WO2024112741A1 - Dna methylation barcodes for identifying brain cells - Google Patents

Abstract

Methods are provided for identifying a brain cell in a biological sample, based on the methylation status of multiple methylation markers in genomic DNA. Also provided are kits that can be used for such methods.

Description

DNA METHYLATION BARCODES FOR IDENTIFYING BRAIN CELLS

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to US Provisional Application No. 63/427,789 filed on November 23, 2022, herein incorporated by reference in its entirety.

INCORPORATION OF SEQUENCE LISTING

The electronic sequence listing, submitted herewith as an xml file named “Sequence.xml” (2,262,545 bytes), created on November 17, 2023, is herein incorporated by reference in its entirety.

FIELD

Methods are provided for identifying a brain cell (or its DNA), for example by detecting genomic DNA from the brain cell, in a biological sample, based on the methylation status of multiple methylation markers in genomic DNA. Also provided are kits that can be used for such methods.

ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

This invention was made with government support under U01MH121282 and UM1MH130994 awarded by The National Institute of Mental Health. The government has certain rights in the invention.

BACKGROUND

High-throughput epigenomic profiling has been used to elucidate the gene regulatory programs underlying tremendous cellular complexity in brains (1-3). 5’ -methylcytosines (5mCs) are the most common modified bases in mammalian genomes. Most 5mCs in vertebrate genomes occur at cytosine - guanine dinucleotides (CpGs). CG differentially methylated regions (DMRs) are often considered indicative of cis-regulatory elements (CREs) (4, 5). In vertebrate neuronal systems, however, 5mCs are also abundantly detected in non-CG (or CH, H=A, C, or T) contexts (6). Both CG- and CH-methylation (mCG and mCH) are highly dynamic during brain development and show cell-type specificity (!, 4, 7). They are also essential for gene regulation and brain functions (8). In addition, gene regulation also requires proper 3D conformation of chromatin folding, which is organized into active (A) or repressive (B) compartments, topologically associating domains (TADs), and chromatin loops (9). These 3D structures facilitate the interaction between gene promoters and their regulatory elements, providing additional but yet critical layers of regulatory mechanisms. DNA methylation and chromatin conformation interplay and coordinate in regulating gene expression and these processes are highly correlated (3). Surveys on these epigenomic features of brain cells can deepen our understanding of gene regulation underlying the complexity of human brains. Here, DNA methylation and chromatin conformation was comprehensively profiled in adult human brain cells from cortical and subcortical regions using single-nucleus epigenomic sequencing technologies. SUMMARY

DNA methylation and chromatin conformation were profiled in adult human brain cells using single and multiomic single-nucleus epigenomic sequencing technologies. These epigenomic cell maps complement single ccll/nuclcus transcriptomc-bascd brain cell census approaches by providing a genomewide view of brain cell non-coding regions (45). Moreover, such epigenomic information allows annotation of cell type-specific regulatory elements and provides a comprehensive description of the unique and dynamic nature of 3D genome chromatin structures found in cell types across brain regions)!, 2). These results are also provided in Tian et al., Single Cell DNA Methylation and 3D Genome Architecture in the Human Brain, Science, vol 382, issue 6667, eadf5357(2023), DOI:10.1126/science.adf5357, herein incorporated by reference in its entirety.

Based on the discovery of particular methylation patterns for specific brain cell types and subtypes, provided herein are methods for identifying a brain cell (or brain cell DNA) in a biological sample obtained from a subject. Such methods can be less invasive than obtaining a brain sample, for example when diagnosing a brain disorder. The methods can include treating genomic DNA of the biological sample with bisulfite to convert unmethylated cytosines of CpG dinucleotides to uracil, measuring methylation status of at least 30 different methylation markers in the genomic DNA of the biological sample; and identifying a brain cell in the biological sample based on the measured methylation status of the at least 30 different methylation markers. In some examples, identifying the brain cell in the biological sample determines the type of brain cell, such as determining that the brain cell is a ASC, Amy-Exc, CAI, HIP-Misc2, CA3, CB, Chd7, DG, Foxp2, HIP-Miscl, L2/3-IT, L4-IT, L5/6-NP, L5-ET, L5-IT, L6-CT, L6-IT, L6-IT-Car3, L6b, Lamp5, Lamp5-Lhx6, MGC, MSN-D1, MSN-D2, ODC, OPC, PKJ, PN, Pvalb, Pvalb-ChC, Sncg, Sst, SubCtx-Cplx. THM-Exc, THM-Inh, THM-MB, VLMC, or Vip brain cell. In one example, the sample is a blood sample. In one example, the subject is a human. Exemplary methylation markers are provided in Table 1, Table 2 and FIGS. 25A-25B. In some examples, the methylation markers include or consist of chrl0_35445343, chrl2_l 17087703, chrl5_101709645, chrl7_39612776, chrl_30127036, chrl4_58598194, chrl_25968447, chrl8_55401769, chrl0_30583971, chrl l_41004020, chrll_61298863, chrl2_l 32525847, chrl7_75231867, chr9_l 22207624, chrl0_l 12991920, chrl0_26124733, chrl3_l 13337880, chrl3_44573331, chrl6_89747288, chrl7_49578655, chrl9_53976302, chrl0_l 12219535, chrll_99359784, chrl6_52967325, chr4_3374470, chr22_49391985, chr4_38356557, chr5_175435725, chrl_209331007, and chr2_73008588S, wherein these refer to human chromosomes. Each group in Table 1 and 2 (e.g., chrl0_35445343) is an exemplar of a group of sites with the same methylation status. Thus, one can select any one member from each of the groups provided to generate a combination as done herein.

In some examples, the method diagnoses one or more diseases in the subject, based on the brain cells identified. In some examples, the method can further include administering to the subject an effective amount of one or more therapeutic agents when a particular brain cell(s) is identified (see Table 3). Also provided are kits that can be used with the method, such as one that includes nucleic acid probes for detecting methylation markers. Such kits can include additional elements, such as bisulfite, one or more restriction endonucleases (such as one or more that specifically cleave methylated (or unmethylated) DNA (e.g., Notll, BstUI, Hpall, MspI, Smal, Dpnl, or Asci)), one or more antibodies specific for 5- methylcytidine or methyl-CpG binding domain (MBD) proteins, or combinations thereof.

The foregoing and other objects and features of the disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGs. 1A-1I. Epigenomic profiling of human brain cells with snmC-seq3 and snm3C-seq. (FIG. 1A) Human brain structures and regions covered. (FIG. IB) Schematics of profiling modalities of snmC- seq3 and snm3C-seq. (FIG. 1C) Iterative clustering and annotation of human brain nuclei. Cells from the whole mC dataset, from the inhibitory/non-telencephalic neuron cell class, and from the SubCtx-Cplx major type are visualized successively using t-distributed stochastic neighbor embedding (t-SNE), colored by the cell groups annotated in the corresponding iterations. (FIG. ID) CH-methylation of excitatory and inhibitory markers (SLC17A1 and GAD1) of the major type SubCtx-Cplx. (FIG. IE) Human brain cells are colored by the dissection regions. (FIG. 1 F) 2D visualization of brain nuclei profiled by snm3C-seq. (FIG. 1H) Variation of global CG- and CH-methylation across brain cell types. (FIG. 1G) The robust dendrogram of the major types and the meta info of subtype numbers, brain structure, and donor origins. The color palettes are shared across this study. (FIG. II) Correlations between global DNA methylation and gene expressions of MECP2 and DNMT1 across major types.

FIGs. 2A-2C. Sample information and QC metrics. (FIG. 2A) Cell number distributions of donors (top), epigenetic profiling assays (mid), and neuronal/non-neuronal cell types (bottom) from different brain regions. (FIG. 2B) QC metrics are used in filtering cells in snmC-seq and snm3C-seq. (FIG. 2C) Coverage per cell distributions of genomic features of genes and lOOkb-bins in mC and m3C datasets.

FIGs. 3A-3F. Clustering and annotation of brain cell types. (FIG. 3A) 2D t-SNE visualization of mC cells colored by 40 major types. (FIG. 3B) 2D t-SNE visualization of mC cells colored by 188 subtypes. (FIG. 3C) The robust dendrogram of the subtypes and the corresponding meta info of brain structures, donor origins, and epigenetic profiling assays. (FIG. 3D) The thalamus major type THM-Inh is hypomethylated in genes EPHB1 and EPHA1 which are specifically expressed by habenular nuclei of thalamus. (FIG. 3E) Subtypes of SubCtx-Cplx major type show highly variable DNA methylation in the genes of neurotransmitter receptors, transporters, and neuropeptides. (FIG. 3F) Regional diversity of single-cell embedding computed from chromatin conformation. The embedding is the same as in FIG. 1G, while colored by the dissection regions.

FIGs. 4A-4B. Global methylation levels across major types. (FIG. 4A) Global CG- and CH- methylation levels of major types. (FIG. 4B) Pearson correlation between global CG- and CH-methylation levels and gene expression of DNA methylation readers/modifiers across major types. FIGs. 5A-5B. Integration between modalities. (FIG. 5A) 2D t-SNE visualization of integration results between snmC, scRNA, and snATAC datasets. The integration shows cell types and regional diversity are consistent among the three modalities. (FIG. 5B) Heatmap shows the cross-tabulation between scRNA cluster labels and transferred mC annotation. The count number was normalized by rows.

FIGs. 6A-6N. Diversity of 3D genome structures across major types. (FIG. 6A) Frequency of contacts against genomic distance in each single cell, Z-score normalized within each cell (column). The cells are grouped by major type and then ordered by the median log2 short/long ratio over cells. The y-axis is binned at log2 scale. (FIG. 6B) log2 short/long ratio of major types, ordered the same as in FIG. 6A. (FIG. 6C) Imputed contact maps of four major types. (FIG. 6D) Heatmaps show the correlation matrices of distance normalized contact maps in FIG. 6C, and line plots show the first principal component of the correlation matrices. (FIG. 6E) Zoom in view of two matrices in FIG. 6D and the corresponding correlation matrices of mCG across cells. (FIGs. 6F-6G) Imputed contact matrices (heatmap), boundary probabilities (blue lines), insulation scores (orange lines), differential boundaries (red dots in line plots), and differential loops (cyan dots in heatmaps) of excitatory IT neurons at FOXP2 locus (a marker of cell type L4-IT; FIG. 6F) or CGE-derived inhibitory neurons at LAMP5 locus (a marker of Lamp5 and Lamp5-Lhx6; FIG. 6G). Grey shade represents the gene body (TSS to TES). (FIG. 6H) t-SNE plot of cells (n=5,707) using domains (top) or loops (bottom) as features, colored by major types. (FIG. 61) PCC between compartment score, boundary probability, or loop interaction strength and AT AC signals, mCG and mCH fractions of the bin(s) across all major types for all genes (left) or top DEGs only (right). Sample sizes are 1188, 2047, 173615, 1024, 1716, 148250 from left to right for each subplot. (FIG. 6J) PCC between compartment scores, boundary probabilities, or loop interaction strength and gene expression across all major types for different categories of overlap (x-axis) using all genes (left) or top DEGs (right). Sample sizes are 619, 1259, 710, 1716, 168938, 56027, 247125, 55, 343, 84, 417, 6684, 9303, 81904 from left to right. (FIGs. 6K-6L) Proportion of significantly positively or negatively correlated compartment (FIG. 6K) or domain boundary (FIG. 6L) out of all the bins located at different positions relative to a gene, average across the top neuronal DEGs. (FIG. 6M) Proportion of significantly correlated loop pixels out of all the loop pixels (left), ratio between positively and negatively correlated loop pixels (middle), or average PCC of significantly correlated loop pixels (right) located at different positions relative to a gene, average across the top neuronal DEGs. (FIG. 6N) The number of genes, out of the top neuronal DEGs, having significantly positively correlated compartments, domain boundaries overlap the gene body, or loop pixels within the gene body or with at least one anchor overlaps the TSS or TES of the gene. 35 genes were not included in any of the three circles.

FIGs. 7A-7K. Diversity of contact distances across major types. (FIG. 7A) Raw (top) and imputed (bottom) contact map of L2/3-IT (neuron, left), ODC (non-neuron, middle), and the subtraction of ODC from L2/3-IT (right) at 100 kb resolution. The color bars are shared within each row. (FIG. 7B) Frequency of contacts against genomic distance in all major types. Contacts are grouped in an arithmetic scale of distance while the x-axis shows a log scale of distance, so sample points are denser on the right than on the left. (FIG. 7C) Contact distance of mouse brain cells from Tan et al. 2021 (left) and Liu, Zhou et al. 2021 (right). Heatmap shows frequency of contacts against genomic distance in each single cell, Z-score normalized within each cell (row). The x-axis is binned at log2 scale. The bars show the major type and log2 cis/trans ratio (when the information is available) of each cell. Boxplot shows the log2 short/long ratio of major types. Color palettes are shared between the major type bars and the boxes. Centerline denotes the median; box limits denote the first and third quartiles; and whiskers denote 1.5 x the interquartile range. (FIG. 7D) Frequency of contacts in L2/3-IT (dark) or ODC (light) raw (top) or imputed (bottom) contact map against genomic distance for the top 100 DEGs with a higher expression level in L2/3-IT than ODC (Blue) or reversely (Orange). The contacts are grouped in an arithmetic scale of distance while the x-axis shows a log scale of distance, so sample points are denser on the right than on the left. (FIG. 7E) Median log2 ratio between short and long-range contact (defined in Methods) frequencies against average UMI detected per cell. The color palettes are shared across the whole manuscript. (FIGs. 7F-7G) The ratio between L2/3-IT and ODC of frequency of contacts grouped by genomic distance and the difference (left) or summation (right) of compartment scores at the two anchors of a contact (Methods), Z-score normalized within each distance (row). Raw compartment scores were used in (FIG. 7F) and imputed compartment scores in (FIG. 7G). (FIGs. 7H-7I) Saddle plots of the four cell types are shown in FIGs. 2C-2E. The axes are ranked by the compartment score of the cell types. Values are average distance-normalized raw (FIG. 7H) or imputed (FIG. 71) contacts. The number at the corner represents the ratio between BB and BA interaction strength (top left) or the ratio between AA and AB interaction strength (bottom right). (J to M) The relationship across major types between log2 short/long ratio and interaction strength between BB compartment, AA compartment, AB compartment, and compartment strength (AA+BB)/(AB+BA) (FIGs. 7J -7K), or intra-domain interaction strength, inter-domain interaction strength, and insulation score (inter/intra) (FIGs. 7L-7M) on raw (FIGs. 7J-7L) or imputed (FIGs. 7K-7M) contact maps.

