WO2018119216A1 - Deconvolution and detection of rare dna in plasma - Google Patents

Abstract

Some embodiments relate to a method for detecting the presence of one or more nucleic acids indicative of a health condition, tissue of origin, germ layer of origin or organ of origin in a mixture of nucleic acids comprising performing methylation analysis on a sample comprising a plurality of nucleic acids and determining whether the sample includes a plurality of methylation haplotype blocks indicative of the presence one or more nucleic acids indicative of a health condition, tissue of origin, germ layer of origin or organ of origin wherein the methylation haplotype blocks comprise a plurality of methylation sites for which the methylation status is coordinated.

Description

DECONVOLUTION AND DETECTION OF RARE DNA IN PLASMA

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the priority benefit of U.S. Provisional Patent Application No. 62/438,401, filed December 21, 2016, the entire contents of which is incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED R&D

[0002] This invention was made with government support under Grant Number

R01GM097253 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

Field of the Invention

[0003] Some embodiments described herein relate to compositions and methods for detecting a target nucleic acid in a sample. For example, some embodiments may be used for non-invasive detection of tumors or organ damage. Other embodiments may be used, for example, for detection of fetal aneuploidy at a very early stage of pregnancy.

Description of Related Art

[0004] CpG methylation in mammalian genomes is a relatively stable epigenetic modification, which can be transmitted across cell division (Wigler et al. (1981)) through DNMT1, and dynamically established, or removed by DNMT3 A/B and TET proteins. Due to the processivity of some of these enzymes, physically adjacent CpG sites on the same DNA molecules can share similar methylation status, although discordant CpG methylation has also been observed, especially in cancer cells. The theoretical framework of linkage disequilibrium (Slatkin (2008)), which was developed to model the coordinated segregration of adjacent genetic variants on human chromosomes among human populations, can be applied to the analysis of CpG co-methylation in cell populations. A number of studies related to the concepts of methylation haplotypes, epi-alleles, or epi-haplotypes have been reported, albeit at small numbers of genomic regions or limited numbers of cell/tissue types. Recent data production efforts, especially by large consortia such as the NIH RoadMap Epigenomics project (Bernstein et al. (2010)) and the EU Blueprint Epigenome project (Jones et al. (2005)) have produced a large number of whole-genome, base-resolution bisulfite sequencing data sets for many tissue and cell types. These public data sets, in combination with additional WGBS data generated, allowed full-genome characterization of local coupled CpG methylation across the largest set of human tissue types available to date to be performed, and annotate these blocks of co- methylated CpGs as a distinct set of genomic features.

[0005] DNA methylation is cell-type specific, and the pattern can be harnessed for deconvoluting the relative cell composition of heterogeneous samples, such as different white blood cells in whole blood (Houseman et al. (2016)), fetal components in maternal cell-free DNA (Sun et al. (2015)), or circulating tumor DNA in plasma (Sun et al. (2015)). Most of these recent efforts rely on the methylation level of individual CpG sites, and are fundamentally limited by the technical noise and sensitivity in measuring single CpG methylation. Very recently, Lehmann-Werman et al. demonstrated a superior sensitivity with multi-CpG haplotypes in detecting tissue-specific signatures in circulating DNA (Lehmann-Werman et al. (2016)). The markers in that study were discovered from Infinium 450k methylation array data, which represent only a very limited fraction of the human genome.

SUMMARY OF THE INVENTION

[0006] Some embodiments described herein provide accurate tissue-of-origin mapping based on comparing the patterns and abundance of methylation haplotypes against a reference set of human reference tissues and provide accurate quantitative estimation of the cancer DNA fraction.

[0007] Some embodiments are described in the following numbered paragraphs:

1. A method for detecting the presence of one or more nucleic acids indicative of a health condition, tissue of origin, germ layer of origin or organ of origin in a mixture of nucleic acids comprising:

performing methylation analysis on a sample comprising a plurality of nucleic acids; and

determining whether said sample includes a plurality of methylation haplotype blocks indicative of the presence one or more nucleic acids indicative of a health condition, tissue of origin, germ layer of origin, organ of origin or any combination thereof, wherein said methylation haplotype blocks comprise a plurality of methylation sites for which the methylation status is coordinated. 2. The method of Paragraph 1, wherein said methylation analysis is performed on cell-free DNA.

3. The method of any one of Paragraphs 1 and 2, wherein said methylation analysis is performed on cell-free DNA in a blood sample.

4. The method of any one of Paragraphs 1-3 wherein said plurality of methylation haplotype blocks comprises at least 2, at least 3, at least 4, at least 5, at least 10, at least 20, at least 40, at least 50, at least 100, at least 200, at least 300, at least 400, at least 500 or more than 500 methylation haplotype blocks.

5. The method of any one of Paragraphs 1-4, wherein said health condition is a tumor.

6. The method of Paragraph 5, further comprising determining whether said sample includes a plurality of methylation haplotype blocks indicative of the presence of one or more nucleic acids indicative of a normal tissue or normal organ corresponding to the tissue or organ of origin of said tumor.

7. The method of any one of Paragraphs 1-6, wherein said health condition is fetal aneuploidy.

8. The method of any one of Paragraphs 1-7, wherein said sample is a blood sample.

9. The method of any one of Paragraphs 1-8, further comprising quantitating the level of said one or more nucleic acids indicative of a health condition, tissue of origin, organ of origin or any combination thereof in said sample.

10. The method of any one of Paragraphs 1-9, wherein said methylation analysis is performed using a technique selected from the group consisting of bisulfite methylation analysis, reduced representation bisulfite sequencing, WGBS, BSPP, micro-droplet PCR, selector probe based methods, and MeDiP.

11. The method of any one of Paragraphs 1-10, further comprising determining a methylated haplotype load or unmethylated haplotype load for each methylation haplotype block, wherein said methylation haplotype load comprises the normalized fraction of methylated haplotypes at different lengths and the unmethylated haplotype load comprises the normalized fraction of unmethylated haplotypes at different lengths. 12. The method of any one of Paragraphs 1-11, wherein said methylation haplotype blocks have an average size of 95bp.

13. The method of any one of Paragraphs 1-12, wherein said methylation haplotype blocks have a minimum of 3 CpGs per block.

14. The method of any one of Paragraphs 1-13 further comprising quantifying the level of said plurality of methylation haplotype blocks indicative of the presence of one or more nucleic acids indicative of a health condition, tissue of origin, germ layer of origin, organ of origin or any combination thereof in said sample.

15. The method of Paragraph 6 further comprising quantifying the level of said plurality of methylation haplotype blocks indicative of the presence of a tumor in said sample and quantifying the level of said plurality of methylation haplotype blocks indicative of the presence of one or more nucleic acids indicative of a normal tissue or normal organ corresponding to the tissue or organ of origin of said tumor in said sample.

16. A method of identifying methylation haplotype blocks comprising: determining methylation haplo types in a plurality of nucleic acid segments; combining the methylation haplotypes and calculating methylation linkage disequilibrium on the combined methylation haplotypes; and

partitioning each segment into a plurality of methylation haplotype blocks, wherein said methylation haplotype blocks comprise a plurality of methylation sites for which the methylation status is coordinated.

17. The method of Paragraph 16, wherein said methylation haplotypes are determined for a portion of a genome.

18. The method of any one of Paragraphs 16 and 17, wherein said methylation haplotypes are determined across a whole genome.

19. The method of any one of Paragraphs 16-18, wherein said methylation haplotype blocks are defined as the genomic region in which the r² value of two adjacent CpG sites is no less than 0.5.

20. The method of any one of Paragraphs 16-19, wherein said methylation haplotype blocks are identified in nucleic acids from a tumor tissue.

21. The method of any one of Paragraphs 16-20, wherein said methylation haplotype blocks are identified in nucleic acids from a known type of tissue. 22. The method of any one of Paragraphs 16-21, wherein said methylation haplotype blocks are identified in nucleic acids from a fetus.

23. The method of any one of Paragraphs 16-22, wherein said methylation haplotype blocks are identified in nucleic acids from an embryonic stem cell.

24. The method of any one of Paragraphs 16-23, wherein said methylation haplotype blocks are identified in nucleic acids from a known germ layer.

25. The method of any one of Paragraphs 16-24, wherein said methylation haplotype blocks have an average size of 95bp.

26. The method of any one of Paragraphs 16-25, wherein said methylation haplotype blocks have a minimum of 3 CpGs per block.

27. The method of any one of Paragraphs 16-26, wherein said methylation haplotype blocks are identified in nucleic acid regions from a Whole Genome Bisulfite Sequencing analysis.

28. The method of any one of Paragraphs 16-27, wherein said methylation haplotype blocks are identified in data sets from methylation analysis of ENCODE cell lines or tissue samples.

29. The method of any one of Paragraphs 16-28, wherein said methylation haplotype blocks are identified in data sets from methylation analysis of Infinium HumanMethylation450 BeadChip (HM450K).

30. The method of any one of Paragraphs 16-29, further comprising calculating the pairwise correlation coefficient of adjacent CpG methylation levels across different sample sets for block partitioning.

31. The method of any one of Paragraphs 16-30, further comprising determining methylation haplotype load for each methylation haplotype block, wherein said methylation haplotype load comprises the normalized fraction of methylated haplo types at different lengths.

32. The method of any one of Paragraphs 16-30, further comprising determining unmethylated haplotype load for each methylation haplotype block, wherein said unmethylated haplotype load comprises the normalized fraction of unmethylated haplotypes at different lengths.

BRIEF DESCRIPTION OF THE DRAWINGS [0008] Figures l(a)-l(e). Identification and characterization of human methylation haplotype blocks (MHBs). Fig. 1(a) Schematic overview of data collection, generation, and analysis. Fig. 1(b) An example of MHB at the promoter of the gene APC. Fig. 1(c) Smooth scatterplots of methylation linkage disequilibrium decay of adjacent CpG sites over larger distances. 500,000 adjacent CpG loci in MHB regions were randomly sampled and their corresponding r² values within different sets of cell types were plotted to demonstrate the differential decay characteristics. The dotted lines at high linkage (r² = 0.9) is where stem and progenitor cells (10 WGBS samples), normal adult tissue cells (49 WGBS samples), and primary tumor (6 WGBS samples) cells were found to have 94.8%, 91.2% and 87.8% of CpGs respectively. Fig. 1(d) Co-localization analysis of MHBs with known genomic features. Genome distribution (left) and CpG-island relationships (right). Fig. 1(e). Enrichment of MHBs in known genomic features. Bootstrap random sampling regions with same size for 10,000 times to estimate empirical statistical significance and enrichment factor (fold-change).

[0009] Figure 2. Comparison of methylation haplotype load with four metrics used in the literature. Five patterns of methylation haplotype combinations are used to illustrate the difference between methylation frequency, methylation entropy, epi-polymorphism and methylation haplotype load. Methylation haplotype load can discriminate all the five patterns while other metrics cannot.

[0010] Figures 3(a)-3(b). Heatmaps of tissue specific MHBs. Fig. 3(a) Heatmap of MHL values for tissue specific MHBs selected by MHL. Fig. 3(b) Heatmap of uMHL values for tissue specific MHBs selected by uMHL.

[0011] Figure 4. Comparison of signal to noise ratio between average methylation frequency (AMF) and methylation haplotype load (MHL) metrics at tissue specific differentially methylated loci (Lokk et al. (2014)). For most loci, the MHL metric had a much higher signal to noise ratio than the AMF metric even though these loci were selected using AMF for another data set.

[0012] Figure 5. Heatmap of the MHL in plasma samples in test sets and primary cancer tissues for colon cancer markers (left) and lung cancer markers (right). Cancer markers were identified by comparison of the respective cancer tissues against background (normal plasma set aside for features selection).

[0013] Figure 6. Boxplots of average MHL in plasma samples in test sets and cancer tissues for colon cancer markers (left) and lung cancer markers (right). The cancer markers were significantly (Two Sample one-sided T-Test) different between the test sets of normal plasma (NP) and cancer plasma (CCP = colon cancer plasma, LCP = lung cancer plasma). The marker regions were highly methylated in tumor tissues (CCT = colon cancer tissue, LCT = lung cancer tissue).

[0014] Figure 7. Simulated standard curves for estimation of tumor fraction. The mean for each cancer fraction from 20 simulations plotted with standard deviations as error bars. A fitted linear model on the standard curve for colon cancer had an adjusted r² of 0.9621 and the fitted linear model for lung cancer had an adjusted r² of 0.9573.

[0015] Figure 8. The tumor fraction between test sets of cancer and normal plasma samples. Cancer plasma (n = 30 colon cancer, n= 29 lung cancer) had significantly elevated tumor fractions (Two Sample t-test with unequal variance) when compared with normal plasma (n=23) using either colon cancer markers (left) or lung cancer markers (right).

[0016] Figures 9(a)-9(c). Results of MARS- based binary classification for test plasma data sets. The set of tissue-specific markers derived from an independent set of normal tissue data was able to segregate each class of plasma samples from the other classes in a binary fashion. Fig. 9(a) Normal vs other. Fig. 9(b) Colon vs other. Fig. 9(c) Lung vs other.

[0017] Figure 10. Confusion matrix of MARS-based feature selection and PLSDA prediction of tissue-of-origin in the test plasma data set. The set of lung and colon tissue specific markers identified from an independent data set was able to correctly classify 74% of the test plasma samples.

[0018] Figures 11 (a)- 11(c). Characteristics of MHB in human genome. Fig. 11(a) Distribution of MHB sizes. Fig. 11(b) Distribution of CpG density (CpGs/bp) in MHB regions. Fig. 11(c) Co-localization of MHB with known genomics features breaking down based on CpG density. MHBs were placed in quartiles where the CpGs/bp of MHBs within quartiles were as follows (0, 0.46), (0.046, 0.096), (0.096, 0.155), and (0.155, 0.6). The 1^st quartile (MHBs with lowest CpG density) was mostly CGI shelves or shores, and was enriched for LAD, LOCK, and enhancers.

[0019] Figures 12(a)-12(b). Validation of MHB with Illumina 450k methylation array and RRBS data. Fig. 12(a) Pearson correlation coefficient (r²) versus absolute LD r². Fig. 12(b) The Pearson correlation coefficient r² in RRBS and HM450K were significantly higher in overlapped MHBs with WGBS compared with the MHBs without overlapping with WGBS MHBs. IN: denotes RRBS or HM450K regions within MHB. OUT: denotes RRBS or HM450K regions beyond MHB regions.

[0020] Figure 13. The distribution of incidence of cancer-associated high-methylated haplotypes (caHMH) in colon cancer (CRC) and lung cancer (LC) plasma samples. Y-axis denotes the frequency of caHMH and x-axis denotes the incidence (number of samples) of the caHMH in cancer plasmas. A majority of caHMH are patient specific.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art pertinent to the methods and systems described. As used herein, the following terms and phrases have the meanings ascribed to them unless specified otherwise. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entirety.

[0022] "A," "an," and "the" include plural referents, unless the context clearly indicates otherwise. For example, "a nucleic acid" as used herein is understood to represent one or more nucleic acids. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0023] "About" is used herein to mean approximately, roughly, around, or in the region of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a deviation of ±10% and preferably ±5%.

[0024] "Comprise," "comprises," "comprising," "include," "includes," and "including" are interchangeable and not intended to be limiting. Furthermore, where the description of one or more embodiments uses the term "comprising," those skilled in the art would understand that, in some specific instances, the embodiment or embodiments can be alternatively described using the language "consisting essentially of and/or "consisting of."

[0025] The following abbreviations are used throughout the application: Methylation Haplotype Block (MHB); Methylation Haplotype Load (MHL); Unmethylated Haplotype Load (uMHL); Group Specific Index (GSI); Circulating cell-free DNA (cfDNA); Reduced Representation Bisulfite Sequencing (RRBS); single-cell Reduced Representation Bisulfite Sequencing (scRRBS); Whole Genome Bisulfite Sequencing (WGBS); The Cancer Genome Atlas project (TCGA); The Encyclopedia of DNA Elements (ENCODE); Gene Expression Omnibus (GEO); Lung Cancer (LC); Colorectal or colon cancer (CRC); cancer associated High Methylation Haplotype (caHMH); tissue-specific Methylation Haplotype Block regions (tsMHB): Colorectal or colon cancer tissue (CCT); colorectal or colon cancer plasma (CCP); lung cancer tissue (LCT); lung cancer plasma (LCP); normal plasma (NP).

[0026] "Amplification" refers to any known procedure for obtaining multiple copies of a target nucleic acid or its complement, or fragments thereof. The multiple copies may be referred to as amplicons or amplification products. Amplification, in the context of fragments, refers to production of an amplified nucleic acid that contains less than the complete target nucleic acid or its complement, e.g., produced by using an amplification oligonucleotide that hybridizes to, and initiates polymerization from, an internal position of the target nucleic acid. Known amplification methods include, for example, replicase-mediated amplification, polymerase chain reaction (PCR), reverse transcription polymerase chain reaction (RT-PCR), ligase chain reaction (LCR), strand-displacement amplification (SDA), and transcription- mediated or transcription-associated amplification.

[0027] "Complementary" means that a contiguous nucleic acid base sequence is capable of hybridizing to another base sequence by standard base pairing (hydrogen bonding) between a series of complementary bases. Complementary sequences may be completely complementary (i.e. no mismatches in the nucleic acid duplex) at each position in an oligomer sequence relative to its target sequence by using standard base pairing (e.g., G:C, A:T or A:U pairing) or sequences may contain one or more positions that are not complementary by base pairing (e.g., there exists at least one mismatch or unmatched base in the nucleic acid duplex), but such sequences are sufficiently complementary because the entire oligomer sequence is capable of specifically hybridizing with its target sequence in appropriate hybridization conditions (i.e. partially complementary). Contiguous bases in an oligomer are typically at least 80%, preferably at least 90%, and more preferably completely complementary to the intended target sequence.

[0028] "Configured to" denotes an actual arrangement of a nucleic acid sequence configuration of a referenced oligonucleotide. For example, a primer that is configured to generate a specified amplicon from a target nucleic acid has a nucleic acid sequence that hybridizes to the target nucleic acid or a region thereof and can be used in an amplification reaction to generate the amplicon. Also as an example, an oligonucleotide that is configured to specifically hybridize to a target nucleic acid or a region thereof has a nucleic acid sequence that specifically hybridizes to the referenced sequence under stringent hybridization conditions.

[0029] "Configured to specifically hybridize to" means that an oligonucleotide is designed to have a nucleic acid sequence that can hybridize with a target nucleic acid or region thereof. The oligonucleotide is designed to function as a component of an assay for amplification and detection of a target nucleic acid (or a region thereof) in a sample, and therefore is designed to hybridize with a target nucleic acid (or a region thereof) in the presence of other nucleic acids that may be found in testing samples.

[0030] "Fragment" refers to a piece of contiguous nucleic acid that contains fewer nucleotides than the complete nucleic acid.

[0031] "Hybridization" or "annealing" refer to the base-pairing interaction of one nucleic acid with another nucleic acid (typically an antiparallel nucleic acid) that results in formation of a duplex or other higher-ordered structure (i.e. a hybridization complex). The primary interaction between the antiparallel nucleic acid molecules is typically base specific, e.g., A/T and G/C. It is not a requirement that two nucleic acids have 100% complementarity over their full length to achieve hybridization. Nucleic acids hybridize due to a variety of well characterized physio-chemical forces, such as hydrogen bonding, solvent exclusion, base stacking and the like. An extensive guide to the hybridization of nucleic acids is found in Tijssen (1993) Laboratory Techniques in Biochemistry and Molecular Biology— Hybridization with Nucleic Acid Probes part I chapter 2, "Overview of principles of hybridization and the strategy of nucleic acid probe assays," (Elsevier, New York), as well as in Ausubel (Ed.) Current Protocols in Molecular Biology, Volumes I, II, and III, 1997, which is incorporated by reference.

[0032] "Nucleic acid" or "nucleic acid molecule" refers to a multimeric compound comprising two or more covalently bonded nucleosides or nucleoside analogs having nitrogenous heterocyclic bases, or base analogs, where the nucleosides are linked together by phosphodiester bonds or other linkages to form a polynucleotide. Nucleic acids include RNA, DNA, or chimeric DNA-RNA polymers or oligonucleotides, and analogs thereof. A nucleic acid backbone can be made up of a variety of linkages, including one or more of sugar- phosphodiester linkages, pep tide-nucleic acid bonds, phosphorothioate linkages, methylphosphonate linkages, or combinations thereof. Sugar moieties of the nucleic acid can be ribose, deoxyribose, or similar compounds having known substitutions (e.g. 2'-methoxy substitutions and 2'-halide substitutions). Nitrogenous bases can be conventional bases (A, G, C, T, U) or analogs thereof (e.g., inosine, 5-methylisocytosine, isoguanine). A nucleic acid can comprise only conventional sugars, bases, and linkages as found in RNA and DNA, or can include conventional components and substitutions (e.g., conventional bases linked by a 2'- methoxy backbone, or a nucleic acid including a mixture of conventional bases and one or more base analogs). Nucleic acids can include "locked nucleic acids" (LNA), in which one or more nucleotide monomers have a bicyclic furanose unit locked in an RNA mimicking sugar conformation, which enhances hybridization affinity toward complementary sequences in single-stranded RNA (ssRNA), single-stranded DNA (ssDNA), or double-stranded DNA (dsDNA). Nucleic acids can include modified bases to alter the function or behavior of the nucleic acid (e.g., addition of a 3 '-terminal dideoxynucleotide to block additional nucleotides from being added to the nucleic acid). Synthetic methods for making nucleic acids in vitro are well known in the art although nucleic acids can be purified from natural sources using routine techniques. Nucleic acids can be single-stranded or double-stranded.

[0033] "Primer" refers to an enzymatically extendable oligonucleotide, generally with a defined sequence that is designed to hybridize in an antiparallel manner with a complementary, primer- specific portion of a target nucleic acid. A primer can initiate the polymerization of nucleotides in a template-dependent manner to yield a nucleic acid that is complementary to the target nucleic acid when placed under suitable nucleic acid synthesis conditions (e.g. a primer annealed to a target can be extended in the presence of nucleotides and a DNA/RNA polymerase at a suitable temperature and pH). Suitable reaction conditions and reagents are known to those of ordinary skill in the art. A primer is typically single stranded for maximum efficiency in amplification, but may alternatively be double stranded. If double stranded, the primer is generally first treated to separate its strands before being used to prepare extension products. The primer generally is sufficiently long to prime the synthesis of extension products in the presence of the inducing agent (e.g. polymerase). Specific length and sequence will be dependent on the complexity of the required DNA or RNA targets, as well as on the conditions of primer use such as temperature and ionic strength. Preferably, the primer is about 5-100 nucleotides. Thus, a primer can be, e.g., 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 nucleotides in length. A primer does not need to have 100% complementarity with its template for primer elongation to occur; primers with less than 100% complementarity can be sufficient for hybridization and polymerase elongation to occur. A primer can be labeled if desired. The label used on a primer can be any suitable label, and can be detected by, for example, spectroscopic, photochemical, biochemical, immunochemical, chemical, or other detection means. A labeled primer therefore refers to an oligomer that hybridizes specifically to a target sequence in a nucleic acid, or in an amplified nucleic acid, under conditions that promote hybridization to allow selective detection of the target sequence.

[0034] "Sample preparation" refers to any steps or methods that prepare a sample for subsequent sequencing, amplification, and/or detection of target nucleic acids present in the sample. Sample preparation may include any known method of concentrating components, such as nucleic acids, from a larger sample volume. Sample preparation may include physical disruption and/or chemical lysis of cellular components to release intracellular components into a substantially aqueous or organic phase and removal of debris, such as by using filtration, centrifugation or adsorption. Sample preparation may include use of a nucleic acid oligonucleotide that selectively or non-specifically captures a target nucleic acid and separates it from other sample components.

[0035] "Sequencing" refers to any known procedure, method, or technology for determining the precise order of the nucleosides or nucleoside analogs of a target nucleic acid molecule, or its complement, or fragments thereof. Sequencing, in the context of fragments, refers to determining the precise order of nucleosides or nucleotides within a nucleic acid molecule that contains less bases than the complete target nucleic acid molecule e.g., determined by sequencing amplicons produced by using an amplification oligonucleotide that hybridizes to, and initiates polymerization from, an internal position of the target nucleic acid. Known sequencing methods include, for example, whole-genome sequencing as well as targeted sequencing wherein only subset of genes or regions of the genome are isolated and sequenced.

[0036] Some embodiments described herein allow a quantitative deconvolution of biological samples (for example, human plasma) that contain mixed DNA molecules, based on comparing the patterns and abundance of methylation haplotypes against a reference set of human tissues. Detection and quantification of low-abundant cancer DNA in plasma, and simultaneous mapping to the tissue of origin has been successfully demonstrated. With the high sensitivity and the capability of detecting rare species in heterogeneous samples. Some embodiments described herein are, for example, suitable for non-invasive detection of tumor or other organ damage (diabetes, stroke etc.) in a subject' s plasma, urine, stool, or cerebrospinal fluid, and detection of fetal aneuploidy in maternal blood at a very early stage of pregnancy.

[0037] Some embodiments described herein provide methods of creating a database of patient specific methylation haplotypes and unmethylated haplotypes. Some embodiments described herein provide methods of preparing data of comparative methylation haplotypes and unmethylated haplotypes. Some embodiments described herein include further steps for methods of treatment of diagnosed diseases or conditions associated with methylation haplotypes and unmethylated haplotypes.

[0038] Some embodiments described herein utilize the co-methylation status of multiple adjacent CpG sites in single DNA molecules rather than the methylation status of individual loci and or their local average. Some embodiments described herein suppress the stochastic noise from the low coverage methylation data and therefore have high sensitivity and specificity in both detecting circulating tumor DNA and mapping the tissue-of-origin of the tumor. Additionally, some embodiments described herein provide a set of MHL based biomarkers and a statistical approach to the detection.

[0039] For the quantitative estimation of the level of cancer DNA fractions, a strategy based on a tissue-specific MHL sampling technique which is distinctly different from existing approaches, such as quadratic programming, was developed. Due to the low level of cancer and fetal DNA fragments in the blood (plasma), some embodiments are applicable to even low coverage data based on methylation sequencing, such as RRBS and WGBS, whereas other methods would fail due to the difficulties in dealing with missing values.

[0040] For non-invasive cancer diagnosis, current mature commercial assays in the market use bronchial fluid (EPI PROLUNG BL Reflex assay), or can only be used for specific cancer type detection (EPI PROCOLON blood assay for colon cancer) without origin-tissue prediction. Some embodiments described herein provide accurate tissue-of-origin mapping based on comparing the patterns and abundance of methylation haplotypes against a reference set of human reference tissues and provide accurate quantitative estimation of the cancer DNA fraction.

[0041] Some embodiments described herein relate to a set of markers for cancer detection and tissue-of-origin mapping based on an exhaustive search across the whole genome for methylation haplotype blocks (MHB) that have a higher level of methylation haplotype load (MHL) or higher level of unmethylated haplotype load (uMHL). Some embodiments described herein relate to a statistical approach that takes the information of these markers for the tissue- of-origin mapping and cancer detection. Compared with existing prediction models (such as tree-based: random forest), some embodiments described herein are suitable for sparse methylation sequencing data, which is typical in the clinical setting due to the low amounts of cell-free DNA that can be extracted from patients. Some embodiments described herein are also applicable to detection of fetal aneuploidy in maternal blood. Currently there is a commercial TISSUE OF ORIGIN test from Cancer Genetics Inc. which is an invasive assay that uses tissue biopsies from patients, as compared to non-invasive liquid biopsies that allow far less discomfort for the patients.

[0042] Human peripheral blood contains low levels of DNA molecules from other tissues or cell types, such as circulating cancer stem cells, cell-free DNA from apoptotic cancer cells in cancer patients, or fetal DNA in pregnant women. DNA methylation signals along with the DNA molecules are released into the blood simultaneously and these methylation signals are tissue-specific and can be applied to identify the tissue source of the DNA fragment. Methylation haplotypes provide high sensitivity detection of DNA molecules from DNA samples (WO2015/116837 and PCT/US2015/013562 incorporated herein by reference).

[0043] In some embodiments, DNA molecules are extracted from plasma samples, from for example cancer patients or healthy individuals, and the DNA methylation status of cell-free DNA molecules are assayed by bisulfite methylation sequencing (reduced representation bisulfite sequencing (RRBS), Meissner et al. (2005)). Note that alternative technologies, such as BSPP (Diep et al. (2012)), micro-droplet PCR (Komori et al. (2011)), Selector probes (Johansson et al. (2011)), or MeDiP (Papageorgiou et al. (2011)) can also potentially be used with some differences in the requirement of input materials and/or cost. Other methods for determining the methylation status of cell-free DNA may also be used.

