAAGTGTTUAGUTGGAUTAGRGUTGUTGGA
    AATUTAUUUTGGTGAUUUTURGGUTUUUTGGUUTXGTUTGAATTUUUGGUUATTA
    AAGUAGTGUURGTAUAUAUUTUTGUTGATAURGGGGGAATAUUAGUAAGTTTTAAU
    AUAAUTGAGAAGGAATGRGUUUAGUTRGUTAUTTATAUTGATGATTUAUTTUAATG
    AUAGGTAGAAAGAAATG
297 ATTGGTUTGGTUUTUTTTUTAAUAUUTUUUAUURGGGATGUAGUUAAGAGTGGUTG
    UAGUUTAATTTTUTAUATGTAAAUAATGAUUTUAGTGATGUUUARGGGGUUUUTUT
    UTGGUUTTUTUUUUUTGGGAAAAGAUTGAGTTUTRGAXGGGUATUUUUTUUUUUTU
    RGGAAUUAAGGGUTUTGGGATGTTGAUAGUUUURGUUAUUTUTGAGAAGGGUAGG
    URGTGGAAAAUUATUTUUTUUUTTUUTTUUUUUTUTGUTUTUUTAGUTGGGGUUT
    UTGUAUAATGUAGUTGGGUUA
298 TGGUUUAGUTGUATTGTGUAGAGGUUUUAGUTAGGAAAGGUAGAGGGGGAAGGAA
    GGGAGGAGATGGTTTTUUARGGUUTGUUUTTUTUAGAGGTGGRGGGGGUTGTUAAU
    ATUUUAGAGUUUTTGGTTURGGAGGGGGAGGGGATGUUXGTRGAGAAUTUAGTUTT
    TTUUUAGGGGGAGAAGGUUAGAGAGGGGUUURGTGGGUATUAUTGAGGTUATTGT
    TTAUATGTAGAAAATTAGGUTGUAGUUAUTUTTGGUTGUATUURGGGTGGGAGGTG
    TTAGAAAGAGGAUUAGAUUAAT
299 TTGUUUTUATUTUUAGGUTTTGGAGGAGGGTAGGTGUUTGGUUAGUAGAGTGGUUA
    UTGUTUAUTGGUUUAGAGGAAGUAAGGUUAUUAGUUTGATUUUAUTTUTUUUTUR
    GGUUUATUTTUAUTUUUUTUTUUTUAAUUAUAAGUUUXGUUAAAATAGAGAUUUU
    RGGUTTTGUTUUUUTGUTGUAGGAAGGGAGAGUUAURGUUAGAUAUTGUUTGUUT
    GGTUUTUUTGTTUTGATUTUAUURGGTGUTTGGAATUAAAGAGGAUUTGGUTTUUU
    TUTRGGGATARGTGATTTTUTTT
300 AAGAAAATUARGTATUURGAGAGGGAAGUUAGGTUUTUTTTGATTUUAAGUAURGG
    GTGAGATUAGAAUAGGAGGAUUAGGUAGGUAGTGTUTGGRGGTGGUTUTUUUTTU
    UTGUAGUAGGGGAGUAAAGURGGGGGTUTUTATTTTGGXGGGGUTTGTGGTTGAGG
    AGAGGGGAGTGAAGATGGGURGGAGGGAGAAGTGGGATUAGGUTGGTGGUUTTGU
    TTUUTUTGGGUUAGTGAGUAGTGGUUAUTUTGUTGGUUAGGUAUUTAUUUTUUTUU
    AAAGUUTGGAGATGAGGGUAAG
301 GUUUAGATUAGGUAGRGGGGTRGUUUTUTUUAGGAUTUTUAAGGUAGUTAAGGUT
    GGAGGRGURGGRGAGUUTGGAGAGGGAGGAGTTUAUTAAATTGTGTTGGATGGAAG
    GRGTRGAGGAURGGAGGAATTAATURGATGTGGGGAAGGXGGARGGGGUTARGAG
    GAAAAAAGAGGGGGUAATGTAUAUTUAGUUTTTTUATUAUTRGGRGGGGAGATGGA
    TGGTTTTURGGAURGGGRGTUUUAGRGUUURGGTTAGUTATAGGGAGARGTUAGAG
    RGUTUTGGTURGRGATAGAAGA
302 TUTTUTATRGRGGAUUAGAGRGUTUTGARGTUTUUUTATAGUTAAURGGGGRGUTG
    GGARGUURGGTURGGAAAAUUATUUATUTUUURGURGAGTGATGAAAAGGUTGAG
    TGTAUATTGUUUUUTUTTTTTTUUTRGTAGUUURGTUXGUUTTUUUUAUATRGGATT
    AATTUUTURGGTUUTRGARGUUTTUUATUUAAUAUAATTTAGTGAAUTUUTUUUTUT
    UUAGGUTRGURGGRGUUTUUAGUUTTAGUTGUUTTGAGAGTUUTGGAGAGGGRGAU
    UURGUTGUUTGATUTGGGU
303 ATTTGGUTTGATUTTATTTTTAATATTTTTTAUAUTTTUTUTUTAAAGAAAA
    RGAGTGAATATRGTGATGGGTGUAGTTATGUTGAATAATTGGATGGGAGGARGTGU
    UAGGRGATUTUUAGUUUUTGGGAGURGGARGUUUAXGUTTTUUUTUTGUUTRGTTUT
    UAUAGAUAUATTTGTGGGGTGATTAAUTUAGGAATTUATGUTGUTUAAAGTAAUTA
    UAGTGGTGAGTGTTTTGAURGGTTTGATGTAGAAATUAAGGAAAAUAUUAGAAAAA
    TUAGGGGRGGAGGUUUAA
304 TTGGGUUTURGUUUUUGATTTTTUTGGTGTTTTUUTTGATTTUTAUATUAATTGT
    AAAAUAUTUAUUAUTGTAGTTAUTTTGAGUAGUATGAATTUUTGAGTTAATUAUUU
    UAUAAATGTGTUTGTGAGAARGAGGUAGAGGGAGGXGTGGGRGTURGGUTUUUAG
    GGGUTGGAGATRGUUTGGUARGTUUTUUUATUUAATTATTUAGUATAAUTGUAUUU
    ATUARGATATTUAUTRGUUTTTTTTTTUTTTAGAGAGAAAGTGTAAAAAATATTAAA
    AATAAGATUAAGUUAAAT
305 TGAUTTTTTUATTTUTUTUAAGATGATUATTAGGAGTGGTTTUAAUAAAAUTGAAUA
    UAGAATTTTGAGGGUUUUAATUATGAUTUAAUUAGAGUUUTUUUTGAATTUTTUAT
    GAGTUAGUURGGUUUTUUUUAUTGAUTTUAUUUTAGXGGGUAUUTGTUTTTUTTUT
    TUTTTTATUAUTTTTTGUTTUTUTTTTGGTTTUUAGUTUTGGTTTTUTUUGAATA
    UAUUTTUUAATTUTTUURGGUUUUUTUAGGGAAAUUUAGAGGUAAATTTGAGTGUA
    GGGAGRGGGGGUTTRGU
306 GRGAAGUUUURGUTUTUTGUAUTUAAATTTGUUTUTGGGTTTUUUTGAGGGGGURG
    GGAAGAATTGGAAGGTGTTGGGTUTGAATTUAGTUAGAGUTGGAAAUUAAAAGAGA
    AGUAAAAAGTGATAAAAGAAGAAGAAAGAUAGGTGUUXGUTAGGGTGAAGTUAGT
    GGGGAGGGURGGGUTGAUTUATGAAGAATTUAGGGAGGGUTUTGGTTGAGTUATGA
    TTGGGGUUUTUAAAATTUTGTGTTUAGTTTTGTTGAAAUUAUTUUTAATGATUATUT
    TGAGAGAAATGAAAAAGTUA
307 GGTGTUAGGAGTGGUUUAGGAGAGUAUUURGTTUUURGGUURGUAGGTGGTGTTTG
    UTGGUTUUAGUAGGGUUAGGAGGUUAUUTGUAGUUTGGTGUTUUAGAUTGATGTU
    AUURGGGURGAGTGUTGTGUUTURGGUAAUATTGAUAUXGUUTGGTUUAAUUTUA
    UUUAUURGGGGAAUAAGATUAAUUTUUTRGGUTTTTTTGGGUUTTGTUUAUTGUUTT
    UUUTGUAAAGGTGAGAUUTUAGGUUAGAAGUAGGGUAGARGTUTUAGUTUAGGAU
    UAGUUAUAAAUAGTUATGGTGGT
308 AUUAUUATGAUTGTTTGTGGUTGGTUUTGAGUTGAGARGTUTGUUUTGUTTUTGGU
    UTGAGGTUTUAUUTTTGUAGGGAAGGUAGTGGAUAAGGUUUAAGAAGURGAGGAG
    GTTGATUTTGTTUUURGGGTGGGTGAGGTTGGAUUAGGXGGTGTUAATGTTGURGG
    AGGUAUAGUAUTRGGUURGGGTGAUATUAGTUTGGAGUAUUAGGUTGUAGGTGGU
    UTUUTGGUUUTGUTGGAGUUAGUAAAUAUUAUUTGRGGGURGGGGAARGGGGTGU
    TUTUUTGGGUUAUTUUTGAUAUU
309 GUAGUUUTUTTUAUUTGUUTGGTGAUTUAUTAUAAGUUUTGGGGGAAGGAATGGU
    AGTGGUUUTUTTUAUUTTTAUTGUUTUTGRGGUUAUAATGGGUAGTTGAUATAAUU
    AUUTGUAGGUUURGGGAGUUATXGGGGUUTUTTGAUAXGTGUTUATTAGTGGUTTU
    TGAGGAGRGUUTGUUUUAUUTGUUUUAXGTGUUUUUAXGTUTGGUUAUTUUAGGG
    TUUATTAGRGUTAATRGGUAAATGUUTGTGUTUTUATUTAURGGGAAAAUATUTUU
    UTTUTUUAGAGRGGAGGUUAGU
310 UTGGUUTURGUTUTGGAGAAGGGAGATGTTTTUURGGTAGATGAGAGUAUAGGUAT
    TTGURGATTAGRGUTAATGGAUUUTGGAGTGGUUAGAXGTGGGGGUAXGTGGGGUA
    GGTGGGGUAGGRGUTUUTUAGAAGUUAUTAATGAGUAXGTGTUAAGAGGUUUXGA
    TGGUTUURGGGGUUTGUAGGTGGTTATGTUAAUTGUUUATTGTGGURGUAGAGGUA
    GTAAAGGTGAAGAGGGUUAUTGUUATTUUTTUUUUUAGGGUTTGTAGTGAGTUAUU
    AGGUAGGTGAAGAGGGUTGUT
311 GTGGUUUTUTTUAUUTTTAUTGUUTUTGRGGUUAUAATGGGUAGTTGAUATAAUUA
    UUTGUAGGUUURGGGAGUUATRGGGGUUTUTTGAUAXGTGUTUATTAGTGGUTTUT
    GAGGAGRGUUTGUUUUAUUTGUUUUAXGTGUUUUUAXGTUTGGUUAUTUUAGGGT
    UUATTAGRGUTAATRGGUAAATGUUTGTGUTUTUATUTAURGGGAAAAUATUTUUU
    TTUTUUAGAGRGGAGGUUAGUUTAAAAAUUAGGUURGUAGUUTURGAGGUTUTGA
    AAAUUAAGRGGUTGTTUTGGTU
312 AUUAGAAUAGURGUTTGGTTTTUAGAGUUTRGGAGGUTGRGGGUUTGGTTTTTAGG
    UTGGUUTURGUTUTGGAGAAGGGAGATGTTTTUURGGTAGATGAGAGUAUAGGUAT
    TTGURGATTAGRGUTAATGGAUUUTGGAGTGGUUAGAXGTGGGGGUAXGTGGGGUA
    GGTGGGGUAGGRGUTUUTUAGAAGUUAUTAATGAGUAXGTGTUAAGAGGUUURGA
    TGGUTUURGGGGUUTGUAGGTGGTTATGTUAAUTGUUUATTGTGGURGUAGAGGUA
    GTAAAGGTGAAGAGGGUUAUT
313 ATGGGUUUTGGGGURGURGUUTUAGTGTUTTUTGGTGUTGUAGURGGGUAGGGURG
    AAUUUTGGRGUAUAGUTTUUTGUTGAGTUTUUUTUTUTAAGGUTGTUTGTGGGRGG
    UTUTGURGGUUUUTUUTGUAUUTGUUUAGGUUUTGGGXGGAGGUTUUTUUTUURG
    GGGGGGUTGTGGUUTUAGUAUAGAUUAGGGGAUAGAAGGTGGUTUTTUTTGGUUTT
    GGUTGGGTGTGAAUUAAAGAUTTUUTGTAAGAAATUUUUUTUTUUUTUTUUUTUUT
    TRGUTUUUTUATUTUTUTUUU
314 GGGAGAGAGATGAGGGAGRGAAGGAGGGAGAGGGAGAGGGGGATTTUTTAUAGGA
    AGTUTTTGGTTUAUAUUUAGUUAAGGUUAAGAAGAGUUAUUTTUTGTUUUUTGGTU
    TGTGUTGAGGUUAUAGUUUUUURGGGAGGAGGAGUUTUXGUUUAGGGUUTGGGUA
    GGTGUAGGAGGGGURGGUAGAGURGUUUAUAGAUAGUUTTAGAGAGGGAGAUTUA
    GUAGGAAGUTGTGRGUUAGGGTTRGGUUUTGUURGGUTGUAGUAUUAGAAGAUAU
    TGAGGRGGRGGUUUUAGGGUUUAT
315 UAUTGGAUUATUUAUAUAAUTTTTGAGGATUAGTGGAAATGAAAAUARGGTGUUUR
    GGUAUAAAAUATATTTUATAGUTTGGGTTAGGUAAUAGUAAAGUATUARGUTGAGR
    GURGGGAUUTTUTGAGTGUAGGXGGTGGGXGAAGUUURGAGTUAUAUAUAUUUAR
    GAXGURGGUUUTGUTUUUAUAGRGGUUUTUTGGGGTAGRGAUTGGTATTAUUTGUA
    TTTUARGAGGGAGGAAAUTGAGGUARGAAUTGTTUAGAAGUTGUUUTGAGGTUAUU
    AAGTGAGUTAGGAAGAGGRGT
316 RGUUTUTTUUTAGUTUAUTTGGTGAUUTUAGGGUAOUTTUTGAAUAGTTRGTGUUT
    UAGTTTUUTUUUTRGTGAAATGUAGGTAATAUUAGTRGUTAUUUUAGAGGGURGUT
    GTGGGAGUAGGGURGGXGTRGTGGGTGTGTGTGAUTRGGGGUTTXGUUUAUXGUUT
    GUAUTUAGAAGGTUURGGRGUTUAGRGTGATGUTTTGUTGTTGUUTAAUUUAAGUT
    ATGAAATATGTTTTGTGURGGGGUAURGTGTTTTUATTTUUAUTGATUUTUAAAAGT
    TGTGTGGATGGTUUAGTGT
317 UTUUAGTGTGUUTUAGTTGGTTTATUTGTAAAAATGGGGUUAGGUUARGAUTGGTG
    TTUUUTTTAUAGAGAAGUAUTUUAGGUAGGGGTGGGTGGGGGTGGAAUTRGTTUTU
    AATGGUUUURGGGAUAGUUUTGUAGUUAURGGTGAUTXGGGTTXGTUTGRGGATUT
    TTUURGGUUTUUAUTUUATTUAGGGAUAGUUUTGUAATGGGGUTUUUTUUUAAAA
    AAARGUATGGUUTTUUTGTUUUUUAAAAUUAGUTTAARGGUAGUUATTUUUTUUUT
    UUTURGGGGGUTGAAAAAUUA
318 GGTTTTTUAGUUUURGGAGGAGGGAGGGAATGGUTGURGTTAAGUTGGTTTTGGGG
    GAUAGGAAGGUUATGRGTTTTTTTGGGAGGGAGUUUUATTGUAGGGUTGTUUUTGA
    ATGGAGTGGAGGURGGGAAAGATURGUAGAXGAAUUXGAGTUAURGGTGGUTGUA
    GGGUTGTUURGGGGGUUATTGAGAARGAGTTTTUAUUUUUAUUUAUUUUTGUUTGG
    AGTGUTTUTUTGTAAAGGGAAUAUUAGTRGTGGUUTGGUUUUATTTTTAUAGATAA
    AUUAAUTGAGGUAUAUTGGAGG
319 UAUTUARGGGUTAGUTURGTUAGGTGTTGARGGATGTUAUTUAGGTGTGAGUTUTG
    UAUUTGAGUTUUUUUUTGUAUAUAGGUAGUUAUAAUUAGTUAGTGUAGAGGTGAG
    UTTTGTGGUUAGTGAGGAGURGGTGAGTUAAUUTUUTUUXGUUTARGGGUUUTGAG
    ARGURGGUTURGTGAGUTTGRGGGGTRGAGGGRGUUTATATTAAGUUAAGGUTGAG
    GUAGTGAUAUAUUUTUTTATGGGUUTGUTUTRGUTTUUTGUTTUATTGTUUTGGTUT
    UTUUUTUTRGTATGGAGGATUA
320 TGATUUTUUATARGAGAGGGAGAGAUUAGGAUAATGAAGUAGGGAGRGAGAGUAG
    GUUUATAAGAGGGTGTGTUAUTGUUTUAGUUTTGGUTTAATATAGGRGUUUTRGAU
    UURGUAAGUTUARGGAGURGGRGTUTUAGGGUURGTAGGXGGGAGGAGGTTGAUT
    UAURGGUTUUTUAUTGGUUAUAGGUTUAUUTUTGUAUTGAUTGGTTGTGGUTGUUT
    GTGTGUAGGGGGGAGUTUAGGTGUAGAGUTUAUAUUTGAGTGAUATURGTUAAUA
    UUTGARGGAGUTAGUURGTGAGTG
321 UUAGGUTGUUTGGGTTTTGGTUTUUAUUATGUTAGUTTGGTGTURGAUUTGTGTTGAGAUUU
    TUUUTGUUTUTGGUURGGGTGTUUUATUUAAGUAATGGAUAGGTTGGAAUAGGXGTTXGTA
    GGGAAXGGGUTGAAXGUURGRGGUTUUXGXGATGTUTXGXGATAUTAUUTUUUTXGUUUUX
    GUTUAUTTAAGGAURGGAAGTAGUAAAGUURGURGTRGRGUUUUURGUUURGRGTUTUUUT
    GGTAAUUAGUUTUTUUUUTTUUUTRGUUUATAAGGAGUAAGRGGUAUAAATRGGG
322 UURGATTTGTGURGUTTGUTUUTTATGGGRGAGGGAAGGGGAGAGGUTGGTTAUUAGGGAGA
    RGRGGGGRGGGGGGRGRGARGGRGGGUTTTGUTAUTTURGGTUUTTAAGTGAGXGGGGGXG
    AGGGAGGTAGTATXGXGAGAUATXGXGGGAGURGRGGGXGTTUAGUUXGTTUUUTAXGAAX
    GUUTGTTUUAAUUTGTUUATTGUTTGGATGGGAUAUURGGGUUAGAGGUAGGGAGGGTUTU
    AAUAUAGGTRGGAUAUUAAGUTAGUATGGTGGAGAUUAAAAUUUAGGUAGUUTGG
323 UAATGGUUTUTTTUTTUAGUUTRGGTGGGRGTGGUTGGGGGAAUUUUAGGGRGGGR
    GGGGGGUAGGGGGTGGTGUTGAGTUAUUUAGUUTGGUUAGGTUUUTGUUTGUUAG
    UUUUUTGUUUUUAURGUTAUAGUURGUUURGGATUTAXGAGGUUUAGUUAGUUAU
    UTUTGGAUTUUTGAGAUXGAATTGUAAAUTGUURGGGUUTGGUUTTGAAUTUUTGU
    TGTTTAGGGAUUAAGTUUTGTGGUTUUUAGGGGGGUAUAGTGATUTUTUAAGUTGA
    GUTGGUUTUAGGGUUTUTGUAU
324 TGUAGAGGUTTTGAGGUUAGUTUAGUTTGAGAGATUAUTGTGUUUUUUTGGGAGU
    UAUAGGAUTTGGTUUUTAAAUAGUAGGAGTTUAAGGUUAGGUURGGGUAGTTTGU
    AATTXGGTUTUAGGAGTUUAGAGGTGGUTGGUTGGGUUTXGTAGATURGGGGRGGG
    UTGTAGRGGTGGGGGUAGGGGGUTGGUAGGUAGGGAUUTGGUUAGGUTGGGTGAU
    TUAGUAUUAUUUUUTGUUUUURGUURGUUUTGGGGTTUUUUUAGUUAGGGTGGTTA
    GAGGUTGAAGAAAGAGGUUATTGT
325 AUUUTGTGUAGGGUUTGUATUURGGAAGGUUTUUAUUAGUURGAAUUTGGUURGT
    URGUUUTAGATGGGGUAATRGGRGTTTUTUURGGGAUAGUUTUUTUUUTGGUUTUU
    TGGUUUTRGTUTGUATTGAGAGGUTTGGUUTUTGGTUXGUATGUTGUUUTTUURGT
    GUTGTGGUUTTGUAGUURGGUUTUTUUUUTGUTGTUUUUUTTGGUTUTGGUUTGGU
    UUUTGGGUUUUTGAGTUAUUUUTGAGGTGAUTUAGUAGTUUTTGGAAARGUATGUR
    GAGGARGUAUUUTGUUTGGUU
326 GUUAGGUAGGGTGRGTUUTRGGUATGRGTTTUUAAGGAUTGUTGAGTUAUUTUAGG
    GGTGAUTUAGGGGUUUAGGGGUUAGGUUAGAGUUAAGGGGGAUAGUAGGGGAGA
    GGURGGGUTGUAAGGUUAUAGUARGGGAAGGGUAGUATGXGGAUUAGAGGUUAA
    GUUTUTUAATGUAGARGAGGGUUAGGAGGUUAGGGAGGAGGUTGTUURGGGAGAA
    ARGURGATTGUUUUATUTAGGGRGGARGGGUUAGGTTRGGGUTGGTGGAGGUUTTU
    RGGGATGUAGGUUUTGUAUAGGGTT
327 GGAAUUATTGTTUTGUTGUUUAUAGUTGRGTGGAGGGATTURGGTUUTRGGGTTUA
    GTTGGTGAUAGTGTRGGGTAGGUUTGGGUAGGTGGGAGAGGTRGTGAAGUUUTTTG
    UAGGGUAUTTGGURGUTUATUTGGUAUAGGGGAAGAGGXGUAGUURGTGGUURGG
    UAGTUUAGGAUUTGUTGTTUUUTTUUTAUURGGGGRGGGGUUTGTGGGAAGATATG
    GAAGTRGGGTGAATGAGURGTGUUUAGTGATTTTAAAAAGUAGATTAAAATAAUAT
    AGAAAATGTUAGAGUTUATTG
328 UAATGAGUTUTGAUATTTTUTATGTTATTTTAATUTGUTTTTTAAAATUAUTGGGUAR
    GGUTUATTUAUURGAUTTUUATATUTTUUUAUAGGUUURGUUURGGGTAGGAAGGG
    AAUAGUAGGTUUTGGAUTGURGGGUUARGGGUTGXGUUTUTTUUUUTGTGUUAGAT
    GAGRGGUUAAGTGUUUTGUAAAGGGUTTUARGAUUTUTUUUAUUTGUUUAGGUUT
    AUURGAUAUTGTUAUUAAUTGAAUURGAGGAURGGAATUUUTUUARGUAGUTGTG
    GGUAGUAGAAUAATGGTTUU
329 GUATUUTUAUUTGRGTURGAAGRGUAGATGGAGUUUAAGGGAAAGGUUUTGTAGA
    GGAUUURGTGTGAUTTGGGGUAAAGRGTGGUUTUUUAGGGGTGRGTGGGUAGRGG
    GARGUUUATGGTGTGAURGGGTTTGTGUUTUUATAGGGAUXGTUTGUUUTGTGUAG
    AGAGUUUUTGTGGGGXGGGAAGTGGXGAGUAGURGGUAAGGAGGUUUAGUUAGA
    UAGAAGUAGGGGGGTUAGGGAUATGGGAGGTGGGGGAUUAGUUAGTGAGTUAGAR
    GTGAGGAUTTUAGTGUUAAGGAUTG
330 UAGTUUTTGGUAUTGAAGTUUTUARGTUTGAUTUAUTGGGUUTUTTUUUTGGTTUU
    ATGTUUUTGAUUUUUUTGUTTUTGTUTGGUTGGGUTTTUUTTGURGGUTGUTXGUUA
    UTTUUXGUUUUAUAGGGGUTUTUTGUAUAGGGUAGAXGGTUUUTATGGAGGUAUA
    AAUURGGTUAUAUUATGGGRGTUURGUTGUUUARGUAUUUUTGGGAGGUUARGUT
    TTGUUUUAAGTUAUARGGGGTUUTUTAUAGGGUUTTTUUUTTGGGUTUUATUTGRG
    UTTRGGARGUAGGTGAGGATGU
331 AGGTTUUUUATUUTAGUTUUURGGATUTUUATAGGGAGTGTUUAGGGAUUUTUAAT
    UTUUAGGGUUAUTTUTGUAGGAGUTRGGGTTRGAGGTTUUARGTGGUUAGAAGAGU
    TUAGGTUTUTGAGGGUTGGTGTGUURGGGTAUUUATUXGUATUAUTGUTUTUUTUU
    TGTURGGUTARGUUUAGGGUTGAGTGARGGTGGTGGUAAGTGUTTGTUUTUAGGGU
    AGRGAGGTUTTUTGTTUTGAUAGUAGUAGGGAUTUUTTUATGGUUAUUAGTAAUUU
    UAGTGGGRGGAGGRGUTUUT
332 AGGAGRGUUTURGUUUAUTGGGGTTAUTGGTGGUUATGAAGGAGTUUUTGUTGUTG
    TUAGAAUAGAAGAUUTRGUTGUUUTGAGGAUAAGUAUTTGUUAUUAURGTUAUTU
    AGUUUTGGGRGTAGURGGAUAGGAGGAGAGUAGTGATGXGGATGGGTAUURGGGU
    AUAUUAGUUUTUAGAGAUUTGAGUTUTTUTGGUUARGTGGAAUUTRGAAUURGAG
    UTUUTGUAGAAGTGGUUUTGGAGATTGAGGGTUUUTGGAUAUTUUUTATGGAGATU
    RGGGGAGUTAGGATGGGGAAUUT
333 TUUTTUUTTUTTTUUTTUTTTUTTUUTTUUUTTUTUUTTTUTTTUTTUUTTTUU
    UATTTTGAGARGTAUTUTGGUTUTGTRGUUUAGGUTGGAGRGUAATGGRGUUATUT
    RGGRGUAUTGUAAUUTUUAUUTUURGGGTTUAAGXGATTUTAUTGUUTUAGUUTUU
    RGAGTAGUTGGGAUTAUAGGRGRGUAUTAUUAAGUURGGUTAATTTTTTTTTGTATT
    TTTAGTAGAGAUTGGGTTTUARGATGTTGGURGGGUTGGTUTGGAAGTUTTGAUUTU
    AAGRGTGRGUUUTU
334 GAGGGRGUARGUTTGAGGTUAAGAUTTUUAGAUUAGUURGGUUAAUATRGTGAAA
    UUUAGTUTUTAUTAAAAATAUAAAAAAAAATTAGURGGGUTTGGTAGTGRGRGUUT
    GTAGTUUUAGUTAUTRGGGAGGUTGAGGUAGTAGAATXGUTTGAAUURGGGAGGTG
    GAGGTTGUAGTGRGURGAGATGGRGUUATTGRGUTUUAGUUTGGGRGAUAGAGUU
    AGAGTARGTUTUAAAATGAAAGAAGAGAAAAGAAAAGAAAAGAAAGAAAAGAGAG
    AGAAAGAAGGAAAGAAGGAAGGA
335 AGGUUTUTGUTGAUUTGTAGAAUTTGTTGAUURGGATTTTGATGTUAGTUTUATTGG
    GUUTGURGTTGUTUTTUTTGGGAUAGAAGATUTUTTTGATURGGUUAATTRGGTAGG
    GUTUAGGGGUATUUAGGTTGUTGUUTTTGATGTAGTXGGAGTATTTURGGTAGTGUT
    UTGGGTAUAGGTUUTUATUUARGGGUTUUTTURGTGGGRGTTTUARGGGAUTGGAU
    AGUTTGATGUTGUAGAGAAGUAUUUAUTTGAUATUAATGAAUUTTUUAUUTTGUAG
    TGGTUAGTUAGGUATGA
336 TUATGUUTGAUTGAUUAUTGUAAGGTGGAAGGTTUATTGATGTUAAGTGGGTGUTT
    UTUTGUAGUATUAAGUTGTUUAGTUURGTGAAARGUUUARGGAAGGAGUURGTGG
    ATGAGGAUUTGTAUUUAGAGUAUTAURGGAAATAUTUXGAUTAUATUAAAGGUAG
    UAAUUTGGATGUUUUTGAGUUUTAURGAATTGGURGGATUAAAGAGATUTTUTGTU
    UUAAGAAGAGUAARGGUAGGUUUAATGAGAUTGAUATUAAAATURGGGTUAAUAA
    GTTUTAUAGGTUAGUAGAGGUUT
337 GGGGRGGGGTTRGGURGGGGGRGGRGGUAGGAUUTGAGUAGUUAGGAGGGUTGGGGGAUA
    GTUAGGTUAGGURGGTGGUTAUURGGURGUTGGAGAGGGURGGATGGUARGTGGUAUUAAG
    UAAAAGGAGGUTGAGUUAGAAAGUAGGGAXGGGGUTAGARGAGUAAAGUTGGGUAGGAGG
    GRGAGTTGGGAGGGGURGAGURGGUTGTGRGTGGTUUUTTGGGAGGAGGGGGTGTGGUUAA
    GUAAGUUAAAUAGTTRGGAGGTUAGTGUAAGGAUAAGAUAGUUTGGGUAAARGAGUAG
338 UTGUTRGTTTGUUUAGGUTGTUTTGTUUTTGUAUTGAUUTURGAAUTGTTTGGUTTGUTTGGU
    UAUAUUUUUTUUTUUUAAGGGAUUARGUAUAGURGGUTRGGUUUUTUUUAAUTRGUUUTUU
    TGUUUAGUTTTGUTRGTUTAGUUUXGTUUUTGUTTTUTGGUTUAGUUTUUTTTTGUTTGGTGU
    UARGTGUUATURGGUUUTUTUUAGRGGURGGGTAGUUAURGGUUTGAUUTGAUTGTUUUUU
    AGUUUTUUTGGUTGUTUAGGTUUTGURGURGUUUURGGURGAAUUURGUUUU
339 RGAGTTGGGAGGGGURGAGURGGUTGTGRGTGGTUUUTTGGGAGGAGGGGGTGTGG
    UUAAGUAAGUUAAAUAGTTRGGAGGTUAGTGUAAGGAUAAGAUAGUUTGGGUAAA
    RGAGUAGGGGRGGAGRGTGAGAGUAGAUTGUAURGGATXGUTUAGGUUAGUUUAA
    GUTGAAGAGGAAGGGGUAAGUTUUAGAAGUAGGGGRGGGGURGAUUAAUUTRGUA
    GATUTGUTGGGRGAAGAGUAGUAGUTGGGUUAGUURGATGUTGTGURGGGGUAGG
    TAGTUTRGGAGGUTGUUUAGGGGU
340 UUUUTGGGUAGUUTURGAGAUTAUUTGUUURGGUAUAGUATRGGGUTGGUUUAGU
    TGUTGUTUTTRGUUUAGUAGATUTGRGAGGTTGGTRGGUUURGUUUUTGUTTUTGG
    AGUTTGUUUUTTUUTUTTUAGUTTGGGUTGGUUTGAGXGATURGGTGUAGTUTGUT
    UTUARGUTURGUUUUTGUTRGTTTGTAGGUTGTUTTGTUUTTGUAUTGAUUTURG
    AAUTGTTTGGUTTGUTTGGUUAUAUUUUUTUUTUUUAAGGGAUUARGUAUAGURGG
    UTRGGUUUUTUUUAAUTRGU
341 AAUAGGUUUAAGUUTGTGGUAGGTGGGGGTUAUUUAGUUUAGGRGUTTUUUAUUU
    URGGGUUTGGGUUAGAAGUUUAGGAGUTGGUTGRGGGURGGTTUTUUUUUAUUUA
    UTUTGGGGATGUUTUAGGUUTGGGTTTURGUUTTAGUUTXGUUAGGUUUUAATGAG
    UUTUTGTTTGGUUTGTAGTUAATTGAURGGTTGGAUTTGGGGUAGGTGUTRGAGGA
    GUUUUAUTGAGGGAGGGUAGGTUTUTTGTGRGTAUTGTUUAGUAUATAUAGGAAAT
    TTAGUATTTUTGUUUAUUUAGU
342 GUTGGGTGGGUAGAAATGUTAAATTTUUTGTATGTGUTGGAUAGTARGUAUAAGAG
    AUUTGUUUTUUUTUAGTGGGGUTUUTRGAGUAUUTGUUUUAAGTUUAAURGGTUA
    ATTGAUTAUAGGUUAAAUAGAGGUTUATTGGGGUUTGGXGAGGUTAAGGRGGAAA
    UUUAGGUUTGAGGUATUUUUAGAGTGGGTGGGGGAGAAURGGUURGUAGUUAGUT
    UUTGGGUTTUTGGUUUAGGUURGGGGGTGGGAAGRGUUTGGGUTGGGTGAUUUUU
    AUUTGUUAUAGGUTTGGGUUTGTT
343 UUTGAUUUAUUUAAUTUTUUUAGGGGARGTGGGGGUAUTGGAGUUUUAUAURGUA
    GGRGGTAGUTUAATGUAUURGRGTRGGAGTTUUTUUUURGRGAGRGTGGUAAGGUT
    UAGGGAAGTUURGGGUUUUTGGGGAGGGGGUUTTGURGXGUATUUTGTXGUAGGA
    AURGURGGGUUUTTUUTTURGRGGGAAGXGGUTTGGURGAUUUURGUUUURGUUR
    GGGUUTUTTGGGGGTTTURGGTGUURGGUUAURGTGGGGUTGGGGAUTGAAAGTGA
    TGGGAUTGAAGATGGGGUTGGAA
344 TTUUAGUUUUATUTTUAGTUUUATUAUTTTUAGTUUUUAGUUUUARGGTGGURGGG
    UAURGGAAAUUUUUAAGAGGUURGGGRGGGGGRGGGGGTRGGUUAAGUXGUTTUU
    RGRGGAAGGAAGGGUURGGRGGTTUUTGXGAUAGGATGXGRGGUAAGGUUUUUTU
    UUUAGGGGUURGGGAUTTUUUTGAGUUTTGUUARGUTRGRGGGGGAGGAAUTURG
    ARGRGGGTGUATTGAGUTAURGUUTGRGGTGTGGGGUTUUAGTGUUUUUARGTUUU
    UTGGGAGAGTTGGGTGGGTUAGG
345 TATUUAAATGTGTTTTATATAAAATGAATRGTTTTUAGTGUAUTGAGGAAGTTTTUT
    ATTTAAAGAAATUUTGUTGTGAAUTUTTTTGTGAAGAATGUTTTUUTAATGGAATTA
    GTUAUUAUTGAGTUATTTUTGUAAAUTTUAGGTTTGXGGTTTTGUUTAAGUAAGATU
    TGGURGGAGAAGTGAGATAAATTATAGATGTRGUTAATAAATTAUAGATTAUTUAA
    AGGUAAAAGAGGAAAGAAAAAAAAAAATTGAUTRGTGTATATGAAURGAATTGAGT
    UAGGGGTUTUUAURGGU
346 GURGGTGGAGAUUUUTGAUTUAATTRGGTTUATATAUARGAGTUAATTTTTTTTTTT
    UTTTUUTUTTTTGUUTTTGAGTAATUTGTAATTTATTAGRGAUATUTATAATTTATUT
    UAUTTUTURGGUUAGATUTTGUTTAGGUAAAAUXGUAAAUUTGAAGTTTGUAGAAA
    TGAUTUAGTGGTGAUTAATTUUATTAGGAAAGUATTUTTUAUAAAAGAGTTUAUAG
    UAGGATTTUTTTAAATAGAAAAUTTUUTUAGTGUAUTGAAAARGATTUATTTTATAT
    AAAAUAUATTTGGATA
347 TGGGAGTTUUAGTTRGGGGGUAGAUUAGTGTTUAGAGTURGGGUTUTGUTAUTUAG