FIGs. 8A-8H. Compartment, domain, and loop in brain cells. (FIG. 8A) Saddle plots of the four cell types are shown in FIGs. 2C-2E (Methods). The axes are ranked by the raw (top) or imputed (bottom) compartment score of the cell types. Values are the average correlation of mCG (left) or mCH (right) level between pairs of lOOkb bins. For mCH correlation, only neuronal types are shown. (FIG. 8B) Imputed contact map (top), the correlation between 3C and mCG across single cells (middle), and compartment score computed from raw contact matrices (bottom) at lOOkb resolution. (FIG. 8C) Correlation between 3C and mCG in the triangle region of A compartment segments (n=346,260) and B compartment segments (n=172,045). (FIGs. 8D-8E) Number of domains (top), size of domains in bp (middle), and total basepairs within domains (bottom) of major types quantified within each single cell using all the cells (FIG. 8D) or only the cells with a matched number of contacts within 10 Mb across cell types (FIG. 8E). (FIG. 8F) Relationship between average total unique molecular identifiers (UMIs, x-axis) and average domain count (top, y-axis) or average domain sizes (bottom, y-axis) over single cells across major types. (FIG. 8G) Number of loop pixels (transparent color) and loop summit (solid color) in major types. (FIG. 8H) Proportion of different categories of loops. P denotes loop anchors overlapping with promoters (TSS±2k), DMR denotes loop anchors overlapping with DMRs but not promoters, and N denotes loop anchors overlapping with neither promoters nor DMRs. For all the boxplots, the center line denotes the median; box limits denote first and third quartiles; and whiskers denote 1.5 x the interquartile range.

FIGs. 9A-9C. Specificity of compartment, domain, and loop. (FIG. 9A) Cosine distances between major types are measured by raw compartment score (left), boundary probabilities across all 25kb bins (middle), or imputed contact strengths across all loop pixels identified in at least one cell type (right). (FIG. 9B) t-SNE of human brain cells (n=5,707) using different methods (Methods). (FIG. 9C) Adjusted Rand Index (ARI) between clusters using the cell embedding generated from the different methods as features and cortical excitatory (left) or cortical inhibitory (right) major type labels. The error bars represent the standard error of the mean of K-Means clustering with ten different random seeds for initialization.

FIGs. 10A-10C. Differential loop across brain major types. (FIG. 10A) Aggregate peak analysis (APA, methods) of differential loops between neuron, glia, and non-neuronal cells (i), between excitatory, inhibitory, and MSN neurons (ii), between ASC, ODC and OPC (iii), between excitatory major types (iv), inhibitory major types (v), or MSN-D1 and MSN-D2 (vi). (FIG. 10B) ANOVA statistics of different categories of loop pixels are computed with T (left) or Q (right). (FIG. IOC) LoglO q-value (Fisher exact test, Benjamini-Hochberg procedure) of motif enrichment in differential loops and constant loops compared to their union of them.

FIGs. 11A-11D. Correlation between compartment, domain and epigenome. (FIGs. 11A-11D) Compartment score, ATAC signals, mCG and mCH level of differential compartments at 100 kb resolution between all major types (FIG. 11 A) or all neuronal major types (FIG. 1 IB). (FIGs. 11C-1 ID) Domain boundary probabilities of differential boundaries at 25 kb resolution across all major types (FIG. 11C) or all neuronal major types (FIG. 1 ID), and average ATAC signals, mCG and mCH level of the two lOkb bins on both sides of the boundaries. Values are Z-score normalized within each row. All four heatmaps in the same row share the row and column orders.

FIGs. 12A-12D. Correlation between loop and cpigcnomc. (FIGs. 12A-12C) Interaction strength of differential loops at 10 kb resolution across all major types (FIG. 12A) or neuronal major types (FIG. 12C), and average ATAC signals, mCG and mCH level of the two anchors of the differential loops. Values are Z-score normalized within each row. All four heatmaps in the same row share the row and column orders. (FIGs. 12B, 12D) PCC between interaction strength and average ATAC signal (left), mCG (middle left), or mCH (middle right) level at two anchors or the number of loop pixels (right) with different T and Q ANOVA statistics.

FIGs. 13A-13F. Correlation between compartment and transcription. (FIGs. 13A-13D) Raw compartment scores (left) of differential compartments at lOOkb resolution across all major types (FIGs. 13A, 13C) or neuronal major types (FIGs. 13B, 13D) and expression level (right) of all genes (FIGs. 13A- 13B) or DEGs (FIGs. 13C-13D) whose gene body (top) or promoter (bottom) overlap with the lOOkb bin. Values are Z-score normalized within each row. Left and right heatmaps share the row and column orders. When a bin overlaps multiple genes, the bin is repeated in the left heatmap, and vice versa for a gene overlapping multiple bins. (FIGs. 13E-13F) Average PCC between compartment score and gene expression across all major types (FIG. 13E) or neuronal major types (FIG. 13F) for the bins and genes showing different diversity between cell types. PCC was computed for each pair of lOOkb bin and gene when the bin overlapped the gene promoter (left) or gene body (right). RNA diversity was quantified by the Z-score of Kruskal statistics for expression level between cell types. Compartment diversity was quantified by the Z- score of Mahalanobis distance between cell types.

FIGs. 14A-14E. Correlation between loop and transcription. (FIGs. 14A-14B) Interaction strength (left) of differential loops across all major types (FIG. 14A) or neuronal major types (FIG. 14B) and expression level (right) of DEGs whose gene body is encompassed by the two anchors of the differential loops (top), gene body (bottom) overlap either anchor of the differential loops. Values are Z-score normalized within each row. Left and right heatmaps share the row and column orders. When a loop overlaps multiple genes, the loop is repeated in the left heatmap, and vice versa for a gene overlapping multiple loops. (FIGs. 14C-14D) Interaction strength (left) of differential loops across all major types (FIG. 14CC) or neuronal major types (FIG. 14D) and expression level (right) of DEGs whose gene body is encompassed by the two anchors of the promoter overlap either anchor of the differential loops. Values are Z-score normalized within each row. Left and right heatmaps share the row and column orders. When a loop overlaps multiple genes, the loop is repeated in the left heatmap, and vice versa for a gene overlapping multiple loops. Promoter (FIG. 14E) PCC between compartment score, boundary probability, or loop interaction strength and gene expression across all major types for different categories of overlap described above (x-axis) for all genes (left) or top DEGs only (right). Sample sizes are 711, 1386, 1090, 2331, 295078, 86626, 312990, 69, 396, 96, 460, 14306, 12718, 99281 from left to right.

FIGs. 15A-15F. Correlation between domain and transcription. (FIGs. 15A-15D) Domain boundary probability (left) of differential boundaries at 25kb resolution across all major types (FIGs. 15A, 15C) or neuronal major types (FIGs. 15B, 15D) and expression level (right) of all genes (FIGs. 15A-15B) or DEGs (FIGs. 15C-15D) whose gene body (top) or promoter (bottom) overlap with the 20kb flanking region of the differential boundaries (left end of the 25kb bin). Values are Z-score normalized within each row. Left and right heatmaps share the row and column orders. When a bin overlaps multiple genes, the bin is repeated in the left heatmap, and vice versa for a gene overlapping multiple bins. (FIGs. 15E-15F) Average PCC between boundary probability and gene expression across all major types (FIG. 15E) or neuronal major types (FIG. 15F) for the boundaries and genes showing different diversity between cell types. PCC was computed for each pair of boundary and gene when the flanking 20kb region of boundary overlapped the gene promoter (left) or gene body (right). RNA diversity was quantified by the Z-score of Kruskal statistics for expression level between major types. Boundary diversity was quantified by the Z-score of Chi-Square statistics between major types.

FIGs. 16A-16E. Gene regulation in brain cells. (FIG. 16A) Different major types have specific marker genes in both CG- and CH-methylation. All marker genes shown in the heatmaps are TFs, neurotransmitter receptors, transporters or neuropeptides. (FIG. 16B) The scatter plot of CH-methylation and enrichment of TFs that were assigned to the major types. (FIG. 16C) Heatmap shows average CH- methylation levels of striosome markers among MSN-D1 subtypes. The subtypes MSN-D1 1-5 are hypomethylated in these genes, indicating they are likely from the striosome compartment of striatum. (FIG. 16D) Distribution of Pearson correlations between CG-methylation levels of DMRs and CH-methylation levels of genes. Consideration of differentiation of gene body methylation and DNA loops greatly improves the association between DMRs and genes. (FIG. 16E) Distribution of SYT1 expressions in MSN-D1 and L2/3-IT. L2/3-IT cells have high expression levels.

FIGs. 17A-17H. Gene regulation in brain cells. (FIG. 17A) mCG of cell type-specific DMRs across 188 cell subtypes. (FIG. 17B) CH-hypomethylated transcription factors and the enrichment of their motifs in CG hypo-DMRs. The lower panel showed average methylation fractions of transcription factor PBX3 in its potential binding sites across the whole genome. (FIG. 17C) Workflow of determining putative CREs. (FIG. 17D) Distribution of correlation between methylation of putative CREs and the corresponding genes from different filtering. (FIG. 17E) Numbers of putative CREs and overlapping proportions with open chromatin regions for different filtering. (FIG. 17F) Heatmaps showing mCG of putative CREs, mCH and expression of the target genes, and contact strength of the corresponding loops. (FIG. 17G) The gene body mCH, DMR mCG, and 3D chromatin organization around the gene SYT1 in the major types L2/3-IT and MSN-D1 . (FIG. 17H) Heatmap showing the results of LDSC analysis of the variants associated with the indicated traits or diseases in DMRs identified from major human cell types. The asterisks indicate the magnitude of p-values (*=-l, **=-2, ***=-3, and ****=-4).

FIGs. 18A-18B. Gene regulation in brain cells. (FIG. 18 A) Heatmap showing the results of linkage disequilibrium score regression analysis of the variants associated with the indicated traits or diseases in loop-overlapped DMRs identified from human major cell types. (FIG. 18B) Examples of complexity and heterogeneity of risk variants overlapping DMRs and corresponding chromatin conformation, DNA methylation, chromatin accessibility, and gene expression levels. Upper panel, risk variant rs2789588 and gene KCNQ5. Lower panel, risk variant rsl7194490 and gene CNTN4. In each subfigure, the circle(s) in the left panel denotes the implicated loops, the lower right panel shows the zoom- in view of the blue boxed regions, and the upper right panel shows the expression distribution of the corresponding genes.

FIGs. 19A-19K. Regional axes of cortical and subcortical cells. (FIG. 19A) Workflow of determining regional axis from single-nucleus DNAm. (FIG. 19B) 2D visualization of cortical neurons in regional spaces, colored by dissection locations. (FIG. 19C) The common regional axis among cortical neurons. The scatter plot showed how regional indices vary in each cortical region. (FIG. 19D) Schematic of example cortical dissection locations. (FIG. 19E) Regional gradients in mCG of rDMRs, and mCH and expression of rDMGs in L2/3-IT cells. (FIG. 19F) Regional difference in chromatin conformation around NR2F1. The blue and purple numbers showed respectively the relative domain strength and promoter strength of each domain. The relative domain strengths (blue numbers) are ratios between the summations of all bins within each domain; the relative promoter strengths (purple numbers) are ratios between the summations of all bins related to the bin of NR2F1 promoter within each domain. (FIG. 19G) Zoom-in view of example differential-loop-overlapping rDMRs marked in FIG. 19F. In the decreasing domain (left), the methylation fractions increase from VIC to A46 to LEC, while the methylation fractions decrease in the increasing domain (right). (FIG. 19H) Inhibitory neurons in basal ganglia showed an L-D-V axis in DNA methylation (FIG. 191) 2D t-SNE visualization of MSN-D1. Cells from NAC, CaB and Pu were highlighted. (FIG. 19J) Regional differences of gene body mCH-methylation and expression of LSAMP in MSN-D1. (FIG. 19K) Regional difference in chromatin conformation around LSAMP in MSN-D1.

FIGs. 20A-20I. Regional axes of cortical and subcortical cells. (FIG. 20A) The gene NR2F1 has higher expression levels in L2/3-IT cells from VIC and LEC than A46. (FIG. 20B) It also has concordant lower CH-methylation levels in L2/3-IT cells from V 1C and LEC than A46. (FIG. 20C) Chromatin conformation around the gene NR2F1 shows gradient changes in domain and loop strength. The two associated chromatin domains change in opposite directions. (FIG. 20D) Zoom-in view of example differential-loop-overlapping rDMRs from the “increasing” domain. The methylation levels decrease from VIC to A46 to LEC. (FIG. 20E) The number of regionally differential features is shown in bar plots. (FIGs. 20F-20G) Distributions of Pearson correlations between methylation levels of rDMG (CH, left) or rDMR(CG, right) and regional axes determined in cortical regions (left) and basal ganglia (right), respectively. Considerable features show methylation gradients along the axes, manifested by Pearson correlations close to -1 or 1. (FIG. 20H) The embedding of major types MSN-D2, Foxp2, and Chd7 in regional spaces colored by dissection regions show that they share similar regional axes. (FIG. 201) The consensus regional axis of basal ganglia was constructed in the same way as in FIG. 4C.

FIGs. 21A-21J. Cross-species comparison between human and mouse brain cell methylomes. (FIG. 21 A) Integration of single-cell methylomes between human and mouse brains, visualized using 2D t- SNE. (FIG. 21B) Discrepancy between cell types of human and mouse brains in cell types L4-IT, HIP- Miscl, and HIP-Misc2. (FIG. 21C) CH-hypomethylation and gene expression of TF TSHZ2 in the cell types HIP-Miscl and HIP-Misc2. (FIG. 2 ID) Correlated global mCH and mCG of conserved cell types between human and mouse. (FIG. 21E) Schematic of cross-species matching of cell type DMRs. (FIG. 21F) Overall, -50% of DMRs have orthologous sequences in the other species, among which -25% are reciprocal DMRs. (FIG. 21G) Distribution of cross-species correlation of DMR methylations (red) and the randomly shuffled background (black). (FIG. 21H) Examples of methylation fractions of hcCnsvDMRs. (FIG. 211) The enrichment of the hcCnsvDMRs in the histone modification marks. (FIG. 21 J) Browser view of hcCnsvDMRs around gene INPP5J in major type Pvalb. The regions colored by red are the cell type-specific distal enhancers validated in Ref (54).