[0044] In some embodiments, regardless of the specific sample preparation methods or sequencing platforms used, bisulfite sequencing reads (single-ends or paired-ends) are used as the input for the proposed analytical framework for detection of cancer and their tissue-of- origin. Methylation haplotypes and their abundance may be derived from the raw sequencing reads. Each haplotype represents the combination of binary methylation status (methylated or unmethylated) at multiple CpG sites of one sequencing read. A computational pipeline (implemented with Perl) was developed to deal with methylation haplotype and further derived metrics, such as methylation haplotype (successive methylation allele combination), methylation haplotype block (linkage disequilibrium regions), highly methylated haplotype (HMH), and methylation/unmethylated haplotype load (MHL/uMHL) (weighted methylation status by haplotype length).

[0045] To identify the most informative marker for detecting cancer or tissue mapping, the term "methylation haplotype block" (MHB) was defined to describe genomic regions in which the methylation status of CpG pairs within are in linkage disequilibrium and could be taken as co-methylation regions. A set of Whole Genome Bisulfite Sequencing (WGBS) data was compiled, such as from stem cell, cancer cell, and normal adult tissues, in order to exhaustively search the entire human genome. A total of 147,888 MHBs in the human genome were identified.

[0046] A metric was defined, called methylation haplotype load (MHL) for each MHB (as described in WO2015/116837), which is the normalized fraction of methylated haplotypes at different lengths to indicate the methylation status and complexity of the methylation population. MHL is superior to other metrics (such as methylation level, methylation entropy (Xie, H. et al, (2011)), and epi-polymorphism (Landan et al, (2012)) for distinguishing different methylation patterns. In addition, MHL is bounded between 0 and 1, which allows for direct comparison of different regions across many data sets without normalization.

[0047] A metric was defined, called unmethylated haplotype load (uMHL) for each MHB, which is the normalized fraction of unmethylated haplotypes at different lengths to indicate the methylation status and complexity for the unmethylated population.

[0048] A MHL matrix for a set of human tissues (61 published samples/data sets) was built encompassing all the 147,888 identified MHBs in the entire human genome. From this matrix, tissue-specific MHBs were identified. After including additional training data subsets comprising plasma from cancer patients and healthy controls, sets of 154 MHBs for binary prediction of tissue-of-origin between colon, lung, and normal (no solid tissue) and 295 MHBs for cancer types classification (colon versus lung) non-invasively in the blood were identified (Table 5(a)-(b)). The invention demonstrated binary classification AUCs of 0.856, 0.725, and 0.751 in independent test sets from normal, colon cancer, and lung cancer plasma respectively (Fig. 9(a)-9(c)). Distinguishing between colon cancer and lung cancer plasma achieved classification accuracies of 70% and 78% for test sets comprising colon cancer and lung cancer plasma respectively using cancer type classification (Fig. 10). [0049] The disclosed method was also applicable to tracking metastasized secondary tumors. Significantly higher original tissue markers (46 and 79 for two metastasized cancer samples) in the metastasized cancers (primary colon to liver and primary breast to lung) were identified with MHL measurement and a maximum marker count approach to infer its primary cancer source.

[0050] Adjacent CpG sites in mammalian genomes tend to be co-methylated due to the processivity of enzymes responsible for adding or removing the methyl group. Yet discordant methylation patterns have also been observed, and found to be related to stochastic or uncoordinated molecular processes. The invention focused on a systematic search and investigation of regions in the human genome that exhibit highly coordinated methylation.

[0051] By examining the co-methylation patterns of multiple adjacent CpG sites, termed methylation haplotypes, in single bisulfite sequencing reads, a greedy- searching strategy was applied to define blocks of tightly coupled CpG sites, called methylation haplotype blocks (MHBs), based on 53 sets of whole genome bisulfite sequencing (WGBS) data, including 43 published sets from human adult tissues, ESC, and in vitro differentiated cell lines, as well as 10 sets from human adult tissues generated in this invention. The MHBs were further validated with 101 sets of RRBS ENCODE data, and 1,274 sets of Illumina450k methylation array data from TCGA tumor and normal samples. Globally, MHBs are enriched in, but only partially overlap with, several well-known genomic features, including CpG islands, promoters, enhancers and VMRs.

[0052] To perform quantitative analysis of the MHBs, a metric called methylation haplotype load (MHL) was computed, which covers both average methylation level and methylation complexity, and therefore is more informative than average methylation level or Shannon entropy. Using a feature selection strategy, a set of tissue-specific MHBs was identified that cluster by developmental germ-layers. Interestingly, examination of these MHBs revealed two distinct mechanisms for fate commitment during development: epigenetic silencing of pluripotent genes, such as NANOG, for mesoderm induction; and epigenetic induction (or de-suppression) of lineage-specific factors for ectoderm commitment.

[0053] Furthermore, to examine MHBs in cancers and explore its clinical utility, 162 sets of RRBS data from primary tumor tissues and matched plasma from patients with lung cancer, colon cancer, or pancreatic cancer were generated, as well as plasma controls from healthy individuals. Compared with normal tissues and stem cells, primary tumor tissues exhibit a distinct methylation pattern within MHBs, related to locally disordered methylation recently discovered in chronic lymphocytic leukemia (CLL). Importantly, a subset of blocks (Table 4) was derived that can estimate the tumor content from circulating DNA in the plasma (Fig. 8). Finally, prediction of tissue-of-origin was performed on plasma using tissue specific methylation haplotype blocks (Table 5).

[0054] A manuscript entitled "Identification of methylation haplotype blocks aids in deconvolution of heterogeneous tissue samples and tumor tissue-of-origin mapping from plasma DNA" by Guo et al. (Nat Genet 2017 Apr;49(4):635-642), the disclosure of which is incorporated herein by reference in its entirety, including all figures, tables, supplementary figures and supplementary tables therein or related thereto.

Examples

[0055] An exhaustive search of tissue-specific methylation haplotype blocks across the entire human genome was performed, and block- level metrics including methylation haplotype load (MHL) and unmethylated haplotype load (uMHL) were proposed, for a systematic discovery of informative markers. Applying the disclosed method's analytical framework and identified markers, accurate determination of tissue origin as well as estimation of tumor load in clinical plasma samples from patients of lung cancer (LC) and colorectal cancer (CRC) (Fig. 1(a)) was demonstrated.

[0056] Identification and characterization of methylation haplotype blocks. To investigate the co-methylation status of adjacent CpG sites along single DNA molecules, the concept of genetic linkage disequilibrium was extended (Slatkin (2008); Shoemaker et al. (2010)) and the r² metric determined to quantify the degree of coupled CpG methylation among different DNA molecules of the same samples. CpG methylation status of multiple CpG sites in single- or paired-end Illumina sequencing reads were extracted to form methylation haplotypes, and pairwise "linkage disequilibrium" of CpG methylation r² was calculated from the abundance of different methylation haplotypes (see Methods). The full human genome was partitioned into blocks of tightly coupled CpG methylation sites, called methylation haplotype blocks (MHBs) (Fig. 1(b)), using a r² cutoff of 0.5. Using slightly different cutoff values, such as 0.3 or 0.7, for partitioning of the human genome into genetic haplotype blocks, resulted in only minor quantitative differences in the block size and number without affecting the global pattern (data not shown). [0057] To characterize the global pattern and distribution of MHBs, starting with 51 sets of published Whole Genome Bisulfite Sequencing (WGBS) data from human primary tissues (Schultz et al. (2015); Heyn et al. (2012)), as well as the HI human embryonic stem cells, in vitro derived progenitors (Xie, W. et al. (2013)), and human cancer cell lines (Blattler et al. (2014); Heyn et al. (2016)). An additional WGBS data set from 10 adult tissues from a single human donor was also generated and included. Across this set of 61 samples (>2000x combined genome coverage) a total of -55 billion methylation haplotype informative reads covering 58.2% of autosomal CpGs were identified. The uncovered CpG sites were either in regions with low mappability, or CpG sparse regions where there are too few sites within Illumina read pairs for deriving informative haplo types. 147,888 MHBs with an average size of 95bp and minimum 3 CpGs per block were identified, representing -0.5% of the human genome that tends to be tightly co-regulated on the epigenetic status at the level of single DNA molecules (Fig. l l(a)-l l(b)). The majority of CpG sites within the same MHBs are near perfectly coupled (r^{2 ~}1.0) regardless of the sample type. Methylation LD was found to extend further along the DNA in stem cells and progenitors, compared with normal adult tissue, both in the fraction of tightly coupled CpG pairs (94.8% versus 91.2%, P-value<2.6xl0^~16), and the over-representation of partially coupled CpG pairs that are over 100 bp apart while the linkage was slightly decayed in primary cancer data sets (87.8%, mixture of CRC and LC), which was validated by another independent WGBS data set from kidney cancer (Chen et al. (2016)) (Fig. 1(c)). Gene Ontology analysis show cancer loss of linkage regions was significantly associated with number of cancer related pathways and functions. This is consistent with previous observations on a smaller BSPP data set comprising 2,020 CpG islands (Shoemaker et al. (2010)) for culture cell lines and another previous report (Shao et al. (2014)). Interestingly, in tumor samples, a reduction of perfectly coupled CpG pairs was observed, which could be related to the pattern of discordant methylation recently reported in variable methylation regions (VMR) (Landau et al. (2014); Hansen et al. (2011)).

[0058] While WGBS data allowed MHBs across the entire genome to unbiasedly be identified, the 61 sets of data did not represent the full diversity of human cell/tissue types. To validate the presence of MHBs in a wider range of human tissues and culture cells, 101 published reduced representation bisulfite sequencing (RRBS) data sets from ENCODE cell lines and tissue samples were examined, as well as 637 sets of Infinium HumanMethylation450 BeadChip (HM450K) data including 11 normal human tissues from the TCGA project. The ENCODE RRBS data sets were generated with short (36bp) Illumina sequencing reads, greatly limiting the length of methylation haplotypes that can be identified. Similarly, Illumina methylation arrays only report average CpG methylation of all DNA molecules in a sample, preventing a methylation linkage disequilibrium analysis. Therefore, the invention calculated the pairwise correlation coefficient of adjacent CpG methylation levels across different sample sets for block partitioning. Note that the presence of such correlated methylation blocks is a necessary but not sufficient condition for MHBs (Fig. 12(a)). Nonetheless, the absence of correlated methylation blocks in these data sets would invalidate the pattern of MHBs. 23,517 and 2,212 correlated methylation blocks from ENCODE RRBS and TCGA HM450K array data, respectively, were identified, among which 8,920 and 1,258 have significant overlaps with WGBS-defined MHBs. Additionally, significantly higher correlation among the CpGs within the MHB regions compared to CpG loci outside MHBs in the HM450K and RRBS data sets was observed, further supporting the block-like organization of local CpG co-methylation across a wide variety of cells and tissues (Fig. 12(b)). Taken together, the MHBs identified represent a distinct class of genomic features where local CpG methylation is established or removed in a highly coordinated manner at the level of single DNA molecules, presumably due to the processive activities of the related enzymes coupled with the local density of CpG dinucleo tides.

[0059] Co-localization of methylation haplotvpe blocks with known regulatory elements. The MHBs established by 61 sets of WGBS data appear to represent a distinct type of genomic feature that partially overlaps with multiple well-documented genomic elements (Fig. 1(d), Fig. 11). Among all the methylation blocks, 60,828 (41.1%) were located in intergenic regions and 87,060 (58.9%) regions in transcribed regions. These MHBs were significantly (p-value<10^~6) enriched in enhancers (enrichment factor=7.6), super-enhancers (enrichment factor=2.3), promoter regions (enrichment factor=14.5), CpG islands (enrichment factor=70.4), and imprinted genes (enrichment factor=54.6). In addition, modest depletion in LAD was observed (Guelen et al. (2008)) and LOCK regions (Wen et al. (2009)) (46% and 37% of the expected values), and modest enrichment in TAD (Dixon et al. (2012)). Importantly, a very strong (26-fold) enrichment in variable methylation regions (VMR) was observed (Hansen et al. (2011)) (Fig. 1(e)), suggesting that increased epigenetic variability in a cell population or tissue can be coordinated locally among hundreds of thousands of genomic regions (Pujadas et al. (2012)). A subset of MHBs that do not overlap with CpG islands was examined, and a consistent enrichment pattern (Fig. 1(e)) was observed, suggesting that local CpG density alone does not account for the enrichment.

[0060] Previous studies on mouse and human samples (Irizarry et al. (2009); Ziller et al. (2013)) demonstrated that dynamically methylated regions were associated with regulatory regions such as enhancer-like regions marked by H3K27ac and transcription factor binding sites. In human, 21.8% of autosomal CpGs were found to be differentially methylated across 30 human cell and tissue types (Hansen et al. (2011)). These CpGs were enriched at low to intermediate CpG density promoters. Using publicly available histone mapping data for human adult tissues, co-localization of methylation haplotype blocks with marks for active promoters (H3K4me3 with H3K27ac) was found, but not for active enhancers (Leung et al. (2015)) (no peak for H3K4mel). Meanwhile, enhancers were found to tend to overlap with CpG sparse MHBs, whereas the overlap with super-enhancers were independent of CpG density (Fig. 11(c)). Therefore, MHBs likely capture the local coherent epigenetic signatures that are directly or indirectly coupled with transcriptional regulation.

[0061] Block-level analysis of human normal tissues and stem cell lines with methylation haplotype load. To enable quantitative analysis of the methylation patterns within individual MHBs across many samples, a single metric to define the methylated pattern of multiple CpG sites within each block is needed. Ideally this metric is not only a function of average methylation level for all the CpG sites in the block, but can also capture the pattern of co-methylation on single DNA molecules. For this purpose, methylation haplotype load (MHL) and unmethylated haplotype load (uMHL) were defined, where the first is a weighted mean of the fraction of fully methylated haplotypes and substrings at different lengths (i.e. all possible substrings) and the latter is a weighted mean of the fraction of fully unmethylated haplotypes and substrings at different lengths. Compared with other metrics used in the literature (methylation level, methylation entropy, epi-polymorphism, and haplotypes counts), MHL is capable of distinguishing blocks that have the same average methylation but various degrees of coordinated methylation (Fig. 2). In addition, MHL and uMHL are bounded between 0 and 1 , which allows for direct comparison of different regions across many data sets without normalization.

[0062] The invention addressed whether treating MHBs as individual genomic elements and performing quantitative analysis based on MHL and uMHL would provide an advantage over previous approaches using the weighted average methylation in genomic windows. To this end, the invention sought to identify tissue specific MHBs from a collection of human solid tissues WGBS datasets based on the MHL and uMHL. A group specific index for each MHB (see Methods) was computed using either MHL or uMHL for every tissue type and then each MHB was assigned to one or more tissues based on their respective GSI. If no other tissue type have a GSI that is at least 80% of the maximum GSI, then only the tissue type with the maximum GSI is reported. From the top 500 MHBs assigned to each tissue, the top tissue specific MHL or uMHL regions were selected using average MHL or uMHL values in blood cells of less than 0.05, and average non-blood cell values greater than 0.4. Using a maximum GSI of greater than 0.6 as a threshold resulted in the identification of 1,290 and 15,377 tissue specific MHL and uMHL regions respectively. To identify the most informative MHL or uMHL marker regions for cancer detection or tissue mapping the top 10% of the identified MHL or uMHL regions determined by GSI value are reported in Tables 1(a) and 1(b). The tissue specific regions using MHL and uMHL were visualized using heatmaps (Fig. 3(a)-3(b)). To demonstrate that MHL was a better metric than AMF, a set of MHBs overlapping with published tissue specific methylated regions (Lokk et al. (2014)) were identified. Using this set of MHBs, the performance between MHL and average methylation fraction in the MHL regions (AMF) were compared. Both MHL and AMF were able to identify tissue specific MHBs, but MHL has better signal (average value from within the tissue specific group) to noise (average value from other groups) than average methylation (Fig. 4).

[0063] The human adult tissues used in this invention have various degrees of similarity amongst each other. The invention hypothesized that this is primarily defined by their developmental lineage, and that the related MHBs might reveal epigenetic insights related to germ layer speciation. All the data sets based on the three germ layers were grouped, and searched for MHBs that have differential MHL. In total 114 ectoderm- specific MHBs (99 hyper- and 15 hypo-methylated), 75 endoderm specific MHBs (58 hyper- and 17 hypo- methylated) and 31 mesoderm specific MHBs (9 hyper- and 22 hypo-methylated) were identified. The invention speculated that some of these MHBs might capture binding events of transcription factors (TF) specific to developmental germ-layers. Compared with ENCODE TFBS data (The ENCODE Project Consortium (2012)), distinctive patterns of TFs binding to layer specific MHBs were observed. For layer specific MHBs with hypo-methylation MHL, which tends to represent activation signals, 53 TF binding events in mesoderm specific MHBs, 71 in endoderm specific MHB, and 2 in ectoderm specific MHBs were identified. Gene ontology analysis showed TFs binding to mesoderm exhibit negative regulator activity, while TFs binding to endoderm exhibited positive regulator activity. For layer specific MHBs with hyper- methylation MHL, which tend to represent repressive signals, 38 TF binding events in mesoderm specific MHBs, 102 in endoderm specific MHB, and 145 in ectoderm specific MHBs were identified. Interestingly, ectoderm and endoderm shared few bounded TFs, while mesoderm tissues share multiple groups of TFs with ectoderm and endoderm. Two endoderm specific hyper- MHL regions were identified, which are related to ESRRA and NANOG. This is consistent with a previous finding that mouse ES cells differentiated spontaneously into visceral/parietal endoderm upon NANOG knock-out (Mitsui et al. (2003)). Gene ontology analysis showed that hypo-MHL regions shared by mesoderm and endoderm might have regulatory functions in the fate commitment towards multiple tissues, whereas ectoderm specific hyper-MHL regions might induce the ectoderm development by suppressing the path towards the immune lineage. These observations are indicative of two distinctive "push" and "pull" mechanisms in the transition of cell states that have been harnessed for the induction of pluripotency by over-expressing lineage specifiers (Shu et al. (2013)).

[0064] Methylation-haplotype based analysis of circulating cell-free DNA in cancer patients and healthy donors. A unique aspect of methylation haplotype analysis is that the pattern of co-methylation, especially within MHBs, is robust for capturing low-frequency alleles among a heterogeneous population of molecules or cells, in the presence of biological noise or technical variability (i.e. incomplete bisulfite conversion or sequencing errors). To explore the clinical potential, the invention focused on the methylation haplotype analysis of cell-free DNA from healthy donors and cancer patients, of which various low fractions of DNA molecules were released from tumor cells and potentially carry epigenetic signatures different from blood. 4-122ng (average 20ng) of cell-free DNA from an average of 866μί human plasma from 75 normal individuals and 59 cancer patients were isolated, except for four with unusually high yield due to cell lysis. Due to the limited DNA availability, scRRBS was performed (Guo et al. (2013)) on 1 to 10 ng of cfDNA from 134 plasma samples and obtained an average of 13 million paired-end 150bp reads per sample. On average, 57.7% WGBS- defined MHBs were covered in the RRBS data set from the clinical samples.

[0065] The invention sought to detect the presence of tumor specific signatures in the plasma samples, using the methylation haplotypes identified in the reference tumor tissues and in normal samples used as the negative controls. For five lung cancer plasma samples and five colorectal cancer plasma samples, matched primary tumor tissues were also obtained, and generated RRBS data (30 million reads per sample) from lOOng of tumor genomic DNA. The invention focused on MHBs with low MHL (i.e. genomic regions that have low or no methylation) in the blood, and determined whether cancer-associated highly methylated haplotypes (caHMH) can be detected. The invention provides in some embodiments that such haplotypes are present only in the tumor tissues and the matched plasma from the same patient, but not in whole blood or any other non-cancer samples. These highly confident tumor signatures in circulating DNA were considered. caHMH in all cancer patient plasma samples (Average=36, interquartile range (IQR)=17) were detected. These caHMHs were associated with 320 genes, some of which are known to be aberrantly methylated in human cancers such as WDR37, VAX1, SMPD1 (Table 2) The 49 additional cancer plasma samples with no matched tumor samples were analyzed, using 65 normal plasma ssamples as background and negative control. On average 60 (IQR=31) caHMH were identified for each cancer plasma sample. Interestingly, a significant fraction (35%) of caHMH identified with matched tumor- plasma pairs were also detected in the expanded set of cancer patient plasma samples. A majority of caHMHs were found to be individual specific while few caHMHs were present in at least 53% (16/30) and 62% (18/29) cancer plasma samples for CRC and LC (Fig. 13). Improving the sampling depth, by either using more input cfDNA or reducing sample loss during analysis, will likely increase the number of caHMHs commonly observed in multiple patients.

[0066] The tumor load in cancer plasma samples was quantified, using non-negative decomposition with quadratic programming, on the RRBS data from primary cancer biopsies (LC and CRC) and the WGBS data from 10 normal tissues. (Table 3) The invention estimated that a predominant fraction, 72.0% (IQR=40%) in cancer and normal plasma samples were contributed by white blood cells, which is consistent with the levels recently reported based on shallow whole genome bisulfite sequencing (69.4%) (Sun et al. (2015)). Primary tumor and normal tissue-of-origin contributed at the similar level of 2.3% (IQR=3.7%) and 3.0% (IQR=4.4%). In contrast, the similar analysis applied to normal plasma only found residual tumor contributions (0.17%, IQR=2.9% for CRC and 1.0%, IQR=3.1% LC) to normal plasma, which were significantly lower (P=3.4xl0^~5 and 5.2xl0^~10 for CRC and LC, respectively) than for cancer plasma. 76.7% plasma samples from CRC patients and 89.6% from LC patients were found to have a detectible contribution from tumor tissues while only 13% and 26% normal plasmas have certain (low) tumor contribution. Therefore, circulating cell-free DNA contains a relatively stable fraction of molecules released from various normal tissues, whereas tumor cells released DNA molecules that can be more abundant in tumor cells than in normal tissues (Tables 3(a)-3(d)). The fractions of white blood cells observed are lower than what was reported previously (Sun et al. (2015)), most likely due to the inclusion of 10 normal tissue types in the deconvolution analysis.

[0067] The invention sought to use the information from normal human tissues, primary tumor biopsies, and cancer cell lines to improve the detection of cfDNA. The invention selected a subset of MHBs that show high MHL in primary cancer biopsies and low MHL in normal control plasma. A subset of MHBs that have high MHL in cancer tissues and low MHLs in normal plasma was identified for each cancer type (Table 4(a)-(b)). Cancer plasma showed significantly higher MHL in these regions than independent normal plasma (P= 1.2xl0^~13 and 2.2xl0^~16 for CRC and LC, respectively) (Fig. 5 and Fig. 6). By computationally mixing the sequencing reads from cancer tissues and whole blood samples (WBC), synthetic admixtures at various levels of tumor fraction were created to calibrate the relationship between tumor load and the MHL values in these regions (Fig. 7). A fitted linear model on the standard curve for colon cancer markers had an adjusted R-squared value of 0.9621 and for lung cancer markers the adjusted R-squared value was 0.9573. Note that these MHBs were selected without using any information from the cancer plasma samples, and hence they should be applicable to other cancer plasma samples. Tumor load estimation was performed on test sets of cancer and normal plasma samples. Cancer plasma was found to have significantly higher tumor load than normal plasma (Two Sample t-test with unequal variance, =0.005074 for colon cancer plasma versus normal and =0.0002783 for lung cancer plasma versus normal plasma) (Fig. 8).

[0068] Recent studies (Sun et al. (2015); Lehmann-Werman et al. (2016); Snyder et al. (2016)) have demonstrated that epigenetic information imbedded in cfDNA has the potential for predicting tumors tissue-of-origin. Here the invention addresses whether a MHL-based framework and a set of targets derived from whole genome data would allow for the prediction of tissue-of-origin with quantifiable sensitivity and specificity, which is crucial for future clinical applications. Training WGBS tissue data from the following tissues: colon, lung, neural, heart, liver, lung, pancreas, and stomach were compiled and a set of 15,000 MHBs selected using their Group Specific Index (GSI) was created. Note that the MHBs with a high GSI score tended to be methylated in fewer tissue types. 20 colon cancer plasma, 20 lung cancer plasma, and 30 normal plasma samples were randomly sampled to create training data sets from the RRBS plasma data sets. The remaining (10 colon, 10 lung, and 39 normal) were held out as test data sets. An ensemble MARS (Multivariate adaptive regression splines) model was generated using the training data sets (Friedman, (1991)). The invention also employed K- means clustering of the MHBs using WGBS data to generate 50 clusters and each MARS model in the ensemble only saw a feature set consisting of 3 features sampled from a cluster (3 features x 150 clusters = 450 features for each model). To minimize overfitting of training data sets each model selected at most 2 features to use during classification. The first classifier was an ensemble model with 100 MARS models with 154 MHB features (Table 5(a)). In a manner analogous to a random forest classifier, the scores from the resulting ensemble are averaged to compute a prediction score. By utilizing these prediction scores as a binary classifier, the invention was able to obtain a colon vs non-colon AUC of 0.725, a lung vs non-lung AUC of 0.751, and a normal vs abnormal AUC of 0.856 (Fig. 9(a)-9(c)). Note that these AUC values were obtained using an initial marker set identified from an independent training set of normal WGBS tissue samples only; no cancer tissue samples were used in the initial feature selection, suggesting that plasma samples can be segregated using only tissue specific markers.

[0069] To obtain a prediction of tissue-of-origin, the invention focused on colon and lung cancer plasma. First, the top MHBs features that were assigned to either colon, lung, or both tissues ranked by GSI were selected. An ensemble of 500 MARS models identifying 295 unique tissue specific features was made (Table 5(b)). PLSDA (partial least squares discriminant analysis) implemented in the caret R package was used to perform the classification. The classification using this model was assessed using independent test data sets and the accuracy for classifying colon cancer plasma to colon tissue was found to be 70% (7/10) and the accuracy for classifying lung cancer plasma to lung tissue was 78% (7/9) (Fig. 10).

[0070] In this invention a well-established concept in population genetics, linkage disequilibrium (LD), was extended to the analysis of co-methylated CpG patterns. While the mathematical representations are identical, there are two key differences. First, traditional linkage disequilibrium (LD) was defined for human individuals in a population, whereas in this invention the analysis was performed on the diploid genome of individual cells in a heterogeneous cell population. Second, linkage disequilibrium in human populations depend on the mutation rate, frequency of meiotic recombination, effective population size and demographic history. The LD level typically decays over the range of hundreds of kilobases to megabases. In contrast, CpG co-methylation depends on DNA methytransferases and demethylases, which tend to have lower processivity, and, in the case of hemi- methy transferases, much lower fidelity compared with DNA polymerases (Williams et al. (2011)). Therefore, methylation LD decays over much shorter distances ranging from tens to hundreds of bases, with the exception of imprinting regions. Even if longer-read sequencing methods were used no radical change of the block-like pattern presented in this work is expected, which is supported by a recent study (Saito et al. (2015)). Nonetheless, these short and punctuated blocks capture discrete entities of epigenetic regulation in individual cells widespread in the human genome. Such a phenomenon can be harnessed to improve the robustness and sensitivity of DNA methylation analysis, such as the deconvolution of data from heterogeneous samples including circulating cell-free DNA.

[0071] Epigenetic abnormalities tend to be more widespread across the genome (compared with somatic mutations), and hence enabling the integration of the sparse coverage across many loci to achieve very accurate prediction by direct counting of methylated haplotypes within the appropriate tissue-specific features.

Methods

[0072] Normal and cancer samples. Ten human primary tissues were purchased from BioChain. Cancer tissue and plasma samples were collected from UCSD Moores Cancer Center and normal plasma samples were obtained from UCSD Shiley Eye center under IRB protocols approved by UCSD Human Research Protections Program (HRPP). .

[0073] Generation of DNA libraries for sequencing. Extracted genomic DNA were prepared for bisulfite sequencing using published protocols. For whole genome bisulfite (WGBS) and reduced representation bisulfite sequencing (RRBS), the DNA fragments were adapted to barcoded methylated adaptors (Illumina). For WGBS, the adapted DNA were converted using the EZ DNA Methylation Lightning kit (Zymo Research) and amplified for 10 cycles using iQ SYBR Green Supermix (BioRad). For RRBS, the adapted DNA were converted using the MethylCode™ Bisulfite Conversion kit (Thermo Fisher Scientific) and amplified using the PfuTurboCx polymerase (Agilent) for 12-14 cycles. Libraries were pooled and size selected using 6% TBE polyacrylamide gels. Libraries were sequenced using the Illumina HiSeq platform for paired-end 100-111 cycles, the Illumina MiSeq platform for paired-end 75 cycles, and the GAIIx (WGBS only) for single-end 36 cycles. [0074] Methylation haplotvpe blocks (MHB). The human genome was separated into non-overlapping "sequenceable and mappable" segments using a set of generated WGBS data from 10 tissues from a 25-year adult male individual. Mapped reads from WGBS data sets were converted into methylation haplotypes in each segment. Methylation linkage disequilibrium was calculated on the combined methylation haplotypes. Each segment was partitioned into methylation haplotype blocks (MHBs). MHBs were defined as the genomic region in which the r² value of two adjacent CpG sites is no less than 0.5. MHB regions inferred by WGBS data sets were also validated by bulk data of methylation level. Takai and Jones's sliding-window algorithm (Takai et al. (2002)) was applied for methylation high linkage regions in the HM450K (TCGA) and the RRBS (ENCODE) data set. Finally, simulation analysis to investigate the relationship between LD and correlation of average 5mC of two CpG loci were conducted based on random sampling of different methylation haplotypes with 1000 individuals, and each individual sampling 10 methylation haplotypes.