    RGUURGAGGUAGRGUUTUUUUATTUAARGGGGGURGTGGUAATTUUUTGAUATGAT
    TUATGAUUAUATAATAUATURGGAAAUTTUTUTUUAUXGUUTUURGTUTGGGURGT
    RGUUUURGGUUTGGGAGAUTUUAGGTUTUAGAGTUTUTGUUUUUARGGGRGATUA
    GTGUTGUUUAGTGGAAAAATAATGUUAGURGRGUAUUAAAATTAGGTGTAAAATTA
    AUATTTTTTGGAAGUUAUTTT
348 AAGTGGUTTUUAAAAAATGTTAATTTTAUAUUTAATTTTGGTGRGRGGUTGGUATTA
    TTTTTUUAUTGGGUAGUAUTGATRGUURGTGGGGGUAGAGAUTUTGAGAUUTGGAG
    TUTUUUAGGURGGGGGRGARGGUUUAGARGGGAGGXGGTGGAGAGAAGTTTURGG
    ATGTATTATGTGGTUATGAATUATGTUAGGGAATTGUUARGGUUUURGTTGAATGG
    GGAGGRGUTGUUTRGGGRGUTGAGTAGUAGAGUURGGAUTUTGAAUAUTGGTUTGU
    UUURGAAUTGGAAUTUUUAT
349 RGGRGTGUTTUTTGGUAAAUATUTUUTTGAGGATGURGUTGUAGUAUTTGAGUTGU
    TURGAGAUTTTGUTGUTUTTUTUTGGTGUTGGGTGUTGUTGAGAGTRGGGUARGTUU
    TTUTTTGGAGGTTTUAUAGGURGGUTGUTUTUURGUXGUTGGUUUAGUTTGGTGGT
    UTTGGGUTURGGGGGUAGRGAGGGTGGUTRGTGAATGGGGTUAATGGTGGTGGGGG
    TGGTGGTGTUTGUTTTUUTUTTUAUTUUUTTUTTTGTUTGUUAAGAAUARGGARGUU
    AAUAGGUAUAGTUAGAAG
350 UTTUTGAUTGTGUUTGTTGGRGTURGTGTTUTTGGUAGAUAAAGAAGGGAGTGAAG
    AGGAAAGUAGAUAUUAUUAUUUUUAUUAUUATTGAUUUUATTUARGAGUUAUUUT
    RGUTGUUUURGGAGUUUAAGAUUAUUAAGUTGGGUUAGXGGRGGGAGAGUAGUR
    GGUUTGTGAAAUUTUUAAAGAAGGARGTGUURGAUTUTUAGUAGUAUUUAGUAUU
    AGAGAAGAGUAGUAAGGTUTRGGAGUAGUTUAAGTGUTGUAGRGGUATUUTUAAG
    GAGATGTTTGUUAAGAAGUARGURG
351 TGGTUTGUTTUAAGTUUTAUUTGGUUUUTGGUAAGTUUUAUTTGGTGAUATUTTGT
    GUUTGGGTUUTTGAGGGUTGUUUUAGATURGRGATTGTUUTGGGGAURGGTAGTTU
    UTUUURGGATGUUAGUAAAGUTUUUTUUAGUUTUUAXGUUTGUAUAGTUTUUAGT
    ATGUUTTUAAUAGUUATTAGTUAUUUTUTGTGAGTUAGAUUUURGGTUUTGUUAGG
    UUAAUUTGUTTGGGGUUTUAGUAGRGGGGGUTGGRGAGGUUAGTTTTUTUUAGRGG
    TTUTAAGURGUTRGAGGGTGG
352 UAUUUTRGAGRGGUTTAGAAURGUTGGAGAAAAUTGGUUTRGUUAGUUUURGUTG
    UTGAGGUUUUAAGUAGGTTGGUUTGGUAGGAURGUGGGTUUAUTUAUAUAUUUT
    GAUTAATGGUTGTTGAAGGUATAUTGGAGAUTGTGUAGGXGTGGAGGUTGGAGGGA
    GUTTTGUTGGUATURGGGGAGGAAUTAURGGTUUUUAGGAUAATRGRGGATUTGGG
    GUAGUUUTUAAGGAUUUAGGUAUAAGATGTUAUUAAGTGGGAUTTGUUAGGGGUU
    AGGTAGGAUTTGAAGUAGAUUAG
353 AUUTGGTRGGUUAURGGUAGUTRGGGGAAGAAGGGRGRGTGGRGRGUUUAUTUUA
    RGGTGUTGAAGAGUAGURGRGURGUUAGUTRGUAUARGTTGTRGATGUUUAGUAUR
    GRGUURGURGRGURGUUUUUTGRGURGAAGRGTURGGUXGURGUAGGGTAGGGUT
    UAGRGRGUAGUAGUTGRGRGATUAGTTRGGAUAURGGUTGUUURGGGAAGAGGTU
    TURGURGUTRGUUAUTGURGUUAGRGURGAGUURGGGGGGUTGUURGAGGAGGRG
    GUUARGGUAUUAGGUAGRGAGTGU
354 GUAUTRGUTGUUTGGTGURGTGGURGUUTUUTRGGGUAGUUUUURGGGUTRGGRGU
    TGGRGGUAGTGGRGAGRGGRGGAGAUUTUTTUURGGGGUAGURGGTGTURGAAUTG
    ATRGRGUAGUTGUTGRGRGUTGAGUUUTAUUUTGRGGXGGURGGARGUTTRGGRGU
    AGGGGGRGGRGRGGRGGGRGRGGTGUTGGGUATRGAUAARGTGTGRGAGUTGGRGG
    RGRGGUTGUTUTTUAGUAURGTGGAGTGGGRGRGUUARGRGUUUTTUTTUUURGAG
    UTGURGGTGGURGAUUAGGT
355 TGGUAGAGATAUAAATTUUTGATGGUAGAGGAGGGAGAGAGAGTGTGGGTGARGA
    TGAUAATTGAAUTGAGAUUUAAAGGAGGTAGGGGAGAUATATGGGRGTUTUTGGG
    AAGATGGTUUURGGGAAAGUAUAGUUTTTAGAUAGGUUUXGAGGUAGGAGUUTGT
    UTGAUTUAURGGAGGAGUTTGGAGGAGGUTGAGGTGGUUTAAGTRGATTAAGUAGG
    GTGGGGAGGGAAGAGGRGATGGTGURGTGAGAUUAAGUAGGGUUTTGAGGTUTGG
    GGGGAGAAUTTTGGUTTTTAUTUT
356 GAGTAAAAGUUAAAGTTUTUUUUUUAGAUUTUAAGGUUUTGUTTGGTUTUARGGU
    AUUATRGUUTUTTUUUUUUUUAUUUTGUTTAATRGAUTTAGGUUAUUTUATGGTT
    TUUAAGUTUUTURGGTGAGTUAGAUAGGUTUUTGUUTXGGGGUUTGTUTAAAGGUT
    GTGUTTTUURGGGGAUUATUTTUUAGAGARGUUUATATGTUTUUUUTAUUTUUTT
    TGGGTUTUAGTTUAATTGTUATRGTUAUUUAUAUTUTUTUTUUUTUUTUTGUUATUA
    GGAATTTGTATUTUTGUUAG
357 AGAGGAGGGAGAGAGAGTGTGGGTGARGATGAUAATTGAAUTGAGAUUUAAAGGA
    GGTAGGGGAGAUATATGGGRGTUTUTGGGAAGATGGTUUURGGGAAAGUAUAGUU
    TTTAGAUAGGUUURGAGGUAGGAGUUTGTUTGAUTUAUXGGAGGAGUTTGGAGGA
    GGUTGAGGTGGUUTAAGTRGATTAAGUAGGGTGGGGAGGGAAGAGGRGATGGTGU
    RGTGAGAUUAAGUAGGGUUTTGAGGTUTGGGGGGAGAAUTTTGGUTTTTAUTUTGA
    GGAAGGTGGGAGUUAUAGAGGUTT
358 AGUUTUTGTGGUTUUUAUUTTUUTUAUAUTAAAAUUUAAAUTUUUTUUTTTAGGAUU
    TUAAGGUUUTGUTTGGTUTUARGGUAUUATRGUUTUTTUUUTUUUUAUUUTGUTTA
    ATRGAUTTAGGUUAUUTUAGUUTUUTUUAAGUTUUTUXGGTGAGTUAGAUAGGUTU
    UTGUUTRGGGGUUTGTUTAAAGGUTGTGUTTTUURGGGGAUUATUTTUUUAGAGAR
    GUUUATATGTUTUUUUUAUUTUUTTTGGGTUTUAGTTUAATTGTUATRGTUAUUUAU
    AUTUTUTUTUUUTUUTUTG
359 TGGGRGTUTUTGGGAAGATGGTUUURGGGAAAGUAUAGUUTTTAGAUAGGUUURG
    AGGUAGGAGUUTGTUTGAUTUAURGGAGGAGUTTGGAGGAGGUTGAGGTGGUUTA
    AGTRGATTAAGUAGGGTGGGGAGGGAAGAGGRGATGGTGUXGTGAGAUUAAGUAG
    GGUUTTGAGGTUTGGGGGGAGAAUTTTGGUTTTTAUTUTGAGGAAGGTGGGAGUUA
    UAGAGGUTTUTAGAUAGAAGAAGGAUAAGURGGAUTUAGGATAUUAGGGTGGGGG
    TATUTGTGGGGGATAAAGGGAGAA
360 TTUTTUUTTTATUUUUUAUAGATAUUUUUAUUUTGGTATUUTGAGTURGGUTTGTU
    UTTUTUTGTUTAGAAGUUTUTGTGGUTUUUAUUTTUUTUAGAGTAAAAGUUAAAG
    TTUTUUUUUUAGAUUTUAAGGUUUTGUTTGGTTTUAXGGUAUUATGGUUTUUUUU
    TUUUUAUUUTGUTTAATRGAUTTAGGUUAUUTUAGUUTUUTUUAAGUTUUTURGGT
    GAGTUAGAUAGGUTUUTGUUTRGGGGUUTGTUTAAAGGUTGTGUTTTUURGGGGAU
    UATUTTUUUAGAGARGUUUA
361 GGUTTTGTGAAAUUAAUUAGGAAGAATGAAAUAUAGAGUTGGTURGAUAUUUAGU
    TRGAGGGAGGGGGGURGGAAGUTTUTGGAAGTTGGUTGUUUUTAAGUAGGGGUUA
    UTUTAGUUUAUAAGGUUAAGTTGGUAGAGGUAGAXGAGGGGAUTUTGXGGUTUAA
    GTUARGGGUUAGGAGUURGUAGUTGURGGGUTGGAAAGGTUAGAGURGGUTUTGR
    GTUTGGUTGRGURGGUAAGAAGUUAUAATTARGUAGGUAAAAGAGUURGGGGATT
    AGUUUUAGUAUUTGGGAUUUTGAAT
362 ATTUAGGGTUUUAGGTGUTGGGGUTAATUUURGGGUTUTTTTGUUTGRGTAATTGTG
    GUTTUTTGURGGRGUAGUUAGARGUAGAGURGGUTUTGAUUTTTUUAGUURGGUAG
    UTGRGGGUTUUTGGUURGTGAUTTGAGUXGUAGAGTUUUUTXGTUTGUUTUTGUUA
    AUTTGGUUTTGTGGGUTAGAGTGGUUUUTGUTTAGGGGUAGUUAAUTTUUAGAAGU
    TTURGGUUUUUUTUUUTRGAGUTGGGTGTRGGAUUAGUTUTGTGTTTUATTUTTUUT
    GGTTGGTTTUAUAAAGUU
363 AGGUTGAARGGAATTGGGAGUAGAGUUUTGRGGTAGGAUAGAGAUTTRGUAAAGU
    URGGAGUAUAUAGUAGUAUUURGTUTTUTAAAGGAUAATTTTGGGAAAAUTUTTGU
    UTAATATTUTGGUAUTAAGGATUATTUTGTUAUATUUUXGUTUTGGAUTAUAAGUU
    TGUAAGUUUUATURGGGGUAGGGTTTUUTUATTUUTGTGUAURGTGGAAGUUUTGTG
    UUTGUUUAGGGUUTGGUAUTTGTARGTAUTTGAAAAUUTRGTGTGGAGTAAAGAGA
    GGGGTGATGTGUAAAGGUUTT
364 AAGGUUTTTGUAUATUAUUUUTUTUTTTAUTUUAUARGAGGTTTTUAAGTARGTAU
    AAGTGUUAGGUUUTGGGUAGGUAUAGGGUTTUUARGGTGUAUAGGAATGAGGAGU
    UUTGUUURGGATGGGGUTTGUAGGUTTGTAGTUUAGAGXGGGGATGTGAUAGAATG
    ATUUTTAGTGUUAGAATATTAGGUAAGAGTTTTUUUAAAATTGTUUTTTAGAAGARG
    GGGTGUTGUTGTGTGUTURGGGUTTTGRGAAGTUTUTGTUUTAURGUAGGGUTUTGU
    TUUUAATTURGTTUAGUUT
365 AGUUAGGUTAAAUUAGRGTGTUUUAATGAGGGGUUUTGGGUTGAGTGGAGGAAAT
    GGGTGRGGTGGAGGTGGGTTTGGUTGGGUAUAGRGGGUARGTGTGGGTAAGRGGGT
    GGGGURGGTTGTGRGGGTGGUUTATUTGGGGUAAGUAGUXGAGGURGAUTGTGTUR
    GGRGTGTGGTTGAGUARGGGUAGGTGTUTGGRGGTGAUUUTGUARGTUTGGTGTTT
    AUUTGGUUUTGGGTUTGARGTGGGURGRGUUTGGUTGUTGGRGGGAUAGTGTGTTA
    TUTGUUTGRGGARGUTTURGG
366 URGGAAGRGTURGUAGGUAGATAAUAUAUTGTUURGUUAGUAGUUAUURGKUUUU
    UARGTUAGAUUUAGGGUUAGGTAAAUAUUAGARGTGUAGGGTUAURGUUAGAUAU
    UTGUURGTGUTUAAUUAUARGURGGAUAUAGTRGGUUTXGGUTGUTTGUUUUAGAT
    AGGUUAUURGUAUAAURGGUUUUAUURGUTTAUUUAUARGTGUURGUTGTGUUUA
    GUUAAAUUUAUUTUUAURGUAUUUATTTUUTUUAUTUAGUUUAGGGUUUUTUATT
    GGGAUARGUTGGTTTAGUUTGGUT
367 UUTTGGUTUAGGTTGGGGAGGGRGTUATGAGTUATGAGGTGGGRGTTGUATTTGTU
    AGTTGTGUAGURGRGUAUUAURGAGTAGTUTGGRGGUAGRGRGTURGRGTTRGATT
    GRGTUTGGUURGUAGGAGGUURGGTUUAGUAGUUUTTUXGUAUUAGGGTUAURGG
    RGRGRGATAUUUTGGGGGRGGGATRGGGGUTRGTGUTUTGUTTUURGAAAUUUTTU
    TUUUTUUAGTUTUAGRGTTUTTUUTUUTUUUTUTATIUTTTUAUTTTGGAGTTAUT
    TUUTUUUUTUUUTUUTTUUU
368 GGGAAGGAGGGAGGGGAGGAGGTGTAGGTGAAAGTGAAAGGATAGAGGGAGGAGG
    AAGAARGUTGAGAUTGGAGGGAGAAGGGTTTRGGGAAGUAGAGUARGAGUUURGA
    TUURGUUUUUAGGGTATRGRGRGURGGTGAUUUTGGTGXGGAAGGGUTGUTGGAUR
    GGGUUTUUTGRGGGUUAGARGUAATRGAARGRGGARGRGUTUURGUUAUAUTAUT
    RGGTGGTGRGRGGUTGUAUAAUTGAUAAATGUAARGUUUAUUTUATGAUTUATGAR
    GUUUTUUUUAAUUTGAGUUAAGG
369 UAGGUTGGAGTGUAATGGRGRGATUTRGGUTUAUTGUAAUTTUTGUUTUTRGGGTT
    UAAGUAATTUTTUTAUUTTAGUUTUUTGAGTAGUTGGGATTAUAGGTAUUTGURGU
    UATGUURGGUTAATTTTTTAATTTGTTTTTAGTAGAGAXGGGGTTTUAUUATGTTGG
    UUAGGURGGTUTAUAAUTUUTGATUTUAGGTGATUTAUURGUUTRGGUUTUUUAAA
    TTAUAGGTGTTATUATTAGGATTUTTGGUAGAUAGGAGTGTTGTAGGGGATGGAAGT
    GGATAGTAGGAGGUTUTG
370 UAGAGUUTUUTAUTATUUAUTTUUATUUUUTAUAAUAUTUUTGTUTGUUAAGAATU
    UTAATGATAAUAUUTGTAATTTGGGAGGURGAGGRGGGTAGATUAUUTGAGATUAG
    GAGTTGTAGAURGGUUTGGUUAAUATGGTGAAAUUUXGTUTUTAUTAAAAAUAAAT
    TAAAAAATTAGURGGGUATGGRGGUAGGTAUUTGTAATUUUAGUTAUTUAGGAGGU
    TAAGGTAGAAGAATTGUTTGAAUURGAGAGGUAGAAGTTGUAGTGAGURGAGATRG
    RGUUATTGUAUTUUAGUUTG
371 TGAATGAUUTGGGUAGUATTTUTUUAUUTGRGUTTGUATTTGUTAGAUAGTUTGTGA
    UTUTUTGTGGGAGAAAAUAUAAGAAAURGGUUUUTUTGUTGGTTUUUUAUUTGGU
    UTGGUTUTUUTGTTUTUUAUUUTGUAUAUTUATGUUTXGGAAUUTGUTTUTUUTUT
    GAGUTUUUTUAUAGTGGUURGGUUUARGTGGUUTTTAATUTGUUUAUATUAGAGU
    UTUUAUUTURGGUUTATGGUUUATUAGAGGUAGUTGGAGURGGGUATUUTUUUUA
    RGTGGGUUTTTGAGGATGGGA
372 TUUUATUUTUAAAGGUUUARGTGGGGAGGATGUURGGUTUUAGUTGUUTUTGATGG
    GUUATAGGURGGAGGTGGAGGUTUTGATGTGGGUAGATTAAAGGUUARGTGGGUR
    GGGUUAUTGTGAGGGAGGUTUAGAGGAGAAGUAGGTTUXGAGGUATGAGTGTGUA
    GGGTGGAGAAUAGGAGAGUUAGGUUAGGTGGGGAAUUAGUAGAGGGGURGGTTTU
    TTGTGTTTTUTUUUAUAGAGAGTUAUAGAUTGTUTAGUAAATGUAAGRGUAGGTGG
    AGAAATGUTGUUUAGGTUATTUA
373 GGGRGGGGUUTGTGRGGTUTGRGGRGRGGAGURGAGTGGGUTGRGGGGATGRGGGG
    GAUUAGUTGRGTGGGRGGRGGRGURGAGAGUUURGGAGGRGRGGGGUTGAGRGAG
    GGUURGRGGGGGRGUTGGUTGRGUTTGGUTURGGTATGXGUUTAUTTUUTUTGRGT
    UTXGUTAGUTGURGTGUTGUTRGURGTGTAUTARGGTUTUATUTGGGTAUUUARGR
    GGTUTUURGRGGUAUURGURGGUUUAUAGUUUAGRGRGURGTUUUUTURGTGTGUT
    GTTURGUTTRGGGRGTGURGUUT
374 AGGRGGUARGUURGGGRGGGUAGUAUARGGAGGGGARUUKUKGUTUUUUTUTUUU
    URGGRGGGTGURGRGGGAGAURGRGTGGGTAUUUAGATGAGAURGTAGTAUARGG
    RGAGUAGUARGGUAGUTAGXGAGARGUAGAGGAAGTAGGXGUATAURGGAGUUAA
    GRGUAGUUAGRGUUUURGRGGGUUUTRGUTUAGUUURGRGUUTURGGGGUTUTRG
    GRGURGURGUUUARGUAGUTGGTUUUURGUATUUURGUAGUUUAUTRGGUTURGR
    GURGUAGAURGUAUAGGUUURGUUU
375 AAGTGTATTTTUAAGGTATGAGGGGUUUAGAGGAUAUTGTUUUAAAAGUAGTGGTT
    GTGAGAGTGGUTTTGGAGTUAGGUTGAUAGTUTGGAAAUTTUUAGGTURGUTUTGA
    AGTGURGGUTGUATGAUUAGUUUTUUAGUUTGTGTUXGUTTRGGUUTTUTTTGTGU
    AAGTGAGAGUATTGUTGATUUUUURGGGGTGGRGAGGGGGRGUARGTUAGTGAUUT
    RGUATGGTGUUTGUUAGGUARGTGGTURGTGTTTUATGATTUTTTGAGAGUTTTGGA
    GUAGUTUUAAGAAGAUTUT
376 GAGTUTTUTTGGAGUTGUTUUAAAGUTUTUAAAGAATUATGAAAUARGGAUUARGT
    GUUTGGUAGGUAUUATGRGAGGTUAUTGARGTGRGUUUUUTRGUUAUUURGGGGG
    GATUAGUAATGUTUTUAUTTGUAUAAAGAAGGURGAAGXGGAUAUAGGUTGGAGG
    GUTGGTUATGUAGURGGUAUTTUAGAGRGGAUUTGGAAGTTTUUAGAUTGTUAGUU
    TGAUTUUAAAGUUAUTUTUAUAAUUAUTGUTTTTGGGAUAGTGTUUTUTGGGUUUU
    TUATAUUTTGAAAATAUAUTTT
377 TAATTTTAAAUAAAAUTTTUUATGAGUAAUTAAATATTTAAAATGTGTTTTTUUATA
    AAAGTGAATUAGUTUAGTTUTGUAGGUTGAAAATAUAAUAAGGAGGATURGGGTTG
    UAGAAAGUAGAGGGUUAUUTAGAURGTGTUTGAGAGAXGGGGAGAAAGUAGUTGT
    UTGUTGTGUAUUAGAGGUUTUTAGGGAUUURGGUAGUAAUUURGTGGRGGGUUAU
    AUTTGGGAGUTGATTTGTTTTUAGAAUUAUUAGUTAAGUUAUATGAGUUAGGAGUU
    TGGTTATUUATTUAAAGUUUA
378 TGGGUTTTGAATGGATAAUUAGGUTUUTGGUTUATGTGGUTTAGUTGGTGGTTUTGA
    AAAUAAATUAGUTUUUAAGTGTGGUURGUUARGGGGTTGUTGURGGGGTUUUTAG
    AGGUUTUTGGTGUAUAGUAGAUAGUTGUTTTUTUUUXGTUTUTUAGAUARGGTUTA
    GGTGGUUUTUTGUTTTUTGUAAUURGGATUUTUUTTGTTGTATTTTUAGUUTGUAGA
    AUTGAGUTGATTUAUTTTTATGGAAAAAUAUATTTTAAATATTrAGTTGUTUATGGA
    GAGTTTTGTTTAAAATTA
379 GUUTUUAGAUURGAAATUUUUUAUTGAAGUUATTUUUAGGAGGAGGGGUUTUAUT
    GGGGUUTUAAGGUAGUATUAGUATTTURGGTGAUAGGUAUAGUAATTTATUAGUTU
    AUTGGUTUTUTAUTGAGAAUAAGGUAAGURGGGGUUTGUXGAGGGTATGAUAGGU
    AGGGAGTGATGGGUURGGUUUAGGGUAGGAGGGAGAUAGAAATGGGUAGGAAGA
    GGAGGUTGTUUUUAGUAGUAUTTUTGAGAGGAGGAGUAUUTTTRGGGGAUAUTUT
    GGARGGUAUUUUUAAGUAUAGUUUU
380 GGGGUTGTGUTTGGGGGTGURGTUUAGAGTGTUUURGAAAGGTGUTUUTUUTUTUA
    GAAGTGUTGUTGGGGAUAGUUTUUTUTTUUTGUUUATTTUTGTUTUUUTUUTGUUU
    TGGGURGGGUUUATUAUTUUUTGUUTGTUATAUUUTXGGUAGGUUURGGUTTGUUT
    TGTTUTUAGTAGAGAGUUAGTGAGUTGATAAATTGUTGTGUUTGTUAURGGAAATG
    UTGATGUTGUUTTGAGGUUUUAGTGAGGUUUUTUUTUUTGGGAATGGUTTUAGTGG
    GGGATTTRGGGTUTGGAGGU
381 TGAGAGUAGUUAGAUARGTAGTGATUAGGGAAAGTRGAAAGTGUAGATGGGTTRG
    UAAARGTGGAUTUTUTAGTTTTGGGTUTGUAGATGGGGURGGUUAUUAXGTGUTUT
    UTGAGTTUTUTTTUUAAGTAUAGATUUUTURGGAGARGGAAUATTGTTURGUUTTTA
    ATTUTTUUUAGGAGUTGRGGAGGAAGGXGTGAGAAURGGAGUURGGGGTGAUTTGR
    GGGGGAGGGGATRGUTTUUURGTRGUUUAUAUUTGUUTAAUUUARGUUUARGGRG
    GURGUAAAGGRGAUAURGRGT
382 ARGRGGTGTRGUUTTTGRGGURGURGTGGGRGTGGGTTAGGUAGGTGTGGGRGARG
    GGGAAGRGATUUUUTUUUURGUAAGTUAUUURGGGUTURGGTTUTUAXGUUTTUUT
    URGUAGUTUUTGGGAAGAATTAAAGGRGGAAUAATGTTURGTUTURGGAGGGATUT
    GTAUTTGGAAAGAGAAUTUAGAGAGUAXGTGGTGGURGGUUUUATUTGUAGAUUU
    AAAAUTAGAGAGTUUARGTTTGRGAAUUUATUTGUAUTTTRGAUTTTUUUTGATUA
    UTARGTGTUTGGUTGUTUTUA
383 AUAAGRGGTTGGATTTRGAGAGGAUATUAAGAGUARGTUAAGAGUARGTUAAGAG
    UAUARGGAUAGGUAUTGGUARGURGGUAGGTUATTGAURGGUAGAAUAGAGTTTG
    GUUAGGGUTGTUAGAGAAGAGTRGGGURGUUAAGUAGUUXGAUTTUUAGRGGAAA
    AUUATUTGUUTTUTGGUTUUTUUATUTGUTGAGAGUTAUTTUUAUTUAATAAAAUU
    TTGUAUTUATTUTUUAAAUUUAUATGAGATUUAATTUTTURGGTAUAUUAAGGUAG
    GAAUUURGAGATAUAGAAAGUUU
384 GGGUTTUTGTATUTRGGGGTTUUTGUUTTGGTGTAURGGAAGAATTGGATUTUATG
    TGGGTITGGAGAATGAGTGUAAGGTTTTATTGAGTGGAAGTAGUTUTUAGUAGATG
    GAGGAGUUAGAAGGUAGATGGTTTTURGUTGGAAGTXGGGUTGUTTGGRGGUURGA
    UTUTTUTUTGAUAGUUUTGGUUAAAUTUTGTTUTGURGGTUAATGAUUTGURGGRG
    TGUUAGTGUUTGTURGTGTGUTUTTGARGTGUTUTTGARGTGUTUTTGATGTUUTUT
    RGAAATUUAAURGUTTGT
385 AUTTGAAGTUAGGAGTTRGTGAAUAGUUTGGUUAAUATGGTGAAAUUUTGTUTUTA
    UTAAAAAAAGAAAAATTAGURGGGTGTGGTGGGRGUUTGTAAUUUUAGUAUTTTGG
    GAGGUTGAGGTGGGTGGATUAUTTGAAGTUAGGAGTTXGTGAAUAGUUTGATUAAU
    ATGGTGAAAUUUTGTUTUTAUTAAAAAUAUAAAAATTAGURGGGTGTGGTGGTGGG
    TGUUTGTAATUUUAGUTAUTUAGGAGAUTGAGGUAGGAGGATUAUTTGAAURGGG
    GAGGUAGAGGTTGUAGAGAGT
386 UTUTUTGUAAUUTUTGUUTUUURGGTTUAAGTGATUUTUUTGUUTUAGTUTUUTGA
    GTAGUTGGGATTAUAGGUAUUUAUUAUUAUAUURGGUTAATTTTTGTGTTTTTAGTA
    GAGAUAGGGTTTUAUUATGTTGATUAGGUTGTTUAXGAAUTUUTGAUTTUAAGTGA
    TUUAUUUAUUTUAGUUTUUUAAAGTGUTGGGGTTAUAGGRGUUUAUUAUAUURGG
    UTAATTTTTUTTTTTTTAGTAGAGAUAGGGTTTUAUUATGTTGGUUGUTTAAA
    GAAUTUUTGAUTTUAAGTG
387 AAATUTTTTTUUTGUUTGUATTTTUTTAUATAAAGUAATUTAUTAUTGUUATRGGTT
    UATTUAUTUAURGGAAUUTGTUTTGUUAGGAUUTGAUUTUAGUAGAUTGAGTUATA
    UUAGUATUATUUTTGTTGGGGUUUAGGTUTGUATUUXGUTTURGGUUUUAGUUUUA
    UTGTTAGUTUUATUAGGTUUTUTGGGGUAUAUUAAGGAGGURGTTTTUTLTUUUTTT
    TTUTGAATTAGATUUUUAGAAAUAAGAUATUAGGUTTUUTGGGGAAATUTAATTTT
    GUTUATGAATTTGAUUAT
388 ATGGTUAAATTUATGAGUAAAATTAGATTTUUUUAGGAAGUUTGATGTUTTGTTTUT
    GGGGATUTAATTUAGAAAAAGGGAGAGAAAARGGUUTUUTTGGTGTGUUUUAGAG
    GAUUTGATGGAGUTAAUAGTGGGGUTGGGGURGGAAGXGGGATGUAGAUUTGGGU
    UUUAAUAAGGATGATGUTGGTATGAUTUAGTUTGUTGAGGTUAGGTUUTGGUAAGA
    UAGGTTURGGTGAGTGAATGAAURGATGGUAGTAGTAGATTGUTTTATGTAAGAAA
    ATGUAGGUAGGAAAAAGATTT
389 UAAGGTUUAGGTUUUAGUUTUUUUAURGURGUURGRGUUUTUUTAGGUUTRGGAG
    RGGRGUTTTTUTGRGGUUTRGAAGGTGGGGTGGGAAAGTTTGGGGAGTUURGGUTU
    TUAUAGUUTGTRGTGAGAAUTGUUUURGGGGAATTRGTUXGURGTARGGAAAAAUT
    GGURGGAGUAGAGTRGTURGRGGTTURGRGGTRGRGGGTGGAAGGTGAAGGTRGAG
    GGAGGTUAGGUTGUTTUTGRGTGTUUTGARGGUTGGRGTGTTUTUTTGAGATGGGUT
    RGGGUTAUTTGGUUAGUTTU
390 GAAGUTGGUUAAGTAGUURGAGUUUATUTUAAGAGAAUARGUUAGURGTUAGGAU
    ARGUAGAAGUAGUUTGAUUTUUUTRGAUUTTUAUUTTUUAUURGRGAURGRGGAA
    URGRGGARGALTUTGUTURGGUUAGTTTTTURGTARGGXGGARGAATTUUURGGGG
    GUAGTTUTUARGAUAGGUTGTGAGAGURGGGAUTUUUUAAAUTTTUUUAUUUUAU
    UTTRGAGGURGUAGAAAGGRGURGUTURGAGGUUTAGGAGGGRGRGGGRGGRGGT
    GGGGAGGUTGGGAUUTGGAUUTTG
391 URGAGGGAGUUAGGUUAUAGUTGAUAGGAAGGUAGAAGGTGGUAGGAGGGGAGG
    TTGRGUTGUAUUTUTGGGTTGUUUAGGUUAAUUTGUUAGGUAGGAGGGGGAAGUU
    RGTGUUUAUTTTAUUATGAURGGGAAGATGATGGUAGUUAUXGTGGATTTGAGGAT
    UUAGAGUAURGUUAGGUAGAGGATUTGUAUUAGGGTGAAGAGGTGGATURGGRGU
    AGRGGUARGTGURGUAGGAAGGUATGGTURGGUTGGTGUTTGGUTGGUATUAGGAA
    GAGUTTGUAGRGTTUUUAGAAUTA
392 TAGTTUTGGGAARGUTGUAAGUTUTTUUTGATGUUAGUUAAGUAUUAGURGGAUUA
    TGUUTTUUTGRGGUARGTGURGUTGRGURGGATUUAUUTUTTUAUUUTGGTGUAGA
    TUTTTUTGUUTGGRGGTGUTUTGGATUUTUAAATUUAXGGTGGUTGUUATUATUTTU
    URGGTUATGGTAAAGTGGGUARGGGUTTUUUUUTUUTGUUTGGUAGGTTGGUUTGG
    GUAAUUUAGAGGTGUAGRGUAAUUTUUUUTUUTGUUAUUTTUTGUUTTUUTGTUAG
    UTGTGGUUTGGUTUUUTRGG
393 AAATTAUURGGGRGTGGTGGTGGGTGUUTGTAATUUUAGUTAUTUAGGAGGURGAG
    GUAGGAGAAURGUTTGAAUURGGGAGGUAGAGUATAGGTTGTTGGAGGGTTGAAG
    GTGUAUUUAGUAGAGAUTGGUATAUAGGAGGTUUTGUAAXGGUUUUAGGAAAUUT
    UTGGGTUUAGTAAGAGUTTUAGUAGGAGGTAGAAUUATAURGGGUAGGAGTGUUT
    GGAAAGGUTTUAAGGUAAUTUUUTUUAAAGTLTTrGGUUUAAUUUTAUAUTGTUAG
    GUTGTTAAAGGUUATTTAAAAGUT
394 AGUTTTTAAATGGUUTTTAAUAGUUTGAUAGTGTAGGGTTGGGUUAGGAUTTTGGA
    GGGAGTTGUUTTGAAGUUTTTUUAGGUAUTUUTGUURGGTATGGTTUTAUUTUUTG
    UTGAAGUTUTTAUTGGAUUUAGAGGTTTUUTGGGGUXGTTGUAGGAUUTUUTGTAT
    GUUAGTUTUTGUTGGGTGUAUUTTUAAUUUTUUAAUAAUUTATGUTUTGUUTUURG
    GGTTUAAGRGGTTUTUUTGUUTRGGUUTUUTGAGTAGUTGGGATTAUAGGUAUUUA
    UUAUUARGUURGGGTAATTT
395 AGGAAAAAAUAGUAGUUUAAGAATRGGGUUTUUUTGTTAUAGUAGGAGTRGUATU
    TATTTATATATGTTATGTUTTATTGUTUAGUAAUUAGUTUTRGGURGGGGRGTGGGU
    RGGGAAGAGGGGTUTUUTGGTGUAGXGGGTTGGRGTGAUTUATUAURGURGXGUAU
    TUTGGUUTUTGGGUUTAGGTTAAUAGAUTUURGGGTTTUAGGUTGGGUUUAGGRGG
    UUAGGUUUTUUUTGUTGAGGAATUTGGGTTGGGGUAGTGUUAGUTUUUTGUTTUTU
    AUUTGGUUAUAGAAGGGGTA
396 TAUUUUTTUTGTGGUUAGGTGAGAAGUAGGGAGUTGGUAUTGUUUUAAUUUAGAT
    TUUTUAGUAGGGAGGGUUTGGURGUUTGGGUUUAGUUTGAAAUURGGGAGTUTGT
    TAAUUTAGGUUUAGAGGUUAGAGTGXGRGGRGGTGATGAGTUARGUUAAUUXGUT
    GUAUUAGGAGAUUUUTUTTUURGGUUUARGUUURGGURGAGAGUTGGTTGUTGAG
    UAATAAGAUATAAUATATATAAATAGATGRGAUTUUTGUTGTAAUAGGGAGGUURG
    ATTUTTGGGUTGUTGTTTTTTUUT
397 AUUUAGGAATTUTTTTUUTTTTTTTTGAGARGGRGTUTUTGTRGUUUAGGUTGGAG
    TGUAGTGGRGUAGTUTRGUUTAAUTGUAAGUTURGUUUURGGGTTUATGUUATTUT
    UUTGUUTUAGUUTUTTGAGTAGUTGGAAUTAUAGGXGUUTGUUAUUAUAUURGGU
    UAATTTTTTGTATTTTTAGTAGAGARGGGGTTTUAURGTGTTAGUTAGGATGGTUTR
    GATUTUUTGAUUTRGTGATUUAUUUAUUTUAGUUTUTUAAAGTGUTGGGATTAUAG
    GUTTGAAUUAUTGRGUUU
398 GGGRGUAGTGGTTUAAGUUTGTAATUUUAGUAUTTTGAGAGGUTGAGGTGGGTGGA