FIGs. 22A-22G. Cross-species comparison between human and mouse brain cell methylomes. (FIG. 22A) Integration of single-cell methylomes between human and mouse brains shows cell type conservation across species in non-neurons. (FIG. 22B) The cell types of HIP-Miscl and HIP-Misc2 both feature CH-hypomethylation and gene expression of IncRNA AL109930.1. (FIG. 22C) Boxplots show a detailed comparison of global CG- and CH-methylation levels of conserved cell types between the human and mouse. (FIG. 22D) Cell type-specific numbers of DMRs in different cross-species matching categories. (FIG. 22E) Comparison to histone modification marks in mouse forebrains shows that the hcCnsvDMRs are depleted from heterochromatic regions (H3K9me3) as well as enriched in regions of enhancers (H3K27ac & H3K4mel), promoters (H3K4me3), and poised enhancers (H3K27m3) (FIGs. 22F-22G) GO term enrichment analysis show that hcCnsvDMRs are highly enriched in biological processes related to forebrain development (FIG. 22F) and in cellular components related to dendrites and synapses (FIG. 22G).

FIGs. 23A-23C. snMCodes for brain cell types. (FIG. 23A) Detailed workflow of the derivation of snMCodes (Methods). (FIG. 23B) Example of highly cell-type-specific differentially methylated CpG sites. (FIG. 23C) Prediction accuracy of snMCodes increases with the number of features used, which show saturation around 800-900.

FIGs. 24A-24F. snMCodes for brain cell types. (FIG. 24 A) Workflow of deriving snMCodes. (FIG. 24B) snMCodes derived from all three donors. (FIG. 24C) Examples of cell-type specificity of snMCode features. (FIG. 24D) Heatmap showing confusion matrix of snMCodes in predicting cell types. (FIG. 24E) Cell-type-prediction accuracy in cross-donor test. (FIG. 24F) snMCodes predict human cell types with a limited number of CpG sites at single -cell resolution.

FIGs. 25A-25B. Table showing correlation of methylation status of markers for numerous cell types. The chromosome position is the start site (see Table 2). H indicates that the group is highly methylated at that position for that cell type, L indicates that the group is not methylated at that position for that cell type, and N indicates that the group may be methylated or not methylated at that position for that cell type (e.g., methylation status not relevant for determining the identity of that cell type). Methylation fractions with <=20% were designated as low and >=80% were designated as high. Thus, one can determine the methylation status for at least 30 of the 200 markers listed, and based on the status (methylated or not) for each marker, determine the type of brain cell present (e.g., ASC cell, CAI cell, etc.).

SEQUENCE LISTING

The nucleic acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, as defined in 37 C.F.R. 1.822. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand. In the accompanying sequence listing:

SEQ ID NOS: 1 - 2415 are exemplary probe sequences that can be used to determine whether the CpG markers provided herein are methylated or not.

DETAILED DESCRIPTION

A profound understanding of cellular diversity and distinctive gene regulatory mechanisms in the human brain is pivotal for elucidating brain functions and formulating therapeutics for brain disorders. Provided herein is a comprehensive single-cell DNA methylation and 3D genome structure atlas of human brains with 524,010 deeply sequenced nuclei from 46 distinct brain regions, permitting us to identify 188 epigenetically distinct cell types. The extensive profiling of brain regions allows for the identification of cell types specific to subcortical regions and compare epigenetic diversity within the same cell type across different brain regions. Additionally, the 3D genome diversity across brain cell types and regions was facilitated by a 30-fold increase in cell profiling via snm3C-seq. Moreover, the specificity of domains and loops across 29 cell types was determined, pushing the cell type resolution extensively beyond previous studies (28, 57-59).

Single-nucleotide resolution DNAm has proven valuable in predicting epigenetic age (60), tracing cell lineage (61, 62), and diagnosing life-threatening diseases (63, 64). The intricate regulatory information encoded in DNAm has enabled us to distill a set of single-cell methylation barcodes (scMCodes) for reliable cell-type identification. Given that circulating-free DNA (cfDNA) methylation is a robust tool for cancer diagnosis (58) and provided biomarkers for brain disorders (59), the disclosed scMCode method is a transformative tool for the non-invasive diagnosis of brain disorders. It can be used to identify pathological brain cell types and inform treatment selection.

Overall, this multimodal human brain cell atlas enriches our understanding of brain cells with a foundational epigenomic perspective. It offers not only an invaluable resource for exploring cell type diversity, gene regulation complexity, regional variation, and evolutionary conservation within brain cells but also provides the essential elements, such as putative regulatory elements, for the development of innovative genetic tools for cell type-specific targeting.

1. Terms

Unless otherwise noted, technical terms are used according to conventional usage. Definitions of many common terms in molecular biology may be found in Krebs et al. (eds.), Lewin’s genes XII, published by Jones & Bartlett Learning, 2017. As used herein, the singular forms “a,” “an,” and “the,” refer to both the singular as well as plural, unless the context indicates otherwise. For example, the term “a cell” includes single or plural cells and can be considered equivalent to the phrase “at least one cell.” As used herein, the term “comprises” means “includes.” Unless otherwise indicated “about” indicates within five percent. It is further to be understood that any and all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for descriptive purposes, unless otherwise indicated. Although many methods and materials similar or equivalent to those described herein can be used, particular suitable methods and materials are described below. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. To facilitate review of the various embodiments, the following explanations of terms are provided:

Administration: The introduction of a composition (such as one containing an agent that prevents or treats a brain disorder) into a subject by a chosen route. Administration can be local or systemic. For example, if the route is intravenous, the composition is administered by introducing the composition into a vein of the subject. Similarly, if the route is intramuscular, the composition is administered by introducing the composition into a muscle of the subject. If the chosen route is oral, the composition is administered by ingesting the composition. Exemplary routes of administration of use in the methods disclosed herein include, but are not limited to, oral, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, intraosseous, intracerebroventricular, and intravenous), sublingual, rectal, transdermal (for example, topical), intranasal, vaginal, and inhalation routes. Administration can also be local, such as to the brain of a subject.

As used herein, the term "co-administer" (or "co-administration") refers to administration of two or more agents within about 2 hours of each other, for example, as part of a clinical treatment regimen. In other embodiments, "co-administer" refers to administration of two or more agents within 1 hour of each other. In other embodiments, "co-administer" refers to administration of two or more agents within 30 minutes of each other. In other embodiments, "co-administer" refers to administration of two or more agents within 15 minutes of each other. In other embodiments, "co-administer" refers to administration of two or more agents at the same time, either as part of a single formulation or as multiple formulations that are administered by the same or different routes. A single “dose” refers to co-administration of agents at the same time.

Array/microarray: An intentionally created collection of molecules (such as peptides or nucleic acid molecules) in addressable locations on or in a substrate (such as plastic or glass). The molecules in the array can be identical or different from each other. A “microarray” is an array that is miniaturized so as to require or be aided by microscopic examination for evaluation or analysis.

The array of molecules (“features”) makes it possible to carry out a very large number of analyses on a sample at one time. In certain example arrays, one or more molecules (such as nucleic acid molecules) will occur on the array a plurality of times (such as twice), for instance to provide internal controls. The number of addressable locations on the array can vary, for example from at least one, to at least 2, to at least 3, at least 4, at least 5, at least 6, at least 10, at least 20, at least 30, at least 50, at least 75, at least 100, at least 150, at least 200, at least 300, at least 500, least 550, at least 600, at least 800, at least 1000, at least 10,000, or more. In some examples, arrays include positive and/or negative controls. In particular examples, an array includes nucleic acid molecules, such as oligonucleotide sequences that are at least 15 nucleotides (nt) in length, at least 20 nt, at least 30 nt, or at least 40 nt, at least 50 nt, such as about 50 nucleotides in length. In particular examples, an array includes probes or primers to detect methylation of genomic DNA at particular locations in the genome, such as at least 30 of the locations listed in Table 1 or 2 or FIGS. 25A-25B.

Brain disorder: A disease of any part of the brain, which may disrupt the normal functioning of the brain, such as cognition, motor skills, and mood. Includes diseases such as Parkinson disease, dementia (such as with Lewy bodies), Alzheimer's, multiple sclerosis, epilepsy and other seizure disorders, stroke, transient ischemic attack (TIA), Huntington’s disease, bipolar disorder, neuroticism, and amyotrophic lateral sclerosis (ALS). Complementarity: The ability of a nucleic acid to form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick base pairing or other non-traditional types. Complementary nucleotides are, generally, A and T (or A and U), or C and G. A percent complementarity indicates the percentage of residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary). "Perfectly complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence. "Substantially complementary" as used herein refers to a degree of complementarity that is at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100% over a region of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, or more nucleotides, or refers to two nucleic acids that hybridize under stringent conditions.

Epigenetic: Relating to, being, or involving a modification in gene expression that is independent of DNA sequence. Epigenetic factors include modifications in gene expression that are controlled by changes in DNA methylation and chromatin structure. For example, methylation patterns may correlate with gene expression.

Gene: The basic physical and functional unit of heredity, which is part of the genomic DNA. Includes particular gene sequences (such as protein coding sequence exons, intervening introns and associated expression control sequences) and its flanking sequence. Methylation in a particular region is generally indicative of the methylation status at proximal genomic sites. Accordingly, determining a methylation status of a gene region (such as those provided in Table 1, Table 2 and FIGS. 25A-25B) can include determining a methylation status of a methylation marker within or flanking about 10 bp to 50 bp, about 50 to 100 bp, about 100 bp to 200 bp, about 200 bp to 300 bp, about 300 to 400 bp, about 400 bp to 500 bp, about 500 bp to 600 bp, about 600 to 700 bp, about 700 bp to 800 bp, about 800 to 900 bp, 900 bp to 1 kb, about 1 kb to 2 kb, about 2 kb to 5 kb, or more of a named gene, or CpG position.

Genomc/gcnomic: All of the genetic material in the chromosomes of an organism. DNA derived from the genetic material in the chromosomes of a particular organism is genomic DNA.

Hybridization: To form non-covalent base pairs between complementary regions of two strands of DNA, RNA, or between DNA and RNA, thereby forming a duplex molecule. Triple-stranded hybridization is also possible. Hybridization conditions resulting in particular degrees of stringency will vary depending upon the nature of the hybridization method and the composition and length of the hybridizing nucleic acid molecules. Generally, the temperature of hybridization and the ionic strength (such as the Na⁺ concentration) of the hybridization buffer determine the stringency of hybridization. Calculations regarding hybridization conditions for attaining particular degrees of stringency are discussed in Sambrook et al., (1989) Molecular Cloning, second edition, Cold Spring Harbor Laboratory, Plainview, NY (chapters 9 and 11). The following is an exemplary set of hybridization conditions and is not limiting:

Very High Stringency (allows hybridization between sequences that share at least 90% identity) Hybridization: 5x SSC at 65°C for 16 hours Wash twice: 2x SSC at room temperature (RT) for 15 minutes each

Wash twice: 0.5x SSC at 65°C for 20 minutes each

High Stringency (allows hybridization between sequences that share at least 80% identity )

Hybridization: 5x-6x SSC at 65°C-70°C for 16-20 hours

Wash twice: 2x SSC at RT for 5-20 minutes each

Wash twice: l SSC at 55°C-70°C for 30 minutes each

Low Stringency (allows hybridization between sequences that share at least 50% identity) Hybridization: 6x SSC at RT to 55°C for 16-20 hours

Wash at least twice: 2x-3x SSC at RT to 55°C for 20-30 minutes each.

Inhibiting or treating a disease: Inhibiting a disease, such as, but not limited to, a brain disease, refers to inhibiting the full development of a disease. In several examples, inhibiting a disease refers to lessening symptoms of the particular disease. “Treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition related to the disease. Treatment can be measured using success or indicia of success in the attenuation or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement, remission, diminishing of symptoms or making the condition more tolerable to the patient, slowing in the rate of degeneration or decline, making the final point of degeneration less debilitating, improving a subject’s physical state. The treatment may be assessed by objective or subjective parameters; including the results of a physical examination or tests.

Isolated: An “isolated” biological component (such as a nucleic acid molecule or protein or organelle) has been substantially separated or purified away from other biological components in the cell of the organism in which the component naturally occurs, i.e., other chromosomal and extra-chromosomal DNA and RNA, proteins and organelles. Nucleic acids and proteins that have been “isolated” include nucleic acids and proteins purified by standard purification methods. The term also embraces nucleic acids and proteins prepared by recombinant expression in a host cell as well as chemically synthesized nucleic acids and proteins.

Label: A detectable compound or composition that is conjugated directly or indirectly to another molecule, such as a nucleic acid molecule, to facilitate detection of that molecule. Specific, non-limiting examples of labels include fluorophores, luminescent molecules, enzymatic linkages, and radioactive isotopes. In one example, a “labeled antibody” refers to incorporation of another molecule in the antibody. Various methods of labeling nucleic acid molecules are known and may be used. Exemplary labels that can be used, include, but arc not limited to, the following: radioisotopes or radionuclcotidcs (such as ^3:>S, ⁿC, ¹³N, ¹⁵O, ¹⁸F, ¹⁹F, ^99mTc, ¹³¹1, ³H, ¹⁴C, ¹⁵N, ⁹⁰Y, "Tc, ^{l n}In and ¹²⁵I), fluorescent labels (such as fluorescein isothiocyanate (FITC), rhodamine, lanthanide phosphors), enzymatic labels (such as horseradish peroxidase, beta-galactosidase, luciferase, alkaline phosphatase), chemiluminescent markers, biotinyl groups, or magnetic agents, such as gadolinium chelates.

Mammal: This term includes both human and non-human mammals. Similarly, the term “subject” includes both human and veterinary subjects, such as non-human primates, rats, mice, dogs, cats, horses, cows and pigs. In some examples, a subject is selected that has or is suspected of having a brain disorder. In an example, a subject is a human, such as a human having or suspected of having a brain disorder.

Nucleic acid molecule: Any polymer or oligomer composed of nucleotide units (ribonucleotides, deoxyribonucleotides, peptide nucleic acids, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof) linked via phosphodiester bonds, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof. Includes chemical variants thereof, such as methylated, hydroxymethylated or glucosylated forms of these bases, and the like. The polymers or oligomers may be heterogeneous or homogeneous in composition. Exemplary nucleic acids include DNA and RNA, and mixtures thereof, and may exist permanently or transitionally in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states.

Includes nucleotide polymers in which the nucleotides and the linkages between them include non- naturally occurring synthetic analogs, such as, for example and without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptidenucleic acids (PNAs), and the like. It will be understood that when a nucleotide sequence is represented by a DNA sequence (z.e., A, T, G, C), this also includes an RNA sequence (i.e., A, U, G, C) in which “U” replaces “T.”