[0075] Methylation haplotvpe load (MHL). A methylated haplotype load (MHL) for each candidate region was defined, which is the normalized fraction of methylated haplotypes (MH) at different lengths:

MHL = ^ί_1 ' -

∑i=i ^wi

Wj = ί

[0076] Unmethylated haplotvpe load (uMHL). An unmethylated haplotype load (uMHL) for each candidate region was defined, which is the normalized fraction of unmethylated haplotypes (UMH) at different lengths:

Wj = ί

[0077] Where 1 is the length of haplotypes, P(MHi) or P(UMHi) is the fraction of fully successive methylated or unmethylated haplotype with i loci respectively. For a haplotype of length L, all the sub-strings with length from 1 to L were considered in this calculation, wt is the weight for i-locus haplotype. wt = i or wt = f was typically used to favor the contribution of longer haplotypes. In the present invention, wt = i was applied. Quantile normalization, standardization (scale) as well as the batch effect elimination (Johnson et al. (2007)) were applied.

[0078] Developmental germ layers and tissue specific MHB regions. In order to investigate the layer and tissue specific MHB regions, group specific index (see below) was applied. An empirical threshold of 0.6 was selected to filter out layer and tissue specific MHB regions. Layer specific MHB regions were selected to show the ability to distinguish between the different development layers. Tissue specific MHB regions were further used for tissue mapping and cancer diagnosis.

_{1 0}MHLj

_{GSI =} A/ = l ¹ \ )MHL_max

n— 1 n indicates the number of the groups. MHL(j) denotes the average of MHL of j^th group.

MHLmax denotes the average of MHL of highest methylated group.

[0079] Deconvolution analysis. The deconvolution references were constructed from normal human solid tissues, WBC, colorectal cancer tissues (CCT), and lung cancer tissues (LCT). Tissue specific MHB regions for normal human tissues were selected for brain, colon, esophagus, heart, intestine, kidney, liver, lung, and stomach using candidate features for deconvolution based on non-negative decomposition with quadratic programming (Sun et al. (2015); Houseman et al. (2012); Gong et al. (2013)). Raw MHL signals were logit transformed before deconvolution analysis on plasma samples. Samples with less than 30% whole blood content from deconvolution analysis were considered to have failed due to poor library complexity.

[0080] Tumor load estimation using tumor specific MHBs. Pruning and K-nearest neighbors (KNN) imputation was performed on the MHL matrix with only the RRBS plasma and RRBS tumor tissue samples removing samples with low coverage and imputed missing values. Thus 30 colon cancer plasma, 29 lung cancer plasma, 69 normal plasma, 4 colon cancer tissues, and 5 lung cancer tissues remained. The 69 healthy normal plasma samples were split into "training" and "test" sets; with 46 samples set aside for feature selection and training while the remaining 23 samples were used as a completely independent data set to test the quantitation. Tumor specific methylation haplotype blocks were identified by 2-tailed t-test with a False Discovery Rate (FDR) of 0.001 and a minimum difference cutoff of 0.3. Two sets of markers were identified separately for colon cancer and lung cancer. To calibrate the relationship between tumor load and MHL values, 20 sets of simulations in which mixed sequencing reads from cancer tissue samples and normal plasma samples at a 1:5, 1 : 10, 1:20, 1: 100, and 0: 1 ratio were generated (totaling 100 simulated data sets for each cancer tissue). The average MHL value for these regions was computed for each region and a linear regression model was generated using these values and the known cancer tissue proportions for each cancer tissue. The model was applied to the average MHL value in these regions for test sets which included 30 colon cancer plasma, 29 lung cancer plasma, and 23 normal plasma samples. The estimated tumor loads for normal versus colon cancer and for normal versus lung cancer were compared using the colon cancer and lung cancer markers respectively.

[0081] Cancer plasma classification. Training WGBS data were collected to generate an MHL matrix and the top 15,000 MHBs by GSI were selected. These MHBs were clustered using K-means into 50 marker groups with the WGBS data matrix. Each cluster should have similar methylation patterns across each tissue type. In order to avoid overfitting, 20 colon cancer plasma, 20 lung cancer plasma, and 30 normal plasma samples were randomly selected to create a training data set from the RRBS plasma samples. The remaining samples (10 colon, 10 lung, and 39 normal) were held out as a test data set. For building the classifiers, an ensemble MARS (Multivariate Adaptive Regression Splines) model (Friedman, (1991)) implemented in the Earth R package (https://cran.r-project.org/web/packages/earth/index.html) was trained on the training data set using features from the top 15,000 MHBs ranked by the Group Specific Index (GSI). The ensemble MARS model was used to perform classification on the test plasma data set using the binary classifier. For cancer type classification, the features selected using MARS were used in a PLSDA (partial least squares discriminant analysis) to distinguish colon versus lung.

Data Availability

[0082] WGBS and RRBS data are available at the Gene Expression Omnibus (GEO) under accession GSE79279.

Tables:

[0083] Table 1. Top 10% tissue specific MHL and uMHL markers identified by GSI.

[0084] Table 2. Complete list of high methylated haplotype shared between matched primary tumor tissues and plasma for colon cancer (CRC) and lung cancer (LC) patients.

[0085] Table 3. Deconvolution of colon cancer (CRC), lung cancer (LC) and normal plasma into ten tissues using non-negative decomposition with quadratic programming. Samples with white blood cells composition greater than 30% were used to report averages.

[0086] Table 4. Differentially methylated MHB regions between cancer tissues and normal plasma.

[0087] Table 5. The sets of cancer specific and tissue specific markers derived from MARS based features selection on training data sets.

Table la:

Top 10% tissue specific uMHL markers identified by GSI

uMHL Markers

Region Group GSI refMax chrl9:5894163:5894242 vessel 8.75E-01 9.94E-01 chrl6:521904:521925 neural 8.73E-01 9.60E-01 chr2:43295338:43295363 neural 8.71E-01 9.72E-01 chr2:69345847:69345875 vessel 8.71E-01 9.63E-01 chr2:8360246:8360318 vessel 8.69E-01 9.60E-01 chr2:l 10103840:110103879 vessel 8.69E-01 9.44E-01 chrl0:73767213:73767231 neural 8.67E-01 l .OOE+00 chr21 :39450802:39450857 vessel 8.64E-01 9.63E-01 chr8:23201701 :23201725 vessel 8.63E-01 9.29E-01 chr8:96706051 :96706130 vessel 8.63E-01 9.62E-01 chrl0: 17281034:17281085 vessel 8.63E-01 9.76E-01 chrl 8:9535925:9535962 vessel 8.62E-01 9.64E-01 chrl : 196373497: 196373569 vessel 8.61E-01 9.74E-01 chr7:73314135:73314205 vessel 8.61E-01 9.57E-01 chr5 : 168192470 : 168192555 vessel 8.59E-01 9.41E-01 chrl 4 : 83966994 :83967047 vessel 8.59E-01 9.62E-01 chrlO: 14012644: 14012740 vessel 8.59E-01 9.93E-01 chrl6:4420959:4421041 vessel 8.59E-01 9.93E-01 chr2:8360333:8360384 vessel 8.58E-01 9.41E-01 chrl :2899575:2899616 vessel 8.57E-01 9.97E-01 chrl9:41932380:41932387 intestine 8.57E-01 9.37E-01 chr2 :232087015 :232087102 vessel 8.56E-01 9.89E-01 chrl7:738931 :738960 vessel 8.56E-01 9.80E-01 chrl 7 :48243247 :48243305 vessel 8.55E-01 9.83E-01 chrl9:768642:768715 vessel 8.54E-01 9.58E-01 chr2:38460795:38460935 vessel 8.54E-01 9.42E-01 chr6:57123002:57123073 vessel 8.53E-01 9.82E-01 chrl :243368706:243368788 vessel 8.53E-01 9.90E-01 chrl6:73086441 :73086558 vessel 8.53E-01 9.53E-01 chr6:1702288:1702366 vessel 8.52E-01 9.38E-01 chrl0:45676961 :45677042 vessel 8.52E-01 9.71E-01 chrl2:20700689:20700721 vessel 8.52E-01 9.80E-01 chrl2:20254130:20254176 vessel 8.51E-01 9.35E-01 chr2:3496911 :3496968 vessel 8.51E-01 9.23E-01 chrl 1 :69235366:69235449 vessel 8.51E-01 9.82E-01 chrl7:38605979:38605996 liver 8.51E-01 l .OOE+00 chr8:10001048:10001097 neural 8.50E-01 8.60E-01 chrl 1 :44994687:44994725 vessel 8.50E-01 9.53E-01 chr2:l 10861027:110861197 intestine 8.50E-01 8.87E-01 chr3:64702129:64702144 vessel 8.49E-01 9.43E-01 chr7:73389579:73389642 vessel 8.49E-01 9.67E-01 chrl0: 14013737:14013765 vessel 8.49E-01 9.82E-01 chr3:4458679:4458863 vessel 8.49E-01 9.59E-01 chr7:703821 :703897 vessel 8.49E-01 9.78E-01 chrl3: 101302763: 101302821 neural 8.49E-01 8.35E-01 chrl9: 16178379:16178427 vessel 8.48E-01 9.83E-01 uMHL Markers

Region Group GSI refMax chr7:73389660:73389669 vessel 8.48E-01 9.48E-01 chr2:43492333:43492418 vessel 8.48E-01 9.47E-01 chrl4:93113577:93113776 vessel 8.48E-01 9.56E-01 chr22:40845219:40845265 vessel 8.48E-01 9.59E-01 chrl :115610338:115610366 vessel 8.47E-01 9.66E-01 chr6:131312703:131312868 vessel 8.47E-01 9.70E-01 chrl6:81520175:81520330 vessel 8.47E-01 9.83E-01 chr20: 19474573:19474667 vessel 8.46E-01 9.81E-01 chrl :244217148:244217329 neural 8.46E-01 8.57E-01 chrl 6 :49822649 :49822660 vessel 8.46E-01 9.62E-01 chrl :202170004:202170040 vessel 8.46E-01 9.99E-01 chr3:8562700:8562922 vessel 8.46E-01 9.60E-01 chr8:1187134:1187185 neural 8.45E-01 l .OOE+00 chrl5:54832956:54833002 vessel 8.45E-01 9.57E-01 chrl l :3168353:3168372 vessel 8.45E-01 9.83E-01 chrl2: 116864174: 116864293 vessel 8.45E-01 9.69E-01 chrl7:31128334:31128406 vessel 8.45E-01 9.83E-01 chr2:72162546:72162581 vessel 8.44E-01 9.72E-01 chr9: 137553753: 137553885 vessel 8.44E-01 9.59E-01 chrl6:66957496:66957553 vessel 8.44E-01 9.88E-01 chr6:169568133:169568353 vessel 8.44E-01 9.36E-01 chr8 : 133466185 : 133466297 vessel 8.43E-01 9.54E-01 chrl2: 124774360: 124774380 vessel 8.43E-01 l .OOE+00 chrl9:3466975:3467064 vessel 8.43E-01 9.82E-01 chr9:98829531 :98829605 vessel 8.43E-01 9.58E-01 chrl7:37279963:37280015 vessel 8.43E-01 9.39E-01 chr9 : 116247804: 116247934 vessel 8.43E-01 9.72E-01 chrl :87223214:87223344 vessel 8.43E-01 9.52E-01 chrl 1 :66138099:66138125 intestine 8.42E-01 9.22E-01 chr5: 142533336: 142533503 vessel 8.42E-01 9.86E-01 chr7:4065672:4065679 vessel 8.42E-01 9.66E-01 chrl7:73831565:73831633 vessel 8.42E-01 9.67E-01 chrl6: 1373394:1373461 neural 8.42E-01 8.62E-01 chrl7:40477211 :40477303 vessel 8.42E-01 9.78E-01 chr6:165341974:165342035 neural 8.42E-01 8.81E-01 chrl 8 :58648459:58648474 vessel 8.42E-01 9.33E-01 chrl0:3928761 :3928829 vessel 8.41E-01 9.68E-01 chrl5:67457875:67458134 vessel 8.41E-01 9.44E-01 chrl9: 10233053:10233111 vessel 8.41E-01 9.42E-01 chrl8:74171483:74171505 vessel 8.41E-01 9.92E-01 chr22 :49409034 :49409082 vessel 8.41E-01 9.19E-01 chr21 :40047317:40047326 vessel 8.41E-01 9.33E-01 chrl :34451152:34451164 vessel 8.41E-01 9.86E-01 chr9: 136357330: 136357347 vessel 8.41E-01 l .OOE+00 chr9:l 16681630:116681838 vessel 8.41E-01 9.21E-01 chr7:5011476:5011523 esophagus 8.41E-01 9.33E-01 chrl6:87261081 :87261131 vessel 8.39E-01 9.76E-01 chr5 : 172194371 : 172194450 vessel 8.39E-01 9.66E-01 uMHL Markers

Region Group GSI refMax chrl9:32450501 :32450625 pancreas 8.39E-01 8.40E-01 chrl5:79052333:79052347 vessel 8.39E-01 l .OOE+00 chrl2: 116756805: 116756874 vessel 8.39E-01 9.58E-01 chrl2:2457684:2457778 vessel 8.39E-01 9.96E-01 chrl 3: 36273480 36273646 vessel 8.39E-01 9.52E-01 chr2: 145764662 145764766 vessel 8.39E-01 9.62E-01 chr4:140968580 140968766 vessel 8.38E-01 9.44E-01 chr7: 158890050 158890132 vessel 8.38E-01 9.15E-01 chr3:71586325:71586633 vessel 8.38E-01 9.82E-01 chr3:125819901 :125819917 vessel 8.38E-01 9.20E-01 chrl8:76551153:76551172 vessel 8.38E-01 9.48E-01 chr22:29347978:29348075 vessel 8.38E-01 9.88E-01 chr2:l 1526450:11526505 vessel 8.38E-01 9.49E-01 chrl4:91765021 :91765059 vessel 8.38E-01 9.94E-01 chr2:10544929:10545012 vessel 8.38E-01 9.64E-01 chr2:217839781 :217839805 vessel 8.37E-01 9.71E-01 chrl2: 109179149: 109179194 vessel 8.37E-01 9.33E-01 chrl :226128702:226128727 vessel 8.37E-01 9.38E-01 chr7 :40240562:40240640 vessel 8.37E-01 9.49E-01 chrl4:75039798:75039894 vessel 8.37E-01 9.50E-01 chr20:56721581 :56721650 vessel 8.37E-01 9.64E-01 chr8:6652013:6652077 vessel 8.36E-01 9.56E-01 chrl6: 1146322: 1146337 vessel 8.36E-01 9.60E-01 chrlO: 15667379: 15667446 vessel 8.36E-01 9.69E-01 chrl5:89560186:89560238 vessel 8.36E-01 9.35E-01 chr7:4707844:4707866 vessel 8.36E-01 9.43E-01 chr5 : 151082200 : 151082218 vessel 8.36E-01 8.84E-01 chr3:193715471 :193715560 vessel 8.36E-01 9.58E-01 chr9:93727370:93727392 vessel 8.36E-01 9.47E-01 chr8:97596962:97597040 vessel 8.36E-01 9.38E-01 chr21 :44484510:44485019 vessel 8.36E-01 9.71E-01 chr3:8279761 :8279814 vessel 8.36E-01 9.59E-01 chrl6:73454353:73454372 vessel 8.36E-01 9.45E-01 chr3: 14279072: 14279273 vessel 8.35E-01 9.78E-01 chr6:168498836:168498871 pancreas 8.35E-01 9.74E-01 chr4:173973114:173973166 vessel 8.35E-01 9.77E-01 chr9:74431770:74431840 vessel 8.35E-01 9.82E-01 chrl2:2396495:2396507 vessel 8.35E-01 9.51E-01 chrl 3: 109807772: 109807837 vessel 8.34E-01 9.61E-01 chr8:145019179:145019191 vessel 8.34E-01 9.41E-01 chrl2: 109182282: 109182346 vessel 8.34E-01 9.87E-01 chr8:23201626:23201644 vessel 8.34E-01 8.96E-01 chrl :171326156:171326309 vessel 8.34E-01 9.06E-01 chr3:30538064:30538174 vessel 8.34E-01 9.46E-01 chrl6:68857417:68857469 vessel 8.34E-01 9.67E-01 chrl7:60774267:60774330 vessel 8.34E-01 9.67E-01 chr7:64020677:64020788 vessel 8.34E-01 9.43E-01 chrl :201748589:201748658 vessel 8.34E-01 9.79E-01 uMHL Markers

Region Group GSI refMax chrl9: 18783073:18783151 vessel 8.34E-01 8.95E-01 chrl3: 112161714: 112161827 vessel 8.34E-01 9.56E-01 chrl 1 : 117070485: 117070493 vessel 8.34E-01 9.57E-01 chr7 : 128468433 : 128468462 vessel 8.34E-01 9.36E-01 chrl :2188830:2188947 neural 8.33E-01 8.29E-01 chr8 : 143695065 : 143695081 neural 8.33E-01 8.86E-01 chr6:71790637:71790777 vessel 8.33E-01 9.84E-01 chr7:73406729:73406811 vessel 8.33E-01 9.84E-01 chrl2: 1584268:1584438 vessel 8.33E-01 9.45E-01 chr2: 1657462: 1657556 vessel 8.33E-01 9.28E-01 chr2:121677850:121677924 vessel 8.33E-01 9.24E-01 chrl3:99104177:99104223 vessel 8.33E-01 9.82E-01 chr6:23004460:23004497 vessel 8.33E-01 9.08E-01 chr7:33758956:33759144 vessel 8.33E-01 9.59E-01 chrl 1 :65326863:65326909 vessel 8.33E-01 9.57E-01 chr3 : 134052418:134052557 vessel 8.33E-01 9.33E-01 chrl6: 1038028:1038079 vessel 8.33E-01 9.95E-01 chr7:25810506:25810570 vessel 8.32E-01 9.44E-01 chrl l : 19601607:19601696 vessel 8.32E-01 9.91E-01 chr3:54746711 :54746836 vessel 8.32E-01 9.89E-01 chr3: 126720805: 126720813 vessel 8.32E-01 9.64E-01 chr21 :46453929:46453954 vessel 8.32E-01 9.61E-01 chr4:6773182:6773272 vessel 8.32E-01 9.45E-01 chr5 : 149980906 : 149980972 vessel 8.32E-01 9.59E-01 chr5:77830138:77830190 vessel 8.32E-01 8.86E-01 chrl0:80339365:80339515 vessel 8.32E-01 9.23E-01 chrl7: 12989679:12989753 vessel 8.32E-01 9.26E-01 chrlO: 114344929: 114344989 vessel 8.32E-01 9.41E-01 chr2:36719487:36719574 vessel 8.32E-01 9.65E-01 chrl 4 :75446146 :75446254 vessel 8.32E-01 8.61E-01 chrl 1 : 133895052: 133895366 vessel 8.32E-01 9.55E-01 chrl l :62370671 :62370715 vessel 8.31E-01 9.97E-01 chr5:52897443:52897563 vessel 8.31E-01 8.89E-01 chrl 1 : 130545528: 130545623 vessel 8.31E-01 9.84E-01 chr2:217405801 :217405854 vessel 8.31E-01 9.64E-01 chr6:169018100:169018147 vessel 8.31E-01 9.28E-01 chrl7:75598600:75598659 vessel 8.31E-01 9.48E-01 chrl0:45675475 :45675491 vessel 8.31E-01 9.64E-01 chrl 8:53074420:53074508 neural 8.31E-01 7.93E-01 chr2:54199164:54199243 vessel 8.31E-01 9.28E-01 chr5:168451596:168451712 vessel 8.31E-01 9.28E-01 chr2 :241185226 :241185267 vessel 8.31E-01 9.35E-01 chr7:70120035:70120076 vessel 8.30E-01 9.39E-01 chrl0:30109892:30109931 vessel 8.30E-01 9.74E-01 chr7:2951480:2951552 vessel 8.30E-01 9.50E-01 chrl6:79166842:79167002 vessel 8.30E-01 9.67E-01 chrl :3464719:3464876 vessel 8.30E-01 9.07E-01 chrl 3: 110775448: 110775493 vessel 8.30E-01 9.19E-01 uMHL Markers

Region Group GSI refMax chr20: 19272195:19272440 vessel 8.30E-01 9.84E-01 chrl :9386783:9386877 vessel 8.30E-01 9.70E-01 chr6:41549109:41549179 vessel 8.29E-01 9.60E-01 chrl 1 :63826186:63826257 neural 8.29E-01 8.91E-01 chrl :3286118:3286163 vessel 8.29E-01 9.32E-01 chrl6:88279603:88279618 vessel 8.29E-01 9.79E-01 chr3 : 187769246 : 187769343 vessel 8.29E-01 9.64E-01 chr2:121298318:121298336 vessel 8.29E-01 9.61E-01 chrl0:87796214:87796244 vessel 8.29E-01 9.35E-01 chrl 1 : 111784374: 111784426 vessel 8.29E-01 9.77E-01 chrl6:49686422:49686568 vessel 8.29E-01 9.39E-01 chrl0:711379:711694 vessel 8.28E-01 9.68E-01 chr4:71941315:71941425 vessel 8.28E-01 9.57E-01 chrl 3 :52304379 :52304567 vessel 8.28E-01 9.81E-01 chrl0: 10336914:10336945 neural 8.28E-01 8.62E-01 chrl5:99498725:99498811 vessel 8.28E-01 9.59E-01 chrl5:88153699:88153769 vessel 8.28E-01 9.76E-01 chr5 : 149980623 : 149980743 vessel 8.28E-01 9.73E-01 chrl5:47765811 :47765900 vessel 8.28E-01 9.64E-01 chrl5:36894077:36894154 vessel 8.28E-01 9.72E-01 chr3:73414820:73414881 vessel 8.28E-01 9.26E-01 chrl0:44197849:44197884 pancreas 8.28E-01 8.67E-01 chrl 8:60387698:60387879 neural 8.28E-01 8.60E-01 chr20: 17822381 :17822534 vessel 8.28E-01 9.58E-01 chrl3:31470063:31470114 vessel 8.28E-01 9.67E-01 chr2:66074251 :66074308 vessel 8.28E-01 9.59E-01 chr9: 131398646: 131398694 pancreas 8.28E-01 8.48E-01 chrl :234594452:234594635 liver 8.27E-01 8.36E-01 chrl l : 19778332:19778414 vessel 8.27E-01 9.35E-01 chr6:155593701 :155593747 neural 8.27E-01 8.79E-01 chr5: 1542556: 1542597 vessel 8.27E-01 9.14E-01 chrl7:2362969:2363062 vessel 8.27E-01 8.98E-01 chrl0: 131488146: 131488308 vessel 8.27E-01 9.41E-01 chrl6:86461393:86461510 vessel 8.27E-01 9.20E-01 chrl3: l l 1024091: 111024104 vessel 8.27E-01 9.35E-01 chrlO: 105879872: 105879934 vessel 8.27E-01 9.57E-01 chr2 :216299024 :216299143 vessel 8.27E-01 9.23E-01 chr2 :206620645 :206620696 vessel 8.27E-01 9.67E-01 chr6:90708046:90708215 vessel 8.27E-01 9.21E-01 chrl :3460222:3460269 vessel 8.27E-01 9.80E-01 chrl6:88096861 :88096956 vessel 8.27E-01 9.48E-01 chr7 : 159004650 : 159004678 vessel 8.26E-01 9.08E-01 chr8:22443383:22443437 vessel 8.26E-01 9.93E-01 chr20:35169012:35169055 vessel 8.26E-01 9.93E-01 chrl9:39889822:39889941 liver 8.26E-01 8.82E-01 chrlO: 129721730: 129721745 vessel 8.26E-01 9.38E-01 chr4 : 120636770: 120636877 intestine 8.26E-01 8.81E-01 chr5: 141628521 : 141628586 vessel 8.26E-01 9.23E-01 uMHL Markers

Region Group GSI refMax chr5:59792001 :59792053 vessel 8.26E-01 9.75E-01 chr6: 14925566: 14925731 vessel 8.26E-01 9.37E-01 chr3 : 148729585 : 148729652 vessel 8.26E-01 9.84E-01 chr5:l 17889340:117889421 vessel 8.26E-01 9.03E-01 chrl8:74918812:74918906 vessel 8.26E-01 9.13E-01 chrl9:2523639:2523852 vessel 8.26E-01 9.87E-01 chr2:218692718:218692749 vessel 8.26E-01 9.67E-01 chr7:70133955:70134155 vessel 8.26E-01 9.19E-01 chrl4:37504457:37504520 vessel 8.26E-01 9.28E-01 chr2:121371664:121371708 vessel 8.26E-01 9.93E-01 chrl :203491536:203491617 vessel 8.26E-01 9.47E-01 chrl 1 : 114237690: 114237718 vessel 8.26E-01 9.20E-01 chrl 3 : 111000221: 111000344 vessel 8.26E-01 9.10E-01 chrl8: 12646025:12646103 vessel 8.26E-01 9.00E-01 chrl l :64631168:64631193 vessel 8.26E-01 9.61E-01 chr7:l 135564:1135633 vessel 8.25E-01 9.72E-01 chr5:158945587:158945820 vessel 8.25E-01 9.58E-01 chrl8:46353742:46353814 vessel 8.25E-01 9.54E-01 chr2 : 137330457 : 137330466 vessel 8.25E-01 9.43E-01 chr5:77844053:77844099 vessel 8.25E-01 9.26E-01 chr5 : 177694377 : 177694398 vessel 8.25E-01 9.18E-01 chr20:35168933:35168988 vessel 8.25E-01 9.46E-01 chr3:70048580:70048701 vessel 8.25E-01 9.41E-01 chrl l : 12097899:12098112 vessel 8.25E-01 9.52E-01 chr2:20055744:20055772 vessel 8.25E-01 9.46E-01 chrl :10614315:10614356 liver 8.25E-01 8.10E-01 chrl0: 14012441 :14012468 vessel 8.25E-01 9.80E-01 chrl 2: 111707943: 111708004 vessel 8.25E-01 9.64E-01 chrl :3460137:3460182 vessel 8.25E-01 9.98E-01 chr20: 17830926: 17830968 vessel 8.25E-01 8.96E-01 chr9: 133895273: 133895401 vessel 8.25E-01 9.81E-01 chrl6:68386106:68386174 intestine 8.25E-01 9.04E-01 chr7:2719029:2719102 neural 8.25E-01 9.63E-01 chr2 : 174060123 : 174060220 vessel 8.25E-01 9.47E-01 chrl l : 12136324:12136406 vessel 8.25E-01 9.86E-01 chr2:42226193:42226234 vessel 8.25E-01 9.50E-01 chr22:33313719:33313805 vessel 8.25E-01 9.73E-01 chrl 1 : 126033028: 126033048 vessel 8.25E-01 9.75E-01 chrl l : 1418719:1418773 neural 8.25E-01 8.11E-01 chr22:31489110:31489197 vessel 8.24E-01 9.79E-01 chrl 1 :45260506:45260585 vessel 8.24E-01 9.07E-01 chr2:47040392:47040486 vessel 8.24E-01 9.90E-01 chr3:186819136:186819178 vessel 8.24E-01 9.62E-01 chr3:9153801 :9153977 vessel 8.24E-01 9.38E-01 chr8:73559260:73559345 vessel 8.24E-01 9.72E-01 chrl6:29142419:29142508 liver 8.24E-01 9.36E-01 chrl :9410453:9410468 vessel 8.24E-01 9.66E-01 chr21 :47512644:47512690 vessel 8.24E-01 9.36E-01 uMHL Markers