    TUARGAGGTUAGGAGATRGAGAUUATUUTGGUTAAUARGGTGAAAUUURGTUTUTA
    UTAAAAATAUAAAAAATTGGURGGGTGTGGTGGUAGGXGUUTGTAGTTUUAGUTAU
    TUAAGAGGUTGAGGUAGGAGAATGGUATGAAUURGGGGGRGGAGUTTGUAGTTAG
    GRGAGAUTGRGUUAUTGUAUTUUAGUUTGGGRGAUAGAGARGURGTUTUAAAAAA
    AAAAAAAAAAGAATUUTGGGT
399 AAATAUAGUAGGAGAGAATTUUTUTGAGAUUTAAGATAURGTGUUUTTUUUUUTTG
    GUUTUTUAGUTGUTGURGAGTUUTGGAGAAAATRGGGUATUTGAAUAGAGGURGTG
    TTTGTUUUTGUTURGGUUTTGTGTTUTUATTUUTGUUAXGUUATUATGGATAATGAA
    AGTTGAUTGGUTGURGGGGTTTUUTTTUTUTUTGUUUUTGTUATTTUUATTTGUUAG
    GTUTUATGUUTTTTTTGUAUAGAGTTGTTGTGUTTGGGUTUTAATTTGUUAGGUAGT
    GATAAATTUUAAGAAAA
400 TTTTUTTGGAATTTATUAUTGUUTGGUAAATTAGAGUUUAAGUAUAAUAAUTUTGT
    GUAAAAAAGGUATGAGAUUTGGUAAATGGAAATGAUAGGGGUAGAGAGAAAGGA
    AAUUURGGUAGUUAGTUAAUTTTUATTATUUATGATGGXGTGGUAGGAATGAGAAU
    AUAAGGURGGAGUAGGGAUAAAUARGGUUTUTGTTUAGATGUURGATTTTUTUUAG
    GAUTRGGUAGUAGUTGAGAGGUUAAGGGGGAAGGGUARGGTATUTTAGGTUTUAG
    AGGAATTUTUTUUTGUTGTATTT
401 GUUUTGAGAUAUTAAATGGRGGGGGGGTGGGGGGAGGAAAGGGAAGGRGGUAGAG
    UTUUURGAGURGGGAUAGTUAUTTAUTUTAUAGGUAGTGGGGUURGAUAUAGAUA
    GRGURGUUUURGUUAGUUAGUUTRGUARGUUUTRGGAAGXGUAGGUTUURGGRGU
    TGRGUTGGAGGGTTUUURGGUAUUUUAGUUTUURGTUUUUAGUURGUTGUAUUTU
    RGGGUUUUUUTTAUUUTTGAGAGGUAURGGGAGTTGTRGRGGGGGGGUUTRGGGA
    AATTUUURGGAUUUUTGTGUUAGGA
402 TUUTGGUAUAGGGGTURGGGGAATTTUURGAGGUUUUUURGRGAUAAUTUURGGT
    GUUTUTUAAGGGTAAGGGGGGUURGGAGGTGUAGRGGGUTGGGGARGGGAGGUTG
    GGGTGURGGGGAAUUUTUUAGRGUAGRGURGGGAGUUTGXGUTTURGAGGGRGTG
    RGAGGUTGGUTGGRGGGGGRGGRGUTGTUTGTGTRGGGUUUUAUTGUUTGTAGAGT
    AAGTGAUTGTUURGGUTRGGGGAGUTUTGURGUUTTUUUTTTUUTUUUTRTAUUUU
    UURGUUATTTAGTGTUTUAGGGU
403 AUUAUAGUAUTGUAGGAGGATGAGUUUUTGUAGGAAGGAATGUTGGUTUTUTGGG
    GTAGATAAAGAAGGTTUTGGGGAAGGGAAGGGAGGAAUAGGAAUATGGGUTUUUT
    GUUAGGUTGTUUUAGGTURGGGATGUUATRGGUAAGTGGGXGGGGAUAGGUUTGG
    GTAGATGAUATGGTAGTGAGTAAGTGGGGAGGUAGGUUAGUAGAGGAGUUAGGUT
    UAUUTUUXGUUXGUUUAUUTRGGUUAUAGAURGGGAGGGGTRGGAGUAUTGRGTT
    GGGGTTGATGAGUAGARGAUTGUUA
404 TGGUAGTRGTUTGUTUATUAAUUUUAARGUAGTGUTURGAUUUUTUURGGTUTGTG
    GURGAGGTGGGXGGGXGGGAGGTGAGUUTGGUTUUTUTGUTGGUUTGUUTUUUUA
    UTTAUTUAUTAUUATGTUATUTAUUUAGGUUTGTUUUXGUUUAUTTGURGATGGUA
    TUURGGAUUTGGGAUAGUUTGGUAGGGAGUUUATGTTUUTGTTUUTUUUTTUUUTT
    UUUUAGAAUUUUTUTUUATUTAUUUUAGAGAGUUAGUATTUUTTUUTGUAGGGGUTU
    ATUUTUUTGUAGTGUTGTGGT
405 AGGGAAGGGAGGAAUAGGAAUATGGGUTUUUTGUUAGGUTGTUUUAGGTURGGGA
    TGUUATRGGUAAGTGGGXGGGGAUAGGUUTGGGTAGATGAUATGGTAGTGAGTAA
    GTGGGGAGGUAGGUUAGUAGAGGAGUUAGGUTUAUUTUUXGUUXGUUUAUUTRGG
    UUAUAGAURGGGAGGGGTRGGAGUAUTGRGTTGGGGTTGATGAGUAGARGAUTGU
    UAGGUAGUUATTUAUAGGAAATGGUAUAGARGUAUATTGTTUUAGUTAUUUUUUA
    TUUTUUUTUAGGGGUAAAGTGAATG
406 ATTUAUTTTGUUUUTGAGGGAGGATGGGGGGTAGUTGGAAUAATGTGRGTUTGTGU
    UATTTUUTGTGAATGGUTGUUTGGUAGTRGTUTGUTUATUAAUUUUAARGUAGTGU
    TURGAUUUUTUURGGTUTGTGGURGAGGTGGGXGGGXGGGAGGTGAGUUTGGUTU
    UTUTGUTGGUUTGUUTUUUUAUTTAUTUAUTAUUATGTUATUTAUUUAGGUUTGTU
    UUXGUUUAUTTGURGATGGUATUURGGAUUTGGGAUAGUUTGGUAGGGAGUUUAT
    GTTUUTGTTUUTUUUTTUUUTT
407 GGTTUTAAAUAUAUAAAUUTTTGATGUATUTGGAATTTAUUTTAATUUUTAUUAAT
    TTTTATUAATGGUTUAATATTTGGGGGATTTTUATGGTAATTGUAUTGAATGTATTAA
    UTGGTUAGGGAGGATTAUATUAAGAUUAURGGUTXGAGAAAUAGUAGTUTGTTUUT
    UUAUUUUUARGTUTGUATUUAGGUUUTTUUAUAGAGATUTUATTTUTUUTGUAGAT
    GAUTUATTUAGTGTUTAGGAATURGGTGUTUTGTGGUUAUTAURGAGAGTGGGATA
    TTTTUUUUUATTTTATT
408 AATAAAATGGGGGAAAATATUUUAUTUTRGGTAGTGGUUAUAGAGUAURGGATTUU
    TAGAUAUTGAATGAGTUATUTGUAGGAGAAATGAGATUTUTGTGGAAGGGUUTGGA
    TGUAGARGTGGGGGTGGAGGAAUAGAUTGUTGTTTUTXGAGURGGTGGTUTTGATG
    TAATUUTUUUTGAUUAGTTAATAUATTUAGTGUAATTAUUATGAAAATUUUUUAAA
    TATTGAGUUATTGATAAAAATTGUTAGGAAATTAAGGTAAATTUUAGATGUATUAA
    AGGTTTGTGTGTTTAGAAUU
409 TTTGGGGGGUAGGGAGGGTTUAGTUUUUTUAGGUUTGGUTGTGTUUUUTGUUUUUU
    AUUUAUAATUAGGUUUAGGGTTGGGGGGTGUAUAUUAAGGAGGGGUAGGAAGTGT
    UUAAGAAGUAGAAURGGUTUTGTGTUUUUAGTGGXGGXGGGTGTUTGGGGUAGGA
    GGAGGUTATUTGATUUUTTUUUUAUTGUUURGGUUATGAUUTUUTUUUTUUUTUUU
    TRGUTUUUTUUUTUUTUUUTUUUTUUUTUUUTUUUTUUUTUUTUUUUTTTTUUTU
    GGGTAGUUAGUAUUUTGGGUTG
410 AGUUUAGGGTGUTGGUTAUUUUAGUUATGAAGGAGGAGGGAGGGAGGGAGGGAG
    GGAGGGAGGGAGGGAGGGAGRGAGGGAGGGAGGGAGGAGGTUATGGURGGGGUA
    GTGGGGAAGGGATUAGATAGUUTUUTUUTGUUUUAGAUAUUXGUXGUUAUTGGGG
    AUAUAGAGURGGTTUTGUTTUTTGGAUAUTTUUTGUUUUTUUTTGGTGTGUAUUUU
    UUAAUUUTGGGUUTGATTGTGGGTGGGGGGUAGGGGAUAUAGUUAGGUUTGAGGG
    GAUTGAAUUUTUUUTGUUUUUUAAAG
411 UURGUAAGUUTRGUUUUTUUAGGUUTRGUUUTUUUTUUTTGUAGAGAGTGGUUAA
    GUTRGTGTTUUAGAGGUTGAATGAGGATTTTGTGRGGAAGUURGAUTATGUTTTGAG
    UTUTGTGGGTAAGAUURGGAGAUAUTGGAAGAUAGAGAXGUAGAUAGGAAAGAGG
    UUAAGAUAUTGAUAUAGAUAGAUUUATGUAUUTGAURGGURGAAGAUAGAGUUTR
    GGAUAGUUUUUAUURGUUUUUAGUUUURGRGUUUURGRGUUURGAUTUURGGUAA
    GGUUTGGGAGUUTUTGAGGGTTA
412 TAAUUUTUAGAGGUTUUUAGGUUTTGURGGGAGTRGGGGRGRGGGGGRGRGGGGG
    UTGGGGGRGGGTGGGGGUTGTURGAGGUTUTGTUTTRGGURGGTUAGGTGUATGGG
    UUTGTUTGTGTUAGTGTUTTGGUUTUTTTUUTGTUTTGGGTTUUUGTAAGRTTT
    URGGGTUTTAUUUAUAGAGUTUAAAGUATAGTRGGGUTTURGUAUAAAATUUTUAT
    TUAGUUTUTGGAAUARGAGUTTGGUUAUTUTUTGUAAGGAGGGAGGGRGAGGUUT
    GGAGGGGRGAGGUTTGRGGG
413 UAGATUAGGGTUUTUAGAUTTGTURGGAGGGAGGGUUUTGUATAUUTGUUAARGU
    UUTGTTTGUTGGGAAAGGGGUTGATGTTGUAATGAUAGGTTAAAUAGUAAUAGGAU
    ATTGAUTGGUATUTGUAAGUTGAGUTUAGUTUAGAGAGGXGAGGAGUAUAGGGGA
    GGGAGGAAAATUURGGTGTGGATUTUAUUUAUARGGUUUAUTGGGTGUTUUTGGU
    AGARGGAATTATGGGTGUTTTTAUTUTUTUATTTTAAAAATGTGUTTTTTATGTGTAT
    TGTAAAAGTAAUAGATTUUUA
414 TGGGAATUTGTTAUTTTTAUAATAUAUATAAAAAGUAUATTTTTAAAATGAGAGAGT
    AAAAGUAUUUATAATTURGTUTGUUAGGAGUAUUUAGTGGGURGTGTGGGTGAGAT
    UUAUAURGGGATTTTUUTUUUTUUUUTGTGUTUUTXGUUUTUTGAGUTGAGUTUA
    GUTTGUAGATGUUAGTUAATGTUUTGTTGUTGTTTAAUUTGTUATTGUAAUATUAGU
    UUUTTTUUUAGUAAAUAGGGRGTTGGUAGGTATGUAGGGUUUTUUUTURGGAUAA
    GTUTGAGGAUUUTGATUTG
415 UAUTTGGUTUTRGTGGUTGGGAUAGATTGUTTUUTTUUTUTUTUUTGGGTGUUAGGT
    AGGUUUAGAAAUUAUUTGATGTUAGUAAGGUUTGGUUAUUUAUTGGTGGGGAGGA
    AGTGGGRGGGTGUUUAGGGAUAGATGAGURGGGUAGAXGTGUUUTGAGGUAGUAU
    AGTUAGGGUTGARGTGGGUATTATGUAUUTRGGGGUTTTUAGAGUTGGUTURGGTU
    URGTTTGUUUAUATUAAGUAGGTUAGAGTGGAGAGGGUUAGGGGRGUTGGGGTUA
    AGGUATGUAUTGAUUAGGRGTU
416 GARGUUTGGTUAGTGUATGUUTTGAUUUUAGRGUUUUTGGUUUTUTUUAUTUTGAU
    UTGUTTGATGTGGGUAAARGGGAURGGAGUUAGUTUTGAAAGUUURGAGGTGUAT
    AATGUUUARGTUAGUUUTGAUTGTGUTGUUTUAGGGUAXGTUTGUURGGUTUATUT
    GTUUUTGGGUAUURGUUUAUTTUUTUUUUAUUAGTGGGTGGUUAGGUUTTGUTGA
    UATUAGGTGGTTTUTGGGUUTAUUTGGUAUUUAGGAGAGAGGAAGGAAGUAATUT
    GTUUUAGUUARGAGAGUUAAGTG
417 AUUAUAUTTGAAUATAUAGAUATUUTTTTUUAGGGTGTGTTGTGUTRGATAUUTTT
    AATTUUTGTUTGUATTUUAGGGUUTGUUUAGUUTUTTUUTGGUTUUUUAGUUUAGU
    UTGGTUUTTURGGUUTUUUTGTUATUUUUAUUTUTXGTGTGTGUAUAAGUAGGGAU
    UAGGTAGGGAGAURGGUAGATGUTGUTUTUTGTUUUTGGGGTTTUTTTTUTTAGTGT
    TGUTUUUAUAUUUARGRGATGUTTTAATTAAUTGUUAUAUTUAGGUTTTUTUAGTG
    GGGAGAGTUAGAAATAGA
418 UTATTTUTGAUTUTUUUUAUTGAGAAAGUUTGAGTGTGGUAGTTAATTAAAGUATR
    GRGTGGGTGTGGGAGUAAUAUTAAGAAAAGAAAUUUUAGGGAUAGAGAGUAGUAT
    UTGURGGTUTUUUTAUUTGGTUUUTGUTTGTGUAUAUAXGAGAGGTGGGGATGAUA
    GGGAGGURGGAAGGAUUAGGUTGGGUTGGGGAGUUAGGAAGAGGUTGGGUAGGU
    UUTGGAATGUAGAUAGGAATTAAAGGTATRGAGUAUAAUAUAUUUTGGAAAAGGA
    TGTUTGTATGTTUAAGTGTGGATG
419 TUUUAGUUAUTURGUAGTUAUTUUTGAUUUAGAAAAGAAUAAUUAUAGUTGGGUU
    UAGUAUUURGGGUUAUTUUUTGUAGUTGUUUAUAUATUTGGUAGUTGGGTUUAUT
    TATGUAATGTGGATXGGGTTTTUTTAUATUTGAAATUTGXGTUTUTATUUUTUUTUTG
    AGAUUAGTGTUTUUTGUUAGUTTUUATGGUUURGGGATGAUUTUAUTUTUUUAGGG
    TUTUUUTGRGTUUTGGGAGUTUTGGURGAGGAGUAGUAGGGGUTGATGGUAGAGR
    GGGGGUAGGTUAGAGUTUAGUA
420 GUTGAGUTUTGAUUTGUUUmGUTUTGUUATUAGUUUUTGUTGUTUUTRGGUUAGA
    GUTUUUAGGARGUAGGGAGAUUUTGGGAGAGTGAGGTUATUURGGGGUUATGGAA
    GUTGGUAGGAGAUAUTGGTUTUAGAGGAGGGATAGAGAXGUAGATTTUAGATGTA
    AGAAGUUXGATUUAUATTGUATAAGTGGAUUUAGUTGUUAGATGTGTGGGUAGUT
    GUAGGGAGTGGUURGGGGTGUUGGGUUUAGUTGTGGTTGTTUTTTTUTGGGTUAGG
    AGTGAUTGRGGAGTGGUTGGGAU
421 UUAAARGRGGUAUARGGGGARGGUUUUTUURGGGGTUAGGUTUAUTGGUTUUTTU
    UUTTUAGRGUUAUUAGGUAGGAGGGUUAARGGTUAUAUAGGAGGUAUUUTUAUUT
    GUUTTTGUAUUAGUAAATAAAGTGUATUUUATTTTXGTGTGAGXGTRGGUURGGTG
    AGTUAGUUUTTURGGGUUUTTTUUTGTTUTUAGGGUAGGGGGRGTGRGUTGAGUUA
    GAGGTAGATUTGUAGAAAGGGUUURGAUTGGGUUTRGGGUAGGGURGGRGUUUAU
    UAUAUTUTGGGGGTUAGUTATGU
422 GUATAGUTGAUUUUUAGAGTGTGGTGGGRGURGGUUUTGUURGAGGUUUAGTRGG
    GGUUUTTTUTGUAGATTTTAUUTUTGGUTUAGRGUARGUUUUUTGUUUTGAGAAUAG
    GAAAGGGUURGGAAGGGUTGAUTUAURGGGURGAXGUTUAUAXGAAAATGGGATG
    UAUTTTATTTGUTGGTGUAAAGGUAGGTGAGGGTGUUTUUTGTGTGAURGTTGGUU
    UTUUTGUUTGGTGGRGUTGAAGGGAAGGAGUUAGTGAGUUTGAUUURGGGAGGGG
    URGTUUURGTGTGURGRGTTTGG
423 GUAGGAAGGGUUUAGARGAUAUUUUUAUAGAUATATGUUAGUUUUTURGGGTGAU
    UAAAATUATUTUAGTAAAGGUAGATGAGGUUAAGRGAAAAGGGGTGGGTGGAAGA
    AURGGUTUTGAGTUTUAGUUUAUAGAUAUTRGGAUAUTXGTRGGUURGGTAGGUA
    GGGGTTUUTGGTGGUUTUAGGUTGTUAGGUURGGUUUUUTUURGUAGUTGTUTUUA
    GUTUUUAUUTUUUURGUUUAUUUUUUAGGAUTUUTATTTUAUTGAGGAGATTAAG
    AUUAUUTGGRGAGAAUUUUTUUUA
424 GGGAGGGGTTUTRGUUAGGTGGTUTTAATUTUUTUAGTGAAATAGGAGTUUTGGGG
    GGTGGGRGGGGGAGGTGGGAGUTGGAGAUAGUTGRGGGAGGGGGURGGGUUTGAU
    AGUUTGAGGUUAUUAGGAAUUUUTGUUTAURGGGURGAXGAGTGTURGAGTGTUT
    GTGGGUTGAGAUTUAGAGURGGTTUTTUUAUUUAUUUUTTTTRGUTTGGUUTUATU
    TGUUTTTAUTGAGATGATTTTGGTUAUURGGAGGGGUTGGUATATGTUTGTGGGGGT
    GTRGTUTGGGUUUTTUUTGUT
425 AGGTGAGATUTGGAGGTTGRGGGGUAGTTAGUAAGTGGGAGAGAGUTGUATGRGGG
    GAAGGTGGGAGGRGTTGUAGGAAAGGTGAGGGAGAUAUAGUTGAGUTGTGGTGUT
    GGUUAGUTGGGGUUTTGRGUUTTATURGGGUAUTGTGAXGGUUAUTAAUAGGTTTT
    AAGTAURGGAATGAUATGATRGGATTTGTAATTTAAUTAGATUUTTUTGAUTGUTGT
    TGGGGGAAUAGAUTGTUAAUUTUAUAAUAGUAUTGTUAGUTGAGTATTAGAUAAAT
    GATGAAUUTGGGUUUAGGGA
426 UUUTGGGUUUAGGTTUATUATTTGTUTAATAUTUAGUTGAUAGTGUTGTTGTGAGGT
    TGAUAGTUTGTTUUUUUAAUAGUAGTUAGAAGGATUTAGTTAAATTAUAAATURGA
    TUATGTUATTURGGTAUTTAAAAUUTGTTAGTGGUXGTUAUAGTGUURGGATAAGG
    RGUAAGGUUUUAGUTGGUUAGUAUUAUAGUTUAGUTGTGTUTUUUTUAUUTTTUUT
    GUAARGUUTUUUAUUTTUUURGUATGUAGUTUTUTUUUAUTTGUTAAUTGUUURGU
    AAUUTUUAGATUTUAUUTG
427 TGTGTTAUUUUAGAAAGUAAGGARGUTTUUAAAGATGTTUAGAGUAGTGTTUAAAG
    GGATGUUUAUTGGTUAGTUUUAAURGUTGTGAAUURGGAAAATUTGAGAUTGGTGT
    UAGTTAATTTAGAAAGTTTATTTTGUUAAGGTTGAGGAXGTATGUUTGTGAUAUAGU
    UTUAGGAAGTUUTGATGAUATGTGUUUAAGGTGGTTGGGGTGTAGUTTGATTTTATA
    UAUTTAGGGAGUATGAGAUATUAATTAAGTAUAUTTGAGAAATAUATRGGTTTGGT
    UTAGAAAGGRGGGAUAAU
428 GTTGTLURGUUTTTUTAGAUUAAAURGATGTATTTUTUAAGTGTAUTTAATTGATGT
    UTUATGUTUUUTAAGTGTATAAAATUAAGUTAUAUUUUAAUUAUUTTGGGUAUATG
    TUATUAGGAUTTUUTGAGGUTGTGTUAUAGGUATAXGTUUTUAAUUTTGGUAAAAT
    AAAUTTTUTAAATTAAUTGAUAUUAGTUTUAGATTTTURGGGTTUAUAGRGGTTGGG
    AUTGAUUAGTGGGUATUUUTTTGAAUAUTGUTUTGAAUATUTTTGGAAGRGTUUTT
    GUTTTUTGGGGTAAUAUA
429 TGAGAATAATGTUTGGTATGRGAGGAGUAUUAGUAAATRGTGUTUATUATTUUAGR
    GGAGUAAATTGTTGUTGTUTUTUAURGGGUTTTGGGTTAUTGAGGUTGUTATTTATT
    AAAGTGTGGGTTGTGAUTUATTAUTAGGTUATGAAATXGGTGTAGTGGTAGUAAUU
    AGUUUTTAAAGAAATGAAURGGGGURGGGRGRGGTGGTTUAUAUUTGTAATUUUAG
    UAUTTTGGGAGGURGAGGRGGGTGGATUARGAGGTUAAGAGATRGAGAUUATUUTG
    GUUAAUATGGTGAAAUURG
430 RGGGTTTUAUUATGTTGGUUAGGATGGTUTRGATUTUTTGAUUTRGTGATUUAUURG
    UUTRGGUUTUUUAAAGTGUTGGGATTAUAGGTGTGAAUUAURGRGUURGGUUURG
    GTTUATTTUTTTAAGGGUTGGTTGUTAUUAUTAUAUXGATTTUATGAUUTAGTAATG
    AGTUAUAAUUUAUAUTTTAATAAATAGUAGUUTUAGTAAUUUAAAGUURGGTGAG
    AGAUAGUAAUAATTTGUTURGUTGGAATGATGAGUARGATTTGUTGGTGLTTUUTRG
    UATAUUAGAUATTATTUTUA
431 AGGATGGAGGURGGGGAGGUAGRGURGURGGRGGGGGRGGGRGGURGRGURGUAG
    GRGGUTGGGGUAAGTGGGTGRGGUTUAARGTGGGGGGUARGGTGTTUUTGAUUAUU
    RGGUAGARGUTGTGURGRGAGUAGAAGTUUTTUUTUAGUXGUUTGTGUUAGGGGG
    AAGAGUTGUAGTRGGAURGGGTGAGGUUUURGGGGTGGGRGGRGAGRGGGRGGTG
    GGTUUTURGUTRGUURGARGRGGGGUTGTRGGGUUTGGUTRGUURGUUAGGUTGGG
    GAUURGGURGGGTTUATTTURGA
432 TRGGAAATGAAUURGGURGGGTUUUUAGUUTGGRGGGRGAGUUAGGUURGAUAGU
    UURGRGTRGGGRGAGRGGAGGAUUUAURGUURGUTRGURGUUUAUUURGGGGGUU
    TUAUURGGTURGAUTGUAGUTUTTUUUUUTGGUAUAGGXGGUTGAGGAAGGAUTTU
    TGUTRGRGGUAUAGRGTUTGURGGGTGGTUAGGAAUAURGTGUUUUUUARGTTGAG
    URGUAUUUAUTTGUUUUAGURGUUTGRGGRGRGGURGUURGUUUURGURGGRGGR
    GUTGUUTUUURGGUUTUUATUUT
433 TUTAUTGATGRGGAGAURGAGUUUUAGGGUAGUAGAGUUUTAGUTTRGRGUTAUA
    RGGUTGTGGGRGUTGRGUUUUAGGGUARGGURGGUUUAGGTRGTGGUUUAUTRGG
    GAUURGRGGUTUAURGGTGRGGTTGARGRGGUARGGGAAGXGGTAGGTGUTUAGU
    AUUTUUTUUTRGTUUTGUTRGTRGATGAUURGGUAUTGGRGUAGATARGGRGTGAG
    UTTGGURGGGTTUAGGGRGRGAGUUAGURGATGURGGARGUUUTRGATTRGUTUUU
    AUAGRGRGTUUTUUTURGUUTUA
434 TGAGGRGGAGGAGGARGRGUTGTGGGAGRGAATRGAGGGRGTURGGUATRGGUTGG
    UTRGRGUUUTGAAUURGGUUAAGUTUARGURGTATUTGRGUUAGTGURGGGTUATR
    GARGAGUAGGARGAGGAGGAGGTGUTGAGUAUUTAUXGUTTUURGTGURGRGTUA
    AURGUAURGGTGAGURGRGGGTUURGAGTGGGUUARGAUUTGGGURGGURGTGUU
    UTGGGGRGUAGRGUUUAUAGURGTGTAGRGRGAAGUTAGGGUTUTGUTGUUUTGG
    GGUTRGGTUTURGUATUAGTAGA
435 UTUAUUTTTUUTAGTTTAGAAAATUUUTUAUTGUTTUUUUAATGGAGGUTGUUUUA
    GGAGTGGUUUAGTGGGGUUAAUUAGUTGTTUTATGUUAGUAGUTURGGAGTATGTA
    UATTTUUAUTUTGGTTUAAAUTTGTTUTTUTATTUAXGGUUUUATTAAGAAA
    TUATUTGUAGGUTGGAURGGGTTGGGATGUAGUAAGTTGGTGTGGUTAUTURGAGT
    GTGTGAUAUAUUTGUAGGGGUUTGTGAGUAGTGGGAGGGUUAGAUATGTGGATTU
    UUAGGGUTGGTGGUTTUUTT
436 AGGAAGUUAUUAGUUUTGGGAATUUAUATGTUTGGUUUTUUUAUTGUTUAUAGGU
    UUUTGUAGGTGTGTUAUAUAUTRGGAGTAGUUAUAUUAAUTTGUTGUATUUUAAU
    URGGTUUAGUUTGUAGATGAATGTTnTUTTAATGGGGUXGTGAATAGAAGAAUAA
    GTTTGAAUUAGAGTGGAAATGTAUATAUTURGGAGUTGUTGGUATAGAAUAGUTGG
    TTGGUUUUAUTGGGUUAUTUUTGGGGUAGUUTUUATTGGGGAAGUAGTGAGGGATT
    TTUTAAAUTAGGAAAGGTGAGA
437 AARGUTGAUATUTTTURGGGTGTUTGAAAAUAGAAUTGGUUTTUUTAAGAAUTAAU
    AARGATAUTGTTTTUAGUUARGTTUUTTUUTGTTUTTGUTAUARGUTUTGTUAAAT
    AGGTGGUUAGAGGUURGGGTGUAGATGUAGTGGUTUAXGTUAGTAATUUUAGUAU
    TUTGGGAGGUTGGTGGGRGGATUAUTTGAGGUUAGGAGTTTAAAGAUUAGUTTGGG
    UAAUATGGTGAAAUUUTGTUTUTAUTAAAAATAUAAAAAATTAGURGGGTGTGGTG
    GUAUAAAUUTGTAGTTUUAG
438 UTGGAAUTAUAGGTTTGTGUUAUUAUAUURGGUTAATTTTTTGTATTTTTAGTAGAG
    AUAGGGTTTUAUUATGTTGUUUAAGUTGGTUTTTAAAUTUUTGGUUTUAAGTGATU
    RGUUUAUUAGUUTUUUAGAGTGUTGGGATTAUTGAXGTGAGUUAUTGUATUTGUA
    UURGGGUUTUTGGUUAUUTATTTGAUAGAGRGTGTAGUAAGAAUAGGAAGGGAAR
    GTGGUTGAAAAUAGTATRGTTGTTAGTTUTTAGGAAGGUUAGTTUTGTTTTUAGAUA
    UURGGAAAGATGTUAGRGTT
439 GAGGUUUAUUUARGUUUUUAGUTUARGATATUTGUAGAGATGUUAAAUUUTGGUA
    GAGGAAUTUAGGUUATGTGUTTUAGUUGUTXUUTUAUTUUTUUAUTUUUTGUURGG
    GUUUTGAGUUAGGAGUUAGGUAUAUAGUTGGAUUUATUXGUUAATGUUAUUUAU
    UUTTGTGUUUAGUAUURGGUUUARGGUAGGTGUTUAGTGTGUAGGUUUAUATGTA
    UTAGGTGUAAGGUAARGAUAUAUUAUAUAGGAUAAGGATGUAAAGUAUUTTUTGG
    GUUUTTUTGRGGUTUTGUUTTUUUA
440 TGGGAAGGUAGAGURGUAGAAGGGUUUAGAAGGTGUTTTGUATUUTTGTUUTGTGT
    GGTGTGTRGTTGUUTTGUAUUTAGTAUATGTGGGUUTGUAUAUTGAGUAUUTGURG
    TGGGURGGGTGUTGGGUAUAAGGGTGGGTGGUATTGGXGGATGGGTUUAGUTGTGT
    GUUTGGUTUUTGGUTUAGGGUURGGGUAGGGAGTGGAGGAGTGAGGGAGUAGUTG
    AAGUAUATGGUUTGAGTTUUTUTGUUAGGGTTTGGUATUUTGUAGATATRGTGAG
    UTGGGGGRGTGGGTGGGUUTU
441 GGAGGUAAARGGGAAUURGGUTGGRGGGUTGRGAGURGGTAGGGARGUTGGGGTU
    UAGGGUTGUTGGAUAGUUURGUUUTGTAUUTUTUUUUATAATTUUUTGGTGGGT
    GTURGAAATAGUUURGGGTAATUUUAGGGRGAGGUAGTXGGGAATTAAUUUUAGU
    UTTGAAGTAAGAGAUAGAGGRGTUUAUAGAAGAGGGUTUTGRGRGTUURGGAUTG
    GAUAUAGRGUAGAGTUUATTUUAGGGAUAURGUAAUURGUAAGRGAUUUAGGUUR
    GUTUUAGGGRGGGATURGRGRGGU
442 GURGRGRGGATUURGUUUTGGAGRGGGUUTGGGTRGUTTGRGGGTTGRGGTGTUUU
    TGGAATGGAUTUTGRGUTGTGTUUAGTURGGGARGRGUAGAGUUUTUTTUTGTGGA
    RGUUTUUXGTUTUTTAUTTUAAGGUTGGGGTTAGTTGGAAUUUTTUUTTTUUGUT
    TAUURGGGGUTATTTRGGAUUUAGGATTAAGTGAGGGATGGGGAGAGGTAUAGGGR
    GGGGUTGTUUAGUAGUUUTGGAUUUUAGRGTUUUTAURGGUTRGUAGUURGUUAG
    URGGGTTUURGTTTGUUTUU
443 UATGTGUTGAGATGGAGAAGGRGUUAGTGTUAGUAUTAGAUAGGUTGAGATGTUA
    AGTGGAAATGTUAAGGAGGTGGTGGAGGTGGTGGGAGUTGUAGGGUTGTGAGGUU
    RGGGAGAGGGUUAGAGUTGUAGUTTTAAATTGGAGGGTUAXGGUATGTGGAGGUU
    AAGGAAGUAGATGGGATGTURGGGGAGAGAGTATGGAUTGAAGUAGUTAAAGAAT
    TGUAGUATUTAATGGAUAGGAAGAGGGGUAGRGAUAGRGATGGAGUUTGAGAAGG
    AGGGTGUAGTGTUUUUAAGUUATGT
444 AUATGGUTTGGGGAUAUTGUAUUUTUUTTTTUAGGUTUUATRGUTGTRGUTGUUUU
    TUTTUUTGTUUATTAGATGUTGUAATTUTTTAGUTGUTTUAGTUUATAUTUUUTUUU
    RGGAUATUUUATUTGUTTUUTTGGUUTUUAUATGUXGTGAUUUTUUAATTTAAAGU
    TGUAGUTUTGGUUUUUUURGGGUUTUAUAGUUUTGUAGUTUUUAUUAUUTUUAU
    UAUTTUUUUUTGAUATTTUUAUTTGAUATUTUAGUUTGTUTAGTGUTGAUAUTGGRGU
    UTTUTUUATUTUAGUAUATG
445 UUUTUAGGTTTGGTTTUTGTTGURGUTGTTGTTTTUTTTUTUUAAUATUATAAGUUTUT
    TUUTTATUTTTUUATGTUTGUAUAUAGGAAGRGGUATUAUTTGTTTTTUATGTUUTG
    RGUATRGAGGUAUAUTTTUUGUTUUTUTTTGTGUXGUUAGURGGUUUAGGUUUAUA
    GATGGTAGGAUTTGTGUUUUAGGUTGUTGTGTGAGTUAGAGTUAGGUAGGAAGUAA
    ATGGUAAUTTUAURGRGGTGAUTGAGGAATGUTTAARGAAGGRGURGUUUTTGAUA
    ARGGTGTGGGTTGGTAA
446 TTAUUAAUUUAUAURGTTGTUAAGGGRGGRGUUTTRGTTAAGUATTUUTUAGTUAU
    RGRGGTGAAGTTGUUATTTGUTTUUTGUUTGAUTUTGAUTUAUAUAGUAGUUTGGG
    GUAUAAGTUUTAUUATUTGTGGGUUTGGGURGGUTGGXGGUAUAAAGAGGAGUAG
    AAAGTGTGUUTRGATGRGUAGGAUATGAAAAAUAAGTGATGURGUTTUUTGTGTGU
    AGAUATGGAAAGATAAGGAAGAGGUTTATGATGTTGGAAAAGAAAAUAAUAGRGG
    UAAUAGAAAUUAAAUUTGAGGG
447 TGUTUUTUTTTGTGURGUUAGURGGUUUAGGUUUAUAGATGGTAGGAUTTGTGUUU
    UAGGUTGUTGTGTGAGTUAGAGTUAGGUAGGAAGUAAATGGUAAUTTUAURGRGGT
    GAUTGAGGAATGUTTAARGAAGGRGURGUUUTTGAUAAXGGTGTGGGTTGGTAAAA
    GGAAAUAGURGGGAGUUUTGUAGRGURGGTGURGUUAURGTTTAGTUTGAUTGTGU
    ATTTGAUTAAGTUAUAAGAGGUUAGGUUTGTGAUTTGTURGAGGGAAAAAUUAUU
    AGAAAAUUAGGTGTUTGGGUT
448 AGUUUAGAUAUUTGGTTTTUTGGTGGTTTTTUUUTRGGAUAAGTUAUAGGUUTGGU
    UTUTTGTGAUTTAGTUAAATGUAUAGTUAGAUTAAARGGTGGRGGUAURGGRGUTG
    UAGGGUTUURGGUTGTTTUUTTTTAUUAAUUUAUAUXGTTGTUAAGGGRGGRGUUT
    TRGTTAAGUATTUUTUAGTUAURGRGGTGAAGTTGUUATTTGUTTUUTGUUTGAUTU
    TGAUTUAUAUAGUAGUUTGGGGUAUAAGTUUTAUUATUTGTGGGUUTGGGURGGU
    TGGRGGUAUAAAGAGGAGUA