Conventional notation is used herein to describe nucleotide sequences: the left-hand end of a singlestranded nucleotide sequence is the 5'-end; the left-hand direction of a double-stranded nucleotide sequence is referred to as the 5'-direction. The direction of 5' to 3' addition of nucleotides to nascent RNA transcripts is referred to as the transcription direction. The DNA strand having the same sequence as an mRNA is referred to as the “coding strand;” sequences on the DNA strand having the same sequence as an mRNA transcribed from that DNA and which are located 5' to the 5'-end of the RNA transcript are referred to as “upstream sequences;” sequences on the DNA strand having the same sequence as the RNA and which are 3' to the 3' end of the coding RNA transcript are referred to as “downstream sequences.”

Methylation marker: A CpG position, for example in a genome, that is potentially methylated. Methylation typically occurs in a CpG containing nucleic acid. The CpG containing nucleic acid may be present in, e.g., in a CpG island, a CpG doublet, a promoter, an intron, or an exon of gene. In one example, in the genetic regions provided herein the potential methylation sites encompass the promoter/enhancer regions of the indicated genes. Thus, the regions can begin upstream of a gene promoter and extend downstream into the transcribed region.

Oligonucleotide/polynucleotide: A plurality of joined nucleotides joined by native phosphodiester bonds, at least 6 nucleotides in length, such as at least 8, or at least 20 nucleotides in length. Include sequences of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) which may be isolated from natural sources, recombinantly produced or artificially synthesized and mimetics thereof. An oligonucleotide analog refers to moieties that function similarly to oligonucleotides but have non-naturally occurring portions. For example, oligonucleotide analogs can contain non-naturally occurring portions, such as altered sugar moieties or inter-sugar linkages, such as a phosphorothioate oligodeoxynucleotide.

Particular oligonucleotides and oligonucleotide analogs can include linear sequences up to about 200 nucleotides in length, for example a sequence (such as DNA or RNA) that is at least 6 nucleotides, for example at least 8, at least 10, at least 15, at least 20, at least 21, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 100 or even at least 200 nucleotides long, or from about 6 to about 50 nucleotides, for example about 10-25 or 40-60 nucleotides, such as 12, 15, 20, or 50 nucleotides.

Primer: A single-stranded oligonucleotide capable of acting as a point of initiation for template- directed DNA synthesis under suitable conditions for example, buffer and temperature, in the presence of four different nucleoside triphosphates and an agent for polymerization, such as, for example, DNA or RNA polymerase or reverse transcriptase. The length of the primer can depend on, for example, the intended use of the primer, and generally ranges from 15 to 30 nucleotides. A primer need not reflect the exact sequence of the template but must be sufficiently complementary to hybridize with such template. The primer site is the area of the template to which a primer hybridizes. The primer pair is a set of primers including a 5' upstream primer that hybridizes with the 5' end of the sequence to be amplified and a 3' downstream primer that hybridizes with the complement of the 3' end of the sequence to be amplified.

Methods for preparing and using nucleic acid primers are described, for example, in Sambrook et al. (In Molecular Cloning: A Laboratory Manual, CSHL, New York, 1989), Ausubel et al. (ed.) (In Current Protocols in Molecular Biology, John Wiley & Sons, New York, 1998), and Innis et al. (PCR Protocols, A Guide to Methods and Applications, Academic Press, Inc., San Diego, CA, 1990). PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose.

Probe: Oligonucleotide capable of binding in a base-specific manner to a complementary strand of nucleic acid, and can include a detectable label. In some examples, a probe is a surface-immobilized molecule that can be recognized by a particular target, such as a CpG position.

Sample (or biological sample): A biological specimen containing genomic DNA, RNA (including mRNA), protein, or combinations thereof, which can be obtained from a subject, such as a human.

Examples include, but are not limited to, sputum, saliva, mucus, nasal wash, peripheral blood, tissue (such as brain tissue), cells, urine, tissue biopsy, fine needle aspirate, surgical specimen, feces, cerebral spinal fluid (CSF), bronchoalveolar lavage (BAL) fluid, asopharyngeal samples, oropharyngeal samples, and autopsy material. In one example the sample is a peripheral blood sample.

Selectively measuring: Methods wherein only a finite number of methylation markers or genes (comprising methylation markers) are measured rather than assaying essentially all potential methylation marker (or genes) in a genome. In some examples, “selectively measuring” methylation markers or genes comprising such markers can refer to measuring no more than 1600, 1585, 800, 785, 700, 600, 500, 400, 389, 300, 200, 100, 50, 40, 30, 20, or 10 different methylation markers or genes comprising methylation markers (such as those listed in Table 1, Table 2 and FIGS. 25A-25B).

Solid support/support/substrate: A material or group of materials having a rigid or semi-rigid surface or surfaces. In one example, at least one surface of the solid support is substantially flat, although in some embodiments it may include physically separate synthesis regions for different compounds with, for example, wells, raised regions, pins, etched trenches, or the like. In some examples, the solid support is a bead, resin, gel, microsphere, plate or other geometric configurations. In some examples a solid support is composed of glass or plastic.

Therapeutically effective amount: A quantity of a composition or a cell to achieve a desired effect in a subject being treated. For instance, this can be the amount necessary to treat or prevent a brain disease or disorder. When administered to a subject, a dosage will generally be used that will achieve target tissue concentrations that has been shown to achieve an in vitro effect.

A therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the brain disease/disorder, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The beneficial therapeutic effect can include enablement of diagnostic determinations; amelioration of the brain disease symptoms, improvement of brain function, reducing or preventing the onset of brain disease symptoms. In one embodiment, an “effective amount” is an amount sufficient to reduce symptoms of a brain disease, for example by at least 10%, at least 20%, at least 50%, at least 70%, at least 90%, at least 95%, or even 100% (as compared to no administration of the therapeutic agent), or that delays onset or progression.

II. Overview

The present disclosure provides methods for identifying a brain cell in a biological sample obtained from a subject (such as a mammal, such as a human), based on measuring DNA Cytosine-phosphate- Guanine (CpG) methylation markers that are attached to genomic DNA. The method can include treating genomic DNA of the biological sample to measure or determine whether at least 10 different CpG methylation markers (such as at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 different CpG methylation markers, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, 3000, 4000, 5000 or more different CpG methylation markers) are present or absent, for example by treating genomic DNA with bisulfite (such as sodium bisulfite) to convert unmethylated cytosines of CpG dinucleotides to uracil, by treating genomic DNA with one or more restriction enzymes that specifically cleave methylated (or unmethylated) DNA (e.g., Notll, BstUI, Hpall, MspI, Smal, or Asci), or by treating genomic DNA with one or more antibodies specific for 5-methylcytidine or methyl-CpG binding domain (MBD) proteins (which can be used to isolate methylated DNA from non-methylated DNA, and thus in some examples separating methylated DNA from non-methylated DNA, or enriching for methylated DNA). Such methods can further include sequencing, such as next generation sequencing, for example sequencing of methylated DNA. In some examples, the methods use methylation microarrays, for example arrays that use primers specific for at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 different CpG methylation markers provided herein, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, 3000, 4000, 5000 or more different CpG methylation markers. Exemplary probes that can be used are provided herein, though one skilled in the art will recognize that other probe sequences can be generated that are specific for the CpG methylation markers provided herein.

After measuring or determining the methylation status of at least 30 different methylation markers in the genomic DNA of the biological sample, the method can include identifying a brain cell in the biological sample based on the measured methylation status of the at least 10 different methylation markers (such as at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 different CpG methylation markers, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, 3000, 4000, 5000 or more different CpG methylation markers). For example, a statistical prediction algorithm can be applied to the determined methylation status to identifying the brain cell(s) in the sample. One exemplary approach is to (a) obtaining a linear combination of the methylation marker status of the at least 30 different methylation markers, and (b) applying a transformation to the linear combination to identify the brain cell in the biological sample. In one example, identifying the brain cell(s) in the biological sample includes determining the type of brain cell(s) present, such as determining that the brain cell is a type or subtype listed in Table 3, such as a ASC, Amy-Exc, CAI, HIP- Misc2, CA3, CB, Chd7, DG, Foxp2, HIP-Miscl, L2/3-IT, L4-IT, L5/6-NP, L5-ET, L5-IT, L6-CT, L6-IT, L6-IT-Car3, L6b, Lamp5, Lamp5-Lhx6, MGC, MSN-D1, MSN-D2, ODC, OPC, PKJ, PN, Pvalb, Pvalb- ChC, Sncg, Sst, SubCtx-Cplx. THM-Exc, THM-Inh, THM-MB, VLMC, or Vip brain cell.

The method can further include obtaining a biological cell or tissue sample (e.g., whole blood or a fraction thereof, individual blood cells, saliva, brain tissue). In some examples, the subject is selected as one having or suspected of having a brain disease/disorder. The method can also include extracting genomic DNA from the biological sample. Exemplary samples include blood, urine, feces, saliva, or a brain tissue sample. In a specific example, the sample is a blood sample.

In some examples, the at least 10 different methylation markers (such as at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 different CpG methylation markers, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, 3000, 4000, 5000 or more different CpG methylation markers) include at least 10 different methylation markers (such as at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 different CpG methylation markers, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, 3000, 4000, 5000 or more different CpG methylation markers) of the markers in Table 1 or 2, such as all 1585 markers in Table 1 or all 200 markers in FIGS. 25A-25B. In some examples, the method determines the methylation status of at least 30 different methylation markers that include or consist of chrl0_35445343, chrl2_l 17087703, chrl5_101709645, chrl7_39612776, chrl_30127036, chrl4_58598194, chrl_25968447, chrl8_55401769, chrlO.30583971, chrl l_41004020, chrll_61298863, chrl2_l 32525847, chrl7_75231867, chr9_122207624, chrl0_l 12991920, chrl0_26124733, chrl3_l 13337880, chrl3_44573331, chrl6_89747288, chrl7_49578655, chrl9_53976302, chrl0_l 12219535, chrl 1_99359784, chrl6_52967325, chr4_3374470, chr22_49391985, chr4_38356557, chr5_175435725, chrl_209331007, and chr2_73008588, wherein these refer to human chromosomes.

With regards to the identifiers used for each methylation marker shown in Table 1 and Table 2 each marker is denoted by the human chromosome (e.g., chrlO) and a start nucleotide (e.g., 120517367) and end nucleotide (e.g., 120517369). The methylation marker is the nucleotide between the start and end position, e.g., 120517368 for start 120517367 and end 120517369. FIGS. 25A-25B show the methylation marker positions provided in Table 2. These notations follow the BED (Browser Extensible Data) format to indicate the genome coordinates of the CpG sites in human genome assembly GRCh38 (also known as hg38) generated on December 17, 2013 (see for example NCBI RefSeq assembly GCF.000001405.26 and Submitted GenBank assembly GCA.000001405.15, both herein incorporated by reference in their entireties).