Region Group GSI refMax chr9:16247410:16247417 vessel 8.24E-01 9.76E-01 chrl8:46309140:46309233 vessel 8.24E-01 9.79E-01 chr3:66413019:66413233 vessel 8.23E-01 9.14E-01 chr20: 10641514:10641548 vessel 8.23E-01 9.54E-01 chrlO: 17280749: 17280812 vessel 8.23E-01 9.77E-01 chr7:5592713:5592836 intestine 8.23E-01 8.14E-01 chrl4:23318835:23318857 vessel 8.23E-01 9.86E-01 chr7:42779397:42779584 vessel 8.23E-01 9.61E-01 chrl :61914656:61914841 vessel 8.23E-01 9.79E-01 chrl 9 : 13962429 : 13962502 vessel 8.23E-01 9.20E-01 chr4:76270190:76270273 vessel 8.23E-01 9.13E-01 chrl0:81915105:81915176 vessel 8.23E-01 9.79E-01 chrl 1 :94573359:94573509 vessel 8.23E-01 9.41E-01 chrl 1 :44729756:44729789 vessel 8.23E-01 9.53E-01 chr7:73424958:73425002 vessel 8.23E-01 9.17E-01 chr8:141960637:141960714 vessel 8.23E-01 8.98E-01 chr2:3452386:3452438 fat 8.23E-01 8.23E-01 chr2:101402810:101403044 vessel 8.23E-01 9.79E-01 chr8:77316559:77316617 neural 8.23E-01 8.38E-01 chr2:240733175:240733324 vessel 8.23E-01 9.25E-01 chrl5:26135892:26136025 vessel 8.23E-01 9.09E-01 chr2:107193220:107193348 vessel 8.23E-01 9.14E-01 chr20:39392677:39392771 vessel 8.22E-01 9.35E-01 chrl :3314113:3314144 vessel 8.22E-01 8.57E-01 chr8: 141057820: 141057872 vessel 8.22E-01 9.57E-01 chrl0:5660858:5660911 vessel 8.22E-01 9.61E-01 chr5:8696414:8696485 vessel 8.22E-01 9.70E-01 chrl 3:45289725:45289758 vessel 8.22E-01 9.17E-01 chr7:37039869:37039998 vessel 8.22E-01 9.52E-01 chrl2:32293438:32293717 neural 8.22E-01 9.04E-01 chr5:2515778:2515802 neural 8.22E-01 8.27E-01 chrlO: 10336989: 10337032 neural 8.22E-01 8.49E-01 chr9:72012687:72012707 vessel 8.22E-01 9.64E-01 chrl6:88976391 :88976404 vessel 8.22E-01 9.77E-01 chrl7:30001481 :30001529 vessel 8.22E-01 9.53E-01 chrl6:80752918:80753020 vessel 8.22E-01 9.47E-01 chrl 1 : 130283367: 130283389 vessel 8.22E-01 9.10E-01 chrl6:72928691 :72928785 vessel 8.22E-01 9.75E-01 chrl l : 10714431 :10714466 vessel 8.22E-01 9.51E-01 chrl9: 18783185:18783216 vessel 8.22E-01 9.40E-01 chrl6:61245717:61245888 vessel 8.22E-01 9.57E-01 chr9:129517613:129517699 intestine 8.21E-01 7.94E-01 chr9:124615315:124615387 vessel 8.21E-01 8.99E-01 chr6:15455978:15456143 vessel 8.21E-01 8.72E-01 chr5: 137727491 : 137727661 neural 8.21E-01 8.51E-01 chr3:13560010:13560122 vessel 8.21E-01 9.49E-01 chrl :16346068:16346121 vessel 8.21E-01 9.30E-01 chrl0:711944:712088 vessel 8.21E-01 9.18E-01 uMHL Markers

Region Group GSI refMax chr22:49412171 :49412287 vessel 8.21E-01 9.49E-01 chr2:40355055:40355244 vessel 8.21E-01 9.16E-01 chr22:29146497 29146625 vessel 8.21E-01 9.23E-01 chrl6: 14418702 14418748 vessel 8.21E-01 9.57E-01 chr21 :42496716 42496736 vessel 8.21E-01 9.44E-01 chr2: 1820299: 1820400 vessel 8.21E-01 9.69E-01 chrl 3 : 111922451: 111922625 vessel 8.21E-01 9.42E-01 chr7 : 158207285 : 158207423 neural 8.21E-01 8.86E-01 chrl4:75086815:75086860 vessel 8.21E-01 9.32E-01 chr6:45784561 :45784755 vessel 8.21E-01 8.71E-01 chrl2:98869058:98869255 vessel 8.21E-01 9.13E-01 chrl7:39680190:39680212 neural 8.21E-01 9.27E-01 chr2:3473947:3474025 vessel 8.21E-01 9.20E-01 chr6:16725500:16725574 vessel 8.21E-01 9.80E-01 chr3:123419686:123419782 vessel 8.21E-01 l .OOE+00 chr5 :78099270:78099340 vessel 8.21E-01 9.53E-01 chr4:82057849:82058045 vessel 8.20E-01 9.35E-01 chr7:73465618:73465668 vessel 8.20E-01 9.54E-01 chr7:30818374:30818439 vessel 8.20E-01 9.14E-01 chr4:88461671 :88461843 vessel 8.20E-01 9.81E-01 chrl :3459727:3459820 vessel 8.20E-01 9.70E-01 chrl2: 109179337: 109179529 vessel 8.20E-01 9.65E-01 chrl4:51237067 51237132 vessel 8.20E-01 9.13E-01 chr3:141151136 141151212 vessel 8.20E-01 9.68E-01 chrl :203541608 203541617 vessel 8.20E-01 9.70E-01 chrl8:3622294:3622340 vessel 8.20E-01 9.36E-01 chrl :3459875:3459893 vessel 8.20E-01 9.34E-01 chrl2:52938381 :52938412 vessel 8.20E-01 9.74E-01 chr4:5736721 :5736775 vessel 8.20E-01 9.30E-01 chrl :39933015:39933081 vessel 8.20E-01 9.80E-01 chrl9: 16178735:16178766 vessel 8.20E-01 9.03E-01 chr20:57473842:57473881 vessel 8.20E-01 9.78E-01 chrl2: 123738593: 123738662 vessel 8.19E-01 9.66E-01 chrl6:88677685:88677878 neural 8.19E-01 7.95E-01 chrl :3142374:3142411 vessel 8.19E-01 8.72E-01 chrl7:57565015:57565070 vessel 8.19E-01 9.36E-01 chrlO: 134527781: 134527839 neural 8.19E-01 8.61E-01 chrl0:30083908:30083982 vessel 8.19E-01 9.79E-01 chr2:72366403:72366433 vessel 8.19E-01 9.41E-01 chr4:24732279:24732305 vessel 8.19E-01 9.72E-01 chrl7:75861540:75861581 vessel 8.19E-01 8.97E-01 chr7:66935160:66935181 vessel 8.19E-01 9.33E-01 chrl 4 :69410822 :69410995 vessel 8.19E-01 9.15E-01 chr5:175119757:175119816 vessel 8.19E-01 9.77E-01 chrl6:86965611 :86965651 vessel 8.19E-01 9.94E-01 chr5:52658535:52658625 vessel 8.19E-01 9.62E-01 chr5 : 109775450: 109775504 vessel 8.19E-01 9.29E-01 chr5:73234564:73234688 vessel 8.19E-01 9.39E-01 uMHL Markers

Region Group GSI refMax chr2:161777367:161777468 vessel 8.19E-01 9.72E-01 chrl3:33922144:33922332 vessel 8.19E-01 9.79E-01 chr7 : 120164933 : 120164963 vessel 8.19E-01 9.30E-01 chrl3: 110918379: 110918481 vessel 8.19E-01 9.16E-01 chrl7:2011086:2011131 vessel 8.19E-01 9.69E-01 chr9:7984790:7984898 vessel 8.19E-01 9.40E-01 chrl8:20682264:20682338 intestine 8.19E-01 8.40E-01 chr7:104978120:104978212 vessel 8.19E-01 9.63E-01 chr5 : 166634253 : 166634335 vessel 8.19E-01 9.03E-01 chrl 8:56534875:56534925 vessel 8.19E-01 9.70E-01 chr3 : 187988060: 187988137 vessel 8.19E-01 9.76E-01 chrlO: 121438397: 121438569 vessel 8.19E-01 9.68E-01 chrl9:39182926:39182945 vessel 8.19E-01 9.35E-01 chrl3:99667976:99668059 neural 8.18E-01 8.29E-01 chr7:127584205:127584527 neural 8.18E-01 8.66E-01 chrl l :35651590:35651804 vessel 8.18E-01 9.19E-01 chrl 1 : 103407665: 103407717 vessel 8.18E-01 8.98E-01 chr7 : 135433499: 135433541 vessel 8.18E-01 9.64E-01 chrl :23098725:23098744 vessel 8.18E-01 9.51E-01 chrl :3494166:3494235 vessel 8.18E-01 9.52E-01 chr2:2107292:2107346 neural 8.18E-01 7.72E-01 chr8:101427557:101427651 vessel 8.18E-01 9.11E-01 chrlO: 14016066: 14016097 vessel 8.18E-01 9.41E-01 chrl l : 10647667:10647725 vessel 8.18E-01 9.56E-01 chrl6:75278952:75279001 vessel 8.18E-01 9.60E-01 chr9 : 124089044 : 124089101 vessel 8.18E-01 9.70E-01 chrl7:21185776:21185831 vessel 8.18E-01 9.89E-01 chr3:11178498:11179102 vessel 8.17E-01 9.40E-01 chrl7:57925734:57925805 intestine 8.17E-01 8.84E-01 chr20: 16106391 :16106635 vessel 8.17E-01 9.07E-01 chr2:241536131 :241536192 vessel 8.17E-01 9.91E-01 chr5:76714624:76714674 vessel 8.17E-01 9.08E-01 chr8:42521965:42522125 vessel 8.17E-01 9.75E-01 chrl 1 :36003464:36003500 vessel 8.17E-01 9.59E-01 chr20:23251275:23251362 vessel 8.17E-01 9.59E-01 chrl : 168578476: 168578512 vessel 8.17E-01 9.42E-01 chr20:50186917:50186939 vessel 8.17E-01 8.95E-01 chr3:49556866:49557077 neural 8.17E-01 8.96E-01 chrl0: 131324082: 131324193 vessel 8.17E-01 9.67E-01 chrl :205780103:205780116 vessel 8.17E-01 9.51E-01 chrl :42003200:42003221 vessel 8.17E-01 9.57E-01 chrl 1 :2730324:2730441 vessel 8.17E-01 9.80E-01 chr5: 156988163: 156988221 vessel 8.16E-01 8.84E-01 chrl9:6744481 :6744634 vessel 8.16E-01 8.99E-01 chr20:56472461 :56472592 liver 8.16E-01 8.74E-01 chr6: 1624318: 1624399 vessel 8.16E-01 9.29E-01 chrl2: 106517592: 106517795 vessel 8.16E-01 9.85E-01 chr6:44195262:44195347 vessel 8.16E-01 9.04E-01 uMHL Markers

Region Group GSI refMax chrl9:39182585:39182856 vessel 8.16E-01 9.65E-01 chrlO: 126104092: 126104263 vessel 8.16E-01 9.75E-01 chr2:66528170:66528286 vessel 8.16E-01 9.69E-01 chr22: 19971912:19971946 vessel 8.16E-01 9.42E-01 chr21 :47403346:47403426 vessel 8.16E-01 9.03E-01 chrl6:87234734:87234896 vessel 8.16E-01 9.64E-01 chr2:38611005:38611050 vessel 8.16E-01 9.82E-01 chr2: 12677328: 12677416 vessel 8.16E-01 9.22E-01 chr9:101749596:101749621 vessel 8.16E-01 9.13E-01 chr9:92300357:92300439 vessel 8.16E-01 9.28E-01 chrl4:76461726:76461806 vessel 8.16E-01 9.80E-01 chr6 :159624504:159624617 vessel 8.16E-01 9.82E-01 chr4:57909186:57909239 vessel 8.16E-01 9.74E-01 chr21 :40195044:40195130 vessel 8.16E-01 9.57E-01 chrl :2899714:2899770 neural, vessel 8.16E-01 9.66E-01 chrl :9384754:9384813 vessel 8.16E-01 9.67E-01 chrl6:57149767:57149848 neural 8.16E-01 8.76E-01 chr2: 1656844: 1657056 vessel 8.16E-01 9.72E-01 chrl5:68777293:68777315 vessel 8.16E-01 9.89E-01 chr6: 164506404: 164506437 vessel 8.16E-01 9.35E-01 chr2:218722879:218722891 vessel 8.15E-01 9.67E-01 chr9: 137536001 : 137536060 vessel 8.15E-01 9.40E-01 chrl3: 106439974: 106440058 vessel 8.15E-01 9.44E-01 chr3: 123132072: 123132158 vessel 8.15E-01 9.64E-01 chrl4: 105802382: 105802561 neural 8.15E-01 7.82E-01 chrl 8:7607703:7607797 vessel 8.15E-01 8.85E-01 chrl :2868537:2868570 vessel 8.15E-01 8.53E-01 chrl9: 1081908:1081925 intestine 8.15E-01 9.06E-01 chr7:3322236:3322467 vessel 8.15E-01 9.44E-01 chrl9: 10464320: 10464378 liver 8.15E-01 9.20E-01 chrl2: 125106220: 125106281 vessel 8.15E-01 9.49E-01 chr2 :242668092 :242668152 neural 8.15E-01 8.47E-01 chrl5:26050364:26050411 vessel 8.15E-01 9.66E-01 chrl6: 1033828:1033849 neural 8.15E-01 7.58E-01 chrl5:92573244:92573323 vessel 8.15E-01 9.82E-01 chrl 6 :29206978 :29207023 vessel 8.15E-01 9.69E-01 chrl0:50155412:50155484 vessel 8.15E-01 9.06E-01 chr4:7844482:7844728 vessel 8.15E-01 9.33E-01 chr5:177799176:177799310 vessel 8.15E-01 9.86E-01 chr7:71563965:71564049 vessel 8.15E-01 9.22E-01 chrl8:77398817:77398865 vessel 8.15E-01 9.82E-01 chrl9: 15361966:15362035 vessel 8.15E-01 9.85E-01 chrl :156111362:156111379 vessel 8.15E-01 9.21E-01 chr4:141207852:141207918 neural 8.15E-01 8.40E-01 chrl8:46316977:46317049 vessel 8.15E-01 9.60E-01 chrl9:7580118:7580276 vessel 8.15E-01 9.76E-01 chr2:238322615:238322681 vessel 8.15E-01 9.55E-01 chrl 1 :4726406:4726437 vessel 8.15E-01 9.63E-01 uMHL Markers

Region Group GSI refMax chrl6: 1243486: 1243578 liver 8.14E-01 8.16E-01 chr9:101749649:101749733 vessel 8.14E-01 9.54E-01 chrl l : 12184939:12185109 vessel 8.14E-01 9.59E-01 chrl 5 :26047396 :26047413 vessel 8.14E-01 9.12E-01 chrl :204401170:204401223 vessel 8.14E-01 9.58E-01 chrl :59986591 :59986617 vessel 8.14E-01 9.06E-01 chrl7:43188128:43188157 vessel 8.14E-01 9.70E-01 chrl3:24658482:24658536 neural 8.14E-01 7.67E-01 chr5: 168168241 : 168168258 vessel 8.14E-01 8.15E-01 chrl :55909399:55909463 vessel 8.14E-01 9.66E-01 chr2:20001248:20001401 vessel 8.14E-01 9.92E-01 chr22:45907965:45908083 vessel 8.14E-01 9.42E-01 chr8:21499839:21499917 vessel 8.14E-01 9.58E-01 chrl :203526848:203526898 vessel 8.14E-01 9.59E-01 chr6: 148561802: 148561903 vessel 8.14E-01 9.39E-01 chr2:21676719:21676761 vessel 8.14E-01 9.26E-01 chr21 :30502731 :30502809 vessel 8.14E-01 9.58E-01 chrl5:71621595:71621649 vessel 8.14E-01 9.32E-01 chr2:25078720:25078801 vessel 8.14E-01 9.30E-01 chr6:2355526:2355693 vessel 8.13E-01 9.42E-01 chrl9: 1136134:1136202 intestine 8.13E-01 8.14E-01 chr5 : 141628696 : 141628776 vessel 8.13E-01 9.55E-01 chrl4:89895046:89895080 vessel 8.13E-01 8.91E-01 chrl9:38485266:38485425 pancreas 8.13E-01 7.91E-01 chr21 :47530618:47530659 vessel 8.13E-01 9.26E-01 chrl 7 :42875273 :42875297 vessel 8.13E-01 9.35E-01 chr20:50368876:50368956 vessel 8.13E-01 9.89E-01 chr7:75595987:75596208 vessel 8.13E-01 9.61E-01 chr9:80384641 :80384724 neural 8.13E-01 8.16E-01 chrlO: 123901799: 123901843 vessel 8.13E-01 9.40E-01 chrl 3:98082290 98082421 neural 8.13E-01 8.78E-01 chrl 9: 33674931 33674961 vessel 8.13E-01 9.23E-01 chrl6:88195380 88195408 vessel 8.13E-01 9.09E-01 chrl7:8584339:8584382 vessel 8.13E-01 9.72E-01 chrl 1 :44729854:44729898 vessel 8.13E-01 9.74E-01 chr3: 129899423: 129899521 heart, vessel 8.13E-01 9.71E-01 chrl7: 14047988:14048092 vessel 8.13E-01 9.35E-01 chr22 : 32976039 :32976101 liver 8.13E-01 8.36E-01 chrl 1 :57184788:57184846 vessel 8.13E-01 9.39E-01 chr22:43079771 :43079865 vessel 8.13E-01 9.98E-01 chrl :32045230:32045272 vessel 8.13E-01 9.39E-01 chr2 :242775475 :242775494 vessel 8.13E-01 9.83E-01 chrl :2899810:2899955 vessel 8.13E-01 9.03E-01 chr22:47331564:47331659 liver 8.13E-01 8.83E-01 chr6:37046101 :37046167 vessel 8.12E-01 9.11E-01 chr4:36056662:36056826 vessel 8.12E-01 9.21E-01 chr2: 1566219: 1566233 vessel 8.12E-01 8.87E-01 chrl :3282806:3282902 vessel 8.12E-01 9.80E-01 uMHL Markers

Region Group GSI refMax chrl2:2749661 :2749704 vessel 8.12E-01 9.48E-01 chr7:73119356:73119403 vessel 8.12E-01 8.94E-01 chr21 :44690743:44690783 neural 8.12E-01 8.09E-01 chrl4: 104018772: 104018857 vessel 8.12E-01 9.82E-01 chr2:46893583:46893684 vessel 8.12E-01 9.49E-01 chrl 4 95875180:95875232 vessel 8.12E-01 9.74E-01 chrl 5 27573948:27574019 neural 8.12E-01 8.87E-01 chr20 46756899:46756983 vessel 8.12E-01 9.89E-01 chr2:46531085:46531128 vessel 8.12E-01 9.51E-01 chrl :217203173:217203214 vessel 8.12E-01 9.66E-01 chrl8:71442341 :71442413 vessel 8.12E-01 8.94E-01 chr7:151133987:151134097 vessel 8.12E-01 9.16E-01 chr2 : 144282564 : 144282630 vessel 8.12E-01 9.76E-01 chr3 : 188624320: 188624396 vessel 8.12E-01 9.38E-01 chrl6:4092830:4092845 vessel 8.12E-01 9.07E-01 chr9 : 136437866 : 136437930 vessel 8.12E-01 9.56E-01 chrl :61657038:61657079 vessel 8.12E-01 9.58E-01 chr8 : 142420181 : 142420195 vessel 8.12E-01 9.40E-01 chr8:69783211 :69783254 vessel 8.12E-01 9.73E-01 chrl7:37833823:37833848 vessel 8.12E-01 9.77E-01 chrl l : 12255071 :12255245 vessel 8.12E-01 9.29E-01 chrl5: 100708207: 100708246 vessel 8.12E-01 9.37E-01 chrl6:51868437:51868468 vessel 8.12E-01 9.06E-01 chrl 7 :46343933 :46343974 intestine 8.12E-01 8.75E-01 chrl0:30110183:30110189 vessel 8.12E-01 8.90E-01 chr8:70846160:70846211 vessel 8.12E-01 9.12E-01 chr7 : 132037792 : 132037854 vessel 8.11E-01 9.53E-01 chrl6:49686581 :49686695 vessel 8.11E-01 9.46E-01 chrl7:30821748:30821864 neural 8.11E-01 7.47E-01 chr20:24631061 :24631099 vessel 8.11E-01 9.29E-01 chrl8:74172210:74172240 vessel 8.11E-01 9.23E-01 chr6:41419353:41419617 vessel 8.11E-01 9.58E-01 chrl7:78002601 :78002654 vessel 8.11E-01 8.84E-01 chr2:99427338:99427414 vessel 8.11E-01 9.86E-01 chrl :156271781 :156271977 liver 8.11E-01 8.87E-01 chrl5:56208850:56209086 vessel 8.11E-01 9.61E-01 chrl9: 16178499:16178673 vessel 8.11E-01 8.57E-01 chr9 : 126081436 : 126081458 vessel 8.11E-01 9.68E-01 chr5 : 156988956: 156989239 vessel 8.11E-01 8.74E-01 chr8:23201483:23201545 vessel 8.11E-01 9.40E-01 chrl7: 12554165:12554199 vessel 8.11E-01 9.45E-01 chr7:2500197:2500212 neural 8.11E-01 7.78E-01 chrl 1 : 114167495: 114167693 vessel 8.11E-01 9.80E-01 chrl2: 123579604: 123579635 vessel 8.11E-01 9.18E-01 chr5:36569776:36569815 vessel 8.11E-01 9.62E-01 chr9:101721017:101721046 vessel 8.11E-01 9.44E-01 chrl 1 :7507122:7507225 vessel 8.11E-01 9.34E-01 chrl6:66737688:66737762 vessel 8.11E-01 9.54E-01 uMHL Markers

Region Group GSI refMax chrl9:46286747:46286876 vessel 8.11E-01 9.81E-01 chr2:107381544:107381755 vessel 8.11E-01 8.53E-01 chrl7:74736513:74736621 vessel 8.10E-01 9.65E-01 chrl3:39205072:39205118 vessel 8.10E-01 9.40E-01 chr9 92277644:92277734 neural 8.10E-01 7.89E-01 chr7 465066:465102 vessel 8.10E-01 9.47E-01 chr4 41157591 :41157674 vessel 8.10E-01 9.20E-01 chrl 0: 131694575 : 131694682 neural 8.10E-01 8.35E-01 chr2:109788545:109788604 vessel 8.10E-01 9.53E-01 chr9:285924:285974 vessel 8.10E-01 9.13E-01 chrl :9431472:9431636 vessel 8.10E-01 9.65E-01 chrl 8 :77246357 :77246388 vessel 8.10E-01 9.48E-01 chrl6:66652537:66652773 vessel 8.10E-01 9.71E-01 chrl9:3466761 :3466827 vessel 8.10E-01 9.39E-01 chr2:1565960:1566095 vessel 8.10E-01 8.86E-01 chrl2: 123963634: 123963661 vessel 8.10E-01 9.71E-01 chrl3:21572143:21572171 vessel 8.10E-01 9.65E-01 chrl4:52373819:52373891 vessel 8.10E-01 9.29E-01 chrl :9436026:9436361 vessel 8.10E-01 9.81E-01 chrl5: 100851337: 100851552 vessel 8.10E-01 9.56E-01 chrl0: 13801406:13801461 vessel 8.10E-01 8.38E-01 chrl2:47491451 :47491535 vessel 8.10E-01 9.70E-01 chrl2:57197704:57197748 vessel 8.10E-01 9.71E-01 chrl7:77460860:77460869 neural 8.10E-01 8.69E-01 chr7: 143169791 : 143169807 intestine 8.10E-01 7.65E-01 chrl5:92462388:92462506 vessel 8.10E-01 9.12E-01 chrlO: 11733400: 11733428 vessel 8.10E-01 9.38E-01 chr6: 1867570: 1867643 pancreas 8.09E-01 8.40E-01 chrl 3 : 113698994: 113699050 neural 8.09E-01 7.75E-01 chrl2:77624317:77624349 vessel 8.09E-01 9.63E-01 chr2:12461342:12461469 vessel 8.09E-01 9.53E-01 chrl l : 12352080:12352113 neural 8.09E-01 8.04E-01 chrl8:72063318:72063459 vessel 8.09E-01 9.14E-01 chr21 :44162140:44162220 vessel 8.09E-01 9.31E-01 chrl 3:99023307:99023384 vessel 8.09E-01 9.91E-01 chrl : 179322741 : 179322768 vessel 8.09E-01 9.68E-01 chr9:126927295:126927337 vessel 8.09E-01 9.43E-01 chr6:85592864:85592982 vessel 8.09E-01 9.46E-01 chr8:106155638:106155841 neural 8.09E-01 8.65E-01 chrl3:23951893:23951910 vessel 8.09E-01 9.70E-01 chr22:27501587:27501648 vessel 8.09E-01 8.66E-01 chrl :7728694:7728716 neural 8.09E-01 7.96E-01 chr9 : 137554083 : 137554352 vessel 8.09E-01 9.53E-01 chrl8:53074062:53074313 neural 8.09E-01 8.70E-01 chrl6:72892761 :72892801 vessel 8.09E-01 9.49E-01 chrl0:44339266:44339451 vessel 8.09E-01 9.17E-01 chrlO: 126724009: 126724099 vessel 8.09E-01 9.27E-01 chr9:73204687:73204768 vessel 8.09E-01 9.63E-01 uMHL Markers

Region Group GSI refMax chr22:31440272:31440362 vessel 8.09E-01 9.83E-01 chr20:44457872:44457929 vessel 8.09E-01 8.28E-01 chrl6:79751767:79751800 vessel 8.09E-01 8.38E-01 chrl :22658835:22658882 vessel 8.09E-01 8.65E-01 chr2:8389473:8389584 vessel 8.09E-01 9.80E-01 chr7:98719280:98719357 vessel 8.09E-01 9.45E-01 chrl :203526708:203526778 vessel 8.09E-01 9.86E-01 chr5:53742361 :53742402 vessel 8.09E-01 9.19E-01 chr2: 1820467: 1820494 vessel 8.08E-01 8.77E-01 chrl5:69841259:69841298 vessel 8.08E-01 9.39E-01 chr20:61013114:61013193 vessel 8.08E-01 9.26E-01 chrl5:76470078:76470143 vessel 8.08E-01 9.68E-01 chr7:70480615:70480687 vessel 8.08E-01 8.88E-01 chr9:l 16362067:116362205 vessel 8.08E-01 8.40E-01 chr3:48732676:48732782 neural 8.08E-01 8.43E-01 chrlO: 103406210: 103406384 vessel 8.08E-01 9.45E-01 chr7:30885459:30885500 vessel 8.08E-01 9.82E-01 chrl 5 :92509445 :92509609 vessel 8.08E-01 9.34E-01 chrl5:84361392:84361425 vessel 8.08E-01 9.40E-01 chr2:238322190:238322513 vessel 8.08E-01 9.58E-01 chr3 : 196910630: 196910640 neural 8.08E-01 8.13E-01 chr20:50187210:50187265 vessel 8.08E-01 9.67E-01 chr2:48710712:48710871 vessel 8.08E-01 9.51E-01 chrl8:34366845:34366901 vessel 8.08E-01 9.40E-01 chr21 :43147530:43147588 vessel 8.08E-01 9.70E-01 chrl 1 :36037604:36037621 vessel 8.08E-01 9.24E-01 chr6:160257580:160257599 vessel 8.08E-01 9.58E-01 chrl 5 :66914008 :66914032 vessel 8.08E-01 9.67E-01 chrl0: 134881126: 134881168 vessel 8.08E-01 9.23E-01 chr7:7032037:7032089 intestine 8.08E-01 9.17E-01 chrl0: 13881755:13881845 vessel 8.08E-01 9.46E-01 chr6:11214781 :11215022 vessel 8.08E-01 9.81E-01 chrl4:76446554:76446750 vessel 8.08E-01 9.56E-01 chrl 2 : 124004371 : 124004416 vessel 8.08E-01 9.48E-01 chrl :112400108:112400129 neural 8.08E-01 8.33E-01 chrl5:74496556:74496593 vessel 8.07E-01 9.46E-01 chrlO: 126749370: 126749418 vessel 8.07E-01 9.55E-01 chrl 3 :49528296 :49528490 vessel 8.07E-01 9.66E-01 chr7 : 135440322 : 135440342 vessel 8.07E-01 8.04E-01 chrlO: 16869686: 16869746 vessel 8.07E-01 9.52E-01 chr21 :32532775:32532824 neural 8.07E-01 8.82E-01 chr9:97682657:97682800 vessel 8.07E-01 9.53E-01 chr20:49982779:49982992 vessel 8.07E-01 9.52E-01 chrl6: 19872075:19872241 vessel 8.07E-01 9.51E-01 chr9 92300116:92300178 vessel 8.07E-01 9.54E-01 chr6 37045638:37045671 vessel 8.07E-01 9.71E-01 chrl 225838270:225838425 vessel 8.07E-01 9.04E-01 chr2 5701195:5701296 vessel 8.07E-01 9.68E-01 uMHL Markers