449 UTGTGUTUAAGAGUUAUTTUTTAAURGGGGTGGGAGGAAGUAGUTTUAGGAAUTGU
    TGAGAGAGUAGAAUTUARGUTUUAGGGUTUAGAGUAGGAGGTAGGGTGTGRGGUA
    AGRGUTGGUURGGAUAGAAGUAGAGTGGGUUUTGGTUTXGGGUAGGATGTTTUTGA
    UTUAUATTTUUTGAGGAGAGAAAGUTAAGUTUUTGUUTAATGTUTUTGTUTUUUUT
    TUUAGAAAAATGUUTUAGUTUTTURGGUUTGAAGGAATGGUUTUUTUmGGGUUUU
    ATGATTUTTTUUTGTGTGGG
450 UUUAUAUAGGAAAGAATUATGGGGUURGGGAGGAGGUUATTUUTTUAGGURGGAA
    GAGUTGAGGUATTTTTUTGGAAGGGGAGAUAGAGAUATTAGGUAAAGAGUTTAGUT
    TTUTUTUUTUAGGAAATGTGAGTUAGAAAUATUUTGUUXGAGAUUAGGGUUUAUTU
    TGUTTUTGTURGGGUUAGRGUTTGURGUAUAUUUTAUUTUUTGUTUTGAGUUUTGG
    AGRGTGAGTTUTGUTUUTUAGUAGTTUUTGAAGUTGUTC
    AGAAGTGGUTUTTGAGUAUAG
451 TTTTTTTTTTGAGAUAGAGTUTRGUTUTGTUAUUUAGGUTGGAGTGUAGTGGRGTGA
    TUTRGGUTUAUTGUAAGUTUUAUUTTUURGGGTTUATGUUATTUTUUTGUUTUAGUT
    TUUTGAGTATUTGGGAUTAUAGGUAUTUAUUAUUAXGUURGGUTAATTTTUURTTTT
    TATTTTTAGTGGAGARGGGGTTTUATTGTGTTAGUUAGGATGGTUTRGATUTUUTGA
    UUTRGTGATUAGUURGUUTUAGUUTUUUAAAGTGUTGGGATTAUAGGTGTGAGUUA
    UUTUAUURGGUUTGUTA
452 AGUAGGURGGGTGAGGTGGUTUAUAUUTGTAATUUUAGUAUTTTGGGAGGUTGAG
    GRGGGUTGATUARGAGGTUAGGAGATRGAGAUUATUUTGGUTAAUAUAGTGAAAU
    UURGTUTUUAUTAAAAATAAAAAAAAAAAATTAGURGGGXGTGGTGGTGAGTGUUT
    GTAGTUUUAGATAUTUAGGAAGUTGAGGUAGGAGAATGGUATGAAUURGGGAGGT
    GGAGUTTGUAGTGAGURGAGATUARGUUAUTGUAUTUUAGUUTGGGTGAUAGAGR
    GAGAUTUTGTUTUAAAAAAAAAAU
453 TTGUUTUTTTTGATTTTTTTUTTTGGGUAGGAGTTAGAATGUAAAATAUAGATTUTAT
    UTGTATAAAGUAUAUAAGAGATGUTTGGGATUTGGTGATGUTGUAURGGAGATTTU
    AAUUTGTTTTTUAAAGTGATTUUTAGGGAGTGTGAXGATUTUAAUTUTTTTGGAAGT
    GAUTTGTUAAAUUATGAGUUATGUTGAGTTUAGUAUAAGTAATATGAGGRGAGGUA
    AGGUAAGTGGGTGAGTAAGGAGGAAGUAGUUUAGATGAGURGGUAGAGTGUUUAU
    TGGGAGTGAGGUATGATG
454 ATUATGUUTUAUTUUUAGTGGGUAUTUTGURGGUTUATUTGGGUTGUTTUUTUUTT
    AUTUAUUUAUTTGUUTTGUUTRGUUTUATATTAUTTGTGUTGAAUTUAGUATGGUTU
    ATGGTTTGAUAAGTUAUTTUUAAAAGAGTTGAGATXGTUAUAUTUUUTAGGAATUA
    UTTTGAAAAAUAGGTTGAAATUTURGGTGUAGUATUAUUAGATUUUAAGUATUTUT
    TGTGTGUTTTATAUAGATAGAATUTGTATTTTGUATTUTAAUTUUTGUUUAAAGAAA
    AAAATUAAAAGAGGUAAU
455 AUAAGAGATGUTTGGGATUTGGTGATGUTGUAURGGAGATTTUAAUUTGTTTTTUAA
    AGTGATTUUTAGGGAGTGTGARGATUTUAAUTUTTTTGGAAGTGAUTTGTUAAAUUA
    TGAGUUATGUTGAGTTUAGUAUAAGTAATATGAGGXGAGGUAAGGUAAGTGGGTG
    AGTAAGGAGGAAGUAGUUUAGATGAGURGGUAGAGTGUUUAUTGGGAGTGAGGUA
    TGATGAGGATTAUTRGTRGTGGGAGGUATGAGGGUAUTUTUTGGUAAGGTTUUTTG
    UATUAUUAAAATGAGGTUAU
456 TGAUUTUATTTTGGTGATGUAAGGAAUUTTGUUAGAGAGTGUUUTUATGUUTUUUA
    RGARGAGTAATUTTTUATUATGUUTUAUTUUUAGTGGGUAUTUTGURGGUTUATUTG
    GGUTGUTTUUTUUTTAUTUAUUUAUTTGUUTTGUUTXGUUTUATATTAUTTGTGUTG
    AAUTUAGUATGGUTUATGGTTTGAUAAGTUAUTTUUAAAAGAGTTGAGATRGTUAU
    AUTUUUTAGGAATUAUTTTGAAAAAUAGGTTGAAATUTURGGTGUAGUATUAUUAG
    ATUUUAAGUATUTUTTGTG
457 AGUAAAUAGAGGGTATGGTUUAAUTTGUUTATGAAURGGGAAGUATAATATTTTAA
    TATTTGTGUUTTAAGUAGTTGTTTTATTTTAAAAGUAUAGGAAATUUTGTUTTTTTU
    TGTTATAAAATUTTAUAAAGUTAUTGGAAAGATUTUXGUAGGUUAGTGGTTTTUAA
    AGTGGGTTUUUAGAAUTAGUAAUAGUTGAATUATURGGGAAUTGGTTAGAAATGUA
    AAGTUTRGURGUUAUUUUTUAAUUUUUUAGAUUTAATGAAUUAGAAATTUTGGGG
    TGTGGUUUAGTGGUUTGRG
458 RGUAGGUUAUTGGGUUAUAUUUUAGAATTTUTGGTTUATTAGGTUTGGGGGGTTGA
    GGGGTGGRGGRGAGAUTTTGUATTTUTAAUUAGTTUURGGATGATTUAGUTGTTGUT
    AGTTUTGGGAATRTUAUTTTGAAAAUUAUTGGUUTGXGGAGATUTTTUUAUTAUUTT
    TGTAAGATTTTATAAUAAGAAAAAAGAUAGGATTTUUTGTGUTTTTAAGTAAAAUA
    AUTGUTTAAGGUAUAAATATTAAAATATTATGUTTUURGGTTUATAGGUAAGTTGGA
    UUATAUUUTUTGTTTGUT
459 GUUUTAUUURGUTUTUTURGAUTUUUURGGGUURGGUUTGRGUUTTUUTGRGGTGU
    RGAGGAGRGGTGGRGUUUTGGGTGAAGAAGTUURGURGAGTRGAGGGGRGUAATG
    GAGGAGRGURGGAAUAGGTUTUTUATTURGAGTAGUTAUXGTTGUAUTGTGRGAGT
    GTAAAAGTUAUTTUUAUURGGTUTUAGTTGTTUUAAUUTUAGTTGAAGTGAGGAGG
    TTGGAUTGGAAGGTTTUTGGGGTUAUTUUAGTGAGGUTGGGGTTUTAGTUUUAATU
    TUAURGTGGUAUUUUAAAGGU
460 GUUTTTGGGGTGUUARGGTGAGATTGGGAUTAGAAUUUUAGUUTUAUTGGAGTGAU
    UUUAGAAAUUTTUUAGTUUAAUUTUUTUAUTTUAAUTGAGGTTGGAAUAAUTGAGA
    URGGGTGGAAGTGAUTTTTAUAUTRGUAUAGTGUAAXGGTAGUTAUTRGGAATGAG
    AGAUUTGTTURGGRGUTUUTUUATTGRGUUUUTRGAUTRGGRGGGAUTTUTTUAUU
    UAGGGRGUUAURGUTUUTRGGUAURGUAGGAAGGRGUAGGURGGGUURGGGGGAG
    TRGGGGAGAGRGGGGTAGGGU
461 GGAUAUAATUTUTGTTUTTUAAAGTTGGUAUTAAGAGUTUUTUUTGRGGTTUUUUTT
    UUTUTUUTRGAGUAGUAAAGGRGTGGTUUAUAATGUUUAUUUTGTGGGGTUTAGGG
    GTGUURGGUTTGUTGAUUTUUAGGUUUUUTUTGTGGXGAGGTTTGGAUTGUATAUA
    TGGTGUAGGUUUUTUATUAUTGGAGUTGUUAGGAUAGUAUTGGAGAUUUTAAGUU
    AATAUUTATTTTTGGUAATAATTATUAAGUATTTGTAAAAGUURGGGTATGUTGGUA
    AATUTTTTTAAAATAAGAG
462 UTUTTATTTTAAAAAGATTTGUUAGUATAUURGGGUTTTTAUAAATGUTTGATAATT
    ATTGUUAAAAATAGGTATTGGUTTAGGGTUTUUAGTGUTGTUUTGGUAGUTUUAGT
    GATGAGGGGUUTGUAUUATGTATGUAGTUUAAAUUTXGUUAUAGAGGGGGUUTGG
    AGGTUAGUAAGURGGGUAUUUUTAGAUUUUAUAGGGTGGGUATTGTGGAUUARGU
    UTTTGUTGUTRGAGGAGAGGAAGGGGAAURGUAGGAGGAGUTUTTAGTGUUAAUTT
    TGAAGAAUAGAGATTGTGTUU
463 AUTTGAGRGUTTUTUUAUUUUAGUAGGUURGUTGUUATUAAGGGUTTAUUUTGTGG
    GUTGUUUARGUTGUTGTAAUUAGTGAUUAUAAGUTURGTGGTGTTGAGAAGUAUAT
    GTTTUTUUTUUUARGGUTGTGTAGGTURGGAGTUUTAXGGGUTUAGUUAGTUUUUU
    TGUTUUAGGTTTAAUUAGGURGGAATUAAGATGUUAGGGUUTGGUTGTGUTTTGGA
    GGUTUTTGGTGAGAAUUTGUTTUTGGUUTGGTGUAGGGTGTGGUAGAATUURGATG
    UTTGAGTTTGAATGGTGAAA
464 TTTUAUUATTUAAAUTUAAGUATRGGGATTUTGUUAUAUUUTGUAUUAGGUUAGAA
    GUAGGTTUTUAUUAAGAGUUTUUAAAGUAUAGUUAGGUUUTGGUATUTTGATTUR
    GGUUTGGTTAAAUUTGGAGUAGGGGGAUTGGUTGAGUUXGTAGGAUTURGGAUUT
    AUAUAGURGTGGGAGGAGAAAUATGTGUTTUTUAAUAUUARGGAGUTTGTGGTUAU
    TGGTTAUAGUAGRGTGGGUAGUUUAUAGGGTAAGUUUTTGATGGUAGRGGGUUTG
    UTGGGGTGGAGAAGRGUTUAAGT
465 AAAUTUARGUTGGUUUAAGAGGAGGAAUAGAGAAGUTTUUTGGUTGAGGUUUAGU
    RGAUTGUTGAUURGGAAAAGTTTUTRGAGGTGAUTUAUATUUUUAGUUTUTGUAUA
    TGTGGGTGAGUUAGTTGTAGUTUTGTTUUXGTGAUTGAGUAXGGGAXGURGGAGGT
    ATTUATUAGGUATGAGGTTATUTGUUTAUTTUUUATGTGTUAGURGAGTGAURGAA
    TUTUAGTUUUTTAGUUUUTAUATUUUTAGGGTUUTAGTGGAUTGTAAGUTGGTGAT
466 AAGAGTTGTGUTGUUUTUAUT
    GTGAGGGUAGUAUAAUTUTTATUAUUAGUTTAUAGTUUAUTAGGAUUUTAGGGATG
    TAGGGGUTAAGGGAUTGAGATTRGGTUAUTRGGUTGAUAUATGGGAAGTAGGUAGA
    TAAUUTUATGUUTGATGAATAUUTURGGXGTUUXGTGUTUAGTUAXGGGAAUAGAG
    UTAUAAUTGGUTUAUUUAUATGTGUAGAGGUTGGGGATGTGAGTUAUUTRGAGAA
    AUTTTTTRGGGTUAGUAGTRGGUTGGGUUTUAGUUAGGAAGUTTUTUTGTTTTUTUU
    TUTTGGGUUAGRGTGAGTTTT
467 AUTTGAGRGUTTUTUUAUUUUAGUAGGUURGUTGUUATUAAGGGUTTAUUUTGTGG
    GUTGUUUARGUTGUTGTAAUUAGTGAUUAUAAGUTURGTGGTGTTGAGAAGUAUAT
    GTTTUTUUTUUUARGGUTGTGTAGGTURGGAGTUUTAXGGGUTUAGUUAGTUUUUU
    TGUTUUAGGTTTAAUUAGGURGGAATUAAGATGUUAGGGUUTGGUTGTGUTTTGGA
    GGUTUTTGGTGAGAAUUTGUTTUTGGUUTGGTGUAGGGTGTGGUAGAATUURGATG
    UTTGAGTTTGAATGGTGAAA
468 TTTUAUUATUAAAUTUAAGUATRGGGATTUTGUUAUAUUUTGUAUUAGGUUAGAA
    GUAGGTTTTTAUUAAGAGUUTUUAAAGUAUAGUUAGGUUUTGGUATUTTGATTUR
    GGUUTGGTTAAAUUTGGAGUAGGGGGAUTGGUTGAGUUXGTAGGAUTURGGAUUT
    AUAUAGURGTGGGAGGAGAAAUATGTGUTTUTUAAUAUUARGGAGUTTGTGGTUAU
    TGGTTAUAGUAGRGTGGGUAGUUUAUAGGGTAAGUUUTTGATGGUAGRGGGUUTG
    UTGGGGTGGAGAAGRGUTUAAGT
469 GRGAATAAAAAGUUAGTGTGTGAGUAAGTUTGTGGGAAGATGUATGUAGAGTGTGA
    UAGAGAGTTTAGGGGUTRGTGTGAUAATURGTGGAAATGTTTUTAAAGGRGAGGGT
    ATGTGTGTGGGTGTGAGGAUURGGUTGTTGGATGTTTAXGTATTTTATTAGUTAGAT
    ARGGGAGUTAATAUTUAATTGUAGTGUAUTAAAUATTATTAGGTGGGTATGATTTTG
    AGGGAATGAGGGAAGGGAGAUAAGGTUTGGTGAGATUATUTGTGGGATTATUTGTG
    TGTATTTGUTGGTTTGTA
470 TAUAAAUUAGUAAATAUAUAUAGATAATUUUAUAGATGATUTUAUUAGAUUTTGT
    TTTUUUTTUUTTTUATTUUUTUAAAATUATAUUUAUUTAATAATGTTUUAAGGU
    AATTGAGTATTAGUTUURGTATUTAGUTAATAAAATAXGTAAAUATUUAAUAGURG
    GGTUUTUAUAUUUAUAUAUATAUUUTRGUUTTTAGAAAUATTTUUARGGATTGTUA
    UARGAGUUUUTAAAUTUTUTGTUAUAUTTTTGUATGUATUTTUUUAUAGAUTTGUTU
    AUAUAUTGGUTTTTATTRGU
471 UAGTGAGUTGAGAGUARGUUAUTGUAUTUUAGUUTGGGGGATAGAGTGAGAUTUT
    GTUUUAAAAAAAGAAAAAAAGAAUTGATUUUAAATGTGTGGGGAGAUTGATTTUAG
    TAATAATAAAAUTURGGTUTUUUAUAUAGTUAGUTUTGXGTGAATUUUTUTTTUUU
    TATTGRGATTUUUUTGATTTGAGTGAUAGTAAAAUTURGGTUTUUTGUAUAGUUAG
    UTUTGRGTGAGTUATTUTTTUTUUUUTGTAATTUUUUTGTUTTGATUUATUA
    GTUTGGGUAGUAGGUAAGGT
472 AUUTTGUUTGUTGUUUAGAUAGAGUTGATGGATUAAGAUAGGGGAATTAUAGGGG
    AGAAAGAATGAUTUARGUAGAGUTGGUTGTGUAGGAGAURGGAGTTTTAUTGTUAU
    TUAAATUAGGGGAATRGUAATAGGGAAAGAGGGATTUAXGUAGAGUTGGUTGTGT
    GGGAGAURGGAGTTTTATTATTAUTGAAATUAGTUTUUUUAUAUATTTGGGATUAGT
    TUTTTUTTUTUTTUUUGAGAUAGAGTUTUAUTUTATUUUUUAGGUTGGAGTGUAGT
    GGRGTGUTUTUAGUTUAUTG
473 GGATGTRGGTGTGUUAAUUUUAGUTUUAUUUUAUTGUTAAAGUTTAAGUTUTUUUU
    TUUUURGTTAAGUTGTATGAUUTTGAGTUUTTGTGUUTUAUTGTUUTUATUTGTUA
    AGTGAAAATGUTUUUAGTUUUUAUUTURGGGAGTTGXGTGGGAGGUAUAUATGAA
    UAUUAGGAAAGTGAGTTTATGUAGUURGGGUUAGGGAUTURGGTUTUTGUUTUTGU
    UUTAATUUUUARGGUUTGGGGGAARGTGUAGGGUTGAGGAAGRGUAGUUTUTUUT
    TGGAATUTUAGRGGAAGUTUU
474 GGAGUTTURGUTGAGATTUUAAGGAGAGGUTGRGUTUUTUAGUUUTGUARGTTUU
    UUUAGGURGTGGGGATTAGGGUAGAGGUAGAGAURGGAGTUUUTGGUURGGGUTG
    UATAAAUTUAUTTTUUTGGTGTTUATGTGTGUUTUUUAXGUAAUTUURGGAGGTGG
    GGAUTGGGAGUATTTTUAUTTGAUAGATGAGGAUAGTGAGGUAUAAAGAAUTUAA
    GGTUATAUAGUTTAARGGGGGAGGGGAGAGUTTAAGUnTAGUAGTGGGGTGGAGU
    TGGGGTTGGUAUAURGAUATUU
475 TAATTGAATUAUATAATTUATTTUUATTATUTGAGTTUURGGUTTAGGUTUTTTGAG
    TAUUARGAATUAGGAATGAUTATGUTUUAUTTUAUUUTTRGUTAGTUAAAGAUTGU
    UAGGAGGUURGGGGTTGTGGTATTUAARGTTAUAGAXGTAAGGUUUTUUTGUUUAU
    UUAGUAUTUUAAATATTTUATGAUATATGAAGGUTUTGAUATTGUAAAURGGAUTA
    RGAUAAGUUTTTGAUTTTUURGGGTTGTGAGGAGTTTTAGAAAATAAUTGAGAAGU
    AAUTTTTTTGAGGATGATG
476 UATUATUUTUAAAAAAGTTGUTTUTUAGTTATTTTUTAAAAUTUUTUAUAAUURGGA
    GAAGTUAAAGGUTTGTRGTAGTURGGTTTGUAATGTUAGAGUUTTUATATGTUATGA
    AATATTTGGAGTGUTGGGTGGGUAGGAGGGUUTTAXGTUTGTAARGTTGAATAUUA
    UAAUUURGGGUUTUUTGGUAGTUTTTGAUTAGRGAAGGGTGAAGTGGAGUATAGTU
    ATTUUTGATTRGTGGTAUTUAAAGAGUUTAAGURGGGAAUTUAGATAATGGAAATG
    AATTATGTGATTUAATTA
477 UAAUATTUTTGTATUUAGUATUUTTTGTUATGTUATTUTATAGATGUTUTUAUTAA
    AGTGATGGUUAATTTUUTAUUUTTRGAATURGGGTUTTGGUAAATGGGATGTTAAU
    AAUAGUTUUUAAAUAGAGGATUAUATAGTAUTTGXGTGAGUUUAUUUUUTUTTAT
    GTTUTTUAAGUATGUUATGAGAAUAXGUUTGGGTUAGUUTGUTGAAGGAGUTGAGU
    TGAGTUATUURGGTGAUAGUUAGUTGAUTUTTAGUAGTGAGAGGUAUUUUUAUAA
    AGUTGUTUTGUTGAUUAUU
478 GTGGTUAGUAGAGUAGUTTTGTGGGGGTGUUTUTUAUTGUTAAGAGTUAGUTGGUT
    GTUAURGGGATGAUTUAGUTUAGUTUUTTUAGUAGGUTGAUUUAGGXGTGTTUTUA
    TGGUATGUTTGAAGAAUATAAGAGGGGAGTGGGUTUAXGUAAGTAUTATGTGATUU
    TUTGTTTGGGAGUTGTTGTTAAUATUUUATTTGUUAAAGUURGGATTRGAAGGGTAA
    GGAAATTGGUUATUAUTTTAGTGAGAGUATUTATAGAATGAUATGGUAAAGGATGU
    TGGATAUAAGGAATGTTGU
479 GUTUTUAUTAAAGTGATGGUUAATTTUUTTAUUUTTRGAATURGGGUTTTGGUAAAT
    GGGATGTTAAUAAUAGUTUUUAAAUAGAGGATUAUATAGTAUTTGXGTGAGUUUA
    TTTUUUUTUTTATGTTUTTUAAGUATGUUATGAGAAUAXGUUTGGGTUAGUUTGUTG
    AAGGAGUTGAGUTGAGTUATUURGGTGAUAGUUAGUTGAUTUTTAGUAGTGAGAG
    GUAUUUUUAUAAAGUTGUTUTGUTGAUUAUUUUAGAUAUARGAGUAAAAGAAATG
    TTTAUUATTAUATGTUAUTGAG
480 TUAGTGAUATGTAATGGTAAAUATTTUTTTTGUTRGTGTGTUTGGGGTGGTUAGUAG
    AGUAGUTTTGTGGGGGTGUUTUTUAUTGUTAAGAGTUAGUTGGUTGTUAURGGGAT
    GAUTUAGUTUAGUTUUTTUAGUAGGUTGAUUUAGGXGTGTTUTUATGGUATGUTTG
    AAGAAUATAAGAGGGGAGTGGGUTUAXGUAAGTAUTATGTGATUUTUTGTTTGGGA
    GUTGTTGTTAAUATUUUATTTGUUAAAGUURGGATTRGAAGGGTAAGGAAATTGGU
    UATUAUTTTAGTGAGAGUA
481 UUUUAGUUAAAUUAUTRGAUTGUUUUUUATUAUUTATAUTGGURGTTTTUUUTGG
    AGUUTGUAUUUAAUAGTGGUAAUAUUTTGTGGUURGAGUUUUTUTTUAGUTTGGTU
    AGTGGUUTAGTGAGUATGAUUAAUUUAURGGUUTUUTXGTUUTUAGUAUUATUTU
    UAGRGGUUTUUTURGUUTURGUUTUUUAGAGUUUAUUUUTGAGUTGRGUAGTGUU
    ATUUAARGAUAGUAGTUUUATTTAUTUAGRGGUAUUUAUUTTUUUUARGURGAAU
    AUTGAUATTTTUUUTGAGUUAUA
482 TGTGGUTUAGGGAAAATGTUAGTGTTRGGRGTGGGGAAGGTGGGTGURGUTGAGTA
    AATGGGAUTGUTGTRGTTGGATGGUAUTGRGUAGUTUAGGGGTGGGUTUTGGGAGG
    RGGAGGRGGAGGAGGURGUTGGAGATGGTGUTGAGGAXGAGGAGGURGGTGGGTT
    GGTUATGUTUAUTAGGUUAUTGAUUAAGUTGAAGAGGGGUTRGGGUUAUAAGGTG
    TTGUUAUTGTTGGGTGUAGGUTUUAGGGAAAAGRGGUUAGTATAGGTGATGGGGGG
    UAGTRGAGTGGTTTGGUTGGGG
483 GUAGTGGUTGGGUUUUUAUUUUUUAGGAAAUTUAAAAUUUTGGGUUAGURGRGGG
    TGGRGGGTTGGGGUAGGUAUAAAGAGGGUUTUTGTGRGGURGGUTGGGUTGUUUA
    UAGGATTUTGGGGGAGGAGGURGGAGURGGTTTUXGTUURGTTUTGUTTUUTGRGG
    AGGUTGRGGAATGUURGGAGUTUTGGUUUAGUUTGUUURGTUTGGUUUAUURGUA
    GUUUUTTUUUUATTUUTTTUUAGGGUUTTGGGGTAUAGTUT
    AGGGUUUTGAGAGUUAUUUTUUA
484 TGGAGGGTGGUTUTUAGGGUUUTGTTGUAGAGAAGTUTGUAGUTGTAUUUUAAGGU
    UUTGGAAAAGATGGGGAAGGGGUTGRGGGTGGGUUAGARGGGGUAGGUTGGGUUA
    GAGUTURGGGUATTURGUAGUUTURGUAGGAAGUAGAAXGGGARGGAAAURGGUT
    URGGUUTUUTUUUUUAGAATUUTGTGGGUAGUUUAGURGGURGUAUAGAGGUUUT
    UTTTGTGUUTGUUUUAAUURGUUAUURGRGGUTGGUUUAGGGTTTTGAGTTTUUTG
    GGGGGTGGGGGUUUAGUUAUTGU
485 AGGUAUURGTUAUAARGUURGGUTAATTTTTTTGTATTTTTTAGTAGAGARGGGGTT
    TUAURGTGTTAGUUAGGATGGTUTUAGTUTUUTGAUUTTGTGATUUAUUUAUUTUA
    GUUTUUUAAAGTGUTGGGATTAUAGATGTGAGUTAUXGUAUURGGUUAAGTTUATG
    ATUTTTUTGTAUTUTGAGUUAGTGTTAUTGGUAAAGAATGUUUTGGGUATTGTGGTG
    TGGATGGAAGUUAGGUAUATTGUATUUATTUUTTUUTAGAUTAAGTTGUUTGGUUT
    GTGGAUUTTUTUAGUUAG
486 UTGGUTGAGAAGGTUUAUAGGUUAGGUAAUTTAGTUTAGGAAGGAATGGATGUAA
    TGTGUUTGGUTTUUATUUAUAUUAUAATGUUUAGGGUATTUTTTGUUAGTAAUAUT
    GGUTUAGAGTAUAGAAAGATUATGAAUTTGGURGGGTGXGGTAGUTUAUATUTGTA
    ATUUUAGUAUTTTGGGAGGUTGAGGTGGGTGGATUAUAAGGTUAGGAGAUTGAGA
    UUATUUTGGUTAAUARGGTGAAAUUURGTUTUTAUTAAAAAATAUAAAAAAATTAG
    URGGGRGTTGTGARGGGTGUUT
487 TTURGTGGGGATGUAAUUTRGTTTGUUUUTUTGAUTTUUUUATGAGATUTUTRGUTT
    UUTUUUAUAUUTUUTTTATUUUUUAAUUUUUTGURGGTUUAUUAGGUTGUAGUT
    GGGTUTGRGGGTAGGGGAUATTUUTAGGTUTTGAUXGUUAGAGUAUURGGTUUAGT
    UURGGUUAUAGUUTTTGGUUUAAGTGAGGGUTGGUUTGGGGAUAAGURGAAATUA
    GGGUUUTGGUTGTATUUAGAAAGAGAAUTGAGAUURGTTGUUTUUUAUTGGGUUA
    UUUUURGAUUUUAAUUAUATA
488 ATGTGGTTGGGGTRGGGGGGTGGUUUAGTGGGAGGUAARGGGTUTUAGTTUTUTTT
    UTGGATAUAGUUAGGGUUUTGATTTRGGUTTGTUUUUAGGUUAGUUUTUAUTTGGG
    UUAAAGGUTGTGGURGGGAUTGGAURGGGTGUTUTGGXGGTUAAGAUUTAGGAAT
    GTUUUUTAUURGUAGAUURGUAGUTGUAGUUTGGTGGAURGGUAGGGGGTTGGGG
    GATAAAGGAGGTGTGGGAGGAAGRGAGAGATUTUATGGGGAAGTUAGAGGGGUAA
    ARGAGGTTGUATUUUUARGGAAT
489 UTTATAUURGGTUUTRGUUUUTUUAGRGURGGUUTRGUURGRGUTUUTGAGAAAGU
    UUTGUURGUTURGUTUARGGURGTGUUUTGGUUAAUTTUUTGUTGRGGURGGRGGG
    UUUTGGGAAGUURGTGUUUUUTTUUUTGUURGGGUUTXGAGGAUTTUUTUTTGGUA
    GGRGUTGGGGUUUTUTGAGAGUAGGUAGGUURGGUUTTTGTUTURGRGAGGUUUA
    UUURGGUURGUAUUTTRGUTTTGRGGTUTGAUUUUARGRGUUUUUUTGUAGGGUTG
    GGUURGGGTGAGGGGAGUTTU
490 GAAGUTUUUUTUAUURGGGUUUAGUUUTGUAGGGGGGRGRGTGGGGTUAGAURGU
    AAAGRGAAGGTGRGGGURGGGGTGGGUUTRGRGGAGAUAAAGGURGGGUUTGUUT
    GUTUTUAGAGGGUUUUAGRGUUTGUUAAGAGGAAGTUUTXGAGGUURGGGUAGGG
    AAGGGGGUARGGGUTTUUUAGGGUURGURGGURGUAGUAGGAAGTTGGUUAGGGU
    ARGGURGTGAGRGGAGRGGGUAGGGUTTTUTUAGGAGRGRGGGRGAGGURGGRGU
    TGGAGGGGRGAGGAURGGGTATAAG
491 AGUTUUTTTATUAGAAAGGGUAGURGUAGAGUURGRGTGTGRGRGATGTGGUTGRG
    GGTGGGGAGRGGGRGGRGGGUURGGGAUAURGRGGUUAUTGTTUTAGUUURGUUT
    GGGURGUUTGAURGRGGUTURGUTGRGURGUAGUUURGXGUUUUTUTGGUTUUTGT
    TUURGGGRGRGGGGAGAAGGRGGRGGGGRGRGUUTGGGUURGRGRGGGTGRGAAR
    GRGAGGTUTTTUUTGGGTGUTUUUAGGTRGGAGGATTUUUAGGGRGGGGGUUATUA
    GGGTGGRGAGGAAURGGUAGGG
492 UUUTGURGGTTUUTRGUUAUUUTGATGGUUUURGUUUTGGGAATUUTURGAUUTGG
    GAGUAUUUAGGAAAGAUUTRGRGTTRGUAUURGRGRGGGUUUAGGRGRGUUURGU
    RGUUTTUTUUURGRGUURGGGAAUAGGAGUUAGAGGGGXGRGGGGUTGRGGRGUA
    GRGGAGURGRGGTUAGGRGGUUUAGGRGGGGUTAGAAUAGTGGURGRGGTGTUUR
    GGGUURGURGUURGUTUUUUAUURGUAGUUAUATRGRGUAUARGRGGGUTUTGRG
    GUTGUUUTTTUTGATAAAGGAGUT
493 TGGAAAAGUUAAUTGTGUAAAUATTRGUTTUTAURGTUAUAAGGTGAAAAGGAAAA
    ATGUUAAAAAGGAGAGUTTGGAAAUAUAGUAGAAGAGUAATGAUUUUUTGUAGAG
    AAUATGAAATAAGATURGGUAGTGAUUUUAUTAAAGAUAXGGAAAATAAGGTUUA
    AUUUAGAAUTGGTUAGAGAAUAUUAUTGTGUTTTAGAGTAAUAATTAUAAAGGAA
    AAGAGGGATRGGGUAUTGTAATATUURGGGAUTGUAGUTTGTAUTUTUTGGGTGGT
    GUATTUTGTAATTUAATTAAATU
494 GATTTAATTGAATTAUAGAATGUATTUAUUUAGAGAGTAUAAGUTGUAGTUURGGGA
    TATTAUAGTGUURGATUUUTUTTTTUUTTTGTAATTGTTAUTUTAAAGUAUAGTGGT
    GTTUTUTGAUUAGTTUTGGGTTGGAUUTTATTTTUXGTGTUTTTAGTGGGGTTUAUTG
    URGGATUTTATTTUATGTTUTUTGUAGGGGGTUATTGUTUTTUTGUTGTGTTTUUAA
    GUTUTUUTTTTTGGUATTTTTUUTUTUTTTTUTTGTGARGGTAGAAGRGAATGTTTGUA
    UAGTTGGUTTTTUUA
495 UTGUAGATTGAUAUTGTTAATUAUAAAUAAGUUUAGGGTTGTGTTUAGAGAUAAAG
    TUAGTGTGAURGGTGAUTGTTAUAGUAATAUAAAATAATGGUAGUAGTUUUAUTAG
    URGAGGUUAGUATRGAATAGGGUAAGTTAUTUAAAUAXGTUAUUUTAGRGAUUAU
    TUUAAAUAUUTGTGUTTAAAUTAAUTTAGGGAGUURGGTTTTGUAGGATGTGUAAU
    UARGTTGTGUUUUUTAGGGUTUAUUAGAUTTTAGTAUUTAATGUAGUTAUUUTUAU
    RGTGGUUUAGGTTUUUAGGGA
496 UUUTGGGAAUUTGGGUUARGGTGAGGGTAGUTGUATTAGGTAUTAAAGTUTGGTGA
    GUUUTAGGGGGUAUAARGTGGTTGUAUATUUTGUAAAAURGGGUTUUUTAAGTTAG
    TTTAAGUAUAGGTGTTTGGAGTGGTRGUTAGGGTGAXGTGTTTGAGTAAUTTGUUUT
    ATTRGATGUTGGUUTRGGUTAGTGGGAUTGUTGUUATTATTTTGTATTGUTGTAAUA
    GTUAURGGTUAUAUTGAUTTTGTUTUTGAAUAUAAUUUTGGGUTTGTTTGTGATTAA
    UAGTGTUAATUTGUAGG
467 AAAUAUAGUUAGTUTGTTUTAGUUTUTGTUUTUATTTTUUAUAUUUAGGTTTG
    UUAGTTUUTTGTUUUAUAGTGATGGGUTTGGGAUTATGGGGTGTUUATTURGGGUTT
    UUUTGGUTTGUTTAUTTTUTUATGGGTGUTTTGAGXGUUTTTTTUGAGURGGUTUAG
    GUTTTUUUUUUAUAUUUTITUUTUUUTGUTTUTATUAGGUUAAGGGTTTAGATTT
    TRGGTUAGTGAGTUATUUAAAUUTGGGTGTGGAAAGUAUUTGGGAUAUUAUTTGTA
    TTTGGUTUUTTTTAGUT
498 AGUTAAAAGGAGUUAAATAUAAGTGGTGTUUUAGGTGUTTTUUAUAUUUAGGTTTG
    GATGAUTUAUTGAURGAAGUTUTGAUUUTUAUTGUUAGATAGAAGUAGGGAGGAA
    AGGGTGTGGGGGGAAAGUUTGAGURGGUTUAAAAAAGGXGUTUAAAGUAUUUATG
    AGAAAGTAAGUAAGUUAGGGAAGUURGGAATGGAUAUUUUATAGTUUUAAGUUUA
    TUAUTGTGGGAUAAGGAAUTGGAGUAAAGGGAAGGGGGAAGAAAATGAGGAUAGA
    GGUTAGAAUAGAUTGGUTGTGTTT
499 GTUUUUAAAGGUTGAAUUTTTGATUAATGUAGUUUAAGUTGUARGGGUAGAGAAA
    GGGTGRGGGGTAGGGGURGGGGTTGGGRGUTGAGUTUUTUTGAAURGGTTGUUAGG
    UAAUAGAATGGAAATTUARGGGRGGUTAAATGGAGUTUXGUUAUAAATGTTUTGTG
    GUAAAUURGGAUUUAGTUAUATRGUUUTTTUUUUUUUUUTUUUTTTUUUGGGGUT
    TUTUATUTGTAAATGAGAAGGGTGUAGAGAAGAUTUTTTTUTTRGGAGTUAGTGUUT
    URGGTTTGUAUTGUTTTTUA