Table 1 provides a list of 1585 different methylation markers, the status of which can be analyzed using the disclosed methods. In addition, specific nucleic acid probe sequences are provided that can be used in methods that determine the methylation status for each marker. However, one skilled in the art will appreciate that not all 1585 markers need to be analyzed to identify a particular brain cell type. In some examples, a subset of the markers in Table 1 are analyzed, for example alone or in combination with other methylation markers. In some examples, at least 10 different methylation markers listed in Table 1 (such as at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, or at least 1500 different CpG methylation markers listed in Table 1 are analyzed, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, or 1500 different CpG methylation markers listed in Table 1 are analyzed). In some examples, at least 200 different CpG methylation markers listed in Table 1 are analyzed (such as those in Table 2 or FIGS. 25A-25 B, namely chrl_6954346, chrl_15765576, chrl_16921554, chrl.17535924, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_47930687, chrl_55154499, chrl_82344735, chrl_84779343, chrl_88186554, chrl_89387906, chrl_l 14587732, chrl.213899571, chrl_223535050, chrl0_12981474, chrl0_85659210, chr 10.120517367, chrlO.129558734, chrl 1.6333181, chrl 1.15508856, chrl 1.61601245, chrl 1.64638208, chrl 1.64638406, chrl 1.64638423, chrl 1.64638446, chrl 1.64638487, chrl 1.70828694, chrl 1.70828959, chrl 1_113951238, chrl 1_114069492, chrl2_104666538, chrl2_l 11199420, chrl2_111363167, chrl3_44573330, chrl3_78061219, chrl4_91028417, chrl4_99239938, chrl4_99240729, chrl4_99254307, chrl4_99258195, chrl4_99265134, chrl5_40579060, chrl5_60850769, chrl5_73787074, chrl5_75706213, chrl6_29674272, chrl6_71746304, chrl7_2019280, chrl7_17603475, chrl7_49578654, chrl7_78458835, chrl7_81839462, chrl8_42840569, chrl8_55863146, chrl8_55863406, chrl9_8180812, chrl9_13002909, chrl9_31596154, chrl9_33408728, chr2_520529, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_88493781, chr2_ 106974041, chr2_l 44508216, chr2_ 144509942, chr2_l 59230649, chr2_192676064, chr2_199449983, chr2_214915957, chr2_224976082, chr2_227315087, chr2_234438297, chr20_23049529, chr20_40692864, chr20_52979500, chr20_55284577, chr20_57730506, chr21_21578917, chr21_26832851, chr21_29221598, chr21_29917226, chr21_43913788, chr21_44074575, chr21_45115350, chr22_24425165, chr22_24425431, chr22_24425509, chr22_24426997, chr22_24427299, chr22_24428719, chr22_24434476, chr22_24435262, chr22_24436142, chr22_24438986, chr22_24439355, chr22_24440428, chr22_24441113, chr22_29184668, chr22_36763396, chr22_36763700, chr22_49391984, chr3_l 0546931, chr3_23272516, chr3_41117522, chr3_53425664, chr3_81591988, chr3_l 13902470, chr3_ 142925609, chr3_143082577, chr3_181704950, chr3_181715790, chr3_181724236, chr3_181724559, chr4_3374241, chr4_3374306, chr4_3374416, chr4_3377079, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385479, chr4_3385492, chr4_3385938, chr4_3389755, chr4_3389767, chr4_3393330, chr4_3393693, chr4_3410433, chr4_3411467, chr4_7766077, chr4_54226502, chr4_54226613, chr4_54236780, chr5_6810073, chr5_l 0524872, chr5_43282460, chr5_60340044, chr5_65126330, chr5_l 13040537, chr5_l 15106946, chr5_l 27066418, chr5_150680117, chr5_167983052, chr5_l 72860953, chr5_175441994, chr5_175442086, chr5_175442710, chr5_178604407, chr5_180155581, chr6_36775571, chr6_60830914, chr6_87948947, chr6_96873290, chr6_l 05628390, chr6_l 50204270, chr6_150893713, chr6_158528243, chr6_169961951, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1674842, chr7_1675096, chr7_1677614, chr7_1680106, chr7_2108124, chr7_17586547, chr7_45198338, chr7_94840949, chr7_101915316, chr7_l 57585009, chr7_157897945, chr7_l 57897966, chr7_157897972, chr7_ 159142397, chr7_159231136, chr8_52246671, chr8_57356053, chr8_63031540, chr8_80345362, chr8_84031486, chr8_87977499, chr8_l 18694978, chr8_141800688, chr9_35350760, chr9_73879045, chr9_79193716, chr9_93156181, chr9_ 114250469, chr9_l 14250578, chr9_122212102, chr9_130919223, chr9_134351726, chr9_l 34420684, see FIGS. 25A-25B), at least 389 different CpG methylation markers listed in Table 1 are analyzed (such as chrl_6954205, chrl_6954346, chrl_15437470, chrl_15765576, chrl_16921554, chrl_17535615, chrl_17535924, chrl_20748527, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_47930687, chrl_55154474, chrl_55154499, chrl_82344735, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_l 14587732, chrl_l 14587798, chrl_200664873, chrl_213899571, chrl_223535050, chrl0_12981474, chrl0_85659210, chrl0_85659210, chrl0_96825742, chrl0_120517367, chrl0_120517552, chrl0_129558734, chrll_6333181, chrll_15508856, chrl l_30683884, chrl l_61601245, chrl l_64638030, chrll_64638061, chrll_64638130, chrl l_64638134, chrl l_64638208, chrll_64638406, chrll_64638423, chrl 1_64638446, chrll_64638476, chrl 1_64638487, chrll_66652738, chrll_70828694, chrll_70828726, chrl l_70828942, chrl l_70828959, chrl 1_113951190, chrl 1_113951238, chrl 1_114069492, chrl 1_114069680, chrl 1_118210650, chrl2_104666490, chrl2_104666538, chrl2_l 11199420, chrl2_111363167, chrl2_l 11363249, chrl3_44573330, chrl3_78061219, chrl3_92046041, chrl3_93413326, chrl4_28309117, chrl4_32587882, chrl4_91028417, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99265134, chrl5_39667040, chrl5_40579060, chrl5_60850769, chrl5_73787063, chrl5_73787074, chrl5_75706205, chrl5_75706213, chrl6_29674272, chrl6_29674291, chrl6_71746300, chrl6_71746304, chrl6_79856776, chrl7_2019254, chrl7_2019280, chrl7_17603475, chrl7_17603475, chrl7_49578654, chrl7_49580573, chrl7_58691449, chrl7_78458835, chrl7_78458957, chrl7_81839462, chrl7_81839517, chrl8_31612779, chr!8_42840523, chrl8_42840569, chrl8_55863146, chrl8_55863209, chrl8_55863341, chr!8_55863406, chr!9_8180812, chr!9_13002733, chrl9_13002909, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_33408728, chrl9_33408838, chrl9_39052997, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_4416732, chr2_8535196, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_73008587, chr2_88493781, chr2_ 106974041, chr2_l 15082751, chr2_120543523, chr2_144507406, chr2_144508216, chr2_144509942, chr2_144512702, chr2_l 59230649, chr2_180445347, chr2_l 92676064, chr2_ 199449983, chr2_l 99450146, chr2_20312!062, chr2_214915957, chr2_216827945, chr2_224976082, chr2_227315087, chr2_227315087, chr2_234438247, chr2_234438297, chr20_l 837975, chr20_23049529, chr20_23049808, chr20_40692708, chr20_40692864, chr20_43564715, chr20_49882081, chr20_52979500, chr20_52979806, chr20_53032932, chr20_55284577, chr20_57730506, chr20_57730576, chr21_21578917, chr21_26832783, chr21_26832851, chr21_29221598, chr21_29221717, chr21_29917226, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr22_24425152, chr22_24425165, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425710, chr22_24425816, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24428701, chr22_24428719, chr22_24434350, chr22_24434476, chr22_24435262, chr22_24436130, chr22_24436142, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_49391984, chr3_10546902, chr3_l 0546931, chr3_23272516, chr3_41117522, chr3_53425664, chr3_73746874, chr3_81591988, chr3_81591988, chr3_l 12000443, chr3_l 13902470, chr3_142925609, chr3_143082577, chr3_143082617, chr3_179616279, chr3_181704894, chr3_l 81704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_181724459, chr3_l 81724559, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_9109274, chr4_l 1187567, chr4_ 15944086, chr4_36635749, chr4_38356556, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_87865311, chr5_6810030, chr5_6810073, chr5_l 0524764, chr5_10524872, chr5_43282446, chr5_43282460, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_95429494, chr5_l 13040537, chr5_l 15106946, chr5_127066418, chr5_150680117, chr5_167983052, chr5_172860804, chr5_172860953, chr5_175441994, chr5_175442040, chr5_l 75442086, chr5_175442387, chr5_175442710, chr5_175442710, chr5_178604407, chr5_180155459, chr5_180155581, chr6_33906454, chr6_36775571, chr6_40888325, chr6_60830914, chr6_87948947, chr6_96873290, chr6_105628390, chr6_l 10018487, chr6_120951342, chr6_121099723, chr6_137290533, chr6_l 39254024, chr6_150204270, chr6_150204473, chr6_150893713, chr6_158528243, chr6_ 169961951, chr7_1231081, chr7_1672459, chr7_l 672799, chr7_1672928, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_1675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_17586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_88282441, chr7_94840949, chr7_101915316, chr7_101915318, chr7_102107431, chr7_138971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_157897933, chr7_l 57897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_159142397, chr7_l 59231136, chr8_10296807, chr8_52246671, chr8_52252719, chr8_57356053, chr8_63031540, chr8_80345362, chr8_84031486, chr8_87977499, chr8_1 18694978, chr8_l 18694978, chr8_l 40729234, chr8_l 41800485, chr8_141800688, chr8_144241354, chr9_35350760, chr9_73879045, chr9_79193652, chr9_79193716, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181, chr9_l 14250397, chr9_l 14250449, chr9_l 14250469, chr9_l 14250578, chr9_121830266, chr9_122212102, chr9_122224319, chr9_130919131, chr9_130919223, chr9_134351622, chr9_134351726, chr9_134420593, chr9_134420684), or at least 785 different CpG methylation markers listed in Table 1 are analyzed (such as chrl_6954205, chrl_6954346, chrl_7048907, chrl_15437470, chrl_15765576, chrl_16921554, chrl_17411021, chrl_17535615, chrl_17535924, chrl_20748527, chrl_25729798, chrl_27249955, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_38418368, chrl_43465467, chrl_43465657, chrl_45049761, chrl_47930687, chrl_50837887, chrl_55154474, chrl_55154499, chrl_82344735, chrl_83627211, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_107575614, chrl l 14587732, chrl_l 14587798, chrl_155009422, chrl_174451522, chrl_174451522, chrl_197451335, chrl_200664873, chrl_207434747, chrl_210626571, chrl_213899571, chrl_219915507, chrl_223535050, chrl_241329400, chrl_244054001, chrl_244054019, chrl_244054025, chrl_244054088, chrl_244054213, chrl_244054334, chrl_244054412, chrl_244054487, chrl0_387726, chrl0_1550998, chrl0_1599134, chrl0_1599460, chrl0_1610306, chrl0_1626613, chrl0_1679796, chrl0_1680989, chrl0_1682975, chrl0_1713526, chrl0_1721323, chrl0_1723256, chrl0_1723398, chrl0_1724564, chrl0_1726470, chrl0_1975272, chrl0_3927130, chrl0_12981474, chrl0_33204102, chrl0_34752396, chrl0_44279927, chrl0_44280044, chrl0_59279057, chrl0_59279103, chrl0_71529729, chrl0_80094872, chrl0_85659210, chr!0_85659210, chrl0_87727342, chrl0_91397464, chrl0_92661601, chrl0_96825742, chr!0_107085835, chrl0_120517367, chrl0_120517552, chrl0_124961029, chrl0_129558734, chrl 