Region Group GSI refMax chrl :19740620:19740711 vessel 8.07E-01 9.07E-01 chr21 :44161774:44161828 vessel 8.07E-01 9.53E-01 chr6: 143434808: 143435073 liver 8.07E-01 8.80E-01 chrl0: 121040981: 121041031 vessel 8.07E-01 9.32E-01 chr6 : 154795868 : 154796097 vessel 8.07E-01 8.55E-01 chr2:233105800:233105832 kidney 8.07E-01 7.86E-01 chrl :2006023:2006038 neural 8.07E-01 7.73E-01 chrl :241912764:241912999 vessel 8.07E-01 8.86E-01 chrl :80251396: 80251438 vessel 8.07E-01 9.04E-01 chr8:89270337: 89270376 vessel 8.07E-01 9.38E-01 chr8:22458405: 22458469 vessel 8.07E-01 8.77E-01 chr5:107754120:107754132 vessel 8.07E-01 9.57E-01 chr3 : 194493573 : 194493711 vessel 8.07E-01 9.55E-01 chr5 : 158224572 : 158224690 vessel 8.07E-01 9.82E-01 chr2:20262560: 20262730 vessel 8.07E-01 8.69E-01 chrl9:3460058: 3460132 vessel 8.07E-01 9.41E-01 chr9:92503363: 92503383 vessel 8.07E-01 9.51E-01 chrl 8 46375226:46375356 vessel 8.07E-01 9.01E-01 chr20 17850931 :17851022 vessel 8.06E-01 9.04E-01 chrl 9 2186543:2186661 vessel 8.06E-01 9.61E-01 chr9:97682842:97683006 vessel 8.06E-01 9.71E-01 chr6 : 158460945 : 158461070 vessel 8.06E-01 9.43E-01 chr9:2816879:2817023 vessel 8.06E-01 9.76E-01 chrl : 183187558: 183187637 vessel 8.06E-01 9.47E-01 chrl2: 121344919: 121344964 vessel 8.06E-01 9.67E-01 chr20:3516912C 1:35169198 vessel 8.06E-01 9.00E-01 chrl 5: 86185647 :86185814 vessel 8.06E-01 9.46E-01 chrl6:8461778S :84617843 vessel 8.06E-01 9.38E-01 chrl7:4392650S :43926525 vessel 8.06E-01 9.65E-01 chr8:30420219:30420335 vessel 8.06E-01 9.57E-01 chr6:16541787:16541933 vessel 8.06E-01 9.64E-01 chrl7:78999585:78999726 neural 8.06E-01 8.25E-01 chrlO: 16759844: 16759898 vessel 8.06E-01 9.28E-01 chrl4:95875024:95875083 vessel 8.06E-01 9.93E-01 chr21 :34192080:34192208 vessel 8.06E-01 9.26E-01 chr21 :46454122 :46454165 vessel 8.06E-01 9.39E-01 chrl8: 13436078:13436235 vessel 8.06E-01 9.80E-01 chrlO: 130094981: 130095001 vessel 8.06E-01 9.48E-01 chr6:169178590:169178687 vessel 8.06E-01 9.89E-01 chrl5:58815128:58815195 vessel 8.06E-01 9.20E-01 chr2:67487963:67487997 vessel 8.06E-01 8.92E-01 chrl8:72913659:72913731 vessel 8.06E-01 9.16E-01 chr22:23624534:23624645 vessel 8.06E-01 9.44E-01 chrl2:2494075:2494199 vessel 8.06E-01 9.18E-01 chrl7:55663160:55663251 vessel 8.06E-01 8.71E-01 chr2:65543343:65543411 vessel 8.06E-01 9.81E-01 chr20:56305784:56305798 vessel 8.06E-01 9.53E-01 chrl 8 :43097228 :43097251 vessel 8.06E-01 9.86E-01 uMHL Markers

Region Group GSI refMax chr9:98829385:98829459 vessel 8.06E-01 9.00E-01 chr9:98812048:98812090 vessel 8.06E-01 9.27E-01 chrl2:93521229:93521358 vessel 8.06E-01 9.68E-01 chrl0:3146921 :3146961 vessel 8.06E-01 9.36E-01 chrl9:28609319:28609354 vessel 8.06E-01 8.70E-01 chrl 3: 113698901: 113698952 neural 8.06E-01 7.96E-01 chr2 :216298546:216298643 vessel 8.05E-01 9.78E-01 chrl :2991642:2991733 vessel 8.05E-01 9.61E-01 chrl7:76858155:76858303 vessel 8.05E-01 9.78E-01 chrl7: 19390397:19390458 vessel 8.05E-01 9.75E-01 chr4: 1205974: 1206025 vessel 8.05E-01 9.28E-01 chrl l : 11606063:11606090 vessel 8.05E-01 9.75E-01 chr7:22757575:22757624 vessel 8.05E-01 9.70E-01 chrl l : 19752027:19752292 vessel 8.05E-01 9.37E-01 chr9:97587850:97588035 vessel 8.05E-01 9.29E-01 chr2:375931 :375958 vessel 8.05E-01 9.16E-01 chrl7:71773282:71773397 vessel 8.05E-01 9.61E-01 chrl2: 128807935: 128807959 vessel 8.05E-01 9.65E-01 chrl3:23732081 :23732140 vessel 8.05E-01 9.48E-01 chr3:59003065:59003100 liver 8.05E-01 8.20E-01 chrl : 157984204 : 157984269 vessel 8.05E-01 9.40E-01 chr7:55112569:55112635 vessel 8.05E-01 9.85E-01 chr20: 17830714: 17830792 vessel 8.05E-01 9.31E-01 chr4:95331866:95332202 vessel 8.05E-01 9.51E-01 chr3 : 122692837 : 122692868 vessel 8.05E-01 9.03E-01 chrl6:2177303:2177329 neural, vessel 8.05E-01 l .OOE+00 chrl5:85826138:85826201 vessel 8.05E-01 8.76E-01 chrl4:76461910:76462138 vessel 8.05E-01 9.54E-01 chr5: 155755991 : 155756019 vessel 8.05E-01 8.44E-01 chr4:57922136 57922184 vessel 8.05E-01 9.57E-01 chr9:15401524 15401532 vessel 8.05E-01 9.68E-01 chrl 9: 3603394 3603412 vessel 8.05E-01 9.17E-01 chrl9:47316636:47316653 vessel 8.05E-01 8.82E-01 chrl l :76360139:76360318 vessel 8.05E-01 8.86E-01 chrl0:729913:729968 vessel 8.05E-01 9.23E-01 chrl 1 : 114003718: 114003831 vessel 8.05E-01 9.42E-01 chrl7:75775848:75775881 vessel 8.05E-01 9.53E-01 chrl2: 116737894: 116737988 vessel 8.05E-01 9.32E-01 chr21 :44694448 :44694461 liver 8.04E-01 8.95E-01 chr5 : 167372652 : 167372700 vessel 8.04E-01 9.18E-01 chrl0:61408493:61408669 vessel 8.04E-01 9.36E-01 chr5 : 156989353 : 156989478 vessel 8.04E-01 9.34E-01 chr8:97419822:97419867 vessel 8.04E-01 9.02E-01 chr8:22516858:22516919 vessel 8.04E-01 9.54E-01 chr6:38237680:38237861 vessel 8.04E-01 9.53E-01 chrl :37773917:37773943 neural 8.04E-01 7.70E-01 chr7:95818174:95818283 vessel 8.04E-01 9.66E-01 chr7:73428567:73428618 vessel 8.04E-01 9.58E-01 uMHL Markers

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Region Group GSI refMax chrl2: 124925719: 124925860 vessel 8.01E-01 9.17E-01 chr6 : 157039978 : 157040028 vessel 8.01E-01 8.63E-01 chrl2:54071769:54071918 neural 8.01E-01 8.47E-01 chrl6:4001865:4002028 vessel 8.00E-01 9.70E-01 chrl8: 13542218:13542473 liver 8.00E-01 8.54E-01 chr3:71213389:71213444 vessel 8.00E-01 8.33E-01 chrl4:91622695:91622754 liver 8.00E-01 8.73E-01 chr5:78115075:78115276 vessel 8.00E-01 9.36E-01 chr22:30737410:30737507 vessel 8.00E-01 9.69E-01 chr2:109788226:109788430 vessel 8.00E-01 9.26E-01 chr9:l 12841248:112841282 vessel 8.00E-01 9.45E-01 chr5:95194167:95194199 vessel 8.00E-01 9.88E-01 chrl 1 : 113513456: 113513577 vessel 8.00E-01 8.11E-01 chr7:41956427:41956582 vessel 8.00E-01 9.28E-01 chrl0:31108592:31108620 vessel 8.00E-01 9.61E-01 chrl7: 1038460:1038480 vessel 8.00E-01 9.74E-01 chr5: 158230112:158230269 vessel 8.00E-01 9.67E-01 chrl 1 :75444671 :75444686 vessel 8.00E-01 8.50E-01 chrl2: 116746846: 116746866 vessel 8.00E-01 9.52E-01 chr9:97535350:97535437 vessel 8.00E-01 9.56E-01 chrl8: 10376914:10377078 vessel 8.00E-01 9.25E-01 chrl 1 : 1552850: 1552939 vessel 8.00E-01 9.73E-01 chrl8:76551122:76551148 vessel 8.00E-01 8.19E-01 chr9 : 133734023 : 133734044 vessel 8.00E-01 9.43E-01 chr5 : 136955094 : 136955232 vessel 8.00E-01 9.90E-01 chrl9:42528857:42528937 vessel 8.00E-01 9.74E-01 chrl7:77993088:77993180 liver 8.00E-01 8.60E-01 chr9 :139466646:139466672 vessel 8.00E-01 9.51E-01 chr4 : 129440877 : 129440895 vessel 8.00E-01 9.07E-01 chr2:135118406:135118696 vessel 8.00E-01 9.57E-01 chr8: 1895423: 1895593 vessel 8.00E-01 8.96E-01 chrl 6 : 89900228 :89900472 intestine 8.00E-01 8.66E-01 chrl8:53533397:53533431 vessel 8.00E-01 8.91E-01 chr8:1734515:1734583 vessel 8.00E-01 9.27E-01 chr5:146783414:146783535 vessel 8.00E-01 9.21E-01 chrlO: 129721163: 129721395 vessel 8.00E-01 9.26E-01 chrl6:88976512:88976545 vessel 8.00E-01 8.82E-01 chrl7: 12534611 :12534640 vessel 8.00E-01 8.99E-01 chr8 : 124552202 : 124552287 vessel 8.00E-01 9.68E-01 chr5:4983978:4984033 vessel 8.00E-01 8.65E-01 chr4:2589345:2589376 vessel 8.00E-01 9.62E-01 chrl4:23318984:23319004 vessel 8.00E-01 9.39E-01 chr3: 125978692: 125978717 vessel 8.00E-01 9.38E-01 chr7 : 137668500: 137668714 vessel 7.99E-01 9.45E-01 chr22:29707734:29707797 neural 7.99E-01 8.65E-01 chr6:168811258:168811288 vessel 7.99E-01 8.85E-01 chrl 1 :48086058:48086140 vessel 7.99E-01 9.48E-01 chrl :32581854:32581901 vessel 7.99E-01 9.52E-01 uMHL Markers

Region Group GSI refMax chrl0:63817039:63817096 vessel 7.99E-01 9.83E-01 chrlO: 104679620: 104679676 vessel 7.99E-01 9.47E-01 chrl8:72913820:72914028 vessel 7.99E-01 8.76E-01 chrl8:8381961 :8382108 vessel 7.99E-01 9.32E-01 chr2:43691730:43692049 vessel 7.99E-01 9.77E-01 chrl 6 :66260739 :66260808 vessel 7.99E-01 8.07E-01 chrl :3314034:3314111 vessel 7.99E-01 8.05E-01 chrl5:47732211 :47732323 vessel 7.99E-01 9.53E-01 chrl6:88228206:88228258 intestine 7.99E-01 8.48E-01 chr7:75595743:75595885 vessel 7.99E-01 9.21E-01 chrl7:77302405 77302421 vessel 7.99E-01 9.62E-01 chr7: 133043576 133043707 vessel 7.99E-01 9.54E-01 chr22:31640170 31640177 vessel 7.99E-01 9.54E-01 chrl :25916675:25916756 vessel 7.99E-01 9.21E-01 chrl : 184120477 : 184120508 vessel 7.99E-01 9.43E-01 chr5:131713182:131713241 vessel 7.99E-01 9.30E-01 chrl4:75019600:75019659 vessel 7.99E-01 9.45E-01 chrl6: 16088347:16088528 vessel 7.99E-01 9.66E-01 chr7:l 135687:1135764 vessel 7.99E-01 9.33E-01 chr2:98775072:98775082 vessel 7.99E-01 9.37E-01 chrl0:5605504:5605530 vessel 7.99E-01 9.39E-01 chrl4:92391559:92391578 vessel 7.99E-01 9.16E-01 chr8:20834957:20835064 vessel 7.99E-01 9.36E-01 chr7:73414105:73414180 vessel 7.99E-01 l.OOE+00 chr3 : 114225764: 114225848 vessel 7.99E-01 9.48E-01 chrl 9 :47242589 :47242709 vessel 7.99E-01 9.22E-01 chr3:41042033:41042081 vessel 7.99E-01 9.30E-01 chrl9:57429326:57429374 vessel 7.98E-01 9.44E-01 chr7:41735421 :41735459 vessel 7.98E-01 9.70E-01 chrl 1 : 10886639: 10886702 vessel 7.98E-01 9.58E-01 chrl0:664325:664473 vessel 7.98E-01 9.17E-01 chr5:38469431 :38469488 vessel 7.98E-01 9.51E-01 chrl6: 15237718:15237812 vessel 7.98E-01 9.86E-01 chrl9:4571622:4571663 vessel 7.98E-01 9.20E-01 chr7 : 139458285 : 139458300 liver 7.98E-01 8.65E-01 chr9 : 116967656: 116967726 vessel 7.98E-01 9.49E-01 chrl6: 19656482: 19656576 vessel 7.98E-01 9.59E-01 chrl6: 12865231 :12865387 vessel 7.98E-01 9.77E-01 chr6:3766566:3766739 vessel 7.98E-01 9.28E-01 chrl 5 :60705703 :60705745 vessel 7.98E-01 9.76E-01 chrl :85070440:85070481 vessel 7.98E-01 8.60E-01 chrl3:99622769:99622853 heart, vessel 7.98E-01 9.55E-01 chr2 : 197962437 : 197962594 vessel 7.98E-01 9.66E-01 chr8:70180168:70180286 vessel 7.98E-01 8.72E-01 chr7: 141768483: 141768503 vessel 7.98E-01 9.25E-01 chrlO: 102642706: 102642787 vessel 7.98E-01 9.89E-01 chrl l : 19837610:19837706 vessel 7.98E-01 8.96E-01 chrl6:2176909:2176936 vessel 7.98E-01 9.19E-01 uMHL Markers

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Region Group GSI refMax chrlO: 105408583: 105408600 vessel 7.95E-01 9.13E-01 chr5:2387936:2388031 vessel 7.95E-01 8.59E-01 chr5:2729492:2729508 vessel 7.95E-01 9.36E-01 chr20:41766979:41766991 vessel 7.95E-01 9.07E-01 chr3 : 184409648 : 184409750 vessel 7.95E-01 9.11E-01 chrl0:88493041 :88493164 vessel 7.95E-01 9.25E-01 chr6 : 132270440: 132270682 vessel 7.95E-01 9.80E-01 chr22:44756989:44757220 vessel 7.94E-01 9.13E-01 chrl4:68831611 :68831749 vessel 7.94E-01 8.91E-01 chrl4:92367927:92368071 vessel 7.94E-01 9.11E-01 chrl2:2411416:2411598 vessel 7.94E-01 9.24E-01 chr22 : 18049263 : 18049365 liver 7.94E-01 8.26E-01 chrl0: 14065428:14065473 vessel 7.94E-01 8.83E-01 chr7:111977285:111977345 vessel 7.94E-01 9.65E-01 chrl :27445356:27445391 vessel 7.94E-01 9.69E-01 chrl :7074131 :7074170 vessel 7.94E-01 9.38E-01 chrl7: 15313380:15313443 vessel 7.94E-01 9.62E-01 chrl2: 102820870: 102820961 vessel 7.94E-01 9.04E-01 chrl7:71936239:71936248 vessel 7.94E-01 8.45E-01 chrl 3 :22665786:22665867 vessel 7.94E-01 9.02E-01 chrl6:85187520:85187614 vessel 7.94E-01 9.75E-01 chr8:6442958:6443017 vessel 7.94E-01 9.11E-01 chrl4:91107941 :91108028 vessel 7.94E-01 9.90E-01 chr8:25806426:25806443 vessel 7.94E-01 9.64E-01 chrl6:85620451 :85620532 vessel 7.94E-01 8.04E-01 chr21 :43951304:43951331 neural 7.94E-01 7.97E-01 chrl2:94581206:94581313 neural 7.94E-01 8.38E-01 chrlO: 134527606: 134527777 neural 7.94E-01 7.96E-01 chr22:26143790:26143817 vessel 7.94E-01 8.69E-01 chr7:4296052:4296381 vessel 7.94E-01 8.87E-01 chr3 : 134034372 : 134034636 vessel 7.94E-01 9.45E-01 chrlO 28111467:28111604 vessel 7.94E-01 8.67E-01 chrl 7 79391325:79391366 vessel 7.94E-01 9.35E-01 chrl 4 96520629:96520665 vessel 7.94E-01 9.12E-01 chr2: 18699763: 18699825 vessel 7.94E-01 9.71E-01 chrl7:925744:925782 vessel 7.94E-01 8.75E-01 chr21 : 17442467 : 17442664 neural 7.94E-01 8.12E-01 chrl4:90042589:90042653 vessel 7.94E-01 9.12E-01 chr6: 158509133: 158509238 vessel 7.94E-01 9.58E-01 chr8 : 141629654 : 141629773 kidney 7.94E-01 8.44E-01 chrl6:85196321 :85196364 vessel 7.94E-01 9.71E-01 chrl :203525849:203525916 vessel 7.94E-01 9.61E-01 chrl6:521619:521899 neural 7.94E-01 8.59E-01 chrl7:38612725:38612772 vessel 7.94E-01 9.17E-01 chrl5:81605401 :81605471 vessel 7.94E-01 9.10E-01 chr9 : 135994555 : 135994742 neural 7.93E-01 9.64E-01 chrl7:79543666:79544106 vessel 7.93E-01 9.50E-01 chrl7:79012377:79012405 vessel 7.93E-01 9.70E-01 uMHL Markers

Region Group GSI refMax chr21 :45968533:45968547 vessel 7.93E-01 9.44E-01 chr21 :42619547:42619640 vessel 7.93E-01 9.69E-01 chr20: 19830589:19830718 vessel 7.93E-01 9.76E-01 chrlO: 14712906: 14712935 neural 7.93E-01 8.81E-01 chr2:145465753:145465804 vessel 7.93E-01 8.25E-01 chr5:59504641 :59504726 vessel 7.93E-01 9.03E-01 chr6:4613067:4613243 vessel 7.93E-01 9.23E-01 chrl8: 11269160:11269181 vessel 7.93E-01 9.54E-01 chr9:84113892:84113906 vessel 7.93E-01 9.48E-01 chrl6:85418413:85418592 intestine 7.93E-01 8.38E-01 chr20: 17817173:17817268 vessel 7.93E-01 9.43E-01 chrl8:77398686:77398709 vessel 7.93E-01 l .OOE+00 chrl :2005083:2005710 neural 7.93E-01 9.11E-01 chr2 :44502707 :44502779 intestine 7.93E-01 7.91E-01 chr9 : 132743907 : 132744043 liver 7.93E-01 8.91E-01 chr8:30343080:30343196 vessel 7.93E-01 9.10E-01 chrl 4 :56056039 :56056048 vessel 7.93E-01 9.31E-01 chrl :6445478:6445510 vessel 7.93E-01 9.52E-01 chrl :10168307:10168493 vessel 7.93E-01 9.08E-01 chr3: 11645230: 11645368 vessel 7.93E-01 9.65E-01 chr4:13415653:13415732 vessel 7.93E-01 9.51E-01 chr7:33732757:33732843 vessel 7.93E-01 9.04E-01 chr3:9289465:9289502 neural 7.93E-01 7.70E-01 chrl 4 :76445973 :76446021 vessel 7.93E-01 9.92E-01 chr3 :72640590:72640767 vessel 7.93E-01 9.38E-01 chr7:67319367:67319425 neural 7.93E-01 7.89E-01 chr2 :159950921 :159951154 vessel 7.92E-01 9.46E-01 chr2: 10545557: 10545645 vessel 7.92E-01 9.72E-01 chrl 3 : 110874293 : 110874360 vessel 7.92E-01 9.51E-01 chrl0:74677129:74677157 vessel 7.92E-01 9.23E-01 chrl2: 124948015: 124948049 neural 7.92E-01 7.85E-01 chrl7:72445156:72445231 vessel 7.92E-01 9.75E-01 chrl5:26076118:26076279 vessel 7.92E-01 9.71E-01 chr7 : 100761027 : 100761057 vessel 7.92E-01 9.50E-01 chrl0:5587760:5587894 vessel 7.92E-01 9.11E-01 chr2 :217544422 :217544603 vessel 7.92E-01 9.73E-01 chr2:1743862:1743888 vessel 7.92E-01 8.09E-01 chrl9:2513246:2513267 vessel 7.92E-01 9.54E-01 chr9:l 10501886:110502051 vessel 7.92E-01 9.73E-01 chrl 2 :66025456 :66025636 vessel 7.92E-01 9.75E-01 chrl9:45323868:45323940 vessel 7.92E-01 9.27E-01 chr5: 141225844: 141225865 neural 7.92E-01 9.00E-01 chrl 7 :79026865 :79026951 vessel 7.92E-01 9.85E-01 chrl :16625787:16625849 vessel 7.92E-01 9.80E-01 chr2:238321665:238321816 vessel 7.92E-01 9.20E-01 chr5: 148345506: 148345687 vessel 7.92E-01 9.73E-01 chrl :172113662:172113921 vessel 7.92E-01 9.71E-01 chr4:7369242:7369265 vessel 7.92E-01 9.10E-01 uMHL Markers

Region Group GSI refMax chrl :11979065:11979214 vessel 7.92E-01 9.70E-01 chrl6:585886:585937 liver 7.92E-01 8.80E-01 chr4: 124707773: 124707972 vessel 7.92E-01 9.42E-01 chr8: 109355301 : 109355329 vessel 7.92E-01 8.33E-01 chrl2: 107799287: 107799331 vessel 7.92E-01 8.97E-01 chr2:218722958:218723051 vessel 7.92E-01 8.87E-01 chr9 : 132476798 : 132476839 vessel 7.92E-01 9.13E-01 chrl 9: 13108902: 13109094 vessel 7.92E-01 9.59E-01 chr6:155398687:155398778 vessel 7.92E-01 9.07E-01 chrl0:35256271 :35256338 vessel 7.92E-01 9.64E-01 chr4:15429515:15429573 vessel 7.92E-01 9.29E-01 chr8 :67405522 :67405594 neural, vessel 7.92E-01 8.89E-01 chrl6: 1533917:1533944 neural 7.92E-01 7.09E-01 chrl0:63797212:63797266 vessel 7.92E-01 8.82E-01 chrl2: 125242958: 125242996 vessel 7.92E-01 9.37E-01 chr21 :33835784:33836018 vessel 7.92E-01 7.98E-01 chr8 : 134194805 : 134194894 vessel 7.92E-01 9.23E-01 chrl :53992643:53992661 vessel 7.92E-01 9.97E-01 chr2:72058564:72058590 vessel 7.92E-01 9.25E-01 chrl7:47768524:47768612 vessel 7.91E-01 9.59E-01 chr7:70868724:70868738 vessel 7.91E-01 9.27E-01 chr7:l 135787:1135880 vessel 7.91E-01 9.19E-01 chrl l :69981466:69981483 vessel 7.91E-01 9.04E-01 chrl0:44406319:44406371 vessel 7.91E-01 9.72E-01 chrl7:62321657:62321769 vessel 7.91E-01 8.43E-01 chr9: 16276328: 16276511 vessel 7.91E-01 9.60E-01 chr22:26150622:26150652 vessel 7.91E-01 9.03E-01 chrl3: l l 1173782: 111173824 vessel 7.91E-01 9.64E-01 chr9 : 132465990: 132466044 vessel 7.91E-01 8.89E-01 chr9 :137601605:137601641 vessel 7.91E-01 9.03E-01 chrl2:2378226:2378306 vessel 7.91E-01 9.42E-01 chr6:3868913:3868926 vessel 7.91E-01 8.56E-01 chrl 3 : 110956979: 110957046 vessel 7.91E-01 9.19E-01 chr3:10619418:10619432 vessel 7.91E-01 9.31E-01 chrl6:73454450:73454527 vessel 7.91E-01 7.99E-01 chrl5:63305915:63305934 vessel 7.91E-01 9.61E-01 chr7:4734422:4734577 vessel 7.91E-01 9.52E-01 chrlO: 121006525: 121006629 vessel 7.91E-01 9.38E-01 chr8 :144951293:144951312 pancreas 7.91E-01 9.25E-01 chr2 :223917511 :223917627 vessel 7.91E-01 9.00E-01 chrl6:72892847:72892919 vessel 7.91E-01 8.71E-01 chrl5:88525288:88525358 vessel 7.91E-01 8.77E-01 chrl8:76680559:76680740 pancreas 7.91E-01 8.21E-01 chrl6:79785861 :79785893 vessel 7.91E-01 9.69E-01 chrl 3 : 113257964: 113257997 vessel 7.91E-01 9.67E-01 chrl5:62851448:62851528 vessel 7.90E-01 9.67E-01 chrl7:47651712:47651734 vessel 7.90E-01 9.79E-01 chrl5:94039831 :94039861 vessel 7.90E-01 8.86E-01 uMHL Markers

Region Group GSI refMax chrl2: 108788025: 108788069 vessel 7.90E-01 9.26E-01 chrl 1 :63823800 63823819 neural 7.90E-01 8.00E-01 chr5: 106553748 106553861 vessel 7.90E-01 9.36E-01 chrl2:43135893 43136097 vessel 7.90E-01 8.94E-01 chrl :20081194:20081286 vessel 7.90E-01 9.44E-01 chr3:73560709:73560905 vessel 7.90E-01 9.25E-01 chr3 : 123836445 : 123836611 vessel 7.90E-01 9.04E-01 chrl :7603622:7603720 vessel 7.90E-01 8.99E-01 chr6: 158464875: 158465035 vessel 7.90E-01 9.46E-01 chr6:131958144:131958342 vessel 7.90E-01 8.98E-01 chrl5:67458370:67458404 vessel 7.90E-01 9.35E-01 chr8:22458256:22458378 vessel 7.90E-01 9.49E-01 chr7:94025305:94025363 vessel 7.90E-01 9.64E-01 chr6:16431273:16431391 vessel 7.90E-01 9.09E-01 chr20:56523021 :56523183 vessel 7.90E-01 9.04E-01 chr5:50219227:50219301 vessel 7.90E-01 7.47E-01 chr21 :47403142 :47403214 vessel 7.90E-01 8.68E-01 chr9:136801147:136801304 intestine 7.90E-01 8.17E-01 chrl 8:9535708:9535902 vessel 7.90E-01 9.25E-01 chrl8:9809125:9809169 vessel 7.90E-01 9.09E-01 chr4:101089727:101089795 vessel 7.90E-01 9.35E-01 chr20:60833682:60833702 vessel 7.90E-01 9.20E-01 chr2:66528452:66528529 vessel 7.90E-01 9.80E-01 chr20:22707146:22707191 vessel 7.90E-01 8.44E-01 chrl0:44776635:44776761 vessel 7.90E-01 8.66E-01 chr3:52869083:52869162 vessel 7.90E-01 9.16E-01 chr9:129155547:129155601 vessel 7.90E-01 8.97E-01 chrl :11039869:11039880 neural 7.90E-01 8.00E-01 chrl6:4461722:4462177 neural 7.90E-01 8.30E-01 chr5 : 173252378 : 173252404 vessel 7.90E-01 8.73E-01 chr9:124042382:124042419 vessel 7.90E-01 9.78E-01 chrl8:56719116:56719243 vessel 7.90E-01 9.24E-01 chrl l : 11425708:11425747 vessel 7.89E-01 8.33E-01 chrl2:52056721 :52056773 liver 7.89E-01 8.09E-01 chrl :39847630:39847734 vessel 7.89E-01 9.26E-01 chrl2: 114327643: 114328085 vessel 7.89E-01 9.52E-01 chrl6:27256643:27256871 vessel 7.89E-01 9.53E-01 chrl 3 : 111830279: 111830297 vessel 7.89E-01 9.46E-01 chrl9:49804030:49804037 vessel 7.89E-01 8.62E-01 chrl l : 133371858: 133371874 vessel 7.89E-01 9.54E-01 chrlO: 105378386: 105378436 vessel 7.89E-01 9.49E-01 chr2:21500056:21500255 vessel 7.89E-01 8.37E-01 chrl4:69419282:69419313 vessel 7.89E-01 9.48E-01 chrl0:80913511 :80913602 vessel 7.89E-01 8.73E-01 chrl4:69203310:69203388 vessel 7.89E-01 8.57E-01 chrl6:29706207:29706243 vessel 7.89E-01 9.41E-01 chr8:49493773:49493912 vessel 7.89E-01 8.98E-01 chrl0: 13869492:13869597 vessel 7.89E-01 9.58E-01 uMHL Markers