500 TGAAAAGUAGTGUAAAURGGAGGUAUTGAUTURGAAGAAAAGAGTUTTUTUTGUA
    UUUTTUTUATTTAUAGATGAGAAAAUTUAGTGGGGTGGGAGGGGGGAGAAAGGGR
    GATGTGAUTGGGTURGGGTTTGUUAUAGAAUATTTGTGGXGGAGUTUUATTTAGUR
    GUURGTGAATTTUUATTUTGTTGUUTGGUAAURGGTTUAGAGGAGUTUAGRGUUUA
    AUUURGGUUUUTAUUURGUAUUUTTTUUTGUURGTGUAGUTTGGGUUGGUUUUAGG
    UAAAGGTTUAGUUTTTGGGGAU
501 UTUUAURGURGGUTRGUUUUUTGAGGAGGGGGUTGGGUUAGGGUUTRGGUTGAUR
    GGGGAGGAAGAAGGGGAGUAGAGAAAAAUATGAGTUAUAGURGTGTGTUAUTGGA
    GRGUATTTUAATTUUUTGUATUAUAGGAGGTGTGGAAGGUXGUUTRGGGGAURGGG
    RGRGGGAGGTGRGUURGAGAAGGUUURGGGURGGUUTGUAGGGRGRGURGUTURG
    UUTGRGUUUTTTUUTUUUTAURGUUUTUUURGUUATUTTUUUUTTTGGUTTUUTTU
    TRGUTRGGTGUAAUAAGTUTTT
502 AAAGAUTTGTTGUAURGAGRGAGAAGGAAGUUAAAGGGGAAGATGGRGGGGAGGG
    RGGTGGGGGAGGAAAGGGRGUAGGRGGAGRGGRGRGUUUTGUAGGURGGUURGGG
    GUUTTUTRGGGRGUATUTUURGRGUURGGTUUURGAGGXRGGUUTTUUAUAUUTUU
    TGTGATGUAGGGAATTGAAATGRGUTUUAGTGAUAUARGGUTGTGAUTUATGTTTTT
    UTUTGUTUUUUTTUTTUUTUUURGGTUAGURGAGGUUUTGGUUUAGUUUUUTUUTU
    AGGGGGRGAGURGGRGGTGGAG
503 UUTGAAGAGUATTUTUUUTGAGTGUTUAATGATATGUUAGAGUATGTUTUAAATGR
    GGAGGATGGGGAGGURGGUTUUUTGGUAGATUTTUATGGAGAAGUTGAUTUUAGU
    RGGUTTGTGTGUURGTUUUAGAGGAGRGGAAAUAGAGUXGAAGUUUAUAUUUUUA
    GGGUUUAGGUUUAGUUUTTUUAAGTURGGAGUTUAUUUAGUUTGUUUUTRGGUTU
    UTTUATUUTUUTUUAGAUAURGTUUUTTUTTUTGTUTUTGUATTTUUUATUUTUTUR
    GUUUUTUUUTGTGUTGUTUTGT
504 AUAGAGUAGUAUAGGGAGGGGRGGAGAGGATGGGAAATGUAGAGAUAGAAGAAG
    GGARGGTGTUTGGAGGAGGATGAAGGAGURGAGGGGUAGGUTGGGTGAGUTURGG
    AUTTGGAAGGGUTGGGUUTGGGUUUTGGGGGTGTGGGUTTXGGUTUTGTTTURGUT
    UUTUTGGGARGGGUAUAUAAGURGGUTGGAGTUAGUTTUTUUATGAAGATUTGUUA
    GGGAGURGGUUTUUUUATUUTURGUATTTGAGAUATGUTUTGGUATATUATTGAGU
    AUTUAGGGAGAATGUTUTTUAGG
505 ATGTUTGGGAGGUUAAAAGUATUTUTUAGAUAGTUTUTAUAGGAUTUTTUUAGGTU
    URGGAAGUURGAGRGAGUTTUUTGGAGGAGGTGGUTGGGGAGAGTGGAGGAGURG
    GTAGGGGTRGUTGTGUTTGRGRGRGUURGTUUAGGAAUTXGURGGGGUTGTGGGGA
    GGGGGRGURGGUUTGGAGAGGAUAATGTAUAGTUTGTTUTAAUAUUUAUUUAUTU
    UAAARGUAUAUTTUUUAUUURGTUTUTTGTUUUTUUUAGUUURGGGGUTAGAUUUT
    GAGGGUTRGGGURGUAUUTUAU
506 GTGAGGTGRGGUURGAGUUUTUAGGGTUTAGUUURGGGGUTGGGAGGGAUAAGAG
    ARGGGGTGGGAAGTGTGRGTTTGGAGTGGGTGGGTGTTAGAAUAGAUTGTAUATTG
    TUUTUTUUAGGURGGRGUUUUUTUUUUAUAGUUURGGXGAGTTUUTGGARGGGRG
    RGRGUAAGUAUAGRGAUUUUTAURGGUTUUTUUAUTUTUUUUAGUUAUUTUUTUU
    AGGAAGUTRGUTRGGGUTTURGGGAUUTGGAAGAGTUUTGTAGAGAUTGTUTGAGA
    GATGUTTTTGGUUTUUUAGAUAT
507 GGAGRGUTAARGRGUAGTGGGAGGGAAGGAGAGGAUTGAAGAGAGARGGGGGAGG
    GGAGAGGAGGGGTRGGUTGUUAGGUUTAGGTGGGGTGAATURGUAGUTGGGUTGA
    UTUAAGRGGAGGAGURGGAAGGAUAUUURGRGAGGUTTXGGGGRGRGUTTTTAGG
    GAGGRGURGUUTUUAGUTTTGTGUUAGAAAGTGGGGGTTGRGGUTUAGGUTTGAAT
    UUAAGAAAGGUTURGGGTGGAAUTUUTGGGUAUUTTGGGTUUTTAUTTTGUUTTUA
    GGRGUTGGUUAURGTTGGGAUTT
508 AGTUUUAARGGTGGUUAGRGUUTGAAGGUAGAGTAAGGAUUUAGGGTGUUUAGGA
    GTTUUAUURGGAGUUTTTUTTGGATTUAAGUUTGAGURGUAAUUUUUAUUGGTT
    UAUAAAGUTGGAGGRGGRGUUTUUUTAAAAGRGRGUUUXGAAGUUTRGRGGGGTG
    TUUTTURGGUTUUTURGUTTGAGTUAGUUUAGUTGRGGATTUAUUUUAUUTAGGUU
    TGGUAGURGAUUUUTUUTUTUUUUTUUUURGTUTUTUTTUAGTUUTUTUUTT
    UUUAUTGRGRGTTAGRGUTUUU
509 TATUAGAATUUAUATAUUUAGGTGGGTTTAGGAUUTUTAGGUUTUTUUUTUAGGU
    UATAGGAGUAUUUAUUURGGGUTLTUTUTGGAGGGGUAGUUUUAAGGAAUUTGTTG
    GGGTAAUTTGTTTGUTUUUUAUAUUURGGGAATGTGUXGTUUTTTUAGGUURGUUU
    AUURGGATTUUTGTGUAGGGAGTUAGURGAUAUAGUATGTTGUATGTGUUUTGTGG
    GGAUARGTTUTGUUTUUTGTUAGGGGGAGGAGGUTGGRGGURGTGUUTGTGUTGUR
    GUAUUTUAGUTUUUUAURGAA
510 TRGGTGGGGAGUTGAGGTGRGGUAGUAUAGGUARGGURGUUAGUUTUUTUUUUUT
    GAUAGGAGGUAGAARGTGTUUUUAUAGGGUAUATGUAAUATGUTGTGTRGGUTGA
    UTUUUTGUAUAGGAATURGGGTGGGRGGGUUTGAAAGGAXGGUAUATTUURGGGG
    TGTGGGGAGUAAAUAAGTTAUUUUAAUAGGTTUUTTGGGGUTGUUUUTUUAGAGG
    AGUURGGGGTGGGTGUTUUTATGGUUTGAGGGAGAGGUUTAGAAAGTUUTAAAUU
    UAUUTGGGTATGTGGATTUTGATAU
511 AGAGGATTTAAGAUTUAUUUAGGGUAAAUAUTGGGAUUAUTGTAAGAGRGUTGGA
    AUATTUTGUUTUTTGAGTGAAGGGGUUTTUTTTUTAGUUTUTATGGUAUTGAGGGGT
    GRGURGGUTGGTGGAGGAGUAGTURGATGGAGUUUTGXGTTUUURGGGGAUAUAG
    GGUUAAGUTTTGAGGTGGAAAGTTTUTGGTTUTGAAAUAAUAAGGAGAGAGTUTGT
    TTTTUTTUUTAAAATTTGGAUTUTTGTUTGUAUAAAUTUTGGTUTGTTTTGUARGGTT
    TGTGTGUUTTTTTTTUUUT
512 GGGAAAAAAAGGUAUAUAAAURGTGUAAAAUAGAUUAGAGTTTGTGUAGAUAAGA
    GTUUAAATTTTAGGAAGAAAAAUAGAUTUTUTUUTTGTTGTTTUAGAAUUAGAAAU
    TTTUUAUUTUAAAGUTTGGUUUTGTGTUUURGGGGAAXGUAGGGUTUUATRGGAUT
    GUTUUTUUAUUAGURGGRGUAUUUUTUAGTGUUATAGAGGUTAGAAAGAAGGUUU
    UTTUAUTUAAGAGGUAGAATGTTUUAGRGUTUTTAUAGTGGTUUUAGTGTTTGUUU
    TGGGTGAGTUTTAAATUUTUTT
513 TGUUTUTGAGTUTAAAARGGUAGTGGUUTAGGAGUAUAGGGUUTGGGGUUAUGGU
    UAGTGUUAUAUUTAAUUTGAGATATGTUUAGAGUTGAGGTUTAGUTUAUAGUATUT
    GTGRGTRGGGGAAGUTGGUTGRGGTUARGGURGGTGUAGXGGUUUAAGGAGTUUA
    UAAAGUAGTAAUUTTGGUUUAUAUUAUAGUTURGGTGUATTTGGAGAGGGGGUUU
    AGTUTAGGUTGAAGTTGGGGGGAGUUTGGUUAGGGUUTGGGUAUUAGGRGUAGGA
    UAGAGGGAAAGGUUTUUAGUTUUT
514 AGGAGUTGGAGGUUTTTUUUTUTGTUUTGRGUUTGGTGUUUAGGUUUTGGUUAGGU
    TUUUUUUAAUTTUAGUUTAGAUTGGGUUUUUTUTUUAAATGUAURGGAGUTGTGGT
    GTGGGUUAAGGTTAUTGUTTTGTGGAUTUUTTGGGUXGUTGUAURGGURGTGAURG
    UAGUUAGUTTUUURGARGUAUAGATGUTGTGAGUTAGAUUTUAGUTUTGGAUATAT
    UTUAGGTTAGGTGTGGUAUTGUUUUTGUUUUUAGGUUUTGTGUTUUTAGGUUAUTG
    URGTTTTAGAUTUAGAGGUA
515 GUAGUUUTGGGGRGTGGGGGGRGGUTGTTTUUTGUTGUUUUTTGGGUTGUUAUUTG
    UURGAGUTGUUAGUUAUAGTTGGAUTTUUTTUUAGUUUTURGGGGTGUUTGUATTU
    UUAUATTRGAGAUAGGUAGTGAGAGGGAGTGAGGGGXGATGATGTUTGUAGUUUA
    UAAGAGUUTURGGGUAGTAGUUAGGUUUUTUUGUTUAGUUTGAUUTGUUTGGUUT
    UUAGUAGGGTGUTATGGUUUTGGGAGGUUUTGGUTTUTCGGGAATTTGUUTTUUU
    UUUTGRGUTUTGUTUTGUTGTG
516 AUAGUAGAGUAGAGRGUAGGGUAGGGGAGGAAAGGGGGUAGAAGUUAGGGUUTU
    UUAGGGUUATAGUAUUUTGUTGGAGGUUAGGUAGGTUAGGUTGAGUAGAGGGGUU
    TGGUTAUTGUURGGAGGUTUTGTGGGUTGUAGAUATUATXGUUUUTUAUTUUUTU
    TUAUTGUUTGTUTRGAATGTGGGAATGUAGGUAUUURGGAGGGUTGGAAGGAAGTU
    UAAUTGTGGUTGGUAGUTRGGGUAGGTGGUAGUUUAAGGGGUAGUAGGAAAUAGU
    RGUUUUUUARGUUUUAGGGUTGUU
517 TUTUTUUTGGGUUAAGUTTTGTGGATGUUUAGUUTGGGGURGRGGGGAGUTGGUAG
    GTUAGTGGUAGAUAUTGGTGGGUAGAUUTAGTGTUTGGTAGAAUAGGUATUAAGG
    AAGTGGTGAURGGAGGGAAGUUAAGTGUAUTUAAAUUUTXGGGTGAGTUATUAUR
    GURGGGTUTTTUAUAGUTGUTGAAAGTGAGUAAUAGTGATGAAGGTTTGTGAGTTT
    UTGRGTGAGRGAGTGAATGGAUUAGTAGUAGTTTUUAGGTTGTGGAAGAGRGTTUU
    UTUUURGGGATGGGGAUAUTTG
518 UAAGTGTUUUUATUURGGGGAGGGAARGUTUTTUUAUAAUUTGGAAAUTGUTAUTG
    GTUUATTUAUTRGUTUARGUAGAAATTTUAUAAAUUTTUATUAUTGTTGUTUAUTTT
    UAGUAGUTGTGAAAGAUURGGRGGTGATGAUTUAUUXGAGGGTTTGAGTGUAUTTG
    GUTTUUUTURGGTUAUUAUTTUUTTGATGUUTGTTUTAUUAGAUAUTAGGTUTGUU
    UAUUAGTGTUTGUUAUTGAUUTGUUAGUTUUURGRGGUUUUAGGUTGGGUATUUA
    UAAAGUTTGGUUUAGGAGAGA
519 GGUTGGTUTTGAAUTUUTGGGUTUAAGAGUTUUAUUTGUUTUAGUUTUUUAAAGTG
    AGUUAUUAGGUUTAUURGGTUUTTTUUTUUATGUTTUTGTGGUUTTTUUTUUTGTT
    TAGXGAGUTUTGAUATTUAUTUATAGGTAGGAAUAAAGUUUTUUATTGGTTAGTUT
    GGGUTGAGGTGGGXGTGTGTGTTTUTGTATUAGTGATUTGTTTTURGGUAGGUUTUT
    UUUTGAGGGGAGAGUTGGTAGUTTUUATGTAAGTGGUAGGGUATAUTTUAUTAAAT
    AAAAGATGTGTGGGTGAG
520 UTUAUUUAUAUATUTTTTATTTAGTGAAGTATGUUUTGUUAUTTAUATGGAAGUTA
    UUAGUTUTUUUUTUAGGGAGAGGUUTGURGGAAAAUAGATUAUTGATAUAGAAAU
    AUAUAXGUUUAUUTUAGUUUAGAUTAAUUAATGGAGGGTTTTTGTTUUTAUUTATGA
    GTGAATGTUAGAGUTXGUTAAAUAGGAGGAAAGGUUAUAGAAGUATGGAGGAAAA
    GGAURGGGTAGGUUTGGTGGUTUATTTTGGGAGGUTGAGGUAGGTGGAGUTUTTGA
    GUUUAGGAGTTUAAGAUUAGUU
521 UAAGUATUTTAGTGATGTGAGTUATUAAAAUTTUUTUUTGGGTUTGUTTTGAGUUU
    UAUUTTUUTUUTUUTGUAGTUATGTTTUTTAGUUTUAGGGUUUTGGGGRGGAR
    GGAUAUTUUUUUAGUAGUUTGUTTTUUAGAGGUUAUTGXGUTGUTUAGUTURGGG
    GGUURGTUUTURGTGGATUUUTUUAGGUUUAGUAGAGTGTTTGAUUARGGGUUTGA
    URGGGAGGGGAGARGUUAUUTUUTGGGGAUTTGUAUUUUAAUUAGUAUUAUTGTU
    ATGAGAUAUURGGAGGUUAGUA
522 TGUTGGUUTURGGGTGTUTUATGAUAGTGGTGUTGGTTGGGGTGUAAGTUUUUAGG
    AGGTGGRGTUTUUUUTUURGGTUAGGUURGTGGTUAAAUAUTUTGUTGGGUUTGGA
    GGGATUUARGGAGGARGGGUUUURGGAGUTGAGUAGXGUAGTGGUUTUTGGAAAG
    UAGGUTGUTGGGGGAGTGTURGGGRGTURGUUUUAGGGUUUTGAGGUTAAGAGUA
    TGAUTGUAGGAGGAGGAAGGTGGGGUTUAAAGUAGAUUUAGGAGGAAGTTTTGAT
    GAUTUAUATUAUTAAGATGUTTG
523 TGATGAUUAGGUAUTGUTATTUTTTAGGURGGGATTTUUUUAAGUUTTGGTATTTTT
    AAAAATARGTTATAGTTUUUTTGAAAUTUTUTUUTTATUAUUTUUAUUTTGTTT
    TUATUTUUUAUTUUTTGGUAUUUTUTGTUTUUUUAXGGTGTUUUUATGARGUTGUU
    TGUATGUUUATTGGUUUUAGUUTGGGAGUTTUTUAGAGARGUURGGGUUAGAUAT
    GGUTGUAGATAGAGUUAAGAGGGTGGUUTRGGGTGGUTGGTGGUAGTUTUUTGGUT
    GTGGGGGUAGAAGTGGGGG
524 UUUUUAUTTUTGUUUUUAUAGUUAGGAGAUTGUUAUUAGUUAUURGAGGUUAUUU
    TUTTGGUTUTATUTGUAGUUATGTUTGGUURGGGRGTUTUTGAGAAGUTUUUAGGU
    TGGGGUUAATGGGUATGUAGGUAGRGTUATGGGGAUAUXGTGGGGAGAUAGAGGG
    TGUUAAGGAGTGGGAGATGAAAAUAGGAAGGTGGAGGTGATAAGGAGAGAGTTTU
    AAGGGAAUTATAARGTATTTTTAAAAATAUUAAGGUTTGGGGAAATUURGGUUTAA
    AGAATAGUAGTGUUTGGTUATUA
525 GUUTAGUUURGRGRGUAUATAUARGTGTGUTUTURGRGRGGAUUTRGGGAAUTTTG
    UUUTUARGUURGRGGRGRGUTTGUUTUURGUURGUUURGGUUTUUAUUUUTGGT
    ATGUUUUTTUUUUAGURGGTUTUUUUTUUUUURGGUTXGGGAAGAAGUUTGUTGG
    GUUAGGGRGUUUTGAUUAUUTUUTRGGAGGURGGUAAAUUTGUUTGAAURGUUUU
    AGAGGAATRGGGUAGGGGUTRGUAUUUUAUUURGGUAGGAGGGUUURGAGAURGA
    UURGGGURGGGGUTURGUAGURG
526 RGGUTGRGGAGUUURGGUURGGGTRGGTUTRGGGGUUUTUUTGURGGGGTGGGGTG
    RGAGUUUUTGUURGATTUUTUTGGGGRGGTTUAGGUAGGTTTGURGGUUTURGAGG
    AGGTGGTUAGGGRGUUUTGGUUUAGUAGGUTTUTTUUXGAGURGGGGGGAGGGGA
    GAURGGUTGGGGAAGGGGUATUTRGAAGGGGTGGAGGURGGGGRGGGRGGGAGGU
    AAGRGRGURGRGGGRGTGAGGGUAAAGTTUURGAGGTURGRGRGGAGAGUAUARG
    TGTATGTGRGRGRGGGGUTAGGU
527 GAAARGGRGGTRGUAGUUUTRGGURGGGUARGRGTGGGGURGTTRGTGGAGRGGTG
    TUTTGUTAGGURGGTTGGGGTAUTTGRGGGGURGGATGGGUTTGAGGGTGAGXGGR
    GGUTGGGGUAGGUTGUUAAAGUURGGGTGGATUTGUTTGTUTTTGAATGUUTTGAT
    GGTUTUUAGAGGGGTAATAGGGGGXGGGTTGAUURGGATGGGGTUUATGUUUTGG
    AAGGGUTTGTGUTURGGAATGGAGUUUATGTRGTTGGGGTGGTGGTAGAGGTTGTA
    GTUAGGAATUATGGGGAAGAG
528 UTUTTUUUUATGATTUUTGAUTAUAAUUTUTAUUAUUAUUUUAARGAUATGGGUTU
    UATTURGGAGUAUAAGUUUTTUUAGGGUATGGAUUUUATURGGGTUAAUUXGUUU
    UUTATTAUUUUTUTGGAGAUUATUAAGGUATTUAAAGAUAAGUAGATUUAUURGG
    GUTTTGGUAGUUTGUUUUAGURGURXGUTUAUUUTUAAGUUUATURGGUUURGUA
    AGTAUUUUAAURGGUUTAGUAAGAUAURGUTUUARGAARGGUUUUARGRGTGUUR
    GGURGAGGGUTGRGAURGURGTTTU
529 TGUTUAGGUTGGAGTGUAGTGGUAAAATUTTGGUTUAUTTUAAUUTURGUUTUURG
    GGTTUAAGUAATTUTUUTGUUTUAGUUTUTUAAGTAGUTGGGATTAUAGGUATGUA
    UUATUAUAUUUAGUTGATTTTGTATTTTTAGTAGAGAXGGGGTTTUAUUARGTTGTT
    UAAGUTGGTUTUAAAUTUUUTGAUUTUAGGTGATUUAUURGUUTTGGUUTUUUAAAG
    TGURGGGATTATAGGTGTGAGUUAURGUAUUTGGGUAATTAGTATTGTATTTAAGA
    GTTTATATTUATATUUATA
530 TATGGATATGAATATAAAUTUTTAAATAUAATAUTAATTGUUUAGGTGRGGTGGUTU
    AUAUUTATAATUURGGUAUTTTGGGAGGUUAAGGRGGGTGGATUAUUTGAGGTUAG
    GAGTTTGAGAUUAGUTTGAAUAARGTGGTGAAAUUUXGTUTUTAUTAAAAATAUAA
    AATUAGUTGGGTGTGATGGTGUATGUUTGTAATUUUAGUTAUTTGAGAGGUTGAGG
    UAGGAGAATTGUTTGAAUURGGGAGGRGGAGGTTGAAGTGAGUUAAGATTTTGUUA
    UTGUAUTUUAGUUTGGGUA
531 TGTTAUTTUATTGAATTUTUATAATAGUTTAATGUTATRGGTTTTUTTUTTAATTTTG
    GGGGUATAGTGGGGAGATAAGUAAAUTGATAUUURGGAGGTTGAGTGAUTUATTUA
    TGGAATGUAGUAGGUURGTGAGTUAAAGXGAGTAUATGGUAAGAUXGAGTGAAGU
    TGGGGAAUAATAGUUAAGUUAAGAGRGTTTTAAAGATAUTTAGUATUTTUATUAUA
    UTGAATUTTTAAGGTGAUAGUAUTTUUAUTRGAUAGUAAAATGTUAGATTUAAUTGT
    TTUTTTURGGTUTTUAAAU
532 GTTTGAAGAURGGAAAGAAAUAGTTGAATUTGAUATTTTGUTGTRGAGTGGAAGTG
    UTGTUAUUTTAGGATTUAGTGTGATGAAGATGUTAAGTATUTTTAAAARGUTUTTGG
    UTTGGUTATTGTTUUUUAGUTTUAUTXGGTUTTGUUATGTAUTXGUTTTGAUTUARG
    GGUUTGUTGUATTUUATGAATGAGTUAUTUAAUUTURGGGGTATUAGTTTGUTTATU
    TUUUUAUTATGUUUUUAAAATTAAGAAGAAAAURGATAGUATTAAGUTATTATGAG
    AATTUAATGAAGTAAUA
533 TTAGTATTAUUAAATATRGAGTUAAGGGUUTGATUAGUUUUAAAAGAATGAGGUAU
    TTTTAATGTGAUAUUATTUUTGGUAGTUTUAGGTTRGGUTUUUUUAGGUUURGGAT
    GUAGATGGUTGTTAGGGGUTGGUUATUUTUATUTUAAXGGTUUTGGAAGGUAUUAU
    TTTUAGGGUATATGUUATGAUTAAUATTURGGTGAGUAATGUTGAUTUAATRGTAG
    AUTGTTATTTUATGTTUUUAGTAUUUTGTGUAGGAAGGGAAGGGAAATGAGTAATA
    GATGTATUAGTUUUATTUAA
534 TTGAATGGGAUTGATAUATUTATTAUTUATTTUUUTTUUUTTUUTGUAUAGGGTAUT
    GGGAAUATGAAATAAUAGTUTARGATTGAGTUAGUATTGUTUAURGGAATGTTAGT
    UATGGUATATGUUUTGAAAGTGGTGUUTTUUAGGAUXGTTGAGATGAGGATGGUUA
    GUUUUTAAUAGUUATUTGUATURGGGGUUTGGGAGAGURGAAUUTGAGAUTGUUA
    GGAATGGTGTUAUATTAAAAGTGUUTUATTUTTTTGGGGUTGATUAGGUUUTTGAUT
    RGATATTTGGTAATAUTAA
535 AGTGGTGGUTGUTGTTTUTRGGTGGUAGAGATGATGUUTGGTTTATTUTTAGTAAAG
    TGUTTAGGARGUTGAGUUTGAGGGGUTUTGGAATGGAAAAAUAAAAUAAAAUAAA
    AUAAAURGGAGGUURGUTUTGUUTGGUTUUTAGAGAUAXGUAAAGUTGGGUAAAG
    GAAGGAGATTGAGGTGGGAUTGAGAUATTGTTGUATTGTGAATGUUURGGTTUUUU
    AUUTUUTGUUUUURGAATUATGATTGTTTTATGRGGTTATTTTTUUUTTTGGTGAGG
    AAAATGGGATGTGGTGTUAA
536 TTGAUAUUAUATUUUATTTTUUTUAUUAAAGGGAAAAATAAURGUATAAAAUAATU
    ATGATTRGGGGGGUAGGAGGTGGGGAAURGGGGUATTUAUAATGUAAUAATGTUTU
    AGTUUUAUUTUAATTTTUUTTUUTTGUUUAGUTTTGXGTGTTUUUTAGGAGUUAG
    AGAGRGGGUUTURGGTTTGTTTTGTTTTGTTTTGTTTTTUGATTGGTTGGAAGGTT
    GUTUAGRGTUUTAAGUAUTTTAUTAAGAATAAAUUAGGUATUATUTUTGUUAURGA
    GAAAUAGUAGUUAUUAUT
537 GGGGTRGGUATGGGUTGGAGUTUAGAGARGGUUAGUTAGGAUTTUAGGAUAUAUA
    GUAAAUTAGUTGRGUUURGUTGAGGGTUAGRGUAUAGURGUUUAUAUAAGGTGTU
    UTUTUUURGGGUTUTUTGGGURGURGGUUTUUTGUTTUUXGTGURGUAGAURGGGA
    TTAGAUTGTGGARGRGGGGAAGGAAGGGGGRGTTGRGARGGGATUTTGAGGGGAGU
    AGGAUTTGUUUUTGUUUUTGRGGRGAAGUTUTAGGUUUTGGUAAGGTTRGGTAUAU
    RGGGGGURGUTUUTUUUUAGGG
538 UUUTGGGGAGGAGRGGUUUURGGTGTAURGAAUUTTGUUAGGGUUTAGAGUTTRG
    URGUAGGGGUAGGGGUAAGTUUTGUTUUUUTUAAGATUURGTRGUAARGUUUUUT
    TUUTTUUURGRGTUUAUAGTUTAATUURGGTUTGRGGUAXGGGAAGUAGGAGGURG
    GRGGUUUAGAGAGUURGGGGAGAGGAUAUUTTGTGTGGGRGGUTGTGRGUTGAUU
    UTUAGRGGGGRGUAGUTAGTTTGUTGTGTGTUUTGAAGTUUTAGUTGGURGTUTUTG
    AGUTUUAGUUUATGURGAUUUU
539 GTGUARGUAGGGAAATAUUTUAUAGGGTAAATTTGGATURGATTGAGAAUAGGAAG
    UUAUAGGUUAATAUAAGGAGGUTUTGTGAGAAUAGATGAUAAAUUAUAAGURGGG
    GAGGGGGAGGAAAGAGUTTTUTGGGUUTGGGGGATGGGXGAGUURGUUAGUAUAU
    UAUAUAUAGUTGRGUTTGGUUTUAGTAATUAAAAUUATUATTAUAGAUUTGARGGT
    TTGGUTGUAGUTGTAAAGAGATAAGUATGTTGGAAGAGAAAAUAGGGUUURGGTG
    AUURGGUUTTAGGGTUTGAGRGU
540 RGUTUAGAUUUTAAGGURGGGTUAURGGGGUUUTGTTTTUTUTTUUAAUATGUTTA
    TUTUTTTAUAGUTGUAGUUAAAURGTUAGGTUTGTAATGATGGTTTTGATTAUTGAG
    GUUAAGRGUAGUTGTGTGTGGTGTGUTGGRGGGUTXGUUUATUUUUUAGGUUUAG
    AAAGUTUTTTUUTUUUUUTUUURGGUTTGTGGTTTGTUATUTGTTUTUAUAGAGUUT
    UUTTGTATTGGUUTGTGGUTTUUTGTTUUUAATRGGATUUAAATTTAUUUTGTGAGG
    TATTTUUUTGRGTGUAUA
541 TGTGRGGGUAGTGGGTTGTGRGGGUAGTGGGTTGTGUATURGGATGTGTAGUAUTU
    AUAUAUTTRGGGTGAUTUTTUUTGGGTAAGUTGTGGATGTGAGTGGGGGUAGUATU
    TGURGTGAUTUATTUTUTUUTUTTTUUATTUUAAGUXGGGTGGGGGAGTTTGGGATT
    TUUAGAUAAGGUUTGGUTUUUUUTGGUAUAGAGGGTGGGAGTGGGGATGGGGAGG
    GAGGAGGGAAGGGTUATGGGAAGGTGGGGUUATGTTTTGTGUTUAATGAAUTGAGA
    AGGGGGAGGGTTUUAGUTGG
542 UAGUTGGAAUUUTUUUUUTTUTUAGTTUATTGAGUAUAAAAUATGGUUUUAUUTTU
    UUATGAUUUTTUUUUUTUUUTUUUUATUUUUAUTUUUAUUUTUTGTGUUAGGGGG
    AGUUAGGUUTTGTUTGGAAATUUUAAAUTUUUUUAUUXGGUTTGGAATGGAAAGA
    GGAGAGAATGAGTUARGGUAGATGUTGUUUUUAUTUAUATUUAUAGUTTAUUUAG
    GAAGAGTUAUURGAAGTGTGTGAGTGUTAUAUATURGGATGUAUAAUUUAUTGUU
    RGUAUAAUUUAUTGUURGUAUAA
543 GUAAUTGGRGUTGGGTAGGUAAAGURGGGAGAAAUTGUTGAGARGAGGTTAGGAT
    TTAAUUTTTAAATTUTGGAGUUATRGGAAAURGAGGGGAGGARGARGGGTGTRGGT
    GUTAATGAGGUTGGGGGRGGGRGATGRGRGGTGGGUUTUXGAGTURGGGGUAGGT
    UTRGGGGGTTUUURGGGGAAGGUUUTGGGAGUUUTTGGUUUTGGRGGUUTURGUU
    ATUAGAUTGGGAATGTUTUTGATTGGGTGGUUAGGAGGRGGTGGUUUTUUTUUURG
    UUUAGUTGAGGGGTGTRGTUTTU
544 GAAGARGAUAUUUUTUAGUTGGGRGGGGAGGAGGGUUAURGUUTUUTGGUUAUUU
    AATUAGAGAUATTUUUAGTUTGATGGRGGAGGURGUUAGGGUUAAGGGUTUUUAG
    GGUUTTUUURGGGGAAUUUURGAGAUUTGUUURGGAUTXGGAGGUUUAURGRGUA
    TRGUURGUUUUUAGUUTUATTAGUAURGAUAUURGTRGTUUTUUUUTRGGTTTURG
    ATGGUTUUAGAATTTAAAGGTTAAATUUTAAUUTRGTUTUAGUAGTTTUTUURGGUT
    TTGUUTAUUUAGRGUUAGTTGU
545 GGGUAUUUTUTGGTGUTTUUAGGUUTGTGAATTGGUAUAGUAGGAUUAUAGAUUT
    UUAAGGTGUUUAUUTGGGGGUTUAGAAUUUTGGRGGGGAAGGTUAGTGUTATUUU
    AURGGAGAAGAGAUUTAGTUTAGUTGAGUUUUTGGUUAGXGGUAAGGAGGAAAGG
    ATGAAUATUAGUUARGUUTGGUAUTGAUTGUUAUAGUUAGAGUUTRGUUUAGUUU
    AAGAATGTTTUTGTTUTAAGAUTTTTTTUTTTTTTGTATTTTAGAGAAGTTUUU
    AAATGTUAUUTTGAAGAUURGG
546 URGGGTUTTUAAGGTGAUATTTGUUTGTGATAATTTUTAAAATAUAAAAAAGAAAA
    AAGTUTTAGAAUAGAAAUATTUTTGGGUTGGGRGAGGUTUTGGUTGTGGUAGTUAG
    TGUUAGGRGTGGUTGATGTTUATUUUTTUUTTTTTTGUXGUTGGUUAGGGGUTUAGU
    TAGAUTAGGTUTUTTUTURGGTGGGATAGUAUTGAUUTTUUURGUUAGGGTTUTGA
    GUUUUUAGGTGGGUAUUTTGGAGGTUTGTGGTUUTGUTGTGUUAATTUAUAGGUUT
    GGAAGUAUUAGAGGGTGUUU
547 UTUATGGAGAGGAGUAGAGATGUAGGAAARGUAAUAGUAGUARGGUAGAAARGUA
    GGAGAAAUAGUUURGUUTUAGAGURGUUUAUUTUUTUURGUUATGUUAGGAAGGG
    UUAGTGTUUUTUUAGARGURGGTGAUTGTUARGTUAGAUAXGTGARGTGTGGUTGT
    GUUUAGATTUTTGGRGGTGAGUUURGGRGAGGGAUUUAGRGGTUTUURGGRGTUTG
    GTTTAGGGGGGGATUTURGUAAGAUUURGUURGUARGTGGUTUUTGTGAGGGGUAU
    TGRGRGRGAAGGUTGTGGTUTG
548 UAGAUUAUAGUUTTRGRGRGUAGTGUUUUTUAUAGGAGUUARGTGRGGGRGGGGT
    UTTGRGGAGATUUUUUUUTAAAUUAGARGURGGGAGAURGUTGGGTUUUTRGURG
    GGGUTUAURGUUAAGAATUTGGGUAUAGUUAUARGTUAXGTGTUTGARGTGAUAG
    TUAURGGRGTUTGGAGGGAUAUTGGUUUTTUUTGGUATGGRGGGAGGAGGTGGGRG
    GUTUTGAGGRGGGGUTGTTTUTUUTGRGTTTUTGURGTGUTGUTGTTGRGTTTU
    UATUTUTGUTUUTUTUUATGAG
549 UTUTUUAUTGTGUAGGUUAUUTGTAGGGAUAGTGUUAGTGGGTGTAGGAGAGGTGG
    RGAGGUTGUAGUAGTGRGGGATGGGUTUUUUAUAUUUUUAAATAUTUUAUATGGG
    GTURGGGGUUTTUUUAGGAUUTGGGUUAGGTGXGUAXGUUTGGGXGGGGUUAGUU
    AGUTRGTGUTGAGTUAURGGGTGURGTUAGTGAGGGUUTGGUUUUAUUUTRGGGAA
    UUAURGGTGUTGGTTTTUUUARGGUTGUTGUURGUTGTGGGUUTTGUTGTUAUUUA
    UAAGGUUUTGGGAGGUUUTGUU
550 GGUAGGGUUTUUUAGGGUUTTGTGGGTGAUAGUAAGGUUUAUAGRGGGUAGUA
    GURGTGGGAAAAUUAGUAURGGTGGTTUURGAGGGTGGGGUUAGGUUUTUAUTG
    ARGGUAUURGGTGAUTUAGUARGAGUTGGUTGGUUUXGUUUAGGXGTGXGUAU
    UTGGUUUAGGTUUTGGGAAGGUUURGGAUUUUATGTGGAGTATTTGGGGGTGTG
    GGGAGUUUATUURGUAUTGUTGUAGUUTRGUUAUUTUTUUTAUAUUUAUTGGUA
    UTGTUUUTAUAGGTGGUUTGUAUAGTGGAGAG