1_6333181, chrll_10175924, chrl l_15508856, chrll_16344746, chrll_28779431, chrll_30683884, chrll_31820115, chrl l_31820310, chrll_46385139, chrll_46398710, chrll_46441679, chrl l_61601245, chrll_64070739, chrl 1_64635621, chrll_64638030, chrll_64638061, chrl 1_64638130, chrl 1_64638134, chrl l_64638208, chrl l_64638406, chrll_64638423, chrll_64638446, chrll_64638476, chrl 1_64638487, chrll_66652726, chrl 1_66652738, chrll_70828694, chrll_70828726, chrll_70828942, chrl l_70828959, chrll_75832244, chrl l_94158916, chrll_l 12260989, chrl 1_113363879, chrl 1_113400998, chrl 1_113408265, chrl 1_113433434, chrl 1_113433544, chrl 1_113444137, chrl 1_113445794, chrl 1_113460726, chrl 1_113468577, chrl 1_113468826, chrl 1_113469191, chrl 1_113469614, chrl 1_113470470, chrll_113951190, chrll_113951238, chrl 1_114062290, chrl 1_114062488, chrl 1_114064208, chrl 1_114064532, chrl 1_114066467, chrl 1_114067705, chrl 1_114069492, chrl 1_114069680, chrl 1_117914441, chrl 1_118210650, chrll_123025323, chrll_127690394, chrll_127690429, chrl 1_131233613, chrl2_2081518, chrl2_2842964, chrl2_30766914, chr!2_47947292, chrl2_53274354, chrl2_53274417, chrl2_70443965, chrl2_77308440, chrl2_88450938, chrl2_88451104, chrl2_92221841, chrl2_93894714, chrl2_93894790, chrl2_94695777, chrl2_95356097, chrl2_98459151, chrl2_104666490, chrl2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl2_l 11363249, chrl2_l 19340812, chrl2_121507866, chrl2_l 22161069, chrl2_122228141, chrl2_127115077, chrl 2_129703529, chrl 3_27238208, chrl 3_2751701 , chrl 3_35695164, chrl 3_4146531 1, chrl3_44573330, chrl3_73025821, chrl _73026371, chrl3_78061219, chrl3_92046041, chrl3_93413326, chrl3_98404428, chrl3_103071728, chrl3_103801301, chrl3_ 106713795, chrl4_28309117, chrl4_32587882, chrl4_36524389, chrl4_36524667, chrl4_62814638, chrl4_72746337, chrl4_72746410, chrl4_91028417, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99244159, chrl4_99244383, chrl4_99245037, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99259778, chrl4_99259851, chrl4_99261299, chrl4_99261349, chrl4_99265134, chrl4_99265442, chrl4_l 04963567, chrl5_27014884, chrl5_39667040, chrl5_40579060, chrl5_60850769, chrl5_61832637, chrl5_64673973, chrl5_70265944, chrl5_70867831, chrl5_73421182, chrl5_73787063, chrl5_73787074, chrl5_75706205, chrl5_75706213, chrl5_84784380, chrl5_98347522, chrl6_3255898, chrl6_3473308, chrl6_21514377, chrl6_21514493, chrl6_29674272, chrl6_29674291, chrl6_49521066, chrl6_71746300, chrl6_71746304, chrl6_73092631, chrl6_79856776, chrl6_84090291, chrl6_85290977, chrl6_86757258, chrl6_87957932, chrl6_89747287, chrl7_2019254, chrl7_2019280, chrl7_6264478, chrl7_8310790, chrl7_17603475, chrl7_17603475, chrl7_19539205, chrl7_19539300, chrl7_29056566, chrl7_29093998, chrl7_31593826, chrl7_32274223, chrl7_49578654, chrl7_49580573, chrl7_51374368, chrl7_58691449, chrl7_62458778, chrl7_68274037, chrl7_74762858, chrl7_75231866, chrl7_75231876, chrl7_78458835, chrl7_78458957, chrl7_79140535, chrl7_81246152, chrl7_81839462, chrl7_81839517, chrl8_7466797, chrl8_7671182, chrl8_22191374, chrl8_24273998, chrl8_28743520, chrl8_31612779, chrl8_31668044, chrl 8_31668223, chrl8_42840523, chrl8_42840569, chrl8_48111878, chrl8_55316591, chr!8_55335150, chrl8_55337856, chrl8_55337859, chrl8_55347406, chrl8_55347692, chr!8_55401620, chr!8_55401726, chrl8_55401962, chrl8_55401962, chrl8_55402070, chrl8_55863146, chr!8_55863209, chrl8_55863341, chrl8_55863406, chrl8_58846286, chrl8_75629703, chrl9_940774, chrl9_940858, chrl9_941208, chrl9_941242, chrl9_941271, chrl9_941471, chrl9_4020451, chrl9_8066130, chrl9_8180812, chrl9_l 1943461, chrl9_l 1943461, chrl9_13002733, chrl9_13002909, chrl9_13027645, chrl9_l 3027708, chrl9_29879973, chrl9_30071371, chrl9_30071556, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_32327361, chrl9_33408728, chrl9_33408838, chrl9_35046673, chrl9_39052997, chrl9_53965120, chrl9_53965266, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_1939158, chr2_4416732, chr2_6286826, chr2_8535196, chr2_8811580, chr2_22449630, chr2_27738485, chr2_27738489, chr2_27738545, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_60479437, chr2_73008587, chr2_79929386, chr2_85447333, chr2_88493781, chr2_96895479, chr2_99699856, chr2_100923151, chr2_106974041, chr2_l 15082751, chr2_120543523, chr2_127840596, chr2_144507406, chr2_144508216, chr2_144509942, chr2_144512702, chr2_148147429, chr2_159230649, chr2_169415560, chr2_180445347, chr2_184141131, chr2_l 92676064, chr2_198316634, chr2_199447280, chr2_ 199449983, chr2_199450146, chr2_201872813, chr2_203121062, chr2_211590141, chr2_211590198, chr2_212520797, chr2_212524214, chr2_214915957, chr2_216827945, chr2_219281611, chr2_219888095, chr2_222470101, chr2_224976082, chr2_227315087, chr2_227315087, chr2_231390519, chr2_232574302, chr2_234438247, chr2_234438297, chr2_236121881, chr20_1400335, chr20_ 1837975, chr20_5670261 , chr20_23049529, chr20_23049808, chr20_34196362, chr20_40692708, chr20_40692864, chr20_43423564, chr20_43564715, chr20_49882081, chr20_52979500, chr20_52979806, chr20_53032932, chr20_54696328, chr20_55284577, chr20_57730506, chr20_57730576, chr20_60889288, chr20_62225257, chr21_21578917, chr21_26832783, chr21_26832851, chr21_28103489, chr21_28103489, chr21_29221598, chr21_29221717, chr21_29917226, chr21_37606568, chr21_40771526, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr21_46510096, chr22_24425152, chr22_24425165, chr22_24425229, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425705, chr22_24425710, chr22_24425754, chr22_24425816, chr22_24425972, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24427448, chr22_24428701, chr22_24428719, chr22_24433075, chr22_24433241, chr22_24433423, chr22_24434088, chr22_24434350, chr22_24434476, chr22_24434989, chr22_24435262, chr22_24436014, chr22_24436130, chr22_24436142, chr22_24437360, chr22_24437763, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24440446, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_29185058, chr22_30737962, chr22_34617159, chr22_34617213, chr22_35114720, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_44940707, chr22_46346927, chr22_48824678, chr22_49391984, chr22_50658490, chr3_8595802, chr3_8596019, chr3_10546902, chr3_10546931, chr3_13191245, chr3_15391356, chr3_22857045, chr3_23272516, chr3_30391151, chr3_32506316, chr3_41117522, chr3_46301401, chr3_53425664, chr3_59955536, chr3_70568431, chr3_73746874, chr3_76628994, chr3_81591988, chr3_81591988, chr3_99932654, chr3_105471988, chr3_l 12000443, chr3_ 112508351, chr3_l 13651082, chr3_l 13902470, chr3_122908926, chr3_142925609, chr3_143082577, chr3_143082617, chr3_l 50033642, chr3_154551207, chr3_164753486, chr3_171894906, chr3_179540277, chr3_179616279, chr3_l 81704894, chr3_181704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_l 81724459, chr3_181724559, chr4_578126, chr4_667460, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_8576626, chr4_8868232, chr4_9109274, chr4_l 1187567, chr4_13785708, chr4_15944086, chr4_25237957, chr4_30170558, chr4_36635749, chr4_38356556, chr4_39815565, chr4_52055928, chr4_53508148, chr4_53840582, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_77897059, chr4_77897104, chr4_87411016, chr4_87865311, chr4_89379269, chr4_152888059, chr5_1554827, chr5_6810030, chr5_6810073, chr5_l 0524764, chr5_10524872, chr5_30772245, chr5_38403906, chr5_43282446, chr5_43282460, chr5_50998048, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_78701917, chr5_89120992, chr5_95429494, chr5_l 00877542, chr5_107099103, chr5_l 13040537, chr5_l 15106946, chr5_127066418, chr5_140543089, chr5_145529393, chr5_150680117, chr5_151512421, chr5_151512485, chr5_151520158, chr5_l 67983052, chr5_l 72860804, chr5_l 72860953, chr5_l 75033106, chr5_l 75441994, chr5_175442040, chr5_175442086, chr5_175442387, chr5_175442710, chr5_175442710, chr5_175692802, chr5_l 75692868, chr5_ 178604407, chr5_180155459, chr5_180155581, chr6_3482654, chr6_33906454, chr6_34036167, chr6_36775571, chr6_40888325, chr6_60830914, chr6_87948947, chr6_91513599, chr6_96873290, chr6_105628390, chr6_108804924, chr6_109824080, chr6_109977550, chr6_109977690, chr6_l 09981771, chr6_109981907, chr6_l 10018487, chr6_l 10439611, chr6_l 17562504, chr6_l 18577805, chr6_l 20951342, chr6_121099723, chr6_l 36924776, chr6_136943473, chr6_137290533, chr6_139254024, chr6_l 50204270, chr6_ 150204473, chr6_150893713, chr6_155123808, chr6_158528243, chr6_162547293, chr6_168301762, chr6_ 169961951, chr7_1231081, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1672933, chr7_1673021, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_1675882, chr7_1676417, chr7_l 676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_6988371, chr7_6988400, chr7_7273541, chr7_8976868, chr7_17586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_54795471, chr7_71592009, chr7_80057215, chr7_88282441, chr7_93580834, chr7_94840949, chr7_101915316, chr7_101915318, chr7_102107431, chr7_135147918, chr7_138971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_l 59142397, chr7_159231032, chr7_159231136, chr8_10296807, chr8_l 3310666, chr8_27662591, chr8_29052797, chr8_41246826, chr8_52246671, chr8_52252719, chr8_52485371, chr8_56439745, chr8_56441389, chr8_56444235, chr8_57356053, chr8_58117688, chr8_58768196, chr8_58986453, chr8_63031540, chr8_64773383, chr8_80345362, chr8_84031486, chr8_87977499, chr8_97191731, chr8_102754235, chr8_l 17042553, chr8_l 18694978, chr8_ 118694978, chr8_122825356, chr8_129464046, chr8_l 40608236, chr8_140729234, chr8_141800471, chr8_141800485, chr8_141800688, chr8_143213111, chr8_l 44241354, chr9_29444070, chr9_29444070, chr9_35350760, chr9_42278765, chr9_73879045, chr9_75657076, chr9_79190169, chr9_79193652, chr9_79193716, chr9_81702877, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181, chr9_109388040, chr9_109719145, chr9_l 11786816, chr9_l 14250397, chr9_l 14250449, chr9_l 14250469, chr9_l 14250578, chr9_l 19121913, chr9_120498228, chr9_121830266, chr9_122212102, chr9_122224319, chr9_127496263, chr9_130919131, chr9_130919223, chr9_134351622, chr9_134351726, chr9_l 34420593, chr9_134420684, chr9_136323313).