Region Group GSI refMax chrl 7 :75724157 :75724205 vessel 7.89E-01 8.95E-01 chr7:105134734:105134810 vessel 7.89E-01 9.09E-01 chrl0:78157310:78157339 vessel 7.89E-01 9.38E-01 chrl :213155773:213155827 vessel 7.89E-01 9.55E-01 chrl7: 12453277:12453304 vessel 7.89E-01 9.07E-01 chrl 1 : 130358485: 130358572 vessel 7.89E-01 9.83E-01 chrl9:3536938:3536990 kidney 7.89E-01 7.85E-01 chr5 : 172030681 : 172030738 vessel 7.89E-01 9.62E-01 chrl :24429671 :24429689 vessel 7.89E-01 9.74E-01 chr3 : 128098054 : 128098098 vessel 7.89E-01 8.66E-01 chrl5:67142607:67142698 vessel 7.89E-01 9.30E-01 chrl7:64536087:64536138 neural 7.89E-01 8.10E-01 chr4:77598869:77598976 vessel 7.89E-01 8.99E-01 chrl0: 10965036:10965181 pancreas 7.89E-01 7.53E-01 chr2 :223917632:223917948 vessel 7.89E-01 8.31E-01 chrl :61742965:61742988 vessel 7.89E-01 8.91E-01 chrl4:21292114:21292310 neural 7.89E-01 7.29E-01 chr2:46564649:46564698 vessel 7.89E-01 8.81E-01 chr9: 109561663: 109561825 vessel 7.89E-01 9.15E-01 chrlO: 112395034: 112395067 vessel 7.89E-01 7.88E-01 chr7:73406549:73406623 vessel 7.89E-01 9.58E-01 chrl 9: 13176607: 13176640 vessel 7.89E-01 9.29E-01 chr4:166300973:166301086 vessel 7.89E-01 9.67E-01 chrl6: 1559867:1559928 vessel 7.89E-01 9.81E-01 chrl :85069466:85069782 vessel 7.89E-01 9.30E-01 chr2:8360458:8360518 vessel 7.89E-01 7.94E-01 chrl2: 116008258: 116008282 neural 7.89E-01 8.08E-01 chr9 : 132456706 : 132456716 vessel 7.89E-01 9.51E-01 chrlO: 10686890: 10686959 vessel 7.89E-01 8.74E-01 chrl 1 :46740703:46740795 liver 7.88E-01 8.46E-01 chr22:37419994:37420244 liver 7.88E-01 7.79E-01 chr21 :47512230:47512291 vessel 7.88E-01 8.70E-01 chrl5:36169148:36169197 vessel 7.88E-01 9.59E-01 chrl4:65147082:65147109 vessel 7.88E-01 9.19E-01 chrl6:49867825:49867955 vessel 7.88E-01 9.73E-01 chr9 : 116464320: 116464372 vessel 7.88E-01 9.07E-01 chrl3: 110953976: 110954153 vessel 7.88E-01 8.15E-01 chrl5:68236450:68236481 vessel 7.88E-01 9.46E-01 chr3 : 122803555 : 122803707 liver 7.88E-01 9.15E-01 chrl 1 : 130735452: 130735480 vessel 7.88E-01 9.24E-01 chrl0:73608417:73608452 neural 7.88E-01 7.89E-01 chrl3: 111013814: 111013913 vessel 7.88E-01 9.63E-01 chrl2:92290560:92290631 vessel 7.88E-01 9.07E-01 chrl6: 14503474: 14503520 vessel 7.88E-01 9.32E-01 chrl6:49615634:49615896 vessel 7.88E-01 9.41E-01 chr8 : 130499865 : 130499936 vessel 7.88E-01 9.17E-01 chrl0:50216911 :50217019 vessel 7.88E-01 9.07E-01 chrl2:20503508:20503619 vessel 7.88E-01 9.37E-01 uMHL Markers

Region Group GSI refMax chr4:7287509:7287534 vessel 7.88E-01 9.35E-01 chrl3:80511183:80511242 vessel 7.88E-01 8.71E-01 chrl l : 12166090:12166124 vessel 7.88E-01 8.65E-01 chr22:38864829:38864862 vessel 7.88E-01 8.37E-01 chr2:39945836:39946013 vessel 7.88E-01 9.44E-01 chr3:71289392:71289422 vessel 7.88E-01 9.31E-01 chr2:1689778:1689882 vessel 7.88E-01 8.04E-01 chrl5:67471125:67471172 vessel 7.88E-01 9.53E-01 chrl3: 114076193: 114076253 vessel 7.88E-01 9.24E-01 chr3:4468948:4469000 vessel 7.88E-01 9.07E-01 chrl 3 : 114064797 : 114064981 vessel 7.88E-01 8.95E-01 chrl6:75520052:75520187 intestine 7.88E-01 8.45E-01 chr2:86452555:86452614 vessel 7.88E-01 8.71E-01 chrl6:65105398:65105960 vessel 7.88E-01 9.54E-01 chr2:235286886:235286969 vessel 7.88E-01 9.20E-01 chrl0:3182566:3182624 vessel 7.88E-01 9.04E-01 chr4 : 129445552 : 129445744 vessel 7.87E-01 9.32E-01 chrl6:49750543:49750635 vessel 7.87E-01 9.44E-01 chrl :150164178:150164217 vessel 7.87E-01 8.23E-01 chrl 3 : 114797349: 114797404 vessel 7.87E-01 9.06E-01 chrl 3:47824530:47824646 vessel 7.87E-01 9.27E-01 chrl 1 : 115882971 : 115883000 vessel 7.87E-01 9.58E-01 chrl8:77398729:77398773 vessel 7.87E-01 9.37E-01 chrl :3282991 :3283074 vessel 7.87E-01 9.49E-01 chrl7: 15416725:15416832 vessel 7.87E-01 9.02E-01 chrl 1 : 12098290: 12098375 vessel 7.87E-01 9.37E-01 chr9: 13444156: 13444186 vessel 7.87E-01 8.91E-01 chr7 : 135430783 : 135430838 vessel 7.87E-01 9.31E-01 chr3 :25927064 :25927249 vessel 7.87E-01 8.72E-01 chr5:65124029:65124117 vessel 7.87E-01 9.78E-01 chrl l : 12455168:12455287 vessel 7.87E-01 9.57E-01 chr2:33295587:33295754 vessel 7.87E-01 8.15E-01 chr2:240386966:240387067 vessel 7.87E-01 9.92E-01 chrl2:2411116:2411340 vessel 7.87E-01 9.61E-01 chr22 :46302183 :46302264 vessel 7.87E-01 9.38E-01 chr5:148851569:148851626 intestine 7.87E-01 8.54E-01 chr6:170491419:170491447 kidney 7.87E-01 8.52E-01 chr2:l 16891317:116891376 vessel 7.87E-01 8.23E-01 chr3:20108380:20108465 vessel 7.87E-01 9.06E-01 chr9:132156886:132156911 neural 7.87E-01 7.58E-01 chrl 1 :76290294:76290405 vessel 7.87E-01 9.16E-01 chr22 :45945164 :45945215 vessel 7.87E-01 9.08E-01 chr2:42279054:42279101 vessel 7.87E-01 9.56E-01 chr3:58151255:58151409 vessel 7.87E-01 9.97E-01 chr8:30073333:30073369 vessel 7.87E-01 9.47E-01 chr9:15250121 :15250232 vessel 7.87E-01 9.80E-01 chrl7: 17780294:17780370 vessel 7.87E-01 9.60E-01 chrl3:39969110:39969133 vessel 7.87E-01 9.51E-01 uMHL Markers

Region Group GSI refMax chr22:31502874:31502905 vessel 7.87E-01 9.74E-01 chrl9:31125579:31125600 pancreas 7.87E-01 8.04E-01 chrl4:84557314:84557472 vessel 7.87E-01 8.52E-01 chr21 :43514198:43514493 vessel 7.87E-01 9.64E-01 chrl 8 :22307046 :22307231 vessel 7.87E-01 9.57E-01 chr8:21916771 :21916803 vessel 7.87E-01 9.14E-01 chr8:22498729:22498809 vessel 7.86E-01 9.68E-01 chr20:30318764:30318781 vessel 7.86E-01 8.10E-01 chr6 : 136257638 : 136257678 vessel 7.86E-01 8.92E-01 chr8:25250313:25250341 neural, vessel 7.86E-01 9.44E-01 chrl :41272962:41273105 vessel 7.86E-01 9.17E-01 chr9:97771885:97771906 vessel 7.86E-01 9.85E-01 chrl 3: 113695160: 113695394 vessel 7.86E-01 8.81E-01 chr2:20380163:20380252 liver 7.86E-01 8.58E-01 chrl6: 19863013:19863115 neural 7.86E-01 9.00E-01 chr8 : 125677517 : 125677565 vessel 7.86E-01 9.55E-01 chr7 : 127670761 : 127670841 neural 7.86E-01 7.69E-01 chr6:168195164:168195233 pancreas 7.86E-01 7.64E-01 chrl5:85493580:85493683 vessel 7.86E-01 9.53E-01 chr22:43031651 :43031853 vessel 7.86E-01 9.73E-01 chrl 3 : 113496626: 113496879 vessel 7.86E-01 8.70E-01 chrl6: 14489990: 14490064 neural 7.86E-01 7.96E-01 chr6:57042660:57042734 vessel 7.86E-01 8.96E-01 chr3:46941526:46941607 vessel 7.86E-01 9.27E-01 chr20:35987305:35987352 vessel 7.86E-01 8.54E-01 chrl6: 14401759:14401838 vessel 7.86E-01 9.52E-01 chrl : 14469003: 14469067 vessel 7.86E-01 9.33E-01 chr20:56534156:56534196 vessel 7.86E-01 9.66E-01 chr9 : 132236150: 132236184 vessel 7.86E-01 9.52E-01 chrl :3050597:3050633 vessel 7.86E-01 9.60E-01 chr7:37524088:37524305 vessel 7.86E-01 8.47E-01 chrl3: 111024166: 111024198 vessel 7.86E-01 9.20E-01 chrl2:6202364:6202394 vessel 7.86E-01 8.65E-01 chrl7:2116086:2116211 vessel 7.86E-01 9.50E-01 chr7:4647117:4647169 neural 7.86E-01 8.68E-01 chr5:55821161 :55821181 vessel 7.86E-01 9.22E-01 chr7:2666687:2666748 vessel 7.86E-01 8.39E-01 chr22:45914756:45914798 vessel 7.86E-01 8.64E-01 chrl6:20624541 :20624773 vessel 7.86E-01 8.82E-01 chr2 237551381 :237551403 vessel 7.86E-01 9.84E-01 chr3 31363948:31364089 vessel 7.86E-01 9.52E-01 chr2 71927938:71927991 vessel 7.86E-01 9.43E-01 chrl 6 : 80972085 :80972168 vessel 7.85E-01 9.86E-01 chrl9:49673692:49673775 intestine, stomach 7.85E-01 8.60E-01 chr2 :236843445 :236843509 neural 7.85E-01 7.69E-01 chrl : 15751369: 15751446 intestine 7.85E-01 8.46E-01 chr5:73045778:73045803 kidney 7.85E-01 9.14E-01 chr6:128738839:128739002 vessel 7.85E-01 9.17E-01 uMHL Markers

Region Group GSI refMax chr4:85725549:85725639 vessel 7.85E-01 9.38E-01 chr3 : 176622338 : 176622418 vessel 7.85E-01 8.82E-01 chr5 : 172926847 : 172926905 vessel 7.85E-01 9.46E-01 chrl6:85240886:85240936 vessel 7.85E-01 8.75E-01 chrl9: 15324808:15324820 vessel 7.85E-01 9.51E-01 chrl0: 16636258:16636309 vessel 7.85E-01 9.18E-01 chrl7:79394818:79394831 vessel 7.85E-01 9.02E-01 chrl9:4373886:4374073 vessel 7.85E-01 9.41E-01 chr22:27641211 :27641248 vessel 7.85E-01 8.96E-01 chrl l : 1418459:1418562 neural 7.85E-01 7.35E-01 chr7:151511780:151511833 neural 7.85E-01 7.76E-01 chrl 5 :68677027 :68677109 vessel 7.85E-01 9.37E-01 chr6 : 157470211 :157470320 vessel 7.85E-01 9.24E-01 chrl9: 18567964:18568032 vessel 7.85E-01 9.50E-01 chr4:183152531 :183152684 vessel 7.85E-01 9.72E-01 chr2:218800243:218800316 vessel 7.85E-01 9.83E-01 chr2:239367426:239367504 vessel 7.85E-01 9.60E-01 chrl3:33163751 :33163849 vessel 7.85E-01 9.22E-01 chr6:5068481 :5068499 liver 7.85E-01 8.40E-01 chrl :42091868:42091905 vessel 7.85E-01 8.60E-01 chr7 : 134374786 : 134374800 vessel 7.85E-01 9.22E-01 chrl6: 15916856:15916909 vessel 7.85E-01 9.74E-01 chr8:41061579:41061651 vessel 7.85E-01 8.97E-01 chrl0:30400645:30400733 vessel 7.85E-01 9.62E-01 chr8:30421070:30421152 vessel 7.85E-01 9.36E-01 chr8: 139613769: 139613920 neural 7.85E-01 7.22E-01 chrlO: 114760378: 114760459 vessel 7.85E-01 9.89E-01 chr5: 167361642: 167361742 vessel 7.85E-01 9.28E-01 chr2 :220634112 :220634129 vessel 7.85E-01 9.17E-01 chrl :3157480:3157571 vessel 7.85E-01 9.26E-01 chr3: 177545779: 177546015 liver 7.85E-01 8.04E-01 chr8:54866663:54866734 vessel 7.85E-01 9.50E-01 chr2:65804282:65804447 vessel 7.84E-01 9.02E-01 chr20:35943041 :35943225 vessel 7.84E-01 9.24E-01 chrl9: 1254191 :1254317 neural 7.84E-01 8.08E-01 chr8:8699113:8699285 vessel 7.84E-01 9.32E-01 chrl 6 51610883:51611016 vessel 7.84E-01 8.73E-01 chrlO 131744697: 131744726 vessel 7.84E-01 8.56E-01 chrl 3 110147363: 110147475 vessel 7.84E-01 9.55E-01 chr5 : 134583058 : 134583072 vessel 7.84E-01 8.62E-01 chrl :27891699:27891725 vessel 7.84E-01 9.55E-01 chr2:47234673:47234721 vessel 7.84E-01 9.27E-01 chr6:74965618:74965651 esophagus 7.84E-01 8.32E-01 chr4:7911612:7911672 vessel 7.84E-01 9.21E-01 chrl9:5059366:5059423 neural 7.84E-01 9.24E-01 chrl 3 :24192625 :24192669 vessel 7.84E-01 9.16E-01 chrl 1 :27536140:27536237 vessel 7.84E-01 9.69E-01 chr5 : 116066604: 116066649 vessel 7.84E-01 9.30E-01 uMHL Markers

Region Group GSI refMax chrl l :7508112:7508197 vessel 7.84E-01 8.82E-01 chr6 : 166879764 : 166879786 vessel 7.84E-01 9.59E-01 chr6:168068881 :168068949 liver 7.84E-01 8.89E-01 chrl 1 : 113424086: 113424149 vessel 7.84E-01 9.27E-01 chr5:151059157:151059183 vessel 7.84E-01 9.50E-01 chr22:43821384:43821428 vessel 7.84E-01 9.18E-01 chr3:53807276:53807287 vessel 7.84E-01 9.49E-01 chrl7:62167638:62167728 vessel 7.84E-01 9.69E-01 chr8:123860971 :123861059 vessel 7.84E-01 9.26E-01 chrl 1 :68894912:68894969 vessel 7.84E-01 9.47E-01 chrl6: 16098416:16098605 vessel 7.84E-01 8.77E-01 chr5:55193804:55193902 vessel 7.84E-01 8.07E-01 chrl0:84118577:84118605 heart 7.84E-01 7.93E-01 chrl :226852160:226852233 vessel 7.84E-01 9.89E-01 chrl9:36180754:36180817 vessel 7.84E-01 9.35E-01 chr20:31144652:31144702 pancreas 7.84E-01 7.25E-01 chrl6:79296157:79296186 vessel 7.84E-01 8.19E-01 chr22: 19863472: 19863495 intestine,vessel 7.83E-01 9.22E-01 chrl2: 105021929: 105021960 vessel 7.83E-01 9.50E-01 chrl5:56209215:56209303 vessel 7.83E-01 8.85E-01 chrl 5 :29261980:29262074 neural 7.83E-01 7.43E-01 chr7 : 132087715:132087737 vessel 7.83E-01 9.36E-01 chr2:151333241 :151333340 vessel 7.83E-01 9.54E-01 chrl9:6485754:6485800 intestine 7.83E-01 8.25E-01 chrl3:31272143:31272303 vessel 7.83E-01 8.99E-01 chr4:166301164:166301272 vessel 7.83E-01 9.20E-01 chr2:121603185:121603207 vessel 7.83E-01 9.02E-01 chr6:45530885:45530911 vessel 7.83E-01 9.34E-01 chrl4:94447303:94447348 vessel 7.83E-01 9.37E-01 chrl :242948252:242948360 vessel 7.83E-01 8.99E-01 chrl9:49481383:49481409 vessel 7.83E-01 9.30E-01 chrl0:52905224:52905373 vessel 7.83E-01 9.02E-01 chr8:25867146:25867194 vessel 7.83E-01 9.14E-01 chrl5: 101912644: 101912745 vessel 7.83E-01 9.07E-01 chr4:40847393:40847513 vessel 7.83E-01 9.08E-01 chrl 7 :70442942 :70443022 vessel 7.83E-01 9.65E-01 chrl 6 : 86060972 :86061154 intestine 7.83E-01 8.22E-01 chrl7: 17448903:17448931 vessel 7.83E-01 9.41E-01 chr5 : 134577993 : 134578042 vessel 7.83E-01 9.07E-01 chrlO: 126644018: 126644097 vessel 7.83E-01 9.57E-01 chr9 : 132248466 : 132248663 vessel 7.83E-01 9.33E-01 chr3:149310847:149311097 vessel 7.82E-01 8.96E-01 chr21 :46549535:46549556 vessel 7.82E-01 9.41E-01 chr8:97399458:97399485 vessel 7.82E-01 9.50E-01 chrlO: 134976229: 134976248 neural 7.82E-01 8.67E-01 chrl7:40672856 40672864 vessel 7.82E-01 9.66E-01 chrl6:29706041 29706152 vessel 7.82E-01 9.84E-01 chrl2:93708655 93708836 intestine 7.82E-01 7.67E-01 uMHL Markers

Region Group GSI refMax chrl7:4231044:4231126 vessel 7.82E-01 8.75E-01 chrlO: 104883494: 104883599 vessel 7.82E-01 9.68E-01 chr3:134115902:134115909 vessel 7.82E-01 9.55E-01 chrl0:81182412:81182519 vessel 7.82E-01 8.66E-01 chrl2:43129874:43129987 vessel 7.82E-01 9.02E-01 chrl6:50619336:50619567 vessel 7.82E-01 9.37E-01 chrl 1 : 133917437: 133917528 vessel 7.82E-01 9.22E-01 chrl2:23568298:23568404 vessel 7.82E-01 9.75E-01 chr9: 13485157: 13485208 vessel 7.82E-01 8.87E-01 chrl : 170677495 : 170677579 vessel 7.82E-01 8.77E-01 chrl7:79027073:79027118 neural 7.82E-01 8.77E-01 chr6:4351916:4351953 vessel 7.82E-01 9.58E-01 chr8:13371792:13371850 vessel 7.82E-01 9.81E-01 chrl0:3366176:3366407 vessel 7.82E-01 9.36E-01 chr7 : 137669463 : 137669576 vessel 7.82E-01 9.20E-01 chr9:124535135:124535408 vessel 7.82E-01 9.16E-01 chr6 : 122273295 : 122273448 vessel 7.82E-01 8.98E-01 chrl0:30932923:30932972 vessel 7.82E-01 9.29E-01 chr8 : 102457944 : 102457961 vessel 7.82E-01 8.08E-01 chr6:89871857:89871883 vessel 7.82E-01 9.05E-01 chrl 1 :40301875:40301907 neural 7.82E-01 7.81E-01 chr2 : 100241347 : 100241372 vessel 7.82E-01 9.52E-01 chr6:43464262:43464281 vessel 7.82E-01 9.57E-01 chrl l :2871840:2871864 neural 7.82E-01 8.29E-01 chrl3:53617306:53617318 vessel 7.82E-01 9.45E-01 chrl2:2482078:2482201 vessel 7.82E-01 7.57E-01 chrl :172114039:172114125 vessel 7.82E-01 9.42E-01 chr2 :216299434:216299546 vessel 7.82E-01 9.67E-01 chrl 3 :27254470:27254486 vessel 7.82E-01 7.89E-01 chr2:38387148:38387190 vessel 7.82E-01 8.78E-01 chr9 : 137426232 : 137426270 neural 7.82E-01 8.22E-01 chrl :19778768:19779073 vessel 7.82E-01 9.21E-01 chr2:20834577:20834625 vessel 7.82E-01 9.27E-01 chrl9: 12732552: 12732570 neural 7.82E-01 9.70E-01 chr5 : 134605567 : 134605740 vessel 7.82E-01 8.57E-01 chrl l : 1929407:1929484 vessel 7.82E-01 9.66E-01 chr7 : 140048950 : 140049086 neural 7.82E-01 8.47E-01 chrl6:73086674:73086828 vessel 7.82E-01 8.89E-01 chrl :62353776:62353847 vessel 7.82E-01 9.58E-01 chr3: 16707220: 16707260 intestine 7.82E-01 7.96E-01 chrl5:99050082:99050108 vessel 7.82E-01 9.28E-01 chrl7:60706523:60706581 vessel 7.81E-01 8.84E-01 chrl5:67142417:67142575 vessel 7.81E-01 9.28E-01 chr20:56576504:56576598 vessel 7.81E-01 9.24E-01 chrl9:5036492:5036562 neural 7.81E-01 8.58E-01 chr20:25030492:25030618 vessel 7.81E-01 9.49E-01 chr6: 1766006: 1766029 vessel 7.81E-01 9.67E-01 chrl8:72839832:72839844 intestine 7.81E-01 7.43E-01 uMHL Markers

Region Group GSI refMax chrl5:99995054:99995113 vessel 7.81E-01 9.19E-01 chrl2: 130612543: 130612596 vessel 7.81E-01 9.07E-01 chr6:37648587:37648654 vessel 7.81E-01 9.27E-01 chrl2: 124984979: 124985033 vessel 7.81E-01 8.60E-01

Table lb:

Top 10% tissue specific MHL markers identified by GSI

MHL Markers

Region Group GSI refMax chr5 : 122422637 : 122422689 vessel 8.44E-01 9.80E-01 chrl6:88293071 :88293119 vessel 8.35E-01 9.71E-01 chrl4:91790551 :91790559 intestine 8.29E-01 9.76E-01 chr7:560607:560650 vessel 8.29E-01 9.12E-01 chrl8:34823918:34823977 intestine 8.28E-01 8.70E-01 chr5 : 122422972 : 122423004 vessel 8.27E-01 9.45E-01 chrl8:52613464:52613527 neural 8.25E-01 7.82E-01 chr4 : 174440618 : 174440652 vessel 8.20E-01 8.88E-01 chr6:6000351 :6000385 vessel 8.20E-01 9.56E-01 chr6:85476611 :85476636 vessel 8.20E-01 9.53E-01 chr2:66810606:66810640 vessel 8.20E-01 9.31E-01 chrl6:73098764:73098784 pancreas 8.18E-01 9.15E-01 chrl :3310806:3310814 pancreas 8.17E-01 8.36E-01 chr8:99961711 :99961827 vessel 8.16E-01 9.06E-01 chr7 : 154720589 : 154720672 neural 8.15E-01 8.17E-01 chr5 : 122423184 : 122423204 vessel 8.10E-01 8.88E-01 chr8:97165649:97165702 vessel 8.03E-01 9.14E-01 chr2:45231186:45231227 vessel 8.03E-01 9.24E-01 chrl7:59532637:59532659 vessel 8.02E-01 9.46E-01 chr5 : 122422007 : 122422064 vessel 8.00E-01 9.31E-01 chrl 1 :2114366:2114498 kidney 7.97E-01 8.05E-01 chr6:6000008:6000046 vessel 7.96E-01 8.05E-01 chr5:72731939:72731975 vessel 7.96E-01 8.41E-01 chr8:71287244:71287415 neural 7.95E-01 9.26E-01 chr6:39966947:39967010 neural 7.93E-01 8.73E-01 chrl5:96909551 :96909595 vessel 7.93E-01 9.30E-01 chr7:560864:560875 vessel 7.92E-01 8.38E-01 chrl5 :53087377 :53087420 pancreas 7.91E-01 7.83E-01 chr7:560685:560695 vessel 7.91E-01 8.47E-01 chr6 : 159655065 : 159655082 fat 7.90E-01 8.71E-01 chr5 : 122422161 : 122422184 vessel 7.90E-01 8.74E-01 chrl :27848198:27848263 liver 7.88E-01 8.51E-01 chr7:561160:561184 pancreas,vessel 7.88E-01 l.OOE+00 chr8:99959774:99959900 vessel 7.87E-01 7.89E-01 chrl6:73098734:73098753 pancreas 7.87E-01 8.02E-01 chr3:73620624:73620814 neural 7.86E-01 9.13E-01 chr4:24801971 :24802055 vessel 7.85E-01 8.70E-01 chrl 9: 13209981 : 13210007 vessel 7.84E-01 7.81E-01 MHL Markers

Region Group GSI refMax chr2 : 177004040: 177004111 vessel 7.84E-01 7.65E-01 chrl7:55520634:55520788 liver 7.83E-01 8.43E-01 chr7:560782:560796 vessel 7.82E-01 7.80E-01 chr5: 158532062: 158532093 vessel 7.80E-01 8.87E-01 chr7:5336543:5336571 liver 7.80E-01 8.23E-01 chr2:45240094:45240129 vessel 7.79E-01 9.15E-01 chr3:23653540:23653753 liver 7.79E-01 7.28E-01 chr2:66810478:66810502 vessel 7.77E-01 8.71E-01 chrl 1 :64509762:64509801 vessel 7.77E-01 8.83E-01 chr5 :72676020:72676058 vessel 7.76E-01 9.25E-01 chr7:25892505:25892545 vessel 7.76E-01 8.16E-01 chrl5:96897012:96897055 vessel 7.75E-01 7.68E-01 chrlO: 126407964: 126408032 vessel 7.75E-01 9.42E-01 chrl :47909185:47909226 vessel 7.74E-01 9.58E-01 chr7:157479397:157479515 neural 7.74E-01 8.12E-01 chr5:72597625:72597716 vessel 7.74E-01 7.40E-01 chr9:97431689:97431863 neural 7.73E-01 7.47E-01 chr8:99961971 :99962204 vessel 7.72E-01 7.37E-01 chr5:81652981 :81653357 neural 7.72E-01 7.79E-01 chrl2:54088920:54088960 vessel 7.72E-01 8.92E-01 chr8:99951082:99951152 vessel 7.71E-01 8.81E-01 chr4:15412389:15412548 neural 7.70E-01 8.16E-01 chrl5:41217790:41217801 vessel 7.70E-01 8.59E-01 chrl 7 :48206061 :48206096 vessel 7.70E-01 9.27E-01 chr2:45231539:45231586 vessel 7.69E-01 7.61E-01 chr9:98785107:98785147 vessel 7.69E-01 8.36E-01 chr4:l 194418:1194505 liver 7.69E-01 8.79E-01 chrl5:74426581 :74426618 fat 7.68E-01 7.56E-01 chrl7: 17628486:17628493 intestine 7.68E-01 8.62E-01 chrl 2 : 30976279 :30976313 neural 7.68E-01 8.54E-01 chrl6:86968517:86968564 vessel 7.67E-01 9.11E-01 chrl6:86959129:86959213 neural 7.66E-01 8.41E-01 chrl l : 110581348: 110581376 vessel 7.66E-01 7.83E-01 chrl7: 17628638:17628722 liver 7.64E-01 8.20E-01 chrl6:51669186:51669276 neural 7.64E-01 8.14E-01 chrlO: 119972986: 119973016 neural 7.63E-01 7.86E-01 chrl 3:28000468:28000558 vessel 7.63E-01 7.92E-01 chr8:99954669:99954686 vessel 7.63E-01 7.38E-01 chrl8:60173469:60173666 neural 7.62E-01 7.69E-01 chrlO: 105452540: 105452576 liver 7.62E-01 7.91E-01 chrl6:89005381 :89005398 vessel 7.60E-01 9.62E-01 chr6:168533689:168533704 vessel 7.60E-01 7.51E-01 chr8:80740825:80740880 vessel 7.59E-01 8.20E-01 chrl9:2240088:2240161 liver 7.59E-01 7.52E-01 chrl2: 115251376: 115251453 kidney 7.58E-01 8.58E-01 chrl8: 12287438:12287452 vessel 7.57E-01 7.15E-01 chr20:39320779:39320848 vessel 7.57E-01 8.55E-01 chrl2:54807242:54807336 neural 7.57E-01 7.35E-01 MHL Markers

Region Group GSI refMax chr2: 177037468: 177037632 vessel 7.57E-01 8.72E-01 chrl0:5489561 :5489690 neural 7.57E-01 8.28E-01 chrl2:54400441 :54400545 vessel 7.56E-01 8.44E-01 chr21 :36901623:36901692 neural 7.56E-01 7.36E-01 chr2 :241395207 :241395347 vessel 7.55E-01 8.71E-01 chrl : 145440313: 145440506 vessel 7.55E-01 7.93E-01 chrl4: 105126561 : 105126572 pancreas 7.55E-01 8.19E-01 chr8 : 102506473: 102506597 vessel 7.55E-01 8.05E-01 chrl 3 :95354223 :95354262 neural 7.54E-01 7.52E-01 chr22:43659543:43659642 neural 7.53E-01 7.43E-01 chr2:10231429:10231487 pancreas 7.53E-01 7.77E-01 chr5 :72676905 :72676924 vessel 7.53E-01 8.17E-01 chrl9: 19571777:19571806 liver 7.53E-01 7.92E-01 chrl7:32705890:32705981 neural 7.52E-01 7.92E-01 chrl5:53098366:53098407 pancreas 7.52E-01 7.64E-01 chrlO: 123355655: 123355837 vessel 7.52E-01 8.06E-01 chr20:3053093:3053103 liver 7.51E-01 8.58E-01 chrl : 170635953 : 170635964 vessel 7.51E-01 8.93E-01 chr5:20041646:20041789 neural 7.51E-01 8.13E-01 chr20:39319423:39319447 esophagus 7.51E-01 7.25E-01 chr7:27194521 :27194570 vessel 7.51E-01 7.12E-01 chrlO: 119300620: 119300704 vessel 7.51E-01 8.79E-01 chr8:99962451 :99962688 vessel 7.51E-01 7.67E-01 chrl5:53087876:53087895 pancreas 7.50E-01 7.66E-01 chr9 : 139740765 : 139740775 pancreas 7.50E-01 8.86E-01 chrl4: 105944278: 105944310 vessel 7.50E-01 9.04E-01 chr9:102587733:102587805 vessel 7.49E-01 8.72E-01 chrl6:81030772:81030844 neural 7.49E-01 8.30E-01 chr2:89166335:89166578 neural 7.49E-01 8.89E-01 chr8:99951364:99951421 vessel 7.48E-01 7.27E-01 chr8:76316319:76316353 vessel 7.48E-01 8.59E-01 chrl2:54408685:54408713 kidney 7.47E-01 7.53E-01 chr9 : 136567964 : 136567975 liver 7.47E-01 7.47E-01 chr5:72526768:72526786 vessel 7.46E-01 7.66E-01 chr2:66809772:66809852 vessel 7.46E-01 8.14E-01 chr2:96814448:96814515 liver 7.46E-01 8.86E-01 chr5:38368165:38368317 neural 7.46E-01 7.62E-01 chrl :110610678:110610715 vessel 7.45E-01 7.56E-01 chrl2:54440712:54440753 vessel 7.45E-01 8.38E-01 chr5 : 122421804 : 122421820 vessel 7.44E-01 9.30E-01 chr7:19149999:19150182 kidney, vessel 7.44E-01 8.83E-01 chrl9: 13124365:13124391 pancreas 7.44E-01 7.18E-01 chrl2: 118314033: 118314075 pancreas 7.43E-01 6.85E-01 Table 2:

Complete list of high methylated haplotype shared between matched primary tumor tissues

and plasma for colon cancer (CRC) and lung cancer (LC) patients.