Also provided herein is a deoxyribonucleic acid identical to 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, or 190-200 of contiguous nucleotide sequence of the sequence including a sequence of SEQ ID NO: 1 to SEQ ID NO: 550.

In embodiments, provided herein is a deoxyribonucleic acid which includes a methylation site set forth in Table 1.

In embodiments, included herein is a deoxyribonucleic acid in which a plurality of methylation sites set forth in Table 1 are methylated or unmethylated. In embodiments, the plurality of methylation sites comprises at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550 methylation sites. In embodiments, the plurality of methylation sites comprises between 1-50, 50-100, 100-250, 100-300, 100-400, 100-500, 100-550, 250-550, or 350-500 methylation sites.

Compositions for Detecting Methylation

Also provided herein are probes and primers that are complementary to one or more of SEQ ID NOS: 1-550. In embodiments, pairs of primers complementary to nucleotide sequences on either side of a methylation site of interest listed in Table 1 are provided. In embodiments, a plurality of probes and/or primers are provided to detect and/or amplify a polynucleotide (e.g., a polynucleotide obtained by bisulfite treatment of DNA) comprising a methylation site of interest. In embodiments, a probe or primer is complementary to a polynucleotide sequence that encompasses the methylation site of interest. In embodiments, the probe or primer is complementary to a sequence that is proximal to the methylation site of interest (e.g., within 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 75, 50, or 25 nucleotides of the methylation site of interest in a genomic or bisulfite-treatment-derived polynucleotide).

In embodiments, a deoxyribonucleic acid selected from SEQ ID NO:551 to SEQ ID NO: 782 is included. In embodiments, the deoxyribonucleic acid selected from SEQ ID NO:551 to SEQ ID NO: 782 is hybridized to a complementary DNA sequence having uridine or cytosine. In embodiments, each of the nucleic acids is different. In embodiments, each of the nucleic acids does not simultaneously have the same sequence selected from SEQ ID NO:551 to SEQ ID NO:782.

In embodiments, aspects include a deoxyribonucleic acid selected from SEQ ID NO:551 to SEQ ID NO:782, hybridized to corresponding a complementary DNA sequence having uridine or cytosine, and in a complex with an enzyme, e.g., a thermostable DNA polymerase. In embodiments, the thermostable DNA polymerase is Taq DNA polymerase.

In some aspects, the method includes deoxyribonucleic acid that has a sequence that is at least 50%-55%, 55%-60%, 60%-65%, 65%-70%, 70%-75%, 75%-80%, 80%-85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical or homologous to a nucleic acid having a sequence of at least one of SEQ ID NO:551 to SEQ ID NO:782.

TABLE 5
SEQ ID NO: Sequence, 5′ to 3′
551        GGGAGAAGAGATTGGAAAA
552        CTAAAAACCTAACACTAACAACATAAT
553        TGTTGTTTAAAATGTTGTTT
554        AACCCTAAATAATTCTTCTC
555        GGGTTGGGTTGAGGTTTT
556        ACACCTTACATCTCATTTACAACTC
557        AATTTGTGAAAAGTTTGTGTA
558        CCCAATCACCTTTAATCT
559        GTTGGGATTTGAAATAGTGA
560        CCTCCACTCACCTAAAACTT
561        TTGGTTAGTGATTATTTATT
562        AAAAATTAATATAAAATTAAAA
563        TTTGTAGGGAGTTAGGGAT
564        TCCTCTATCTCACCCTAAAT
565        TTTGATTGAATTATTTGTGTATT
566        ACTCCCTTACTCCTAAACACT
567        AGTGGAGATEGGTAGGGAGA
568        CCCAAAACTAAAACCAAATATAA
569        TTGTGGTTAAATTTATTG
570        ACCCAACAAAATAATATC
571        TGAGGTAGAGTTGTGTGTATAT
572        ATCAATCAATTCTCATTAAAC
573        GGAAGTTAGGAAGGGTTGT
574        CTCCAACTCCAACTAAAACTC
575        TTEGGGTATTGATTTATTTT
576        AAATTCTACCTACAAACTATACA
577        AGGATGAAGTAATAATTAAATATTG
578        CCCACTCTACCAACTAAAC
579        AGGTTTGTGTTAGTATAAAT
580        TTCTTACCTATATAATTAATAATA
581        GTTGGGTGAATTTTATTAG
582        TCAAAACCTAAACTCTAACA
583        GGATTGGTTTRATATAGAAAGTAT
584        CAAATAATAAATCATAACTCTTAACT
585        TGGGGTAGTTGATGGTTT
586        CTTTCTAACAAAATAAAAAAATTTAA
587        TTGTATTTGAAGTTTGTAGAGATTTATA
588        TTTCCTCCAACAACTCAAT
589        TTATGAGTATGTAGTAGGGTTATTATA
590        AAAATATCAAACAAATTTATCC
591        TGGTTGTTTGTTTTTTATGTATT
592        TCCCTACCTCCCAAATTC
593        TATGATGATTGTTGTAGTGTAGA
594        CCTCCCTAATAACTAAAAATAC
595        GGTGGTTTTGATATTTAGTG
596        CCCAATTACCTAACAAATTA
597        TGGGATAGGTGTAGATATG
598        CAACAAAAACTAAAACACTATAC
599        TTTGGGATTGGTTATTTT
600        AAACCCCTTAACTCTATACC
601        GATTTTTTTGAGAAGAGTATAG
602        AACCACTACCACCTAAATATA
603        GGAGGATAGGGTGTGATT
604        ACATTTTTAACTCTAACTAAAAATAAA
605        TGGAAATGAGGTGAGTTT
606        AAAAAAAAATAAAATAACAATAACTA
607        TGGAGAGTTTAGTTTGTTT
608        CAAAAAAAAATCTAACAAC
609        TGGGTTTTAGTTATGTGGTT
610        ATCAATAATATCCAACAAAATAATAT
611        TTTTTTTAGTTTTTGTATATATATTAG
612        ACCCAAATAATCAACTCTT
613        GTGGTTTTTGGAGATTTA
614        AAACAAACTACAAATAAAATAATAC
615        GGGTTATAGGTTTGAGTTA
616        CCATTAAAAAAAATAAAATC
617        TTGGTAGATTTAGTAAATTTATT
618        AAACTTAAACAACCCTATATAC
619        ATGGTTTTAAAGAGTAGTAGTATAGTT
620        AAATTTACTCATCCCACTTC
621        AGGGGTTGGGATATTGTT
622        AAAAATTTCTCCTTACAAAAAACTAA
623        ATGGGTGTTTGGAATTTTTTA
624        CTACCTCAACCTCCTAAATAACTAA
625        GTGTTTTGTGGTANAGATATAG
626        ATTCTTAAATTAATTCAACTACAT
627        TGGGGGTAAAAGTTATAGTT
628        AAAAAACAAAAAACCAAATAC
629        GTTTTTTGGTTAGTGTGTT
630        CCCCATACTTCTATACTATAAT
631        TTGTTGTTTTTAAAGAAATTATA
632        ATCATCTAAACTTAACTCATCTAA
633        ATTTTTGGGTGTTTTATATT
634        AAACCTCAAACAATAACA
635        ATTAAGGATATTTAGGAGAGTAAG
636        ACACCACAACTTCAAACTAC
637        TGAGGAAGAGAGAAGAGATGATA
638        AAAACTAAACTATAAAACAAAACAAAACTA
639        GGTGGAGGTGTTTTTTATAG
640        CCAAATACTACTTTCAAAATACA
641        ATGGATTATTATTGTGTTATT
642        CATCTCAACCTCATACTAA
643        GGATGATTTAGTAGGGATTGAG
644        ccAAATAAAAACCATTCTCTAAC
645        TTGGATTAAGTATTTTTGATATTA
646        TCCCTAAACCATATATTACTAAA
647        GGGTAGTTTGGTGATTATTATT
648        CCCTTCCCTACTCACAATA
649        ATTTGGTTAGTGATTTAGTTATT
650        TCCCACTTAAAAAATTCTATA
651        AGTGGGGAAGGTAATTGTTAT
652        CTTTCTAATAAAAATTTACTAAAACCTCTA
653        TTTGGTTAGTTTTATTTTTGATTG
654        ATTCCTCCCTATCCCTATTC
655        GGGATAGGGGTTAGAGTAA
656        TCCATAAAAACAAAACACTC
657        TTTTTTAGTATGAGTTATAAATTAT
658        AAAACAAAATCTACCTATATATT
659        TTTTATTAATAAAGTAGGTATGA
660        ACCTTTCTCAAAATTACTAA
661        ATAGGGTTGAGGTTAGAGTTAT
662        CCTCCTCTCCACAATAAA
663        TTTAAGTTTTTTTTTAGTTTTGTAGT
664        CCCCATCCTCTCTATCTC
665        AAATTTAAAATTTAGAGGTTTTTATA
666        AAACTTCACACACAAATCTATATT
667        TTTTTATTTTATTTTTTATTTTTAA
668        ATACCTCCCTAATTATATTATTAA
669        TTTTAGAATATTTAAAGAAGTTAGT
670        TAACCTCACTTTCCTATCA
671        AATTTAGTATAAGATTTGATTTGTTA
672        CCACCTACTCCTTCCTATAC
673        TTTTTTGAAATTGTATGTTAT
674        CAAATCCTTAAAATTCTATAA
675        TTTGAAGTGGTGTTTTAG
676        CCAAAATTCTTCCATACT
677        TGGGTATTTAGTYTTTTGTG
678        AACAAcTACCTCCTTTTACTAAT
679        TATGGTAGGAGGTGGAGTT
680        CCCAATTTTAAAACAATAC
681        AGAGGAAGTAAGGTTATTAGTT
682        ACCAAACAAACAATATCTAA
683        GGTTTTAATTATGATTTAATTAGA
684        CCTACACTCAAATTTACCTCTA
685        AATGGGTAGTTGATATAATTATT
686        CACAAAATCCTAAAACTAAAA
687        AGGATTAGTGGAAATGAAAATA
688        TAACCTCAAAACAACTTCTAAAC
689        TTTTTTTTATAGAGAAGTATTTTAG
690        CCCATTACAAAACTATCC
691        GGTGAGTTTGTGGTTAGTG
692        TTTTCTAAAAAAATCCAATCTA
693        AATGGATAGGTTGGAATAG
694        AAAAAAAAAAAAAAACTAATTAC
695        GAGTTATTTAGTTTGGTTAGGT
696        ACTCAACTTAAAAAATCACTATAC
697        TTTYTTTTGGYTTTTTGGYTTT
698        TCCCCCACACCCATATAA
699        TTAAAAAAAAGTATAATGAGTAGGA
700        CCCACAAAAACTCTCTACA
701        AAAGGAGGTTGAGTTAGAAAGTAG
702        AACTATTTAACTTACTTAACCACACC
703        GGTGTGGTTAAGTAAGTTAAATAGT
704        TACCCCTTCCTCTTCAAC
705        TTTTGATATGATTTATGATTATAT
706        TTTTCCACTAAACAACACTA
707        TTTGAGGGTTGTTTTAGAT
708        ACTCACAAAAAATAACTAATAACTAT
709        AAAGGAGGTAGGGGAGATATA
710        TCAAAATAAAAACCAAAATTCTC
711        AGGTTAAGTTGGTAGAGGTAGA
712        CAAACTCTAAACTCAAAATATATTC
713        TTTTTATTTTAGTTTTTTTGAGTAG
714        CCCTACAACACTCCTATCTA
715        TTTGGAGTTAGGTTGATAG
716        CAACAATACTCTCACTTACAC
717        AGAAAGATTTTTAAATATTTTTAAT
718        AAACCTCTAATACACAACAAA
719        TTTTGAGTTTTTTTTTTTTAAGTAT
720        CAAACAAAACAACACTTAATAC
721        GGTTGAGGTGGGTGGATTA
722        TTTTTTTTTTTTTTTTTTAAAATAAAATCT
723        GGGTGTTTGTAATTTTAGTT
724        ACCTETTAACAACCTAACAATATA
725        GGGTAGATGATATGGTAGTGA
726        AAAAAATAAAAAATAACTAAAACAATAT
727        AGGAAGTGTTTAAGAAGTAGAA
728        CCTAAAACTCTAAATACAATCTC
729        TTTTTAATTTTTGTTTGTATT
730        AAACCACAATCTATTTCTAA
731        TTAGAAAAGAATAATTATAGTTG
732        ACCCTAAAAAAATAAAATC
733        TTGTATTAGTAAATAAAGTGTATTTT
734        AACCCTTTCTACAAATCTAC
735        AGGGGTGGGTGGAAGAAT
736        CTCCTCAATAAAATAAAAATCCTAAAAAATA
737        GGGTTAATTAGTTGTTTTAT
738        CCTACAAATATATCACACACT
739        TTTGTTAAATAGGTGGTTAGA
740        ACCTCAACCTCCTAAATAAC
741        TAGGGTTTAGAGTAGGAGGTAG
742        CAAAAAATATAAATCAAAAACATC
743        GGGATTATAGGTATTTATTAT
744        TAAAAATTAAAAATCATACTTA
745        AAGTGATTTTTAGGGAGTGT
746        TCCATAATAACCTCATTTTAATA
747        TTTTTGGTTGAGGTTTAGT
748        AAACAACACAACTCTTATCAC
749        TATGGTGATTAAAGTATAATAGTT
750        TCCTAAATAAAAAACAACATA
751        TGAAAATGTTTTTAGTTTTTATT
752        AAATACCCTACCTCTTATCTAA
753        GATGGTTAATTTTTTTATTT
754        ACTCCTTCAACAAACTAAC
755        AGGGGATATTTTTAGGTT
756        CCAATCTATTCCTATATAATTAA
757        AGGAGAGTTTGGAAATATAG
758        CAATTCTAAATTAAACCTTATT
759        AATAATGGTAGTAGTTTTATTAG
760        TTCCTATATTAACAACTTACA
761        TTTTTTGGTAGATTTTTAT
762        AAATTAATTTCTATTATTTATATTA
763        AGGTGGTTGGGGAGAGTG
764        CCCTAAAATAAATCAAAAAAAACCTTAA
765        AGGTTTAGGTGGGGTGAAT
766        TAAAATCATCAAAATCCCTTAAAA
767        TTTTTTTTTAGGTTATACTGAGTATT
768        ATCCCCACAAAACACATA
769        TAGGGTAAATATTGGGATTATT
770        TTTCCACCTCAAAACTTAAC
771        GGGTGTTTGTATTTTTATATT
772        ACCTCCCAAAACCATAAC
773        GATGTGAGTGGTGAGGTGGT
774        CAAACCCTTCCAAAACATAAAC
775        TGGGATTATAGGTATGTATT
776        CAATTTCATTTATAAATATAAATAT
777        AGGGGTTGGTTATTTTTATTTT
778        TTTTTAATATTTAATTTTTACCTTCAACT
779        GGTAAGTTGTGGATGTGAGT
780        AAAAAAAACCAAACCTTATCTA
781        TTTTTAGGATTTGGGTTAG
782        AACCTTATAAATAACAACAAAAC

Kit for Detecting Methylation Level of a Thyroid Nodule

Also provided is a kit including a plurality (e.g., at least about 10, 20, 40, 50, 100, 150, 200, 225, or 232) nucleic acids each independently comprising one sequence selected from SEQ ID NO:551 to SEQ ID NO:782, in which the nucleic acids do not simultaneously include the same sequence.

In some aspects, the kit includes deoxyribonucleic acid that has a sequence that is at least 50%-55%, 55%-60%, 60%-65%, 65%-70%, 70%-75%, 75%-80%, 80%-85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identical or homologous to a nucleic acid having a sequence of at least one of SEQ ID NO:551 to SEQ ID NO:782.