Table 1. Exemplary methylation markers and probes chr start end example probe sequence (from top to bottom, SEQ. I D NOS: 1 to 1585) chr6 9035118 9035120 TTTAAAAGTTTCTTTTCAATATTTCGGTAAATAATATCAATTGTTTTTCC chrlO 100072990 100072992 TCCTGGAAGTGAATGAATGGATGCCGGGAAGCTACAATCTCACAGATGAA chr6 72620288 72620290 AG CACCG CACG G AGCAACCTCTCTCG CACCTCCACAGTGCGTG G GTGTG A chrlO 100828496 100828498 CAGTTTCCCCTCCTGCCAGTCCTTCGCCTGTCCCTTGACGCCCTGCATCC chrl 161837399 161837401 TCAGTATG AACTG CAG GTGTGTG CCGTGCCTTTG G ACTTTTTG GTGTCTG chrl8 59627566 59627568 agatgaggtcacactggcttagagcgggacctaatccaatgaatagtgtc chrl l 83537579 83537581 tgtaatcccagcattttgggaggccgaggcgggcagatcaccagagatca chrl l 129969666 129969668 aaaaaaaaaaaaaaattagccgggcgtggtggtgcgtgcctgtaatccca chrl8 7574188 7574190 CACTGCTTAGCCTCTTGATTAATACGGCCGGTATTACCAACATGGTGATG chr9 91222453 91222455 ttcaaacaaatacaataatgctaccgcaaaatgcagttattacgtgttta chr21 46622779 46622781 TCAACAGGAGTGTTTTTCATTTGACGACTTCAGAAGATCCCACGTCTTAC chr20 63081946 63081948 ATAAAGGGCTAGAGACGTAGAAACCGTGGCTGGCATGAGGGAGGAGCTTA chr9 137281028 137281030 AGCCCCGCTGCTGCCGCCTTGTGGCGCGCCCGGCCCAGCCGGTGGCTTCT chr5 116361553 116361555 CATCGTCACCTTCCAAG CG G CCCTCG CG CG ACTG CAG CCAGCCCCGGCGG chr4 88058507 88058509 TTTAAACTCATATGTCAGCACTTTCGTAGTCACTTGCTAGCATGACTTTT chr3 107915549 107915551 AATGTCACGTTTTCTTTAATGACTCGGTAGATTACCTTAGAACAGAGGCA chrl7 62458778 62458780 CTG CTG AG CAG GTTG G CACTAACACG AG CTG G CGTTTGTCCAG ACCTta a chr8 58986453 58986455 AAAGTAACTCTAAG CAACGTG G ATCG AATAAACCTCCAG AGTCAG G AAGT chr6 37006218 37006220 TAGCTGATACTCACCAAGAATTTACGCCCTATGATtaggataaccatata chrlO 106956123 106956125 gcctgggcaacaagaccaaaactccgtctcaaaaaaaaaaaaaaaGTTTC chrlO 108335363 108335365 CAAAGACACAGAATCTAACAACAACGTAACAGGTAATTGAGCTGGAGAAA chrl4 55679980 55679982 TTGCCTTAATACCTGCAACGGCTTCGTTAATTTATTCTGTTCTTAGTTTA chrlO 108862889 108862891 ACAGTCACTtcttcaaagctttgccgcagaagctacaagcattatttcca chr2 156397401 156397403 caaaagcctcaaaagcagggaagccgacagtgcagccttcagtctgtgac chrlO 119410604 119410606 TG CTCCCAG CACTTCCCAG CCACACG GCCCTCACTTG GTTG CTCATAG CC chr5 32631299 32631301 GGGCAGAGGTCCAACCAGGCAGACCGGCCAGCCCACAGCAAGGTCTGGAG chr2 61005128 61005130 ataaaaattagccaggcgtggtgacgcatgcctgtaagcccagctacttg chr8 144242229 144242231 CCCAG ATTCAG GTG GTG CCGTGCACG G CTG G GTCACACCTCTG CTGTCAC chrlO 11207696 11207698 CACATAACTCACATACGGAAGGCCCGATGGCAGCATCGCCCGTCAGCTTC chrlO 11207803 11207805 CTATAAAACTAAGCTAATTGGATACGGTTTCCTTAAAAGTAGATTTCTAC chr8 66011320 66011322 tagacacaggcaaagatttcatgacgaaaatgtcaaaagcaattacatca chr4 77902675 77902677 gattattaatatcaggaatgaaagcggtgacatgaatacatatcccataa chr3 42733336 42733338 AGCTAATGTCATAGGAGAGGCCCACGTATTGGAAGAACAACAGCATAGTC chrlO 112992389 112992391 TGCCCTCCGGGAGACACCCAGACCCGACAGAGAGGCCTTTGTTGGAGCTG chr6 725467 725469 gctgaaggagcttttgggctgagacggtggggtttcctagatgtagaatc chr8 85556739 85556741 TCTTAATTCCCTTTATTCCTGACTCGCAAACACATTTCCTTCTCTAGTAG chrl l 112865051 112865053 G ATG G ACTTACCCTAATTCTG CAACG G ACCTACTTCCCGCCG G G CCCCAT chrl l 112865051 112865053 G ATG G ACTTACCCTAATTCTG CAACG G ACCTACTTCCCGCCG G G CCCCAT chrl4 86470352 86470354 TACTGTACATAATTGATATTTGCTCGGTATTATATCCTGTTTCGTAAAAT chrl8 63087914 63087916 AAATAG AG ATTTTAAAAATCCG AACG ACTTGTG G C AAAACG G GTTTTACC chr21 14871182 14871184 ATACGGAGGTTACTTTCTGCAATACGTGTAGAGGGTAACTGTTCTCCAGT chrlO 35511869 35511871 ACCTGGAGAGATGGAGAGTTGACTCGTGTGTCTCTCCCCAGTGGAGAACG chr6 147500518 147500520 ctgagtattcagttatttttttctcgtttctatacttcccattttatcct chrlO 114188109 114188111 TTCTTCAAACCCG AATG GCATCAACG G AG AAGTAGTTG G CTCCAAAG G AG chr7 114575444 114575446 CATTGGACATTGTACCTTGGGTCACGGCCAAGACAGATGGCAGTGTTATC chr21 42158069 42158071 ttaggaggcagaAAGGGCTTCAGCCGGGGTTGACGCATTCAGATGTGTGC chr22 42646574 42646576 CCAGGGCCCCCGACCTGGCAGGCCCGGTCCTCCCCAGGTGCCAGCTCCCT chrlO 114512228 114512230 GTGCGTAAAAAGGGCTGAAATTAGCGAACTGGGGAAAGAAAATGTGTTAC chrl l 118883931 118883933 GTG ACCAGTCTG GTG ACTCACAG CCG G CACAG CC ATG AACTACCCGCTAA chr9 135941758 135941760 TTGCGCTCACGGGCTGCAGGACGTCGGGCCCTGCCAGCTCTGCCCCCGGA chr7 76305544 76305546 ctcaggaggctgaggcaggggaatcgcttgaacccaggaggcagaagttg chrlO 114571333 114571335 GGTTTCTTTCGGACTGGACGACATCGGCTGTGCACAGAGTTGACAAAGGC chrl2 114671951 114671953 CTCTTTCTCCGCGCAGAGTTTGGGCGACAAGGACATGGAGCTGGAGGAGA chrl7 61405604 61405606 GCAGTTCTTTGGGCCGCTGGGAGCCGGCCAGCCGCTCTTCCTGCACCCTG chrl9 58538912 58538914 CACCCACCCACCACGTTTTCAACG CG CTG ATAGTCCCTAG GCG G GTTCG C chr6 26756234 26756236 TCTTCACGGGTTGCTCAGAAGCTACGGAAGCAAAGTAGAAAGGAGTGAGA chr7 1964753 1964755 CGTG G AAAG CAGGTGGAGGGTAGCCG G G ATCTTG CTTATAACAAACCCAT chr7 1964753 1964755 CGTGGAAAGCAGGTGGAGGGTAGCCGGGATCTTGCTTATAACAAACCCAT chr20 63582957 63582959 gcacagccaccttggaaaacagctcggtcatttccgatacagttaaatga chr21 45434453 45434455 G AG ACCTACTTTCCTTG CTCTCTCCG G G G G G GTTTG CAGC AGTTCTG AG C chr2 46955071 46955073 CCATGTGCAGGATaatgataaatacgcataccctgtatttatcttgctct chrl 224770412 224770414 CAG ATTATTTG GTAGTCAAAGTTCCG G AGTTG CTCCCATCAACTCTCCG G chrlO 119395824 119395826 ggagaagccctgcgcttggaggttcgagtcccagccctgccacctcccgc chr20 48291365 48291367 GTTTTGTGAAACTGGGGAGGGTGGCGTGTGGGGCTCGTTCTATACAATTG chr3 134430495 134430497 GAGATGCCACATGGAGAGATGCCACGGAGAGAGGTAGAGGACCGAACCTA chrlO 119413170 119413172 G GCG GTACCTAG G CTG G G AACCCCCG AACCAGG G CACTTCTCCCCCACCC chr5 160247828 160247830 ggagaatcggttgaacccgggaggcggaggttgcactgagtcaggattgc chr5 160247828 160247830 ggagaatcggttgaacccgggaggcggaggttgcactgagtcaggattgc chr7 114428892 114428894 AATAATTGTATAAATTTATCTCTACGTGTTGTTATTTAGATGTAAAGTTT chrl2 32719406 32719408 AAAATTATCTAATGTGCACCCAATCGAGAAAGAGTTTAAGGTGGCAGGAT chrlO 120517367 120517369 AAGATATCCCAGAGAATTTGCTCTCGCCTTTTGGAGACAGGCCTCTCCAC chrlO 120517552 120517554 CAGTGTTTTAATGG CAGTG CTGTG CG G CTG ATTCACACTCTG CCCTCCAA chrl4 45008380 45008382 gcctcacaaatagctaagactgcacgtgtccaccaccatgcccagctGCA chr4 117877755 117877757 gcatctaccattgtctgttatctgcgttaccaccttcctgtacaagtctc chr2 128280247 128280249 CACTGTGGGGTGGAAGCCGCTGAGCGCCCCACTTGGGGCGGGTGGCTGCC chrl 226712592 226712594 GGTGGTCACCGTGAAGGGAGCGCTCGGCTGGAAGGAAGTGGGCTGGCATT chrl 66250918 66250920 GAAGCTTTTGAAAGCCACCATTTACGTGTGGACTAAGTAGTCTCTAGAGA chrl 58551063 58551065 ctgagcggcacattttcccggtcacGGCTGCTGGAGGATTTAGAGTTTGA chrl 247437780 247437782 gagctataagaaaaactggagtgacggcgaggggtgcttctctgctcacg chrl 39994748 39994750 G CT CTtcctctgtctgca ca cca ccgctcagctgctcgttcca ca tggca chrlO 1247497 1247499 gatagctcttattattttgagatacgtcccattaatGAAGAATGGCCAAA chrlO 1542987 1542989 CTGGATCACAGCTGTCCGTCCGCCCGAGCAGATTCTTGTCCAGGTGTTTT chr6 5724062 5724064 G CCCCAGTG G GTTACACG GGAGGCCG CTCCAG G CAAG G GTTTTCAATTTC chr8 3245755 3245757 ccca atttctgggtgga tctagaa cgga ctatgtgttga cca agggttgt chrlO 124961029 124961031 gttttttttttttagacagagtttcgctctttgttgtccaggctggagtg chr3 70568431 70568433 CCTATAAAACTACAGGTTCTGATACGCTTCTGTGCTGTTCTTATGTTGGA chrlO 73992099 73992101 TG GTCTAG ATAG AG AAG GTTCATCCGTG ATG AG CTG G AG AATG CAgtgtg chrl9 51225987 51225989 TCCTCG GTG CTCATAATC ACCCCACG GCCCCAGGACCACGG CACCAACCT chrlO 1668209 1668211 ggacttgggttcagtctctctctccggttgcaatagttttgagtgaagtc chrlO 1726197 1726199 G AATTTTATTTATTCTCTACAGTG CG GTTG G GTGTAG CCTCTACATATGT chrlO 1661062 1661064 actttccctcacacagaaacattccgagcctgcgataagctcccctccct chrlO 1727111 1727113 GGCTTAAAAATAAACCCGACAGGGCGCTTTGTAAATGTACAATGTAAATC chrl4 105061228 105061230 CACGCATG G CCAACCAG G CTTG GGCGCCGGGGGAGCCCTGCACCAGCCCT chr22 44026938 44026940 GGGAGGGATGGTTGGGATGAGTGACGTGGCCTGTTCCAGAGGAGAGGGGT chr7 5244881 5244883 TTG AG AG GCTTG AAACAggccgggcgcagtggctca ca cctgta atccca chrlO 1372793 1372795 ATCCCAAATAATTATTATTCTTGCCGGTCATAATTGCATACTCATAGTAT chrlO 1654938 1654940 TGTGTG AAG GTG CTG G CCAG CCCACG AG AG CTG G AATG CCAG AGTCACAT chrlO 1717669 1717671 cagcccactgcaacctcctcctcccgggttcaggagattctcccgcccca chr22 29096890 29096892 TACTTTGATTTCTCAACTGACACCCGACACCATGTTTGTCTTGTGTGACT chr21 5068206 5068208 I l l i i GTTC l I I I AAACTGAGTGACGCatggatgtatggatggacggatg chr22 34617213 34617215 cgcgccactgcactccagcctgggcgacagagcgagactccgtctcaaaa chr22 34617159 34617161 tgaggcaggagaatggcgtgaacccgggaggtggagcttgcagtgagccg chrlO 129558734 129558736 TTGGAGAGTACTTGCAGGCAGCCCCGCTCCACACCACTTTTATCATCTTC chrl 200664873 200664875 tttttagtagagatggggtttctccgtgttgaccaggccggtcttgaact chrlO 12981474 12981476 gctgggtttacaggcgtgagccaccgtgcccagccCAGGATCCTTTTGGA chrl9 32044115 32044117 TATACATCAATTTCTGGCAACACACGGCAAGAAAACACAGATGCCCAAAA chrlO 1723106 1723108 CGCTATTCAGTATCTCCCTGGAAACGGGAGCGCATGCCCCTTCTCAGAAG chrlO 1723168 1723170 CATGGTCCTATG ATGTAG CTTTTACG G CCACTG CTAACACACTGTTTCTG chrlO 1318744 1318746 aTTTGTCCCTGTCAGAAGGAATATCGGGGAGTGTGGGAATCTCTCGTTAC chrlO 1666430 1666432 G CCCAG GTG ATCCTCATG ACCAG ACG CGG CTTTG CTACAAG ACAG CTCAG chr4 1245701 1245703 ca cgggtgggca gggtggca cgggcgggca ggAT G G CACAAG CAG GT CAG chrlO 131954864 131954866 ggaagaggaggcgagcttcaaggacggctggagaaaccagaagggcattg chrlO 132541497 132541499 TG CG GTAAATG CCTTACAGTGTACCG GTCCCCAAG CCCTTATccctca ct chr7 87851757 87851759 ggaacctggacttctaacgctacccggcagtaacaagatgacatcctttc chrl4 76713363 76713365 AG CTG G CATTG AATG GGAAGTGGCCGGCG CTTTCAG CCTG G CCAG CG G G C chrlO 132747207 132747209 AGCCCATTAGCATCTGGATGGGGCCGGACCTCCTTGGGACACAGGGGTGG chr2 240622671 240622673 AGATAGGGCTGCAGGGGTGGCGTCCGGCAGCTCTAGCTGGAGAAGCAGGA chr5 4942229 4942231 CCTG CAG G CATCCCC AAGTCCCATCG CAG CACCCG CTTCCTCG G CTGG G A chr7 77909010 77909012 GTACATTTATGTAATTTGAATCTACGATTGTTCTTGACTCCTCTTACCTT chr7 97427528 97427530 TTTCTACTACCATGGAAATATCTTCGAGAGTGCAAATAAGAAActaaaga chrlO 1535173 1535175 CCATGATGGTGAGGGAGGTTCCCACGGTCACGCGTGTGCTGGGATTCTGC chrlO 1535179 1535181 TGGTGAGGGAGGTTCCCACGGTCACGCGTGTGCTGGGATTCTGCTCTTTA chrlO 1686583 1686585 TCCCTCGTCACATGAGTAAGGAAACGTACGGGACTGTGAACCCGCTGGGC chrlO 1569401 1569403 GTCATGAACCCCCAGCCTGCAGAACGTGAGCAGCAGGAGGCATGTAGAGA chrlO 1725175 1725177 GCATCGTGCTAACCTCAGGGGCCGCGTTAACGTGCTGTAAAATAGATACA chrlO 1666355 1666357 TTCTCCTG G G CCG CAG CTCATCTG CG AGTCG G AG CCTCCG AAG G G GG G CC chr20 17913505 17913507 acgcatttcgtcggtcgtaacagacgagaaggagaagatgctgacaatga chr9 124441496 124441498 ACCTCGAGTCACAGCCGCTGCCACCGAGCCCCACCTGCGCCCGCCTGCCT chrlO 1661003 1661005 aacatgccaaccctgagataacctcgtctccaaacagaggcattccaacc chrlO 1360114 1360116 TCCTG C ACGTG G AAG CCAGCCCTG CGTGG G GTG AGCCTG G G ACTGTG G G C chrlO 1357942 1357944 CACAGGACAAGCAGGTTTTTCCTACGTTTGCACAAAGCTCTGCTGACTGT chrlO 1722905 1722907 CACAGTGGAGTGTGCCtatacatacgtgtatatttacccatattcatata chrlO 1722689 1722691 AGAATGAAAAATTCCCTCACCCCTCGTCTTAATTCATTGCATTCCTTAAA