Chr Start End Coordinate Symbol Annotation

1 3527738 3527759 chrl :3527738-3527759 MEGF6 Promoter

1 13839806 13839815 chrl 13839806-13839815 n/a n/a

1 14219586 14219639 chrl 14219586-14219639 n/a n/a

1 17019874 17019889 chrl 17019874-17019889 ESPNP UTR3

1 21836158 21836216 chrl 21836158-21836216 ALPL UTR5

1 22889799 22889812 chrl 22889799-22889812 EPHA8 Promoter

1 23279723 23279744 chrl 23279723-23279744 n/a n/a

1 23280192 23280211 chrl 23280192-23280211 n/a n/a

1 27676453 27676616 chrl 27676453-27676616 SYTL1 Intron

1 29563577 29563710 chrl 29563577-29563710 PTPRU Promoter

1 39981227 39981247 chrl 39981227-39981247 BMP8A Intron

1 44883591 44883606 chrl 44883591-44883606 RNF220 Intron

1 46859961 46859974 chrl 46859961-46859974 FAAH UTR5

1 48190891 48190924 chrl 48190891-48190924 n/a n/a

1 50884393 50884411 chrl 50884393-50884411 DMRTA2 Exon

1 50884419 50884430 chrl 50884419-50884430 DMRTA2 Exon

1 50884472 50884632 chrl 50884472-50884632 DMRTA2 Exon

1 59280289 59280357 chrl 59280289-59280357 n/a n/a

1 59280369 59280455 chrl 59280369-59280455 n/a n/a

1 61517642 61517933 chrl 61517642-61517933 n/a n/a

1 74663749 74663776 chrl 74663749-74663776 LRRIQ3 UTR5

1 92946665 92946767 chrl 92946665-92946767 GFI1 Intron

1 108508530 108508549 chrl 108508530-108508549 VAV3 Promoter

1 119543104 119543127 chrl 119543104-119543127 TBX15 Enhancer

1 150293718 150293852 chrl 150293718-150293852 PRPF3 Promoter

1 156828865 156828914 chrl 156828865-156828914 NTRK1 Promoter

1 158151057 158151116 chrl 158151057-158151116 CD ID Intron

1 171810397 171810513 chrl 171810397-171810513 DNM3 Promoter

1 203096889 203096934 chrl 203096889-203096934 ADORA1 UTR5

1 203598610 203598622 chrl 203598610-203598622 ATP2B4 UTR5

1 214153443 214153464 chrl 214153443-214153464 PROX1 Enhancer

1 215256127 215256195 chrl 215256127-215256195 KCNK2 Promoter

1 234040873 234041006 chrl 234040873-234041006 SLC35F3 Promoter

1 234350457 234350469 chrl 234350457-234350469 SLC35F3 Intron

1 236558377 236558653 chrl 236558377-236558653 EDARADD Promoter

1 242687600 242687610 chrl 242687600-242687610 PLD5 UTR5

1 244894219 244894231 chrl 244894219-244894231 n/a n/a

1 246952304 246952348 chrl 246952304-246952348 LOCI 49134 Promoter

2 3751318 3751336 chr2:3751318-3751336 ALLC Downstream

2 8833584 8833597 chr2:8833584-8833597 n/a n/a

2 11809996 11810041 chr2:l 1809996-11810041 NTSR2 Promoter

2 26521758 26521880 chr2:26521758-26521880 n/a n/a

2 31360797 31360816 chr2:31360797-31360816 GALNT14 Promoter

2 39102723 39102771 chr2:39102723-39102771 DHX57 UTR5

2 47596444 47596455 chr2 :47596444-47596455 EPCAM UTR5

2 47596483 47596505 chr2:47596483-47596505 EPCAM UTR5 Chr Start End Coordinate Symbol Annotation

2 70056907 70056960 chr2:70056907-70056960 GMCL1 UTR5

2 70994743 70994753 chr2:70994743-70994753 ADD2 UTR5

2 73429837 73429858 chr2:73429837-73429858 NOTO Promoter

2 88470034 88470056 chr2:88470034-88470056 THNSL2 UTR5

2 105459218 105459234 chr2 : 105459218-105459234 POU3F3 Enhancer

2 110372264 110372284 chr2:l 10372264-110372284 ANKRD57 Promoter

2 113956590 113956654 chr2 : 113956590- 113956654 LOC440839 UTR3

2 119604037 119604049 chr2:l 19604037-119604049 EN1 Exon

2 119916314 119916319 chr2:l 19916314-119916319 C1QL2 UTR5

2 127783309 127783371 chr2:127783309-127783371 n/a n/a

2 175594922 175594966 chr2 : 175594922- 175594966 n/a n/a

2 176945353 176945373 chr2:176945353-176945373 EVX2 Exon

2 176971839 176971857 chr2:176971839-176971857 HOXD11 Promoter

2 176972805 176972814 chr2:176972805-176972814 HOXD11 Promoter

2 207307674 207307712 chr2:207307674-207307712 ADAM23 Promoter

2 220313255 220313271 chr2 :220313255-220313271 SPEG Exon

2 233351443 233351467 chr2:233351443-233351467 ECEL1 UTR5

2 239755874 239755895 chr2:239755874-239755895 TWIST2 Promoter

3 9988661 9989203 chr3:9988661-9989203 PRRT3 Exon

3 10749398 10749432 chr3:10749398-10749432 n/a n/a

3 10749434 10749467 chr3: 10749434- 10749467 n/a n/a

3 12046446 12046504 chr3: 12046446- 12046504 SYN2 Promoter

3 13324006 13324119 chr3:13324006-13324119 n/a n/a

3 16554839 16555196 chr3:16554839-16555196 RFTN1 UTR5

3 42304944 42304981 chr3:42304944-42304981 CCK Exon

3 54156903 54156978 chr3:54156903-54156978 CACNA2D3 Promoter

3 54156985 54157005 chr3:54156985-54157005 CACNA2D3 Promoter

3 69591310 69591445 chr3:69591310-69591445 n/a n/a

3 119528983 119529218 chr3 119528983-119529218 NR1I2 Intron

3 122641209 122641233 chr3 122641209-122641233 SEMA5B Exon

3 130646225 130646274 chr3 130646225-130646274 ATP2C1 Intron

3 151178854 151178938 chr3 151178854-151178938 IGSF10 Promoter

3 187676563 187676643 chr3 187676563-187676643 n/a n/a

4 124515 124758 chr4: 124515-124758 ZNF718 Intron

4 467665 467684 chr4:467665-467684 ZNF721 UTR5

4 658004 658032 chr4:658004-658032 PDE6B Intron

4 3873182 3873271 chr4:3873182-3873271 n/a n/a

4 5713317 5713393 chr4:5713317-5713393 EVC2 Promoter

4 11370394 11370433 chr4:l 1370394-11370433 MIR572 Promoter

4 11370452 11370520 chr4:l 1370452-11370520 MIR572 UTR5

4 30719538 30719763 chr4:30719538-30719763 PCDH7 Promoter

4 42153515 42153591 chr4:42153515-42153591 BEND4 Intron

4 44449839 44449861 chr4:44449839-44449861 KCTD8 Promoter

4 55098179 55098209 chr4:55098179-55098209 PDGFRA UTR5

4 55991626 55991684 chr4:55991626-55991684 KDR UTR5

4 62067517 62067536 chr4:62067517-62067536 n/a n/a

4 77819160 77819271 chr4:77819160-77819271 ANKRD56 Promoter

4 103940573 103940885 chr4:103940573-103940885 NHEDC1 UTR5

4 103940890 103941101 chr4 : 103940890- 103941101 NHEDC1 Promoter Chr Start End Coordinate Symbol Annotation

4 126236257 126236931 chr4 : 126236257- 126236931 FAT4 Promoter

4 144833142 144833212 chr4:144833142-144833212 GYPE Enhancer

4 151000141 151000246 chr4:151000141-151000246 DCLK2 UTR5

5 191803 191818 chr5:191803-191818 LRRC14B Promoter

5 5139924 5139935 chr5:5139924-5139935 ADAMTS16 Promoter

5 8457467 8457735 chr5:8457467-8457735 n/a n/a

5 43603785 43604084 chr5:43603785-43604084 NNT UTR5

5 43604116 43604165 chr5:43604116-43604165 NNT UTR5

5 55117727 55117748 chr5:55117727-55117748 n/a n/a

5 76476761 76476791 chr5:76476761-76476791 n/a n/a

5 76507004 76507082 chr5 :76507004-76507082 PDE8B Promoter

5 77147764 77147911 chr5:77147764-77147911 n/a n/a

5 113391874 113391904 chr5 113391874-113391904 n/a n/a

5 115298740 115298778 chr5 115298740-115298778 LVRN Promoter

5 150536722 150536746 chr5 150536722-150536746 ANXA6 UTR5

5 155108288 155108355 chr5 155108288-155108355 n/a n/a

5 174151522 174151577 chr5 174151522-174151577 MSX2 UTR5

5 179780701 179780801 chr5 179780701-179780801 GFPT2 Promoter

5 180486476 180486537 chr5 180486476-180486537 BTNL9 Exon

6 1390421 1390427 chr6: 1390421-1390427 FOXF2 Promoter

6 1555484 1555571 chr6: 1555484-1555571 n/a n/a

6 3849234 3849541 chr6:3849234-3849541 FAM50B Promoter

6 11242082 11242134 chr6:l 1242082-11242134 NEDD9 Intron

6 18122712 18122718 chr6:18122712-18122718 NHLRC1 Promoter

6 29760303 29760314 chr6 :29760303-29760314 HCG4 UTR3

6 35888708 35888855 chr6:35888708-35888855 SRPK1 UTR5

6 42072328 42072372 chr6:42072328-42072372 C6orfl32 Exon

6 137818835 137818915 chr6:137818835-137818915 OLIG3 Promoter

6 152129664 152129700 chr6 : 152129664- 152129700 ESR1 Promoter

6 166582820 166582835 chr6:166582820-166582835 T Promoter

6 170581003 170581095 chr6:170581003-170581095 LOCI 54449 Enhancer

7 27138133 27138172 chr7:27138133-27138172 HOXA1 Promoter

7 27146154 27146541 chr7:27146154-27146541 HOXA3 UTR3

7 27147986 27148068 chr7:27147986-27148068 HOXA3 Exon

7 27162225 27162404 chr7:27162225-27162404 HOXA3 UTR5

7 27182613 27183574 chr7:27182613-27183574 HOXA5 UTR5

7 27196517 27196529 chr7:27196517-27196529 HOXA7 Promoter

7 28997143 28997166 chr7:28997143-28997166 TRIL Promoter

7 32110174 32110180 chr7:32110174-32110180 PDE1C UTR5

7 37392844 37393124 chr7:37392844-37393124 ELMOl UTR5

7 43798072 43798080 chr7 :43798072-43798080 BLVRA Promoter

7 44349388 44349523 chr7:44349388-44349523 CAMK2B Intron

7 45002209 45002518 chr7 :45002209-45002518 MYOIG UTR3

7 45002526 45002634 chr7 :45002526-45002634 MYOIG Intron

7 45614570 45614580 chr7:45614570-45614580 ADCY1 Promoter

7 45615005 45615102 chr7:45615005-45615102 ADCY1 Promoter

7 50850278 50850659 chr7:50850278-50850659 GRB10 UTR5

7 56355680 56355715 chr7:56355680-56355715 n/a n/a

7 64022988 64023250 chr7:64022988-64023250 ZNF680 Promoter Chr Start End Coordinate Symbol Annotation

7 65971098 65971186 chr7:65971098-65971186 n/a n/a

7 82792010 82792128 chr7:82792010-82792128 PCLO UTR5

7 100203335 100203366 chr7 100203335-100203366 PCOLCE Exon

7 103629981 103630092 chr7 103629981-103630092 RELN Promoter

7 113727611 113727622 chr7 113727611-113727622 n/a n/a

7 127672078 127672112 chr7 127672078-127672112 LRRC4 Promoter

7 127743728 127743766 chr7 127743728-127743766 n/a n/a

7 130130739 130131267 chr7 130130739-130131267 MESTIT1 UTR5

7 130131358 130131518 chr7 130131358-130131518 MEST UTR5

7 149746006 149746019 chr7 149746006-149746019 n/a n/a

7 150812726 150812750 chr7 150812726-150812750 AGAP3 Intron

7 151216757 151216773 chr7 151216757-151216773 RHEB UTR5

7 153583591 153583622 chr7 153583591-153583622 DPP6 Promoter

7 155247552 155247562 chr7 155247552-155247562 EN2 Promoter

7 155595896 155595952 chr7 155595896-155595952 SHH Exon

7 156400470 156400500 chr7 156400470-156400500 n/a n/a

7 157486226 157486275 chr7 157486226-157486275 PTPRN2 Intron

7 158938119 158938146 chr7 158938119-158938146 VIPR2 Promoter

8 2585693 2585757 chr8:2585693-2585757 n/a n/a

8 4851492 4851508 chr8:4851492-4851508 CSMD1 Promoter

8 9009136 9009388 chr8:9009136-9009388 PPP1R3B Promoter

8 23260741 23260788 chr8:23260741-23260788 LOXL2 UTR5

8 31497559 31497576 chr8:31497559-31497576 NRG1 Promoter

8 37552122 37552160 chr8:37552122-37552160 ZNF703 Promoter

8 37699481 37699558 chr8:37699481-37699558 GPR124 Exon

8 38034584 38034641 chr8:38034584-38034641 LSM1 Promoter

8 41166680 41166708 chr8:41166680-41166708 SFRP1 UTR5

8 49426959 49427414 chr8 :49426959-49427414 n/a n/a

8 54163561 54163585 chr8:54163561-54163585 OPRK1 Promoter

8 54163604 54163694 chr8:54163604-54163694 OPRK1 UTR5

8 55380019 55380033 chr8:55380019-55380033 n/a n/a

8 58055200 58055257 chr8:58055200-58055257 n/a n/a

8 65493709 65493763 chr8:65493709-65493763 BHLHE22 Promoter

8 67874080 67874104 chr8:67874080-67874104 n/a n/a

8 72756057 72756082 chr8:72756057-72756082 MSC Promoter

8 98290011 98290080 chr8:98290011-98290080 TSPYL5 UTR5

8 103750881 103750903 chr8 103750881-103750903 n/a n/a

8 127568853 127569069 chr8 127568853-127569069 FAM84B Exon

8 141108442 141109280 chr8 141108442-141109280 TRAPPC9 Intron

8 144511400 144511448 chr8 144511400-144511448 MAFA Downstream

8 145104394 145104454 chr8 145104394-145104454 OPLAH Downstream

9 113865 113881 chr9:l 13865-113881 n/a n/a

9 113884 113897 chr9:l 13884-113897 n/a n/a

9 19788900 19788911 chr9: 19788900-19788911 SLC24A2 Promoter

9 25677605 25677627 chr9:25677605-25677627 TUSC1 UTR3

9 35689643 35689690 chr9:35689643-35689690 TPM2 Promoter

9 38424066 38424081 chr9:38424066-38424081 IGFBPL1 Promoter

9 89560709 89560739 chr9:89560709-89560739 GAS1 Exon

9 95572080 95572086 chr9:95572080-95572086 ANKRD19 UTR5 Chr Start End Coordinate Symbol Annotation

9 99983989 99984041 chr9:99983989-99984041 KIAA1529 Enhancer

9 101471709 101471724 chr9 101471709-101471724 GABBR2 Promoter

9 101706293 101706314 chr9 101706293-101706314 COL15A1 UTR5

9 120507462 120507562 chr9 120507462-120507562 n/a n/a

9 123656794 123657026 chr9 123656794-123657026 PHF19 Enhancer

9 123657048 123657162 chr9 123657048-123657162 PHF19 Enhancer

9 124888893 124889126 chr9 124888893-124889126 n/a n/a

9 132382398 132382811 chr9 132382398-132382811 C9orf50 Promoter

9 133536491 133536515 chr9 133536491-133536515 PRDM12 Promoter

9 133536616 133536699 chr9 133536616-133536699 PRDM12 Promoter

9 135462555 135462589 chr9 135462555-135462589 BARHL1 Intron

9 137979579 137979590 chr9 137979579-137979590 OLFMl Intron

9 139964715 139964731 chr9 139964715-139964731 C9orfl40 Promoter

10 7708553 7708596 chrl0:7708553-7708596 ITIH5 Promoter

10 20104705 20104724 chrl0:20104705-20104724 PLXDC2 Promoter

10 25465355 25465408 chrl0:25465355-25465408 LOC100128811 Promoter

10 29698362 29698585 chrl0:29698362-29698585 LOC387647 UTR5

10 71626579 71626666 chrl0:71626579-71626666 COL13A1 Intron

10 77158757 77158887 chrl0:77158757-77158887 C10orf41 Promoter

10 80898884 80899123 chrl0:80898884-80899123 ZMIZ1 UTR5

10 81163306 81163339 chrl0:81163306-81163339 ZCCHC24 Intron

10 83634362 83634433 chrl0:83634362-83634433 NRG3 Promoter

10 88123205 88123264 chrl0:88123205-88123264 GRID1 Intron

10 101282028 101282143 chrl0:101282028-101282143 NKX2-3 Enhancer

10 102495446 102495452 chrl 0: 102495446-102495452 PAX2 Enhancer

10 102507681 102507717 chrl 0: 102507681 - 102507717 PAX2 Intron

10 105344583 105344617 chrl0:105344583-105344617 NEURL Exon

10 105452852 105452884 chrl0:105452852-105452884 SH3PXD2A Intron

10 105453074 105453169 chrl0:105453074-105453169 SH3PXD2A Intron

10 111216768 111216809 chrl0:l 11216768-111216809 n/a n/a

10 119301950 119302046 chrl0:l 19301950-119302046 EMX2 UTR5

10 119311968 119311994 chrl0:l 19311968-119311994 EMX20S Enhancer

10 119313192 119313239 chrl0:l 19313192-119313239 EMX20S Enhancer

10 125732491 125732516 chrl0:125732491-125732516 n/a n/a

10 131767467 131767523 chrlO: 131767467-131767523 EBF3 Enhancer

10 133999328 133999363 chrl0:133999328-133999363 DPYSL4 Promoter

10 134222564 134222659 chrl 0: 134222564- 134222659 PWWP2B UTR3

10 135090324 135090391 chrl 0: 135090324-135090391 ADAM8 UTR5

11 397076 397141 chrl 1 :397076-397141 PKP3 Exon

11 518994 519003 chrl 1 :518994-519003 LRRC56 Enhancer

11 726322 726388 chrl 1 :726322-726388 EPS8L2 Exon

11 1874410 1874461 chrl 1 : 1874410-1874461 LSP1 Promoter

11 2021030 2021337 chrl 1 :2021030-2021337 MIR675 Promoter

11 17297912 17298333 chrl l :17297912-17298333 NUCB2 UTR5

11 17740909 17740930 chrl l :17740909-17740930 MYOD1 Promoter

11 24518517 24518550 chrl l :24518517-24518550 LUZP2 Promoter

11 35641254 35641291 chrl 1 :35641254-35641291 FJX1 Exon

11 47236054 47236189 chrl 1 :47236054-47236189 DDB2 Promoter

11 47611788 47611855 chrl 1 :47611788-47611855 C1QTNF4 Exon Chr Start End Coordinate Symbol Annotation

11 60692224 60692379 chrl l 60692224-60692379 TMEM132A Promoter

11 61880088 61880140 chrl l 61880088-61880140 INCENP Enhancer

11 69589140 69589199 chrl l 69589140-69589199 FGF4 Promoter

11 69924935 69924948 chrl l 69924935-69924948 ANOl Promoter

11 71951194 71951198 chrl l 71951194-71951198 PHOX2A Exon

11 72295582 72295589 chrl l 72295582-72295589 PDE2A UTR3

11 72295726 72295758 chrl l 72295726-72295758 PDE2A UTR3

11 72533078 72533338 chrl l 72533078-72533338 ATG16L2 Intron

11 79148648 79148661 chrl l 79148648-79148661 ODZ4 UTR5

11 82443937 82443948 chrl l 82443937-82443948 FAM181B Promoter

11 100998291 100998355 chrl l 100998291-100998355 PGR Exon

11 109963265 109963348 chrl l 109963265-109963348 ZC3H12C Promoter

11 109964113 109964167 chrl l 109964113-109964167 ZC3H12C UTR5

11 134146600 134146621 chrl l 134146600-134146621 GLB1L3 UTR5

12 2163267 2163279 chrl2:2163267-2163279 CACNA1C Promoter

12 2800445 2800521 chrl2:2800445-2800521 CACNA1C UTR3

12 3309861 3309888 chrl2:3309861-3309888 TSPAN9 UTR5

12 7781181 7781237 chrl2:7781181-7781237 n/a n/a

12 9217328 9217429 chrl2:9217328-9217429 LOCI 44571 Promoter

12 29936643 29936653 chr 12:29936643-29936653 TMTC1 UTR5

12 54764364 54764584 chr 12 :54764364-54764584 ZNF385A Intron

12 57869148 57869420 chrl2:57869148-57869420 ARHGAP9 Intron

12 58025887 58025901 chr 12:58025887-58025901 B4GALNT1 Exon

12 58119853 58120184 chrl2:58119853-58120184 LOC100130776 UTR5

12 58131738 58132045 chrl2:58131738-58132045 AGAP2 UTR5

12 122016340 122016373 chrl2:122016340-122016373 KDM2B Intron

12 132195645 132195994 chrl2:132195645-132195994 SFRS8 UTR5

13 19918950 19918983 chrl3:19918950-19918983 LOC100101938 UTR3

13 20139192 20139253 chrl3:20139192-20139253 n/a n/a

13 20692669 20692685 chrl3:20692669-20692685 n/a n/a

13 25115907 25115943 chrl3:25115907-25115943 n/a n/a

13 26625786 26625915 chrl3:26625786-26625915 SHISA2 Promoter

13 48893192 48893246 chrl3:48893192-48893246 RBI Intron

13 52703312 52703361 chrl3:52703312-52703361 NEK5 Promoter

13 100608204 100608226 chrl 3 100608204-100608226 n/a n/a

13 109147798 109147937 chrl 3 109147798-109147937 n/a n/a

13 109148352 109148477 chrl 3 109148352-109148477 n/a n/a

13 110959180 110959184 chrl 3 110959180-110959184 COL4A2 Promoter

13 112723104 112723110 chrl 3 112723104-112723110 SOX1 Exon

13 113764991 113765210 chrl 3 113764991-113765210 F7 Intron

13 114462331 114462426 chrl 3 114462331-114462426 FAM70B Promoter

14 28733691 28733732 chrl4:28733691-28733732 n/a n/a

14 37051685 37051713 chrl4:37051685-37051713 NKX2-8 UTR5

14 38091516 38091570 chrl4:38091516-38091570 n/a n/a

14 42077408 42077482 chr 14 :42077408-42077482 LRFN5 UTR5

14 48143559 48143579 chrl4:48143559-48143579 MDGA2 Promoter

14 77737169 77737210 chrl4:77737169-77737210 NGB Promoter

14 91720063 91720097 chrl4:91720063-91720097 GPR68 UTR5

14 97499682 97499715 chr 14 :97499682-97499715 n/a n/a Chr Start End Coordinate Symbol Annotation

14 101925421 101925446 chrl4:101925421-101925446 n/a n/a

14 105640938 105641002 chrl4:105640938-105641002 NUDT14 Intron

14 105767212 105767276 chrl 4 : 105767212-105767276 BRF1 UTR5

15 23892769 23892883 chr 15 :23892769-23892883 MAGEL2 Promoter

15 26107989 26108171 chrl5:26107989-26108171 ATP10A Promoter

15 26108184 26108248 chrl5:26108184-26108248 ATP10A UTR5

15 27213029 27213059 chr 15 :27213029-27213059 GABRG3 Promoter

15 29034062 29034076 chr 15 :29034062-29034076 n/a n/a

15 29034154 29034183 chrl5:29034154-29034183 n/a n/a

15 33010242 33010280 chrl5:33010242-33010280 GREM1 UTR5

15 35047291 35047296 chrl5:35047291-35047296 GJD2 Promoter

15 40583268 40583755 chr 15 :40583268-40583755 PLCB2 Intron

15 47477259 47477276 chr 15 :47477259-47477276 n/a n/a

15 56035589 56035677 chr 15:56035589-56035677 PRTG Promoter

15 65360274 65360278 chr 15 :65360274-65360278 RASL12 UTR5

15 70354770 70354890 chr 15 :70354770-70354890 TLE3 Intron

15 74044709 74044798 chr 15 :74044709-74044798 C15orf59 Promoter

15 79576092 79576118 chrl5:79576092-79576118 ANKRD34C UTR5

15 79724688 79724701 chr 15 :79724688-79724701 KIAA1024 Promoter

15 89148392 89148460 chrl5:89148392-89148460 MIR7-2 Enhancer

15 97491220 97491238 chrl5:97491220-97491238 n/a n/a

15 100386502 100386576 chrl5:100386502-100386576 n/a n/a

16 128297 128580 chrl6:128297-128580 MPG UTR5

16 610097 610110 chrl6:610097-610110 C16orfl l Promoter

16 1203760 1203786 chrl6: 1203760-1203786 CACNA1H Promoter

16 2009454 2009590 chrl6:2009454-2009590 NDUFB10 UTR5

16 2317602 2317630 chrl6:2317602-2317630 RNPS1 UTR5

16 28074226 28074311 chr 16 :28074226-28074311 GSG1L Promoter

16 30572753 30572772 chr 16:30572753-30572772 ZNF764 Promoter

16 47177577 47177628 chrl6:47177577-47177628 NETO2 UTR5

16 51185385 51185428 chrl6:51185385-51185428 SALL1 Promoter

16 67313433 67313443 chrl6:67313433-67313443 PLEKHG4 UTR5

16 67687484 67687553 chr 16:67687484-67687553 RLTPR Intron

16 68269381 68269396 chrl6:68269381-68269396 ESRP2 Promoter

16 68679063 68679166 chrl6:68679063-68679166 CDH3 UTR5

16 69419782 69420122 chrl6:69419782-69420122 TERF2 UTR5

16 75284386 75284475 chr 16:75284386-75284475 BCAR1 Intron

16 79633394 79633613 chrl6:79633394-79633613 MAF Exon

16 86541944 86542182 chrl6:86541944-86542182 FOXF1 Promoter

16 88454809 88454843 chr 16:88454809-88454843 n/a n/a

16 88600767 88600893 chr 16:88600767-88600893 ZFPM1 Exon

16 90113989 90114077 chrl6:90113989-90114077 LOC100130015 UTR5

17 3438996 3439015 chrl7:3438996-3439015 TRPV3 Intron

17 14205002 14205182 chrl7:14205002-14205182 MGC12916 Promoter

17 17399374 17399399 chrl7:17399374-17399399 RASD1 Promoter

17 18061388 18061524 chrl7:18061388-18061524 MY015A Intron

17 37761831 37761946 chrl7:37761831-37761946 NEUROD2 Exon

17 43047732 43047918 chrl7:43047732-43047918 C1QL1 Promoter

17 43507012 43507098 chrl7:43507012-43507098 SH3D20 Exon Chr Start End Coordinate Symbol Annotation