The kit provided herein may include enzymes, reagents for deamination of cytosine, buffers, vials, plasmid vectors, control DNA, devices for collecting thyroid tissue samples, reagents for isolating DNA, reagents for labeling DNA, labels, or any combinations thereof.

The kit provided herein may include enzymes such as thermostable DNA polymerase enzymes, restriction enzymes, and combination thereof.

In embodiments, the kit(s) may further include enzymes, reagents for deamination of cytosine, buffers, vials, control DNA, devices for collecting blood and/or tissue samples, or reagents for labeling DNA, or any combinations thereof.

In embodiments, a kit provided herein may include a solid carrier capable of adsorbing the nucleic acids containing in a sample of a body fluid, for example blood (whole blood, plasma, or serum). The kit may also contain other components for example, reagents, in concentrated or final dilution form, chromatographic materials for the separation of the nucleic acids, aqueous solutions (buffers, optionally also in concentrated form for final adjusting by the user) or chromatographic materials for desalting nucleic acids which have been eluted with sodium chloride.

In embodiments, a kit provided herein includes materials for purifying nucleic acids, for example, inorganic and/or organic carriers and optionally solutions, excipients and/or accessories. Such agents are known and are commercially available. For solid phase nucleic acid isolation methods, many solid supports have been used including membrane filters, magnetic beads, metal oxides, and latex particles.

In addition, a kit can also contain excipients such as, for example, a protease such as proteinase K, or enzymes and other agents for manipulating nucleic acids. e.g., at least one amplification primer, nucleic acid bases (A, T, G. C, and/or U), and enzymes suitable for amplifying nucleic acids, e.g., DNase, a nucleic acid polymerase and/or at least one restriction endonuclease. Alternatively, a commercial polymerase chain reaction kit may be used to amplify the DNA samples.

Exemplary Techniques for Detecting Specific Sequences

Specific sequences, such as the sequences listed in Table 1 (or portions thereof containing a methylation site of interest), can be detected by numerous methods that are well-established in the art (e.g., PCR-based sequence specific amplification, isozyme markers, northern analysis, sequence specific hybridization, and array based hybridization). In embodiments, the presence or absence of methylation is determined through nucleotide sequencing of the site of interest (e.g., the site in bisulfite-treated DNA or an amplicon thereof). Any of these methods are readily adapted to high throughput analysis.

Some techniques for detecting specific sequences utilize hybridization of a probe nucleic acid to nucleic acids corresponding to the methylation site of interest (e.g., amplified nucleic acids produced using bisulfite-treated DNA as a template or the bisulfite-treated DNA itself). Hybridization formats, including, but not limited to: solution phase, solid phase, mixed phase, or in situ hybridization assays are useful for sequence detection. A non-limiting guide to the hybridization of nucleic acids is found in Tijssen (1993) Laboratory Techniques in Biochemistry and Molecular Biology—Hybridization with Nucleic Acid Probes Elsevier, N.Y., as well as in Sambrook. Berger and Ausubel.

Nucleic acid probes complementary to a methylation site can be cloned and/or synthesized. Any suitable label can be used with a probe. Detectable labels suitable for use with nucleic acid probes include, for example, any composition detectable by spectroscopic, radioisotopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means. Useful labels include biotin for staining with labeled streptavidin conjugate, magnetic beads, fluorescent dyes, radiolabels, enzymes, and colorimetric labels. Other labels include ligands which bind to antibodies labeled with fluorophores, chemiluminescent agents, and enzymes. A probe can also constitute radiolabelled PCR primers that are used to generate a radiolabelled amplicon. Labeling strategies for labeling nucleic acids and corresponding detection strategies can be found, e.g., in Haugland (2003) Handbook of Probes and Research Chemicals Ninth Edition by Molecular Probes, Inc. (Eugene Oreg.). Additional non-limiting details regarding sequence detection strategies are found below.

PCR, RT-PCR and LCR are in particularly broad use as amplification and amplification-detection methods for amplifying nucleic acids (e.g., those comprising a methylation site), facilitating detection of the nucleic acids of interest.

In embodiments, real time PCR or LCR is performed on the amplification mixtures described herein. e.g., using molecular beacons or TaqMan™ probes. A molecular beacon (MB) is an oligonucleotide or peptide nucleic acid (PNA) which, under appropriate hybridization conditions, self-hybridizes to form a stem and loop structure. The MB has a label and a quencher at the termini of the oligonucleotide or PNA; thus, under conditions that permit intra-molecular hybridization, the label is typically quenched (or at least altered in its fluorescence) by the quencher. Under conditions where the MB does not display intra-molecular hybridization (e.g., when bound to a target nucleic acid, e.g., to a region of an amplicon during amplification), the MB label is unquenched. Details regarding standard methods of making and using MBs are well established in the literature and MBs are available from a number of commercial reagent sources. See also, e.g., Leone et al. (1995) “Molecular beacon probes combined with amplification by NASBA enable homogenous real-time detection of RNA.” Nucleic Acids Res. 26:2150-2155; Tyagi and Kramer (1996) “Molecular beacons: probes that fluoresce upon hybridization” Nature Biotechnology 14:303-308; Blok and Kramer (1997) “Amplifiable hybridization probes containing a molecular switch” Mol Cell Probes 11:187-194; Hsuih et al. (1997) “Novel, ligation-dependent PCR assay for detection of hepatitis C in serum” J Clin Microbiol 34:501-507; Kostrikis et al. (1998) “Molecular beacons: spectral genotyping of human alleles” Science 279:1228-1229; Sokol et al. (1998) “Real time detection of DNA:RNA hybridization in living cells” Proc. Natl. Acad. Sci. U.S.A. 95:11538-11543; Tyagi et al. (1998) “Multicolor molecular beacons for allele discrimination” Nature Biotechnology 16:49-53; Bonnet et al. (1999) “Thermodynamic basis of the chemical specificity of structured DNA probes” Proc. Natl. Acad. Sci. U.S.A. 96:6171-6176; Fang et al. (1999) “Designing a novel molecular beacon for surface-immobilized DNA hybridization studies” J. Am. Chem. Soc. 121:2921-2922; Marras et al. (1999) “Multiplex detection of single-nucleotide variation using molecular beacons” Genet. Anal. Biomol. Eng. 14:151-156; and Vet et al. (1999) “Multiplex detection of four pathogenic retroviruses using molecular beacons” Proc. Natl. Acad. Sci. U.S.A. 96:6394-6399. Additional details regarding MB construction and use is found in the patent literature, e.g., U.S. Pat. No. 5,925,517 (Jul. 20, 1999) to Tyagi et al. entitled “Detectably labeled dual conformation oligonucleotide probes, assays and kits;” U.S. Pat. No. 6,150,097 to Tyagi et al (Nov. 21, 2000) entitled “Nucleic acid detection probes having non-FRET fluorescence quenching and kits and assays including such probes” and U.S. Pat. No. 6,037,130 to Tyagi et al (Mar. 14, 2000), entitled “Wavelength-shifting probes and primers and their use in assays and kits.”

PCR detection and quantification using dual-labeled fluorogenic oligonucleotide probes, commonly referred to as “TaqMan™” probes, can also be performed. These probes are composed of short (e.g., 20-25 base) oligodeoxynucleotides that are labeled with two different fluorescent dyes. On the 5′ terminus of each probe is a reporter dye, and on the 3′ terminus of each probe a quenching dye is found. The oligonucleotide probe sequence is complementary to an internal target sequence present in a PCR amplicon. When the probe is intact, energy transfer occurs between the two fluorophores and emission from the reporter is quenched by the quencher by FRET. During the extension phase of PCR, the probe is cleaved by 5′ nuclease activity of the polymerase used in the reaction, thereby releasing the reporter from the oligonucleotide-quencher and producing an increase in reporter emission intensity. Accordingly, TaqMan™ probes are oligonucleotides that have a label and a quencher, where the label is released during amplification by the exonuclease action of the polymerase used in amplification. This provides a real time measure of amplification during synthesis. A variety of TaqMan™ reagents are commercially available, e.g., from Applied Biosystems (Division Headquarters in Foster City, Calif.) as well as from a variety of specialty vendors such as Biosearch Technologies (e.g., black hole quencher probes). Further details regarding dual-label probe strategies can be found, e.g., in WO92/02638.

Other similar methods include e.g. fluorescence resonance energy transfer between two adjacently hybridized probes. e.g., using the “LightCycler™” format described in U.S. Pat. No. 6,174,670.

Amplification and Sequencing Primers

In embodiments, methylation sites are detected using primers, e.g., to amplify and/or sequence polynucleotides comprising the methylation sites.

Suitable primers can be designed and is not intended that the present subject matter be limited to any particular primer or primer pair. For example, primers can be designed using any suitable software program, such as LASERGENE™, e.g., taking account of publicly available sequence information. Flanking sequences for the methylation sites identified herein are publicly available; accordingly, suitable amplification primers can be constructed based on well understood base-pairing rules. The sequence of any amplicon can be detected as has already been discussed above. e.g., by sequencing, hybridization, array hybridization, PCR, LCR, or the like.

In embodiments, the primers are radiolabelled, or labeled by any suitable means (e.g., using a non-radioactive fluorescent tag), to allow for rapid visualization of differently sized amplicons following an amplification reaction without any additional labeling step or visualization step. In embodiments, the primers are not labeled, and the amplicons are visualized following their size resolution, e.g., following agarose or acrylamide gel electrophoresis. In embodiments, ethidium bromide staining of the PCR amplicons following size resolution allows visualization of the different size amplicons.

It is not intended that the primers be limited to generating an amplicon of any particular size. The primers can generate an amplicon of any suitable length for detection (e.g., by sequencing or hybridization). In embodiments, amplification produces an amplicon at least 20 nucleotides in length, or alternatively, at least 50 nucleotides in length, or alternatively, at least 100 nucleotides in length, or alternatively, at least 200 nucleotides in length. Amplicons of any size can be detected and/or sequenced using various technologies described herein and known in the art.

Detection of Methylation Levels Using Sequencing

Sequencing is the process of determining the precise order of nucleotides within a DNA molecule. The advent of rapid DNA sequencing methods has greatly accelerated biological and medical research and discovery. Non-limiting examples and descriptions are provided below. However, embodiments are not limited to the use of a particular sequencing assay, technology, or approach.

Sanger sequencing is a method of DNA sequencing based on the selective incorporation of chain-terminating dideoxynucleotides by DNA polymerase during in vitro DNA replication (Sanger F; Coulson A R (May 1975) J. Mol. Biol. 94 (3): 441-8; Sanger et al. (December 1977) Proc. Natl. Acad. Sci. U.S.A. 74 (12): 5463-7).

In embodiments, next-generation sequencing is used. Non-limiting examples of next-generation sequencing methods include massively parallel signature sequencing (MPSS), single-molecule real-time sequencing, ion semiconductor sequencing, pyrosequencing, sequencing by synthesis, sequencing by ligation, chain termination. DNA nanoball sequencing, helicos single molecule sequencing, single molecule real time sequencing, nanopore DNA sequencing, tunnelling currents DNA sequencing, and sequencing by hybridization.

Many commercially available sequencing technologies, devices, and services are available. In embodiments, an Illumina sequencer is used. In embodiments, PCR products are ligated with a linker and sequenced using a high throughput sequencer, such as an Illumina sequencer. In embodiments, the ligation step can be avoided, omitted, or eliminated by adding a linker to amplification primers.

Array-Based Sequence Detection

Array-based detection can be performed using commercially available arrays, e.g., from Affymetrix (Santa Clara, Calif.) or other manufacturers. Reviews regarding the operation of nucleic acid arrays include Sapolsky et al. (1999) “High-throughput polymorphism screening and genotyping with high-density oligonucleotide arrays.” Genetic Analysis: Biomolecular Engineering 14:187-192; Lockhart (1998) “Mutant yeast on drugs” Nature Medicine 4:1235-1236; Fodor (1997) “Genes. Chips and the Human Genome.” FASEB Journal 11:A879; Fodor (1997) “Massively Parallel Genomics.” Science 277: 393-395; and Chee et al. (1996) “Accessing Genetic Information with High-Density DNA Arrays.” Science 274:610-614.

A variety of probe arrays have been described in the literature and can be used for detection of methylation. For example, DNA probe array chips or larger DNA probe array wafers (from which individual chips would otherwise be obtained by breaking up the wafer) may be used in embodiments described herein. DNA probe array wafers generally comprise glass wafers on which high density arrays of DNA probes (short segments of DNA) have been placed. Each of these wafers can hold, for example, approximately 60 million DNA probes that are used to recognize longer sample DNA sequences (e.g., from individuals or populations, e.g., that comprise methylation sites of interest). The recognition of sample DNA by the set of DNA probes on the glass wafer takes place through DNA hybridization. When a DNA sample hybridizes with an array of DNA probes, the sample binds to those probes that are complementary to the sample DNA sequence. By evaluating to which probes the sample DNA for an individual hybridizes more strongly, it is possible to determine whether a known sequence of nucleic acid is present or not in the sample, thereby determining whether a uracil, thymine, or cytosine is present at a polynucleotide site corresponding to a genomic methylation site. One can also use this approach to control the hybridization conditions to permit single nucleotide discrimination, e.g., for the identification of methylation at a site of interest. Arrays provide one convenient embodiment for detecting multiple methylation sites simultaneously (or in series). Of course, any detection technology (PCR, LCR, and/or sequencing etc.) can similarly be used, e.g., with multiplex amplification/detection/sequencing reactions, or simply by running several separate reactions. e.g., simultaneously or in series.

In embodiments, the use of DNA probe arrays to obtain methylation information involves the following general steps: design and manufacture of DNA probe arrays, preparation of the sample, bisulfite treatment, hybridization of sample DNA to the array, detection of hybridization events and data analysis to determine sequence. In embodiments, an array is used to capture polynucleotides containing a methylation site of interest, and the captured polynucleotides are subsequently amplified and/or sequenced. Preferred wafers are manufactured using a process adapted from semiconductor manufacturing to achieve cost effectiveness and high quality, and are available, e.g., from Affymetrix, Inc. of Santa Clara, Calif.

For example, probe arrays can be manufactured by light-directed chemical synthesis processes, which combine solid-phase chemical synthesis with photolithographic fabrication techniques as employed in the semiconductor industry. Using a series of photolithographic masks to define chip exposure sites, followed by specific chemical synthesis steps, the process constructs high-density arrays of oligonucleotides, with each probe in a predefined position in the array. Multiple probe arrays can be synthesized simultaneously on a large glass wafer. This parallel process enhances reproducibility and helps achieve economies of scale.

In embodiments, DNA probe arrays can be used to obtain data regarding presence of sequences (e.g., corresponding to methylated or unmethylated DNA) of interest. The DNA samples may be tagged with biotin and/or a fluorescent reporter group by standard biochemical methods. The labeled samples are incubated with an array, and segments of the samples bind, or hybridize, with complementary sequences on the array. The array can be washed and/or stained to produce a hybridization pattern. The array is then scanned and the patterns of hybridization are detected by emission of light from the fluorescent reporter groups. Because the identity and position of each probe on the array is known, the nature of the DNA sequences in the sample applied to the array can be determined.

In embodiments, the nucleic acid sample to be analyzed is isolated, bisulfite-treated, amplified and, optionally, labeled with biotin and/or a fluorescent reporter group. The labeled nucleic acid sample may then incubated with the array using a fluidics station and hybridization oven. The array can be washed and or stained or counter-stained, as appropriate to the detection method. After hybridization, washing and staining, the array is inserted into a scanner, where patterns of hybridization are detected. The hybridization data are collected as light emitted from the fluorescent reporter groups already incorporated into the labeled nucleic acid, which is now bound to the probe array. Probes that most clearly match the labeled nucleic acid produce stronger signals than those that have mismatches. Since the sequence and position of each probe on the array are known, by complementarity, the identity of the nucleic acid sample applied to the probe array can be identified. In embodiments, hybridization techniques and conditions that allow only fully complementary nucleotide sequences to hybridize with probes in an array are used.

Prior to amplification and/or detection of a nucleic acid comprising a sequence of interest, the nucleic acid is optionally purified from the samples by any available method, e.g., those taught in Berger and Kimmel, Guide to Molecular Cloning Techniques, Methods in Enzymology volume 152 Academic Press. Inc., San Diego. Calif. (Berger); Sambrook et al., Molecular Cloning—A Laboratory Manual (3rd Ed.), Vol. 1-3. Cold Spring Harbor Laboratory, Cold Spring Harbor. N.Y., 2001 (“Sambrook”); and/or Current Protocols in Molecular Biology. F. M. Ausubel et al., eds., Current Protocols, a joint venture between Greene Publishing Associates. Inc, and John Wiley & Sons, Inc., (supplemented through 2002) (“Ausubel”)). A plethora of kits are also commercially available for the purification of nucleic acids from cells or other samples (see. e.g., EasyPrep™, FlexiPrep™, both from Pharmacia Biotech; StrataClean™, from Stratagene; and, QIAprep™ from Qiagen). Alternately, samples can simply be directly subjected to amplification or detection, e.g., following aliquotting and/or dilution.

Thyroid Cancer Diagnostic System and Processes

FIG. 4 depicts a block diagram illustrating an exemplary thyroid cancer diagnostic system 600. Referring to FIG. 4, the thyroid cancer diagnostic system 600 can include an input module 610, an isolation module 612, a conversion module 614, a detection module 616, a diagnosis module 618, a treatment module 620, and a user interface (UI) module 622. The thyroid cancer diagnostic system 600 can be configured to provide a diagnosis indicative of a presence of thyroid cancer and/or a risk of developing thyroid cancer. Moreover, the thyroid cancer diagnostic system 600 can be further configured to generate a treatment plan for a subject based on the diagnosis. For instance, when the diagnosis indicates a presence and/or risk of thyroid cancer in a subject, the thyroid cancer diagnostic system 600 can recommend one or more treatments including, for example, thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and administration of an active agent.

One or more modules of the thyroid cancer diagnostic system 600 can be realized in digital electronic circuitry, integrated circuitry, specially designed application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs) computer hardware, firmware, software, and/or combinations thereof. The thyroid cancer diagnostic system 600 can further be communicatively coupled with one or more devices including, for example, a device 630. The thyroid cancer diagnostic system 600 can communicate with the device 620 via a wired and/or wireless network 640 (e.g., a wide area network (WAN), a local area network (LAN), and/or the Internet). As shown in FIG. 4, the thyroid cancer diagnostic system 600 can be further coupled with a data store 650.

The input module 610 can be adapted to receive and/or collect a sample of a thyroid nodule obtained from a subject. The isolation module 612 can be configured to isolate DNA from the thyroid nodule sample received by the input module 610 thereby forming isolated thyroid nodule DNA. The conversion module 614 can be configured to treat the isolated thyroid nodule DNA including by contacting the isolated thyroid nodule DNA with one or more bisulfite reagents including, for example, a bisulfite salt. Exposing the isolated thyroid nodule DNA to one or more bisulfite reagents can convert cytosine to uracil while 5-mC is left unmodified. Thus, the 5-mC present in the isolated thyroid nodule DNA will remain in the reacted thyroid nodule DNA. Meanwhile, any cytosine in the isolated thyroid nodule DNA will be replaced by uracil in the reacted thyroid nodule DNA. In embodiments, the treatment of the isolated thyroid nodule DNA can be performed by applying one or more kits (e.g., the Bisulflash DNA Modification Kit (Epigentek) or Imprint DNA Modification Kit (Sigma)).

In embodiments, the conversion module 614 can be further adapted to ensure optimal bisulfite conversion (e.g., with desired DNA fragment size for post-bisulfite ligation) by controlling one or more of a concentration of the bisulfite reagents, temperature, and reaction time period. It should be appreciated that the conversion module 614 can be adapted to use a different and/or additional type of reagent without departing from the scope of the present subject matter. For example, the conversion module 614 can treat the isolated thyroid nodule DNA with potassium chloride, which may reduce the thermophilic DNA degradation associated with the conversion of cytosine to uracil. Moreover, the conversion module 614 can be configured to perform additional processing of the reacted thyroid nodule DNA including, for example, desulphonation (e.g., with an alkalized solution), cleansing (e.g., by elution), and amplification (e.g., using the PCR method).

The detection module 616 can be configured to detect a methylation and/or unmethylation of the thyroid nodule DNA. For instance, the detection module 616 can detect methylation by detecting a presence of uracil in the reacted thyroid nodule DNA generated by the conversion module 614. Alternately and/or additionally, the detection module 616 can detect unmethylation by detecting an absence of uracil in the reacted thyroid nodule DNA. In embodiments, the detection module 616 can be configured detect the presence and/or absence of uracil at specific methylation sites. That is, the detection module 616 can be configured to detect the presence and/or absence of uracil at specific chromosomal positions of certain chromosomes. For example, the thyroid cancer diagnostic system 600 can store a plurality of specific methylation sites (e.g., Table 1) in the data store 650. As such, to detect methylation, the detection module 616 can be configured to obtain, from the data store 650, one or more specific methylation sites at which to test for the presence and/or absence of uracil. Moreover, in embodiments, the detection module 616 can be configured to determine a level of methylation and/or unmethylation at the specific methylation sites. The level of methylation at a particular site can correspond to a proportion of the reacted thyroid nodule DNA that has a cytosine rather than a uracil at that site. By contrast, the level of unmethylation at a particular site can correspond to a proportion of reacted thyroid nodule DNA that has a uracil rather than a cytosine at that site.

In embodiments, the conversion module 614 may amplify the reacted thyroid nodule DNA such as by using a PCR method. The detection of methylation and/or unmethylation in amplified reacted thyroid nodule DNA may require detection of a presence and/or absence of thymidine at a site of interest in amplicons amplified from the reacted thyroid nodule DNA. That is, instead of detecting the presence and/or absence of uracil, the detection module 616 can be configured to detect methylation and/or unmethylation of amplified reacted thyroid nodule DNA by detecting a presence and/or absence of thymidine at specific methylation sites (e.g., as set forth in Table 1).

The diagnosis module 618 can be configured to generate a diagnosis for the subject based on whether the detection module 616 detects methylation and/or unmethylation at the plurality of specific methylation sites (e.g., Table 1). Alternately or additionally, the diagnosis module 618 can be configured to generate a diagnosis for the subject based on a level of methylation and/or unmethylation detected by the detection module 616 at the plurality of specific methylation sites. For instance, diagnosis module 618 can determine that the thyroid nodule is malignant (e.g., cancerous) when the unmethylation level (e.g., proportion of uracil) at different methylation sites exceeds the corresponding thresholds (e.g., as set forth in Table 2). In embodiments, the diagnosis module 618 can further generate a diagnosis for the subject based on one or more of the subject's PTC methylation alternation score, a BTN methylation alternation score, and/or a Composite Cancer Risk Score.

In embodiments, the diagnosis module 618 can be configured to determine a PTC methylation alternation score for the subject. In embodiments, the PTC methylation alteration score can correspond to a number of specific methylation sites (e.g., as set forth in Table 1) that have a uracil level (or corresponding thymidine level if amplicons are being analyzed) equal to or greater than the corresponding thresholds (e.g., as set forth in Table 2). Alternately or additionally, the diagnosis module 618 can be configured to determine a BTN methylation alternation score for the subject. The BTN methylation alteration score can correspond to a number of specific methylation sites (e.g., as set forth in Table 1) that have a uracil level (or corresponding thymidine level if amplicons are being analyzed) equal to or greater than the various corresponding threshold level (e.g., as set forth in Table 3 and/or Table 4).

In embodiments, the diagnosis module 618 can further be configured to compute a Composite Cancer Risk Score for the subject. The diagnosis module 618 can compute the Composite Cancer Risk Score based on the PTC methylation alteration score and the BTN methylation alteration score for the subject. For example, the Composite Cancer Risk Score for the subject can be computed based on equation (1):

$\begin{array}{cc}\frac{\left[\begin{array}{c}\mathrm{the}\mathrm{PTC}\mathrm{methylation}\mathrm{alteration}\mathrm{score}\mathrm{for}\mathrm{the}\\ \mathrm{subject}\end{array}\right]}{\left[\mathrm{BTN}\mathrm{methylation}al\mathrm{teration}\mathrm{score}\mathrm{for}\mathrm{the}\mathrm{subject}\right]}.& \left(1\right)\end{array}$

Alternately or additionally, the Composite Cancer Risk Score for the subject can be computed based on equation (2):

$\begin{array}{cc}\frac{\left[\left(\begin{array}{c}\mathrm{the}\mathrm{PTC}\mathrm{methylation}\\ \mathrm{alteration}\mathrm{score}\mathrm{for}\mathrm{the}\mathrm{subject}\end{array}\right)+1\right]}{\left[\left(\begin{array}{c}\mathrm{BTN}\mathrm{methylation}\mathrm{alteration}\mathrm{score}\mathrm{for}\\ \mathrm{the}\mathrm{subject}\end{array}\right)+1\right]}& \left(2\right)\end{array}$

The treatment module 620 can be configured to formulate a treatment plan for the subject based on the diagnosis generated by the diagnosis module 618. For instance, when the diagnosis generated by the diagnosis module 618 indicates a presence and/or risk of a malignant (e.g., cancerous) thyroid nodule, the treatment module 620 can prescribe one or more treatments including, for example, thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and administration of an active agent. In embodiments, the treatment module 620 can be configured to provide the treatment plan to the device 630 via the network 640. Alternately or additionally, the treatment module 620 can store the treatment plan in the data store 650.

The UI module 622 can be configured to generate a UI through which a user (e.g., a physician) can interface with the thyroid cancer diagnostic system 600. For example, the UI module 622 can provide one or more graphic user interfaces (GUIs) configured to display the diagnosis and/or treatment plan for the subject.

FIG. 5 depicts a flowchart illustrating an exemplary process 700 for diagnosing thyroid cancer. Referring to FIGS. 4-5, the process 700 can be performed by the thyroid cancer diagnostic system 600.

The thyroid cancer diagnostic system 600 (e.g., the input module 610) can receive a sample of a thyroid nodule from a subject (702). The thyroid cancer diagnostic system 600 (e.g., the isolation module 612) can isolate thyroid nodule DNA from the thyroid nodule sample (704). The thyroid cancer diagnostic system 600 (e.g., the conversion module 614) can treat the isolated thyroid nodule DNA with a bisulfite salt to generate reacted thyroid nodule DNA (706). Treating the isolated thyroid nodule DNA with the bisulfite salt can form a reacted thyroid nodule DNA by converting the cytosine present in the isolated thyroid nodule DNA to uracil. In embodiments, the thyroid cancer diagnostic system 600 can further process the reacted thyroid nodule DNA by desulphonating, cleansing, and/or amplifying the reacted thyroid nodule DNA.

The thyroid cancer diagnostic system 600 (e.g., the detection module 616) can detect methylation and/or unmethylation of the isolated thyroid nodule DNA by at least detecting a presence and/or absence of uracil in the reacted thyroid nodule DNA (708). In embodiments, the thyroid cancer diagnostic system 600 can be configured to detect a presence and/or absence of uracil at specific methylation sites (e.g., as set forth in Table 1). Moreover, the thyroid cancer diagnostic system 600 can be configured to detect a level of methylation and/or unmethylation at the methylation sites.

The thyroid cancer diagnostic system 600 (e.g., the diagnostics module 618) can generate a diagnosis for the subject based on the methylation and/or unmethylation of the isolated thyroid nodule DNA (710). For example, the thyroid cancer diagnostic system 600 can generate a diagnosis based on a level of methylation and/or unmethylation at a plurality of specific methylation sites. Each methylation site may be associated with a certain threshold unmethylation level (e.g., as set forth in Table 2). As such, the thyroid cancer diagnostic system 600 can determine that the thyroid nodule from the subject is malignant (e.g., cancerous) if the level of unmethylation at the plurality of methylation sites exceeds the corresponding thresholds.

The thyroid cancer diagnostic system 600 (e.g., the treatment module 620) can formulate, based on the diagnosis, a treatment plan for the subject (712). For example, when the diagnosis indicates that a presence and/or risk of malignant thyroid nodules in the subject, the thyroid cancer diagnostic system 600 can prescribe thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and/or administration of an active agent. The thyroid cancer diagnostic system 600 (e.g., the UI module 622) can provide, via a UI (e.g., GUI at the device 630), the diagnosis and/or the treatment plan for the subject (714).

FIG. 6 depicts a flowchart illustrating an exemplary process 800 for diagnosing thyroid cancer. Referring to FIGS. 4 and 6, the process 700 can be performed by the thyroid cancer diagnostic system 600.

The thyroid cancer diagnostic system 600 (e.g., the input module 610) can receive a sample of a thyroid nodule from a subject (802). The thyroid cancer diagnostic system 600 (e.g., the isolation module 612) can isolate thyroid nodule DNA from the thyroid nodule sample (804). The thyroid cancer diagnostic system 600 (e.g., the conversion module 614) can treat the isolated thyroid nodule DNA with a bisulfite salt to generate reacted thyroid nodule DNA (806).

As shown in FIG. 6, the thyroid cancer diagnostic system 600 (e.g., the conversion module 614) can amplify the reacted thyroid nodule DNA (808). For instance, the thyroid cancer diagnostic system 600 can amplify the reacted thyroid nodule DNA subsequent to treating the isolated thyroid nodule NA with the bisulfite salt to generate the reacted thyroid nodule DNA. The thyroid cancer diagnostic system 600 can detect methylation and/or unmethylation of the isolated thyroid nodule DNA by detecting a presence and/or absence of thymidine in the amplified reacted thyroid nodule DNA (810).

The thyroid cancer diagnostic system 600 (e.g., the diagnostics module 618) can generate a diagnosis for the subject based on the methylation and/or unmethylation of the isolated thyroid nodule DNA (812). Moreover, the thyroid cancer diagnostic system 600 (e.g., the treatment module 620) can formulate, based on the diagnosis, a treatment plan for the subject (814). The thyroid cancer diagnostic system 600 (e.g., the UI module 622) can provide, via a UI, the diagnosis and/or treatment plan for the subject.

It should be appreciated that the process 700 and/or 800 can include different and/or additional operations without departing from the scope of the present subject matter. Moreover, one or more operations of the process 700 and/or 800 can be omitted and/or repeated without departing from the scope of the present subject matter.

Implementations of the present subject matter can include, but are not limited to, methods consistent with the descriptions provided above as well as articles that comprise a tangibly embodied machine-readable medium operable to cause one or more machines (e.g., computers, etc.) to result in operations implementing one or more of the described features. Similarly, computer systems are also described that can include one or more processors and one or more memories coupled to the one or more processors. A memory, which can include a computer-readable storage medium, can include, encode, store, or the like one or more programs that cause one or more processors to perform one or more of the operations described herein. Computer implemented methods consistent with one or more implementations of the current subject matter can be implemented by one or more data processors residing in a single computing system or multiple computing systems. Such multiple computing systems can be connected and can exchange data and/or commands or other instructions or the like via one or more connections, including but not limited to a connection over a network (e.g. the Internet, a wireless wide area network, a local area network, a wide area network, a wired network, or the like), via a direct connection between one or more of the multiple computing systems, etc.

One or more aspects or features of the subject matter described herein can be realized in digital electronic circuitry, integrated circuitry, specially designed ASICs, FPGAs, computer hardware, firmware, software, and/or combinations thereof. These various aspects or features can include implementation in one or more computer programs that are executable and/or interpretable on a programmable system including at least one programmable processor, which can be special or general purpose, coupled to receive data and instructions from, and to transmit data and instructions to, a storage system, at least one input device, and at least one output device. The programmable system or computing system can include clients and servers. A client and server are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other.

These computer programs, which can also be referred to programs, software, software applications, applications, components, or code, include machine instructions for a programmable processor, and can be implemented in a high-level procedural language, an object-oriented programming language, a functional programming language, a logical programming language, and/or in assembly/machine language. As used herein, the term “machine-readable medium” refers to any computer program product, apparatus and/or device, such as for example magnetic discs, optical disks, memory, and Programmable Logic Devices (PLDs), used to provide machine instructions and/or data to a programmable processor, including a machine-readable medium that receives machine instructions as a machine-readable signal. The term “machine-readable signal” refers to any signal used to provide machine instructions and/or data to a programmable processor. The machine-readable medium can store such machine instructions non-transitorily, such as for example as would a non-transient solid-state memory or a magnetic hard drive or any equivalent storage medium. The machine-readable medium can alternatively or additionally store such machine instructions in a transient manner, such as for example as would a processor cache or other random access memory associated with one or more physical processor cores.

To provide for interaction with a user, one or more aspects or features of the subject matter described herein can be implemented on a computer having a display device, such as for example a cathode ray tube (CRT) or a liquid crystal display (LCD) or a light emitting diode (LED) monitor for displaying information to the user and a keyboard and a pointing device, such as for example a mouse or a trackball, by which the user may provide input to the computer. Other kinds of devices can be used to provide for interaction with a user as well. For example, feedback provided to the user can be any form of sensory feedback, such as for example visual feedback, auditory feedback, or tactile feedback; and input from the user can be received in any form, including, but not limited to, acoustic, speech, or tactile input. Other possible input devices include, but are not limited to, touch screens or other touch-sensitive devices such as single or multi-point resistive or capacitive trackpads, voice recognition hardware and software, optical scanners, optical pointers, digital MRI image capture devices and associated interpretation software, and the like.

Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results.

EMBODIMENTS

Embodiments include embodiments P1 to P41 following.

Embodiment P1

A method of detecting methylation or unmethylation of a thyroid nodule DNA of a subject, the method comprising: (i) isolating DNA from a thyroid nodule of said subject thereby forming isolated thyroid nodule DNA, (ii) contacting said isolated thyroid nodule DNA with sodium bisulfite thereby forming a reacted thyroid nodule DNA, (iii) detecting the presence or absence of uracil in said reacted thyroid nodule DNA at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of said thyroid nodule DNA of said subject.

Embodiment P2

The method of embodiment P1, further comprising determining alteration in methylation at a plurality of methylation sites set forth in Table 1.

Embodiment P3

The method of embodiment P2, said alteration comprises increase or loss of uracil level at said plurality of methylation sites.

Embodiment P4

The method of embodiment P3, wherein said uracil level is above a threshold as set forth in Table 2.

Embodiment P5

The method of embodiment P3, wherein said uracil level is above a threshold as set forth in Table 3.

Embodiment P6

The method of embodiment P3, wherein said uracil level is below a threshold as set forth in Table 4.

Embodiment P7

The method of embodiment P3, wherein said subject is a candidate thyroid cancer patient.

Embodiment P8

The method of embodiment P4, wherein said above threshold identifies said thyroid nodule as a cancerous thyroid nodule.

Embodiment P9

The method of embodiment P5, wherein said above threshold identifies said thyroid nodule as a benign thyroid nodule.

Embodiment P10

The method of embodiment P6, wherein said below threshold identifies said thyroid nodule as a benign thyroid nodule.

Embodiment P11

The method of one of the above embodiments, wherein said thyroid nodule is a specimen obtained by biopsy or by surgical resection of said subject.

Embodiment P12

The method of embodiment P11, wherein said subject has undergone thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and administration of an active agent.

Embodiment P13

The method of embodiment P12, wherein said active agent is chosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate). Sorafenib Tosylate, and Vandetanib.

Embodiment P14

A method of determining a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof, said method comprising: (i) isolating DNA from a thyroid nodule of said subject thereby forming isolated thyroid nodule DNA; (ii) contacting said isolated thyroid nodule DNA with sodium bisulfite thereby forming a reacted thyroid nodule DNA; and (iii) detecting the presence or absence of uracil in said reacted thyroid nodule DNA at a methylation site set forth in Table 1: thereby determining said thyroid cancer in said subject.

Embodiment P15

The method of embodiment P14, further comprising selecting a subject that has or is at risk for developing thyroid cancer.

Embodiment P16

The method of embodiment P14, further comprising determining alteration in methylation at a plurality of methylation sites set forth in Table 1.

Embodiment P17

The method of embodiment P16, said alteration comprises increase or loss of uracil level at said plurality of methylation sites.

Embodiment P18

The method of embodiment P17, wherein said uracil level is above a threshold as set forth in Table 2.

Embodiment P19

The method of embodiment P17, wherein said uracil level is above a threshold as set forth in Table 3.

Embodiment P20

The method of embodiment P17, wherein said uracil level is below a threshold as set forth in Table 4.

Embodiment P21

The method of embodiment P17, wherein said subject is a candidate thyroid cancer patient.

Embodiment P22

The method of embodiment P18, wherein said above threshold identifies said thyroid nodule as a cancerous thyroid nodule.

Embodiment P23

The method embodiment P19, wherein said above threshold identifies said thyroid nodule as a benign thyroid nodule.

Embodiment P24

The method of embodiment P20, wherein said below threshold identifies said thyroid nodule as a benign thyroid nodule.

Embodiment P25

The method of embodiments P14-P24, wherein said thyroid nodule is a specimen obtained by biopsy or by surgical resection of said subject.

Embodiment P26

The method of embodiment P25, wherein said subject has undergone thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and administration of an active agent, before said determination.

Embodiment P27

The method of embodiment P26, wherein said active agent is chosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), Doxorubicin Hydrochloride. Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate). Sorafenib Tosylate, and Vandetanib.

Embodiment P28

A method of treating thyroid cancer in a subject determined by the method as set forth in embodiment P22, comprising administering to said subject an active agent for treating thyroid cancer.

Embodiment P29

The method of embodiment P28, wherein said subject has undergone surgery, radiation therapy, radioactive iodine therapy, chemotherapy, or thyroid hormone therapy, before said detection of embodiment 14 at (iii).

Embodiment P30

The method of embodiment P29, wherein said active agent is chosen from Cabozantinib-S-Malate. Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and Vandetanib.

Embodiment P31

The method of one of above embodiments, wherein said subject has or is at risk of papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

Embodiment P32

A deoxyribonucleic acid 5 to 100 nucleotides in length comprising a uracil-containing sequence identical to at least a 5 contiguous nucleotide sequence within a sequence chosen from SEQ ID NO:1 to SEQ ID NO:550.

Embodiment P33

The deoxyribonucleic acid of embodiment P32 identical to 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, or 190-200 of contiguous nucleotide sequence of said sequence chosen from SEQ ID NO:1 to SEQ ID NO:550.

Embodiment P34

The deoxyribonucleic acid of embodiment P32 or P33, wherein said sequence comprises a methylation site set forth in Table 2.

Embodiment P35

The deoxyribonucleic acid of embodiment P34, wherein a plurality of methylation sites set forth in Table 2 are methylated or unmethylated.

Embodiment P36

A deoxyribonucleic acid chosen from SEQ ID NO:551 to SEQ ID NO:782, wherein said nucleic acid is hybridized to a complementary DNA sequence comprising uridine or cytosine.

Embodiment P37

The deoxyribonucleic acid of embodiment P36, further comprising an enzyme in a complex with said hybridized complementary DNA sequence.

Embodiment P38

The deoxyribonucleic acid of embodiment P37, wherein said enzyme is Taq polymerase.

Embodiment P39

A kit comprising 322 nucleic acids each independently comprising SEQ ID NO:551 to SEQ ID NO:782, wherein said nucleic acids do not simultaneously comprise the same SEQ ID NO:551 to SEQ ID NO:782.

Embodiment P40

The kit according to embodiment P39, further comprising: enzymes, reagents for deamination of cytosine, buffers, vials, plasmid vectors, control DNA, devices for collecting thyroid tissue samples, reagents for isolating DNA, reagents for labeling DNA, or any combinations thereof.

Embodiment P41

The kit according to embodiment P40, wherein the enzymes are selected from the group consisting of: thermostable DNA polymerase enzymes, restriction enzymes, and combination thereof.

Further embodiments include embodiments 1-58 following.

Embodiment 1

A method of detecting methylation or unmethylation of a thyroid nodule DNA molecule of a subject, the method comprising: (i) isolating a thyroid nodule DNA molecule from a thyroid nodule of said subject thereby forming an isolated thyroid nodule DNA molecule. (ii) contacting said isolated thyroid nodule DNA molecule with a bisulfite salt thereby forming a reacted thyroid nodule DNA molecule, (iii) detecting the presence or absence of uracil in said reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of said thyroid nodule DNA molecule of said subject.

Embodiment 2

The method of embodiment 1, further comprising detecting the presence or absence of uracil in said reacted thyroid nodule DNA molecule at a plurality of methylation sites set forth in Table 1, wherein said methylation site forms a part of said plurality of methylation sites.

Embodiment 3

The method of embodiment 1, the method further comprising: (i) isolating a plurality of thyroid nodule DNA molecules from said thyroid nodule of said subject thereby forming a plurality of isolated thyroid nodule DNA molecules, wherein said isolated thyroid nodule DNA molecule forms part of said plurality of isolated thyroid nodule DNA molecules, (ii) contacting said plurality of isolated thyroid nodule DNA molecules with said bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, wherein said reacted thyroid nodule DNA molecule forms part of said plurality of reacted thyroid nodule DNA molecules, (iii) detecting the level of reacted thyroid nodule DNA molecules in said plurality of reacted thyroid nodule DNA molecules having a uracil at a methylation site set forth in Table 1, thereby detecting the level of methylation or unmethylation in said plurality of thyroid nodule DNA molecules of said subject.

Embodiment 4

The method of embodiment 3, further comprising determining the level of uracil in said reacted thyroid nodule DNA molecule at a plurality methylation sites set forth in Table 1, wherein said methylation site forms a part of said plurality of methylation sites.

Embodiment 5

The method of embodiment 4, wherein said uracil level is above a threshold as set forth in Table 2.

Embodiment 6

The method of embodiment 4, wherein said uracil level is above a threshold as set forth in Table 3.

Embodiment 7

The method of embodiment 4, wherein said uracil level is below a threshold as set forth in Table 4.

Embodiment 8

The method of one of the above embodiments, wherein said subject is suspected of having thyroid cancer.

Embodiment 9

The method of one of the above embodiments, wherein said thyroid nodule is a specimen obtained by biopsy or by surgical resection of said subject.

Embodiment 10

The method of one of the above embodiments, wherein said subject has undergone thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and/or administration of an active agent.

Embodiment 11

The method of embodiment 10, wherein said active agent is chosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate). Doxorubicin Hydrochloride. Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and/or Vandetanib.

Embodiment 12

A method of detecting a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof, said method comprising:

• • (i) isolating a thyroid nodule DNA molecule from a thyroid nodule of said subject thereby forming an isolated thyroid nodule DNA molecule;
  • (ii) contacting said isolated thyroid nodule DNA molecule with a bisulfite salt thereby forming a reacted thyroid nodule DNA molecule; and
  • (iii) detecting the presence or absence of uracil in said reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1; thereby detecting said thyroid cancer in said subject.

Embodiment 13

The method of embodiment 12, wherein said subject (a) is a woman; (b) is about 20 to about 55 years old; (c) has a mutated Ret Proto-Oncogene; (d) has a grandparent, parent, or sibling who has been diagnosed with thyroid cancer; (e) self-identifies as being Caucasian or Asian; and/or (f) has or has had breast cancer.

Embodiment 14

The method of embodiment 12, further comprising detecting the presence or absence of uracil in said reacted thyroid nodule DNA molecule at a plurality of methylation sites set forth in Table 1, wherein said methylation site forms a part of said plurality of methylation sites.

Embodiment 15

The method of embodiment 12, the method further comprising: (i) isolating a plurality of thyroid nodule DNA molecules from said thyroid nodule of said subject thereby forming a plurality of isolated thyroid nodule DNA molecules, wherein said isolated thyroid nodule DNA molecule forms part of said plurality of isolated thyroid nodule DNA molecules, (ii) contacting said plurality of isolated thyroid nodule DNA molecules with said bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, wherein said reacted thyroid nodule DNA molecule forms part of said plurality of reacted thyroid nodule DNA molecules, (iii) detecting the level of reacted thyroid nodule DNA molecules in said plurality of reacted thyroid nodule DNA molecules having a uracil at a methylation site set forth in Table 1; thereby detecting said thyroid cancer in said subject.

Embodiment 16

The method of embodiment 15, further comprising determining the level of uracil in said reacted thyroid nodule DNA molecule at a plurality methylation sites set forth in Table 1, wherein said methylation site forms a part of said plurality of methylation sites.

Embodiment 17

The method of embodiment 16, wherein said uracil level is above a threshold as set forth in Table 2.

Embodiment 18

The method of embodiment 16, wherein said uracil level is above a threshold as set forth in Table 3.

Embodiment 19

The method of embodiment 16, wherein said uracil level is below a threshold as set forth in Table 4.

Embodiment 20

The method of one of the above embodiments, wherein said subject is suspected of having thyroid cancer.

Embodiment 21

The method of one of the above embodiments, wherein said thyroid nodule is a specimen obtained by biopsy or by surgical resection of said subject.

Embodiment 22

The method of one of the above embodiments, wherein said subject has undergone thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and administration of an active agent, before said determination.

Embodiment 23

The method of embodiment 22, wherein said active agent is chosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and.

Embodiment 24

A method of treating thyroid cancer in a subject determined by the method as set forth in any of embodiments 12 to 23, comprising administering to said subject an active agent for treating thyroid cancer.

Embodiment 25

The method of embodiment 24, wherein said subject has undergone surgery, radiation therapy, radioactive iodine therapy, chemotherapy, or thyroid hormone therapy, before said detection of claim 12 at (iii).

Embodiment 26

The method of embodiment 25, wherein said active agent is chosen from Cabozantinib-S-Malate. Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate). Doxorubicin Hydrochloride. Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate). Sorafenib Tosylate, and Vandetanib.

Embodiment 27

The method of one of the above embodiments, wherein said subject has or is at risk of papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

Embodiment 28

The method of one of the above embodiments, wherein said bisulfite salt is sodium bisulfite.

Embodiment 29

The method of one of the above embodiments, further comprising determining a papillary thyroid carcinoma (PTC) methylation alteration score for said subject, wherein the PTC methylation alteration score is equal to: the number of methylation sites in Table 1 having a uracil level equal to or greater than the corresponding threshold level set forth in Table 2.

Embodiment 30

The method of one of the above embodiments, further comprising determining a benign thyroid nodule (BTN) methylation alteration score for said subject, wherein the BTN methylation alteration score is equal to:

• • (a) the number of methylation sites in Table 1 having a uracil level equal to or greater than the corresponding threshold level set forth in Table 3;
  • (b) the number of methylation sites in Table 1 having a uracil level equal to or less than the corresponding threshold level set forth in Table 4; or
  • (c) the number of methylation sites in Table 1 having a uracil level equal to or greater than the corresponding threshold level set forth in Table 3 plus the number of methylation sites in Table 1 having a uracil level equal to or less than the corresponding threshold level set forth in Table 4.

Embodiment 31

The method of embodiment 29, further comprising calculating a Composite Cancer Risk Score for said subject.

Embodiment 32

The method of embodiment 31, wherein said Composite Cancer Risk Score for said subject equals:

• • [the PTC methylation alteration score for said subject]/[BTN methylation alteration score for said subject].

Embodiment 33

The method of embodiment 31, wherein said Composite Cancer Risk Score for said subject equals:

• • [(the PTC methylation alteration score for said subject)+1]/[(BTN methylation alteration score for said subject)+1].

Embodiment 34

The method of one of embodiments 29 to 33, wherein said subject is identified as being at risk of developing thyroid cancer or diagnosed as having thyroid cancer if (a) the PTC methylation alteration score for said subject is at least 5, 6, 7, 8, 9, or 10; (b) the BTN methylation alteration score for said subject is at least 5, 6, 7, 8, 9, or 10; and/or (c) the Composite Cancer Risk Score for said subject is at least about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0.

Embodiment 35

The method of one of embodiments 29 to 33, wherein said subject is treated for thyroid cancer or directed to receive additional screening for thyroid cancer if (a) the PTC methylation alteration score for said subject is at least 5, 6, 7, 8, 9, or 10; (b) the BTN methylation alteration score for said subject is at least 5, 6, 7, 8, 9, or 10; and/or (c) the Composite Cancer Risk Score for said subject is at least about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0.

Embodiment 36

A deoxyribonucleic acid at least 5 to 100 nucleotides in length comprising a uracil-containing sequence that is identical to a sequence of at least a 5 contiguous nucleotides within a sequence chosen from SEQ ID NO: 1 to SEQ ID NO:550.

Embodiment 37

The deoxyribonucleic acid of embodiment 36, comprising a uracil-containing sequence that is identical to a sequence of at least 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70.70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, or 190-200 contiguous nucleotides within said sequence chosen from SEQ ID NO:1 to SEQ ID NO:550.

Embodiment 38

The deoxyribonucleic acid of embodiment 36 or 37, wherein said sequence comprises a methylation site set forth in Table 1.

Embodiment 39

The deoxyribonucleic acid of one of embodiments 36 to 38, wherein a plurality of methylation sites set forth in Table 1 contain a uracil or a cytosine.

Embodiment 40

A deoxyribonucleic acid chosen from SEQ ID NO:551 to SEQ ID NO:782, wherein said nucleic acid is hybridized to a complementary DNA sequence comprising uridine or cytosine.

Embodiment 41

The deoxyribonucleic acid of embodiment 40, further comprising an enzyme in a complex with said hybridized complementary DNA sequence.

Embodiment 42

The deoxyribonucleic acid of embodiment 41, wherein said enzyme is Taq polymerase.

Embodiment 43

A kit comprising a plurality of nucleic acids each independently comprising SEQ ID NO:551 to SEQ ID NO:782, wherein each nucleic acid of said plurality is unique.

Embodiment 44

The kit according to embodiment 43, further comprising: an enzyme, a reagent for deamination of cytosine, a buffer, a vial, a plasmid vector, a control DNA, a device for collecting a thyroid tissue sample, a reagent for isolating DNA, a reagent for labeling DNA, or any combination thereof.

Embodiment 45

The kit according to embodiment 44, wherein the enzyme comprises a thermostable DNA polymerase enzyme and/or a restriction enzyme.

Embodiment 46

A system for detecting methylation or unmethylation of a thyroid nodule deoxyribonucleic acid (DNA) of a subject, the system comprising:

• • at least one processor; and
  • at least one memory including program code which when executed by the at least one memory provides operations comprising:
  • isolating a thyroid nodule DNA molecule from a thyroid nodule of said subject thereby forming an isolated thyroid nodule DNA molecule;
  • contacting said isolated thyroid nodule DNA molecule with a bisulfite salt thereby forming a reacted thyroid nodule DNA molecule;
  • detecting the presence or absence of uracil in said reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of said thyroid nodule DNA molecule of said subject;
  • generating a diagnosis for said subject based at least in part on the presence or absence of uracil in said reacted thyroid nodule DNA molecule at the methylation site set forth in Table 1; and
  • providing, via a user interface, the diagnosis for said subject.

Embodiment 47

The system of embodiment 46, wherein the system is further configured to detect the presence or absence of uracil in said reacted thyroid nodule DNA molecule at a plurality of methylation sites set forth in Table 1, wherein said methylation site forms a part of said plurality of methylation sites.

Embodiment 48

The system of embodiment 46, wherein the system is further configured to: (i) isolate a plurality of thyroid nodule DNA molecules from said thyroid nodule of said subject thereby forming a plurality of isolated thyroid nodule DNA molecules, wherein said isolated thyroid nodule DNA molecule forms part of said plurality of isolated thyroid nodule DNA molecules, (ii) contact said plurality of isolated thyroid nodule DNA molecules with said bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, wherein said reacted thyroid nodule DNA molecule forms part of said plurality of reacted thyroid nodule DNA molecules, (iii) detect the level of reacted thyroid nodule DNA molecules in said plurality of reacted thyroid nodule DNA molecules having a uracil at a methylation site set forth in Table 1, thereby detecting the level of methylation or unmethylation in said plurality of thyroid nodule DNA molecules of said subject.

Embodiment 49

The system of embodiment 48, wherein the system is further configured to detect the level of uracil in said reacted thyroid nodule DNA molecule at a plurality methylation sites set forth in Table 1, wherein said methylation site forms a part of said plurality of methylation sites.

Embodiment 50

The system of embodiment 49, wherein said uracil level is above a threshold as set forth in Table 2.

Embodiment 51

The system of embodiment 49, wherein said uracil level is above a threshold as set forth in Table 3.

Embodiment 52

The system of embodiment 49, wherein said uracil level is below a threshold as set forth in Table 4.

Embodiment 53

The system of embodiment 49, wherein said subject is a candidate thyroid cancer patient.

Embodiment 54

The system of one of embodiments 46 to 53, wherein said thyroid nodule is a specimen obtained by biopsy or by surgical resection of said subject.

Embodiment 55

The system of one of embodiments 46 to 54, wherein said subject has undergone thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and/or administration of an active agent.

Embodiment 56

The system of embodiment 55, wherein said active agent is chosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), Sorafenib Tosylate, and Vandetanib.

Embodiment 57

The system of one of embodiments 46 to 56, wherein the system is further configured to:

• • formulate, based at least in part on the diagnosis, a treatment plan for said subject; and
  • provide, via the user interface, the treatment plan.

Embodiment 58

The system of embodiment 57, wherein the treatment plan includes one or more of thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and administration of an active agent.

EXAMPLES

Example 1

Human frozen specimens were blindly evaluated by a pathologist. In the study, 28 benign nodules and 40 thyroid cancer specimens were analyzed.

DNA Methylation Profiling

Genomic DNA was isolated by using a standard phenol/chloroform extraction approach followed by ethanol precipitation. Further, genomic DNA underwent Reduced Representation Bisulfite Sequencing (RRBS) procedure. RRBS DNA amplicons were paired-end sequenced by using Hiseq 2500 (Illumina). For each sample, at least 15 million aligned reads were obtained. BTN and PTC specific signatures were determined based on cytosines which are characterized by at least 5 sequencing reads in each sample.

Identification of BTN Specific and PTC Specific DNA Methylation Changes

DNA methylation patterns were analyzed in 114 thyroid specimens including 28 benign nodules, 40 thyroid cancer, and 46 adjacent normal thyroid tissues, to identify the presence of thyroid cancer specific and benign nodule specific signatures. After genome alignment, a search was performed for DNA regions which have BTN or PTC specific alterations. For identification of a DNA region with a BTN specific loss of DNA methylation, DNA regions were identified which had a DNA methylation level in at least 6 out 28 that was at least 2-fold less than the level of methylation in the same DNA region any analyzed PTC specimen, where the lowest value of DNA methylation at this DNA region among all PTC specimens is 20% or higher (FIG. 1A). For identification of DNA regions with BTN specific DNA methylation accumulation, the following criteria were used; a level of DNA methylation in an individual BTN that is at least 2-fold higher than the level of DNA methylation in the same DNA region in any analyzed PTC; where the value of DNA methylation of analyzed BTN specimen is at least 20% or more greater (FIG. 1B). The BTN signature includes DNA regions which were affected by DNA methylation loss in at least 6 out 28 analyzed BTN samples and regions which were affected by DNA methylation accumulation in at least 6 out 28 analyzed BTN samples.

Further, regions were determined which undergo PTC specific DNA methylation alterations. The criteria for the identification of DNA regions with a PTC specific loss of DNA methylation, was: a level of DNA methylation in 6 out of 46 PTC that is 2-fold less than in any analyzed adenoma and any normal matching tissue, where the lowest value of DNA methylation in the region among all non-malignant specimens is 20% or higher. The criteria for the identification of DNA regions with PTC specific DNA methylation accumulation was a level of DNA methylation in an individual PTC that is at least 2-fold higher than the level of methylation in any analyzed adenoma and normal matching tissue, where the value of DNA methylation in analyzed PTC sample should be 20% or higher. There were no DNA regions that were affected by DNA methylation accumulation in at least 6 PTC out 46 analyzed PTC. Therefore, the PTC specific DNA methylation signatures contain only DNA regions which are affected by DNA methylation loss in at least 6 out 46 analyzed PTC.

The total number of identified DNA regions which fall in PTC specific or BTN specific signature is 258, which comprises DNA methylation information for 364 cytosines (FIG. 2A). There are 230 cytosines which characterize the PTC signature and 134 cytosines characterizing the BTN signature.

Evaluation of the cancer specific and benign specific changes revealed that 10 out of 40 thyroid cancer specimens are characterized by few (less than 5) or no cancer specific changes, and 4 out 28 benign nodules indicated very few (less than 5) benign specific changes (FIG. 2A). Since the approach described herein is based on the identification of the tissue specific alterations, these specimens were determined to be “epigenetically indeterminate.”

For specimens with a determinate epigenetic state, clustering analysis revealed a strict separation of thyroid cancer from benign nodules based on DNA methylation levels of cytosines associated with benign and cancer scores (FIG. 2B). Thus, the use of benign and cancer scores can provide a unique thyroid nodule diagnostic tool.

Development of Diagnostic Panel Based on BTN/PTC Signature Scores.

The data disclosed herein demonstrates that analysis of DNA methylation of one or more of 258 DNA regions can provide substantial information regarding a presence of malignancy in thyroid samples. Therefore, DNA methylation analysis within BTN and PTC signature can be used as a PTC diagnostic tool. According to the data, PTC diagnosis can be made by using both BTN and PTC signatures. Each signature can be a score based on the number of specific alterations within the signature for each individual sample. For example, the number of BTN specific alterations within BTN signature DNA regions reflects a BTN signature score. At the same time, the number of PTC specific alterations for DNA regions within PTC signature group indicates PTC signature score.

In order to validate the approach disclosed herein and estimate an accuracy of the proposed signatures, a statistical analysis was performed based on the leave-one-out-cross-validation technique. Specifically, cancer and benign scores were determined for each individual nodule by using benign and cancer signatures which were developed based on DNA methylation patterns of the rest of samples excluding the testing sample. In order to predict benign and cancer scores for 68 nodules, 68 benign and cancer unique predictive signatures were developed.

After cross-validation. DNA methylation signatures (score >=5) were observed in 80% (32 out 40) of thyroid cancers and 82% (23 out 28) of benign nodules (FIG. 3A). These specimens with a determinate epigenetic state were used for the further analysis.

According to the cross-validation observations, both, benign and malignant diagnostic scores provided accurate results for thyroid nodule diagnostics (FIG. 3A). However, a combining of benign and malignant scores into a cancer risk score is associated with even higher diagnostic performance. The cancer risk score was calculated using the following equation: Cancer Risk Score=(cancer score+1)/(benign score+1)

According to the data herein, specimens with cancer risk score above 2.6 represent thyroid cancer and specimens with cancer score below 2.6 are benign nodules. Based on these criteria, all 23 nodules were correctly diagnosed as benign and 30 out 32 thyroid malignancies were diagnosed as a cancer (FIG. 3B). Therefore, the test had a specificity of 100% and a sensitivity of 94%, with a 100% positive predictive value (PPV) and a 92% negative predictive value (NPV). These data suggest that DNA methylation analysis of 258 DNA regions in thyroid specimens can serve as a potential diagnostic tool for the determination of malignancy.

An algorithm for performing a thyroid nodule diagnostic evaluation is shown in FIG. 3C. Specimens with benign and malignant signatures are associated with indeterminate epigenetic state and were excluded from the study. Specimens with a cancer risk score above 2.6 are considered to be malignant, and thyroid nodules with a cancer risk score below 2.6 are considered to be benign.

This scoring approach clearly differentiates benign from malignant specimens. These data suggest that DNA methylation analysis of 258 DNA regions in thyroid specimens, including potentially FNA specimens, can serve as a diagnostic tool for the determination of malignancy.

The data indicates that malignancy of thyroid specimens can be determined by DNA methylation pattern analysis of one or more of 258 different DNA regions.

Claims

1. A method of detecting methylation or unmethylation of a thyroid nodule DNA molecule of a subject, the method comprising: (i) isolating a thyroid nodule DNA molecule from a thyroid nodule of said subject thereby forming an isolated thyroid nodule DNA molecule, (ii) contacting said isolated thyroid nodule DNA molecule with a bisulfite salt thereby forming a reacted thyroid nodule DNA molecule, (iii) detecting the presence or absence of uracil in said reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of said thyroid nodule DNA molecule of said subject.

2. (canceled)

3. The method of claim 1, the method further comprising: (i) isolating a plurality of thyroid nodule DNA molecules from said thyroid nodule of said subject thereby forming a plurality of isolated thyroid nodule DNA molecules, wherein said isolated thyroid nodule DNA molecule forms part of said plurality of isolated thyroid nodule DNA molecules, (ii) contacting said plurality of isolated thyroid nodule DNA molecules with said bisulfite salt thereby forming a plurality of reacted thyroid nodule DNA molecules, wherein said reacted thyroid nodule DNA molecule forms part of said plurality of reacted thyroid nodule DNA molecules, (iii) detecting the level of reacted thyroid nodule DNA molecules in said plurality of reacted thyroid nodule DNA molecules having a uracil at a methylation site set forth in Table 1, thereby detecting the level of methylation or unmethylation in said plurality of thyroid nodule DNA molecules of said subject.

4. The method of claim 3, further comprising determining the level of uracil in said reacted thyroid nodule DNA molecule at a plurality methylation sites set forth in Table 1, wherein said methylation site forms a part of said plurality of methylation sites.

5. The method of claim 4, wherein said uracil level is (a) above a threshold as set forth in Table 2;(b) above a threshold as set forth in Table 3; or(c) below a threshold as set forth in Table 4.

6.-8. (canceled)

9. The method of claim 1, wherein said thyroid nodule is a specimen obtained by biopsy or by surgical resection of said subject.

10. (canceled)

11. (canceled)

12. A method of detecting a thyroid cancer or risk of developing thyroid cancer in a subject in need thereof, said method comprising detecting methylation or unmethylation of a thyroid nodule DNA molecule of said subject by the method set forth in claim 1.

13. The method of claim 12, wherein said subject (a) is a woman; (b) is about 20 to about 55 years old; (c) has a mutated Ret Proto-Oncogene; (d) has a grandparent, parent, or sibling who has been diagnosed with thyroid cancer; (e) self-identifies as being Caucasian or Asian; and/or (f) has or has had breast cancer.

14.-21. (canceled)

22. The method of claim 12, wherein said subject has undergone thyroid surgery, radiation therapy, radioactive iodine therapy, chemotherapy, thyroid hormone therapy, and administration of an active agent, before said determination.

23. The method of claim 22, wherein said active agent is chosen from Cabozantinib-S-Malate, Caprelsa (Vandetanib), Cometriq (Cabozantinib-S-Malate), Doxorubicin Hydrochloride, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Nexavar (Sorafenib Tosylate), and Sorafenib Tosylate.

24. A method of treating thyroid cancer in a subject determined by the method as set forth in claim 12, comprising administering to said subject an active agent for treating thyroid cancer.

25.-27. (canceled)

28. The method of claim 1, wherein said bisulfite salt is sodium bisulfite.

29. The method of claim 12, further comprising determining a papillary thyroid carcinoma (PTC) methylation alteration score for said subject, wherein the PTC methylation alteration score is equal to: the number of methylation sites in Table 1 having a uracil level equal to or greater than the corresponding threshold level set forth in Table 2.

30. The method of claim 12, further comprising determining a benign thyroid nodule (BTN) methylation alteration score for said subject, wherein the BTN methylation alteration score is equal to: (a) the number of methylation sites in Table 1 having a uracil level equal to or greater than the corresponding threshold level set forth in Table 3;(b) the number of methylation sites in Table 1 having a uracil level equal to or less than the corresponding threshold level set forth in Table 4; or(c) the number of methylation sites in Table 1 having a uracil level equal to or greater than the corresponding threshold level set forth in Table 3 plus the number of methylation sites in Table 1 having a uracil level equal to or less than the corresponding threshold level set forth in Table 4.

31. The method of claim 29, further comprising calculating a Composite Cancer Risk Score for said subject, wherein said Composite Cancer Risk Score for said subject equals: [the PTC methylation alteration score for said subject]/[BTN methylation alteration score for said subject]; or[(the PTC methylation alteration score for said subject)+1]/[(BTN methylation alteration score for said subject)+1].

32. (canceled)

33. (canceled)

34. The method of claim 29, wherein said subject is identified as being at risk of developing thyroid cancer or diagnosed as having thyroid cancer if (a) the PTC methylation alteration score for said subject is at least 5, 6, 7, 8, 9, or 10; (b) the BTN methylation alteration score for said subject is at least 5, 6, 7, 8, 9, or 10; and/or (c) the Composite Cancer Risk Score for said subject is at least about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0.

35. The method of claim 29, wherein said subject is treated for thyroid cancer or directed to receive additional screening for thyroid cancer if (a) the PTC methylation alteration score for said subject is at least 5, 6, 7, 8, 9, or 10; (b) the BTN methylation alteration score for said subject is at least 5, 6, 7, 8, 9, or 10; and/or (c) the Composite Cancer Risk Score for said subject is at least about 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0.

36. A deoxyribonucleic acid at least 5 to 100 nucleotides in length comprising a uracil-containing sequence that is identical to a sequence of at least a 5 contiguous nucleotides within a sequence chosen from SEQ ID NO:1 to SEQ ID NO:550.

37. (canceled)

38. The deoxyribonucleic acid of claim 36, wherein said sequence comprises a methylation site set forth in Table 1.

39.-42. (canceled)

43. A kit comprising a plurality of nucleic acids each independently comprising SEQ ID NO:551 to SEQ ID NO:782, wherein each nucleic acid of said plurality is unique.

44. (canceled)

45. (canceled)

46. A system for detecting methylation or unmethylation of a thyroid nodule deoxyribonucleic acid (DNA) of a subject, the system comprising: at least one processor, andat least one memory including program code which when executed by the at least one memory provides operations comprising:isolating a thyroid nodule DNA molecule from a thyroid nodule of said subject thereby forming an isolated thyroid nodule DNA molecule;contacting said isolated thyroid nodule DNA molecule with a bisulfite salt thereby forming a reacted thyroid nodule DNA molecule;detecting the presence or absence of uracil in said reacted thyroid nodule DNA molecule at a methylation site set forth in Table 1, thereby detecting methylation or unmethylation of said thyroid nodule DNA molecule of said subject;generating a diagnosis for said subject based at least in part on the presence or absence of uracil in said reacted thyroid nodule DNA molecule at the methylation site set forth in Table 1; andproviding, via a user interface, the diagnosis for said subject.

47.-58. (canceled)