17 46621993 46622021 chrl7:46621993-46622021 HOXB2 Promoter

17 46641662 46641747 chrl7:46641662-46641747 HOXB3 UTR5

17 46641966 46642036 chr 17 :46641966-46642036 HOXB3 UTR5

17 47574666 47574903 chr 17 :47574666-47574903 NGFR Intron

17 56833042 56833161 chrl7:56833042-56833161 PPM IE Promoter

17 62774654 62774696 chr 17 :62774654-62774696 LOC146880 UTR3

17 74072736 74072749 chr 17 :74072736-74072749 ZACN Promoter

17 74381072 74381119 chrl7:74381072-74381119 SPHK1 UTR5

17 79455513 79455575 chr 17 :79455513-79455575 n/a n/a

17 81057628 81057660 chr 17 :81057628-81057660 n/a n/a

18 4455202 4455210 chrl 8:4455202-4455210 n/a n/a

18 5891068 5891178 chrl8:5891068-5891178 TMEM200C Promoter

18 8706308 8706439 chrl8:8706308-8706439 KIAA0802 Enhancer

18 10726392 10726415 chrl8:10726392-10726415 FAM38B Intron

18 74332372 74332448 chrl8 :74332372-74332448 n/a n/a

18 76740034 76740059 chrl8:76740034-76740059 SALL3 Promoter

18 77376899 77377025 chrl8:77376899-77377025 n/a n/a

19 1071232 1071353 chrl9: 1071232-1071353 HMHA1 Intron

19 1450118 1450129 chrl9: 1450118-1450129 APC2 Promoter

19 2576229 2576291 chrl9:2576229-2576291 GNG7 UTR5

19 3404842 3405130 chrl 9: 3404842-3405130 NFIC Intron

19 3933421 3933495 chrl9:3933421-3933495 ITGB1BP3 UTR5

19 6274084 6274159 chrl9:6274084-6274159 MLLT1 Intron

19 6744852 6744978 chrl9:6744852-6744978 TRIPIO Exon

19 10444873 10444951 chrl9:10444873-10444951 RAVER1 Promoter

19 10445195 10445607 chrl9:10445195-10445607 RAVER1 Promoter

19 10531599 10531608 chrl9:10531599-10531608 PDE4A Promoter

19 12306248 12306298 chr 19 : 12306248- 12306298 n/a n/a

19 14584456 14584478 chrl9:14584456-14584478 PTGER1 Exon

19 16022797 16022848 chrl9:16022797-16022848 CYP4F2 Enhancer

19 16181371 16181533 chrl9:16181371-16181533 TPM4 Intron

19 16437563 16437597 chrl9:16437563-16437597 KLF2 Intron

19 17392927 17393042 chrl9:17392927-17393042 ANKLE 1 Promoter

19 18303568 18304395 chrl9:18303568-18304395 MPV17L2 UTR5

19 23653826 23653836 chrl9:23653826-23653836 n/a n/a

19 30017014 30017126 chrl9:30017014-30017126 VSTM2B Promoter

19 34113352 34113366 chrl9:34113352-34113366 CHST8 UTR5

19 38042272 38042323 chr 19:38042272-38042323 ZNF540 UTR5

19 39261605 39261612 chrl9:39261605-39261612 LGALS7 UTR3

19 39798183 39798269 chrl9:39798183-39798269 LRFN1 UTR3

19 40732582 40732618 chrl9:40732582-40732618 CNTD2 UTR5

19 46974787 46974808 chr 19:46974787-46974808 PNMAL1 UTR5

19 48946520 48946656 chr 19 :48946520-48946656 GRWD1 Promoter

19 48983752 48983868 chrl9:48983752-48983868 CYTH2 UTR3

19 52104699 52104735 chrl9:52104699-52104735 n/a n/a

19 54040763 54041012 chrl9:54040763-54041012 ZNF331 UTR5

19 54412970 54412994 chr 19 :54412970-54412994 CACNG7 Promoter

19 54483370 54483483 chrl9:54483370-54483483 MIR935 Promoter

19 57351416 57351756 chrl9:57351416-57351756 ZIM2 UTR5 Chr Start End Coordinate Symbol Annotation

19 58858757 58858820 chrl9:58858757-58858820 A1BG Exon

19 58867719 58867836 chrl9:58867719-58867836 A1BG Promoter

20 1784445 1784482 chr20: 1784445-1784482 n/a n/a

20 2674280 2674284 chr20:2674280-2674284 EBF4 Promoter

20 5296982 5297005 chr20:5296982-5297005 PROKR2 Promoter

20 5484944 5485022 chr20:5484944-5485022 LOC149837 UTR3

20 5485089 5485267 chr20:5485089-5485267 LOC149837 UTR5

20 10647776 10647921 chr20 : 10647776-10647921 JAG1 Intron

20 13201045 13201055 chr20:13201045-13201055 ISM1 Promoter

20 22549193 22549242 chr20 :22549193-22549242 C20orf56 UTR3

20 22562939 22562952 chr20 :22562939-22562952 C20orf56 Promoter

20 44639238 44639267 chr20:44639238-44639267 MMP9 Exon

20 55841104 55841148 chr20:55841104-55841148 BMP7 Promoter

20 55841151 55841254 chr20:55841151-55841254 BMP7 UTR5

20 57089850 57089875 chr20:57089850-57089875 APCDD1L UTR5

20 57464110 57464262 chr20:57464110-57464262 GNAS UTR5

20 59827735 59827770 chr20:59827735-59827770 CDH4 Promoter

20 59827789 59827831 chr20:59827789-59827831 CDH4 Promoter

20 60877547 60877638 chr20:60877547-60877638 ADRM1 Promoter

21 28216583 28216627 chr21 :28216583-28216627 ADAMTS1 Exon

21 28217665 28217711 chr21 :28217665-28217711 ADAMTS1 UTR5

21 28338515 28338535 chr21 :28338515-28338535 ADAMTS5 Promoter

21 32930369 32930388 chr21 :32930369-32930388 TIAM1 UTR5

21 32931085 32931279 chr21 :32931085-32931279 TIAM1 UTR5

21 32931284 32931321 chr21 :32931284-32931321 TIAM1 UTR5

21 38630603 38630727 chr21 :38630603-38630727 DSCR3 Intron

21 40033433 40033449 chr21 :40033433-40033449 ERG UTR5

22 17083312 17083542 chr22:17083312-17083542 psiTPTE22 UTR5

22 19137099 19137268 chr22:19137099-19137268 GSC2 Promoter

22 19702409 19702465 chr22 : 19702409-19702465 SEPT5 Promoter

22 21738255 21738732 chr22:21738255-21738732 RIMBP3B Promoter

22 38349631 38350197 chr22:38349631-38350197 POLR2F UTR5

22 39572333 39572455 chr22:39572333-39572455 n/a n/a

22 46423321 46423397 chr22 :46423321 -46423397 n/a n/a

22 46476250 46476464 chr22 :46476250-46476464 LOC400931 Enhancer

22 46484636 46484829 chr22 :46484636-46484829 LOC400931 UTR5

22 50706449 50706483 chr22 :50706449-50706483 MAPK11 Intron

22 51158653 51158710 chr22:51158653-51158710 SHANK3 Exon

22 51158990 51159182 chr22:51158990-51159182 SHANK3 Exon Table 3a:

Deconvolution of plasma samples by 10 normal tissues, LCT, and CCT

Average values from only samples with WB > 0.3

Table 3b:

Deconvolution for colon cancer plasma

39959779.1

Table 3c:

Deconvolution for lung cancer plasma

39959779.1

Table 3d:

Deconvolution for normal plasma

39959779.1

39959779.1

39959779.1

Table 4a:

Differentially methylated MHB regions between colon cancer tissues (CCT) and normal plasma.

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

Table 4b:

Differentially methylated MHB regions between lung cancer tissues (LCT) and normal plasma.

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

39959779.1

Table 5a:

The sets of cancer specific markers derived from MARS based features selection on training data sets

Chrom Start End

chrlO 103454457 103454477 chrlO 104352036 104352196 chrlO 10847503 10847691 chrlO 27702716 27702729 chrlO 30110010 30110051 chrl l 106698602 106698622 chrl l 121395074 121395118 chrl l 2020027 2020065 chrl l 33929206 33929320 chrl l 36145336 36145373 chrl l 47416330 47416377 chrl 156087833 156087873 chrl 16159932 16159950 chrl l 62139527 62139609 chrl l 62370212 62370238 chrl 201509291 201509346 chrl 207921424 207921528 chrl2 110033418 110033548 chrl2 25537415 25537441 chrl 245970850 245970891 chrl2 52438106 52438159 chrl2 52889045 52889173 chrl2 54332947 54332963 chrl2 54473544 54473561 chrl2 6901902 6901997 chrl2 96564033 96564157 chrl 3 19918783 19918794 chrl 3 20370973 20371021 chrl 3 34253491 34253585 chrl4 64130579 64130727 chrl4 91818657 91818672 chrl4 98190804 98190884 chrl5 58734402 58734645 chrl5 86298535 86298604 chrl 6 69961433 69961449 chrl7 17295442 17295619 chrl7 21415130 21415142 chrl7 26173343 26173438 chrl7 37211873 37211969 chrl7 64948116 64948158 chrl7 74526150 74526161 chrl7 75143193 75143219 chrl7 76875977 76875998 chrl 8 72916692 72916705 chrl9 1169117 1169138 Chrom Start End chrl9 16178526 16178600 chrl 92946665 92946768 chrl9 3403636 3403711 chrl9 3403810 3403840 chrl9 47496561 47496586 chrl9 50931391 50931435 chrl9 52880780 52880980 chrl9 58220626 58220669 chr20 30816216 30816330 chr20 34391305 34391406 chr20 41153703 41153752 chr2 101926462 101926479 chr2 111141088 111141148 chr2 11884471 11884591 chr21 35197108 35197284 chr2 197040996 197041007 chr2 202945219 202945279 chr2 232348683 232348704 chr2 232745254 232745369 chr22 37942946 37942985 chr22 38104696 38104738 chr22 39148367 39148393 chr2 242195200 242195217 chr22 42815670 42815694 chr22 45692585 45692725 chr22 46022276 46022300 chr2 25138739 25138897 chr2 36717718 36717897 chr2 46219462 46219480 chr2 48776047 48776154 chr2 66673054 66673077 chr2 85637199 85637376 chr2 99155846 99155916 chr3 126645737 126645771 chr3 141098240 141098373 chr3 18284952 18285049 chr3 184056458 184056470 chr3 52250610 52250789 chr4 1195669 1195719 chr4 177420126 177420335 chr4 186808246 186808296 chr4 6697966 6698085 chr4 8727069 8727091 chr5 138730608 138730648 chr5 139725539 139725550 chr5 156570589 156570747 chr5 176831296 176831309 chr6 107012070 107012253 chr6 108984666 108984700 Chrom Start End chr6 133523044 133523327 chr6 149805994 149806024 chr6 158411773 158411853 chr6 159128335 159128361 chr6 163767808 163767820 chr6 170585982 170586062 chr6 170589857 170589872 chr6 21246436 21246559 chr6 37533092 37533142 chr6 43192429 43192519 chr6 43650729 43650959 chr6 43894465 43894595 chr6 43939175 43939212 chr6 71874735 71874758 chr7 100549051 100549245 chr7 100875668 100875696 chr7 101884716 101884822 chr7 140096553 140096723 chr7 157071940 157071954 chr7 17139387 17139535 chr7 33176934 33177005 chr7 36320659 36320695 chr7 39393611 39393625 chr7 41428132 41428227 chr7 56183788 56183856 chr7 601463 601503 chr7 614586 614611 chr7 64019659 64019780 chr7 75018128 75018144 chr8 125766626 125766669 chr8 131076680 131076724 chr9 116327621 116327718 chr9 130517759 130517991 chr9 130955063 130955167 chr9 95964149 95964200 chrlO 81004561 81004609 chrl 162442502 162442619 chrl 212415595 212415691 chrl 235062685 235062859 chrl5 77286562 77286576 chrl 6 17499260 17499310 chrl 6 78636379 78636435 chrl7 16873955 16874009 chrl7 41669725 41669744 chrl7 45786237 45786298 chrl 8400056 8400143 chrl9 49839124 49839203 chrl9 7723032 7723142 chr20 57425892 57425937 Chrom Start End

chr20 62200085 62200109 chr2 174890243 174890269 chr2 5836838 5836852 chr3 196347229 196347361 chr4 68411077 68411095 chr6 155434075 155434119 chr6 2999401 2999433 chr7 50850278 50850660 chrl4 28485394 28485506 chrl9 55766296 55766320 chr22 46480824 46480971

Table 5b:

The sets of tissue specific markers derived from MARS based features selection on training data sets

Chrom Start End

chrlO 12526101 12526198 chrlO 134062557 134062567 chrlO 2992831 2992986 chrlO 71250913 71251031 chrlO 894133 894176 chrl l 10529517 10529548 chrl l 10580059 10580207 chrl l 117454728 117454907 chrl l 125840213 125840218 chrl l 126226966 126226994 chrl l 20626148 20626166 chrl 120906033 120906056 chrl l 2828703 2828805 chrl 154978354 154978371 chrl l 61467518 61467601 chrl 164545706 164545781 chrl l 66871960 66871973 chrl 168687549 168687721 chrl 172291575 172291727 chrl l 85423851 85424008 chrl l 91958190 91958214 chrl 19249130 19249147 chrl l 94600637 94600757 chrl 20821827 20821848 chrl2 121164886 121164929 chrl2 123352751 123352815 chrl2 124905745 124905758 chrl 219786354 219786374 chrl2 214138 214168 chrl 24468442 24468457 chrl 25257913 25257952 Chrom Start End chrl2 58131153 58131181 chrl2 63157011 63157117 chrl2 6336078 6336124 chrl2 63828393 63828590 chrl2 65813665 65813787 chrl2 69440660 69440851 chrl2 92793926 92794091 chrl3 24575928 24576139 chrl3 75981727 75981971 chrl 37941197 37941228 chrl 4045074 4045329 chrl 41898133 41898168 chrl4 24078834 24078895 chrl4 35319476 35319527 chrl4 55170355 55170479 chrl4 62403215 62403374 chrl4 64130579 64130727 chrl4 65708245 65708394 chrl4 73279457 73279546 chrl4 75683126 75683335 chrl4 77089391 77089627 chrl4 78108418 78108650 chrl5 23892535 23892608 chrl5 31850650 31850711 chrl5 61497667 61497716 chrl5 66998995 66999028 chrl5 67179342 67179441 chrl5 67356599 67356824 chrl5 68136062 68136196 chrl5 70488068 70488255 chrl5 76268973 76269064 chrl5 90727362 90727449 chrl 6 11749588 11749704 chrl 6 12510137 12510244 chrl 6 1544949 1545020 chrl 6 16244310 16244423 chrl 6 67687178 67687277 chrl 6 69516112 69516139 chrl 6 71560275 71560421 chrl 6 75279686 75279773 chrl 6 84967640 84967652 chrl 6 86965384 86965400 chrl 6 88096279 88096362 chrl7 16924593 16924617 chrl7 17473311 17473523 chrl7 25821621 25821649 chrl7 29469666 29469741 chrl7 43483074 43483225 chrl7 43506900 43506997 Chrom Start End chrl7 71538984 71539080 chrl7 79456619 79456772 chrl7 950579 950597 chrl8 13447880 13447894 chrl8 14458513 14458531 chrl8 45058265 45058273 chrl8 5489107 5489117 chrl8 74499570 74499587 chrl8 74665755 74665892 chrl9 14673070 14673115 chrl9 18131156 18131182 chrl9 2291605 2291625 chrl9 33879823 33879853 chrl9 35505322 35505399 chrl9 35630532 35630541 chrl9 53088342 53088389 chrl 9563349 9563412 chrl9 58629652 58629666 chr20 17731262 17731276 chr20 32336264 32336332 chr20 3732686 3732700 chr20 3732852 3732883 chr20 47421687 47421875 chr20 50352688 50352798 chr20 62200085 62200109 chr20 62959294 62959302 chr20 8880040 8880231 chr2 106048152 106048370 chr2 109788225 109788402 chr2 110798982 110799019 chr2 14375315 14375355 chr21 44781718 44781727 chr2 175739843 175739898 chr22 20237340 20237395 chr2 231277281 231277433 chr22 32475876 32475936 chr22 34095314 34095472 chr2 236611862 236611872 chr22 38484978 38484992 chr22 45887405 45887583 chr22 46476111 46476156 chr22 46786620 46786697 chr22 50343067 50343097 chr22 50985445 50985457 chr2 39472294 39472340 chr2 86248350 86248380 chr2 97305261 97305286 chr3 106937697 106937906 chr3 113160421 113160434 Chrom Start End chr3 122459452 122459655 chr3 128712749 128712769 chr3 130098135 130098295 chr3 170965322 170965449 chr3 195356987 195357011 chr3 29320866 29320988 chr3 38012448 38012522 chr3 51965036 51965246 chr4 1244005 1244024 chr4 129556483 129556502 chr4 151504097 151504165 chr4 169561292 169561324 chr4 185722597 185722644 chr4 2257619 2257679 chr4 26755387 26755468 chr4 965678 965736 chr5 10624799 10624898 chr5 164830490 164830637 chr5 170041185 170041290 chr5 5140660 5140708 chr5 95198558 95198771 chr6 115682789 115682877 chr6 135642658 135642719 chr6 139858289 139858355 chr6 150623168 150623365 chr6 155434075 155434119 chr6 169351059 169351075 chr6 170574715 170574763 chr6 21246436 21246559 chr6 24981775 24981874 chr6 3136197 3136313 chr6 42213769 42213962 chr6 47427927 47427990 chr7 100875668 100875696 chr7 102963572 102963623 chr7 151290079 151290342 chr7 1577891 1577924 chr7 47419767 47419848 chr8 126645983 126646069 chr8 129040440 129040473 chr8 129103440 129103463 chr8 141523764 141523791 chr8 142189542 142189581 chr8 143408017 143408047 chr8 144361314 144361344 chr8 144361364 144361393 chr8 145654572 145654583 chr8 27530948 27530986 chr8 41979371 41979431 Chrom Start End chr8 53070170 53070416 chr8 8230665 8230840 chr9 116356861 116357046 chr9 130517759 130517991 chr9 130860588 130860681 chr9 130877668 130877724 chr9 134455414 134455516 chr9 136921088 136921169 chr9 138904160 138904187 chr9 140188472 140188494 chr9 6788700 6788803 chr9 86064195 86064250 chrlO 10840659 10840699 chrlO 135174002 135174025 chrlO 6254206 6254244 chrlO 75647560 75647648 chrlO 77109265 77109419 chrlO 80919230 80919249 chrl 151870591 151870681 chrl 156261302 156261327 chrl l 64740009 64740016 chrl 205449277 205449449 chrl2 123402308 123402427 chrl 2164204 2164384 chrl4 106774181 106774432 chrl4 65681455 65681535 chrl 47039258 47039357 chrl4 91818657 91818672 chrl5 79082104 79082154 chrl 6515867 6515873 chrl 6 78636379 78636435 chrl7 17415395 17415403 chrl7 19429425 19429525 chrl7 8371613 8371640 chrl 8433676 8433790 chrl9 1169117 1169138 chrl9 13823667 13823731 chrl9 22610862 22610883 chr20 50073805 50073870 chr20 57417351 57417392 chr20 60760760 60760972 chr21 30612916 30613022 chr21 34399242 34399284 chr21 45705693 45705715 chr21 47581404 47581439 chr2 158694393 158694462 chr2 161348608 161348781 chr2 219124246 219124271 chr2 219147468 219147621 Chrom Start End chr3 123118882 123119159 chr3 13828799 13828855 chr3 48540230 48540315 chr4 154460014 154460117 chr4 19929150 19929272 chr4 54889382 54889454 chr5 112538998 112539022 chr5 1725410 1725419 chr5 17366324 17366430 chr5 66564412 66564447 chr7 158890101 158890118 chr7 79875750 79875982 chr8 22447199 22447304 chr8 81279608 81279654 chr9 102213820 102213912 chr9 95964655 95964697 chrlO 104840711 104840824 chrlO 3917268 3917367 chrl l 120418670 120418806 chrl l 57199801 57200049 chrl2 126978451 126978675 chrl 28431421 28431512 chrl3 107869633 107869814 chrl4 34504893 34504986 chrl 6 23303806 23303916 chrl7 38708456 38708524 chrl9 1221753 1221771 chrl9 48983562 48983583 chrl9 57412139 57412201 chr22 20237221 20237247 chr22 29866375 29866425 chr2 237581359 237581546 chr22 38148519 38148762 chr3 58103818 58103844 chr3 65940157 65940167 chr3 88312669 88312786 chr4 113634382 113634491 chr4 187071070 187071120 chr4 2904348 2904411 chr4 68411077 68411095 chr5 149994824 149994881 chr6 57607668 57607879 chr8 10559717 10559846 chr9 132658755 132658787 chrl 2077786 2077884 chrl 3 21900491 21900523 chrl5 79342608 79342818 chrl7 46697530 46697565 chrl 8 60050875 60051139 Chrom Start End chr2 187482101 187482155 chr3 194014878 194014894 chr9 129511230 129511375 chr9 78871348 78871392 chrlO 121578130 121578169 chrlO 88729962 88730008 chrl5 23115150 23115163 chr22 37942946 37942985 chr3 126645737 126645771 chr5 170041887 170042039 chr6 31869020 31869031 chrl l 128558360 128558418 chrl4 93565785 93565854 chrlO 30327101 30327236 chrlO 6183283 6183437 chrlO 30110010 30110051 chrl7 45786237 45786298 chr3 13063400 13063494 chr2 105990523 105990613

[0088] The disclosures of all references listed herein, including the following references, are incorporated by reference herein in their entireties:

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Claims

WHAT IS CLAIMED IS:

1. A method for detecting the presence of one or more nucleic acids indicative of a health condition, tissue of origin, germ layer of origin or organ of origin in a mixture of nucleic acids comprising:

performing methylation analysis on a sample comprising a plurality of nucleic acids; and

determining whether said sample includes a plurality of methylation haplotype blocks indicative of the presence of one or more nucleic acids indicative of a health condition, tissue of origin, germ layer of origin, organ of origin or any combination thereof, wherein said methylation haplotype blocks comprise a plurality of methylation sites for which the methylation status is coordinated.

2. The method of Claim 1, wherein said methylation analysis is performed on cell- free DNA.

3. The method of any one of Claims 1 and 2, wherein said methylation analysis is performed on cell-free DNA in a blood sample.

4. The method of any one of Claims 1-3, wherein said plurality of methylation haplotype blocks comprises at least 2, at least 3, at least 4, at least 5, at least 10, at least 20, at least 40, at least 50, at least 100, at least 200, at least 300, at least 400, at least 500 or more than 500 methylation haplotype blocks.

5. The method of any one of Claims 1-4, wherein said health condition is a tumor.

6. The method of Claim 5, further comprising determining whether said sample includes a plurality of methylation haplotype blocks indicative of the presence of one or more nucleic acids indicative of a normal tissue or normal organ corresponding to the tissue or organ of origin of said tumor.

7. The method of any one of Claims 1-6, wherein said health condition is fetal aneuploidy.

8. The method of any one of Claims 1-7, wherein said sample is a blood sample.

9. The method of any one of Claims 1-8, further comprising quantitating the level of said one or more nucleic acids indicative of a health condition, tissue of origin, organ of origin or any combination thereof in said sample.

10. The method of any one of Claims 1-9, wherein said methylation analysis is performed using a technique selected from the group consisting of bisulfite methylation analysis, reduced representation bisulfite sequencing, WGBS, BSPP, micro-droplet PCR, selector probe based methods, and MeDiP.

11. The method of any one of Claims 1-10, further comprising determining a methylation haplotype load for each methylation haplotype block, wherein said methylation haplotype load comprises the normalized fraction of methylated haplotypes at different lengths.

12. The method of any one of Claims 1-10, further comprising determining a unmethylated haplotype load for each methylation haplotype block, wherein said unmethylated haplotype load comprises the normalized fraction of unmethylated haplotypes at different lengths.

13. The method of any one of Claims 1-11, wherein said methylation haplotype blocks have an average size of 95bp.

14. The method of any one of Claims 1-12, wherein said methylation haplotype blocks have a minimum of 3 CpGs per block.

15. The method of any one of Claims 1-13, further comprising quantifying the level of said plurality of methylation haplotype blocks indicative of the presence one or more nucleic acids indicative of a health condition, tissue of origin, germ layer of origin, organ of origin or any combination thereof in said sample.

16. The method of Claim 6, further comprising quantifying the level of said plurality of methylation haplotype blocks indicative of the presence of a tumor in said sample and quantifying the level of said plurality of methylation haplotype blocks indicative of the presence of one or more nucleic acids indicative of a normal tissue or normal organ corresponding to the tissue or organ of origin of said tumor in said sample

17. A method of identifying methylation haplotype blocks comprising:

determining methylation haplotypes in a plurality of nucleic acid segments; combining the methylation haplotypes and calculating methylation linkage disequilibrium on the combined methylation haplotypes; and

partitioning each segment into a plurality of methylation haplotype blocks, wherein said methylation haplotype blocks comprise a plurality of methylation sites for which the methylation status is coordinated.

18. The method of Claim 16, wherein said methylation haplotypes are determined for a portion of a genome.

19. The method of any one of Claims 16 and 17, wherein said methylation haplotypes are determined across a whole genome.

20. The method of any one of Claims 16-18, wherein said methylation haplotype blocks are defined as the genomic region in which the r² value of two adjacent CpG sites is no less than 0.5.

21. The method of any one of Claims 16-19, wherein said methylation haplotype blocks are identified in nucleic acids from a tumor tissue.

22. The method of any one of Claims 16-20, wherein said methylation haplotype blocks are identified in nucleic acids from a known type of tissue.

23. The method of any one of Claims 16-21, wherein said methylation haplotype blocks are identified in nucleic acids from a fetus.

24. The method of any one of Claims 16-22, wherein said methylation haplotype blocks are identified in nucleic acids from an embryonic stem cell.

25. The method of any one of Claims 16-23, wherein said methylation haplotype blocks are identified in nucleic acids from a known germ layer.

26. The method of any one of Claims 16-24, wherein said methylation haplotype blocks have an average size of 95bp.

27. The method of any one of Claims 16-25, wherein said methylation haplotype blocks have a minimum of 3 CpGs per block.

28. The method of any one of Claims 16-26, wherein said methylation haplotype blocks are identified in nucleic acid regions from a Whole Genome Bisulfite Sequencing analysis.

29. The method of any one of Claims 16-27, wherein said methylation haplotype blocks are identified in data sets from methylation analysis of ENCODE cell lines or tissue samples.

30. The method of any one of Claims 16-28, wherein said methylation haplotype blocks are identified in data sets from methylation analysis of Infinium HumanMethylation450 BeadChip (HM450K).

31. The method of any one of Claims 16-29, further comprising calculating the pairwise correlation coefficient of adjacent CpG methylation levels across different sample sets for block partitioning.

32. The method of any one of Claims 16-30, further comprising determining methylation haplotype load for each methylation haplotype block, wherein said methylation haplotype load comprises the normalized fraction of methylated haplotypes at different lengths.

33. The method of any one of Claims 16-30, further comprising determining unmethylated haplotype load for each methylation haplotype block, wherein said unmethylated haplotype load comprises the normalized fraction of unmethylated haplotypes at different lengths.