> chrlO 1611485 1611487 TTTTCTCCCTCTTGCTGCTTCACTCGCTGGAGCTCCCCATTCCCCAAATG chrl3 73707942 73707944 TTAG G ATCG CTATGTGTG G AG G G G CGTGTGTACATATGTGTGTGTGCATT chrl3 73707925 73707927 ACAGAATCTGCAATCATTTAGGATCGCTATGTGTGGAGGGGCGTGTGTAC chrlO 13892298 13892300 GCTGAAGGCACAGCTCTTACCCCTCGATCTAGTCCAATTGTATTGAATTT chrl9 45216040 45216042 CCGCCAGGAGACCTCGGCCAGGCACGGCGAGCCCTGGCCCAGGCGGGGTG chrlO 1534652 1534654 TGTTTTACCCTGTG GTCTCATTTCCG G ATG CTG CTACCAATG CCCGTCTC chrlO 1596439 1596441 TTTAATAACACTG ATAATG ACCATCG G CAG CTAG G AG AATAAAGTCCG G C chrlO 1394602 1394604 AGGGAGTGACCTCGTGGAATTTCACGGAGGTTCGTGTGACCAGTGCTGGG chrlO 1552016 1552018 TG AG CG G CTCCAG GTG G CCTCCTG CGTGG AG G CCAAG CCCTCCTCCCG CA chrlO 1611415 1611417 CAAGGGGGAAATTCACTCTCATTTCGTTGGAAAGCAGCTGCCTGGATGAA chrlO 1403853 1403855 ATTGTAGTGCTCCTACAGTCCCCACGTCCTAGCCTCCCCTGCTCCTGCCT chrlO 1727408 1727410 CTGAGTGCTGCCCTGTGTAAAAGACGACAGCTCAGCCCATCTCTCCACAG chrlO 1727713 1727715 TATATATATATAGTGTTG AG ATCACG G AAG GTTA I I I I I GTTCCCTGTTC chrlO 1726447 1726449 CTGTCGCCTTTTCCGTTCCCTATCCGATATCCACAGTATTGAGTGGACGT chrlO 1726436 1726438 ACTCTCG GTG ACTGTCG CCTTTTCCGTTCCCTATCCG ATATCCACAGTAT chrl l 91494016 91494018 ACTGTTTCTG AG A CTG CAGTG AG CCG CTTAG CCACAG CAG CTG CTTTCAA chrl 91197452 91197454 ctgtttttcagcaatctaaactgccggcttcatcttctttctaggacaga chr4 4169964 4169966 cagctgacaaacaggtcatcgtgtcgccgggcctgacttccattctcttt chrl8 49660177 49660179 CATCCACAAAACATACTGCCCCTACGTTTCCTCTACTTCTTTCTCCCCAT chr2 226970614 226970616 GCAGGTGTGTAGCATCAAACATAGCGAGAGGCACTCACCACCTGGAGGAA chr5 173793773 173793775 ggatttgaacccagatcctgaagacgccagggcctttgcccctgtccact chrl l 105521555 105521557 AATACTACCCTCTCCACTCCAACACGCATACACATCACCCTTGAATAATT chr2 76533399 76533401 TCTCAATAGGCTCTAAAACATGACCGTATATTAACAAAGGGTGACTCTTT chrlO 14558632 14558634 TTCCTTCTCCATTTCTGAACTCAGCGTCTAAGGTGATCCTGACTGTGCCT chrl3 111944810 111944812 TACACATG CTG GAG AAAACACTCCCGTG CCAG CCTTTCCCTAGTTTG CTC chrlO 1464103 1464105 cacatgcgctgggggCAGTCACAGCGGGCAGTGTGCCGGAGAAGAGGGTG chrlO 1577668 1577670 G GTG G G AAAG G ACG GTG G GTG G AG CG AATGTG CAG CCCCACCATCCCTG C chrlO 1671760 1671762 ACCTGCAATAAGAGACGCTCCATACGCTGCGTCAAATTGAGGAACATGCA chrlO 1671751 1671753 CATCCAGTAACCTGCAATAAGAGACGCTCCATACGCTGCGTCAAATTGAG chrlO 1680977 1680979 CCGTAGTAGAACACAGTATTCTCACGCCAATAGTGACGGATGTGTGTCTA chrlO 1724818 1724820 CAGAACTTTAATAAGCAGGGGTGTCGTAGGGAGAATGTGGACAGCCACAA chrl7 81312889 81312891 CTGCCACTGTGTGGGACGGAACCCCGTGACCAGGAGTGGGGTCTCCTGGC chr6 165726824 165726826 CAGCGTCTTAACCAGCCCAGTTGCCGACCACAGGAAAACAAGCACAGATC chr4 172578855 172578857 CAAAG AAATTCAAATCTG CATAAG CGTATTTTCTTAG CAAAAG CAAATG A chrl8 1477011 1477013 CAG CACTG CTG G AAG AAATAAAACCG AGTG G CGTG ACAG CAACGTTTAAG chrlO 1508066 1508068 tcaCAAGGGAGATCACACAATTCCCGAGTGGTGCGTTCATCAGGAAGGTC chrlO 1547036 1547038 TGGCAGGAGCAGACAGAAGCCATTCGTCGAGAGCGGGACGCGGGTGGGAG chrlO 1626656 1626658 ATATTTCCGGGCTGCCCCCACACTCGACATGGAAGAACGTGAATGACTTG chrlO 1508075 1508077 AGATCACACAATTCCCGAGTGGTGCGTTCATCAGGAAGGTCAAGTGAGGT chrlO 1686722 1686724 AAGGTCAAAGGCTCTGTCTTAGACCGTTTTATGTGGTGGGCACAAGAATA chrlO 1727852 1727854 ATGCCTCACTCTTTGCCTGTCTCACGGTAGGCACTGGAGATAGATTTACA chrlO 1633241 1633243 agtgcccaagcagggattgagggacgtcttagcctccatgatcacatgag chrlO 1724434 1724436 CACATAGCCTGCCTGGTTTATCTTCGTTCCCAAGGGACAGATGCACCAAG chrlO 1535214 1535216 G G ATT CTG CTCTTTACG CCGTCCCCGGG CAACACAG ACATCAG CTCTTCT chrlO 1535208 1535210 GTG CTG G G ATTCTG CTCTTTACG CCGTCCCCGGG CAACACAG ACATCAG C chrlO 1724748 1724750 ATTCAAAATG GGGGACCCTAG CCACGTCTACCCTTTGTG G GAG AG AG GAT chrlO 1538728 1538730 AGGTCCTTTAGTGCCACTAGAGGACGTCACAACGTCGGGGCCATGGGAGT chrl2 131082380 131082382 G CTG CAAG CCTG CCTCTTTGTTTTCG CTG AGTCCCTG G G AAGTAG ATCTT chr2 119816994 119816996 tgggtcacagatccatgtaatgctcgaattcttttgaaagctgagaCCTA chrlO 1549841 1549843 CAGCCAACTGCGATCCCGGAGAGACGGCAGCCAGGAGAGCCTCTCACCCC chrlO 1711037 1711039 TCTCAG G G CACCATC AG CCAGTG ACGTGTGTTACTCTG AG G CCTG G CCCA chrlO 1543258 1543260 TACCAG GCCTCATCTG G AG G G CTG CG CCAG GTCCTTCCAACTTCAAAG AG chrlO 1543090 1543092 GCTTCCCTGCCTGGGTTGTTGGGACGGAAGGGATTCCACCCTGGGGCGGT chrlO 1710088 1710090 TCCTAAACTTCCACG CCTCAAAACCG G G AAG GTTCACAGTTG AG CG G AAA chrlO 1547973 1547975 ttgtgggcctgaggattcaggacacgtggtacttgcttgaccatatagtt chrlO 1550998 1551000 tattcggccctgtcaaaattcacacgtggaaaccctgactcccaggacct chrlO 1679796 1679798 CGACTGGATCGCTTGGGCTCAACACGGAAACTGAGTGCAGGGGATGCCTG chrlO 1626669 1626671 GCCCCCACACTCGACATGGAAGAACGTGAATGACTTGCCAGGGCCATGGG chrlO 1562547 1562549 a a ctggctcagtacatgccagtta cgatctgta atcgctca tttatctcc chr7 5244971 5244973 agattgagaccatcctggctaacacggtgaaaccccgtctttactaaaaa chrlO 1577694 1577696 AATGTGCAGCCCCACCATCCCTGCCGCACACGACACACAGGGAGCAGCCC chrlO 1666472 1666474 CAG CTCAG ACTGTGTTCCCCCAATCGTGTTCCCG CAG G AAAG CTG CCCG A chrlO 1694923 1694925 CGTG CATCCTG G GG CTCCTTTTCACGTG AAG CCTCTG CATGG AAG GTTAC chrlO 1599460 1599462 CTGTCATCACTATCATCATTTCCACGACCATCTCACATTATGATCCTGTG chrlO 1599134 1599136 TGTG AG CT ACC AGTGTATCTCAG ACGTAAAATTCCAG CTTCCCAGTTTAT chrlO 1721323 1721325 TGTATGTGTTCAGATAAGACCAAACGAATGTTGACGTTGACATAAAATAA chrlO 1610306 1610308 AACCCAGGTGCAGTCTCAACGATACGATATGTCCACAGGCCCCTTTCTCC chrlO 1661397 1661399 TTATCCCTTTCTTCCCCACCCAAACGTCCTCTCATCTCATCTCCCAATAG chrlO 1666792 1666794 TTATATCTGAAAGACTCTGAGACTCGAGATGGCCAATGTTTAACGGCATC chrlO 1723256 1723258 CAGTGTCTTTTCTAAGTGGCGATTCGCTCTACATTGCCCAGAGAACATCT chrlO 1680989 1680991 ACAGTATTCTCACGCCAATAGTGACGGATGTGTGTCTATAAACAAGGGGT chrlO 1712543 1712545 GGCTGTGGTCTGTGGGAAGCAACCCGGGAGGATTGGGAAAGCCCCCCTTA chrlO 1625484 1625486 AATGCTG G G ATCCCAGTG AACAG ACG G CAG G G AATGTTCCTCG G AG G G AA chrlO 1682975 1682977 AATGCCGGCGGTAACACAGCACCGCGGAGGTGGGCTAAGAAGCACGTGGT chrlO 1626613 1626615 AGACTGGCTCCTCTCAAACTCCCACGACGGCCTGTCCTCAGTGATATTTC chrl5 74146200 74146202 gcaggtgcgtgccaccacgcctggcgaattttttgtatttttagtagagg chr8 22243620 22243622 acaagcctaagccaccgtgccTATCG CAAAT ATTT ACTT AAAAAAAAAT C chr8 1757845 1757847 TACTG ATAATTACG G CTATTATCTCG G G GTTATCATTTTCAACAG G AAG A chr6 8839734 8839736 GGTGCCCAACGGGAAAAGCTCTTCCGCACCAGCGTTTTACAAGCCTAGCT chrlO 1711066 1711068 GTTACTCTG AG G CCTG G CCCACCCCG AG CTTG CCAG G CCCC AAAATAG G C chrlO 1717306 1717308 ATTTGGTTGCACAGGGATCTGAGTCGGGGAAGCCCTGGGGACCCCAGGGC chrlO 1726470 1726472 CCG ATATCCACAGTATTG AGTG G ACGTG GTGCTG CCAG CACCTTCTGTG A chrlO 1713526 1713528 TG G GTGTAAATG G CCACAG CAG G ACGGTG CTG CAAG ACTTTCTCACGTG G chrlO 17143716 17143718 TAAGTTTTCCTAAAAATAAATG ATCGTTCAG AG G CCTG CCTTAG G AAG G C chr2 10557495 10557497 cgagattatgccaccacactccagcgtgggcgacagagtgagactcagtc chr2 10557501 10557503 tatgccaccacactccagcgtgggcgacagagtgagactcagtcgcaaaa chr2 10557447 10557449 tgaggcaggaggatcgcttgaacccgggaggcggaggctgcagtgagccg chrl8 22191374 22191376 GTTTTCTCCCACCCGCCCCCCCAACGCCTCTATAAGAATATACAAAATTG chrl3 73025821 73025823 TTAAATAACAGGGTTTATTTATATCGTTGGTATTTATTTCCATTGACATC chrlO 1724564 1724566 GGCCTGCCTGTCATCCTGGGTCCCCGACAGAAAGTGATGATGCTCCTCAT chrlO 1723398 1723400 GTCCCTTCTtaagcaaagaacagccggtggggccggagggaccaggctct chr9 81624163 81624165 ATTCTAATGTGACATAATACCTGACGCATGGTTTCTCTGACCTACCTCCT chr7 7609460 7609462 AAACAT AAATT AT AAT Ccta gcct cggga tcttcggta a gtga cttga cc chr7 106848245 106848247 TATTAAAATTG AATAG CTAACCTTCG G G CACACTATG CAAG GTG CTAATT chrl2 104858423 104858425 actgatcttattgtgaggattatacgacacaacatgtataaaaaaaacct chr8 122825356 122825358 gctggGTCATG ACTCCCTTATG GCCGGGGCATG GTCGTTATACTCAACCA chr2 99699856 99699858 TGTG G G CAACTG CTG AAAG G G AATCG AG G G ATAAACATG ATTCTAACCAA chr5 115106946 115106948 acatacaatatacacacaatggaacgttactcatccataaaaaggaatga chr2 120543523 120543525 cattatttgtgaggcccagtgcaacgggaaaacatgaatccctactcaaa chr22 29185058 29185060 agccaccgtcattattagctccagcgtacaggtgaagagactggggttga chrlO 1975272 1975274 TAATGAGTGATGTGTAATGAGCATCGCTAAACCCACCAAATAATCTTCCA chr2 204434785 204434787 CAGAGTGGGATCCAAAGGCAGAGGCGAGGAAAAGCAAAAATTATCTATGA chr4 31772049 31772051 TTCGATTTCTTATTTTGTTGATAACGGTTTAAAAACTTTTTTTACAAAAT chr7 74183318 74183320 G ACTTCAG GTGTCCTG AATTG G CACG CTCTG CTG ATCTGTTCCTGTTCTA chrl9 11066436 11066438 CTGTCTGACTCAGGTCTCAGACATCGGCTTTGGCCTGAGGGCCTGGAACC chrl6 22272849 22272851 taatttttgtatttttagtagagacggggtttcaccatgttggccaggct chr4 54041134 54041136 tcaccatgttggccaggatggtctcgatctcctgacctcGTGAGGGGATG chrl 237556460 237556462 actacatgcgcctgccacgaggcccggctaatttttttttttttttgtat chrl l 10925589 10925591 ttggta aa aggga a ccta ca cgggcga caga cggagcagcctccaga ata chr8 45729351 45729353 tcgctttgaggatttcgttggaaacgggatgcaatataaaacgtacacag chr22 30472552 30472554 AGAGGACAGATGGCATCTtttgaacgtcacttgcttcatttataaaatgg chr22 19002217 19002219 tctccatgttggccaggctggtctcgaactcctgacctcaagtgatccgc chrlO 29369388 29369390 CCAAGGATAACAAGTCAGAATATTCGAAAAAGTCAGAGGACATTGTAAGA chrl9 4020451 4020453 G GCTTG CCTGTCATCTCGTTGTCTCGTCTCCCG G CC ACTGCAAG G CTG CC chrl9 35046673 35046675 CACATCACCATG G GTG CAGATG G G CG AG CTG GG AG CTCCTGCCACCTTG G chrlO 23513421 23513423 ggcgagtgaaagctcagctccagccgtaacaaacatggaccagaagagtg chrlO 23513396 23513398 acagaggcaaacagcagtagtggacggcgagtgaaagctcagctccagcc chr9 79190169 79190171 TTTTATTCTCTTAC I I I I I GGTTACGTCTTCCAAA I I I I I GTTTCTATAT chr4 13785708 13785710 ctgtctgttctggagattggaagtcgagaatcaaggtgtcagcagcgtta chrl3 112909258 112909260 TGCTTGTGATTCCAGCAGAGGTCTCGGCATCTCGTCCACAGTGAGCTGGT chr4 94410831 94410833 CAACGCTGAGCTGGCGCAATACCACGGAGCACAGACCTTTGAGGAGCACA chrl l 15852550 15852552 CCACATCTACAAAGATGAAGATGACGTGAAGCAAAAATATATAcagttgt chrl l 15852550 15852552 CCACATCTACAAAGATGAAGATGACGTGAAGCAAAAATATATAcagttgt chrl8 26965747 26965749 GCAGCAACAGCAAAAATCATCTGTCGAGTTAAGGGTAAGAAGATCTTATA chrl8 61244954 61244956 gaatgtatccccatcattaagtgacgcatgactgTATTTGGATCTTGTAA chr2 46460276 46460278 gcaatgggtagcttcagcagaactcgccctggtgtccagcccagcccagt chrlO 25083707 25083709 G CCG CTGTGTCATCCCATG CCTG GCG ATAG AAG AAATG AG AG CATCCTTG chrlO 26124732 26124734 ATATTCAAAAATGAGTTTTGTTCACGGAATTAAAGTGTTACTAATTTTAA chr6 145694391 145694393 AATGGCAAAAACAAAGAAATAAAACGCACAAAAAATCTTTTTGTTCAACC chrl5 39828226 39828228 AATGCTGTGGTTGCTTTCCAGCCCCGACAGCAAGCTGACAGAACCATCTT chrl 99920443 99920445 aacaggttcacattctgaggtactcggggctaggacttcaacatacaaat chr3 2528585 2528587 ACTTTACTG ACCCATTTTATTAAACGTAATTTTTTAAAAG CACTTTTAG G chrl 15629316 15629318 AT AT AT AAT AT CCTTT GAT CCggccgggca cagtggctca ca ctta ta a t chrl8 77087501 77087503 CGGATCCCAGGGAGGAGGCGCGGCCGGAGCCAAAGCGCAGAGGCCTCCCT chrlO 48466468 48466470 GCCGACCCCCGCGAGACGCATGCGCGGCGCTCTCGCCCGCTGCGCCGGTC chr5 167264377 167264379 TCCAGTCTTCAGCTTCTTATTTTTCGTAAATCCTGATGTGTTAGACAAGA chr5 167264351 167264353 GGTGGATATGTTCTCTGTCCTCTCCGTCCAGTCTTCAGCTTCTTATTTTT chrl 36953252 36953254 G CTG CCCTTG G G CTCTG G CAAGTG CG G AG CGTTCCCAG CTTG AG CAG AAC chrl l 105648919 105648921 cagactgtggactagagaagctaacggattttctcagggtgacctagctt chrl9 11943461 11943463 aagatagcttgtaaccatatgatccggttgagcatgtaaatgggggtctc chrl9 11943461 11943463 aagatagcttgtaaccatatgatccggttgagcatgtaaatgggggtctc chr2 60479437 60479439 ATG AG G CTG ACCAG AG GCCACCAACGTCAAG CTCTCTCAGGTCTACTAG G chrl7 29093998 29094000 CTTACCTTCTTCTGACACGACTGCCGGGCCTCCTCCACCTCCTCATCCCG

> chr4 25602291 25602293 I I I I I I I ATGCTGGAATGTCTATCCGAGAGTAC I I I I I I I AATAGTTATA chr3 102334993 102334995 ATTCATATTTCTTTCAGAGTGTAGCGTATATCAGTGGTACTTAAAACCCG chr4 44257363 44257365 G AAATTCACTTTG G ATAAGTTAATCG AAAATATTAACTAAG GTCTTTTCG chrl l 9187748 9187750 TGCCTCCTTCCTGAACTCAGACAACGAAGCTCCAAAGAGAAGCCTAAGAC chrlO 71529729 71529731 CTTTAAGACTGTCTCTCCCTTACTCGCCCCCAGCTCCACCTGGCTGGGTG chrl 50837887 50837889 ctcctgagcagctgggactacaggcgtgtgacaccatgcccagctaattt chrl l 112260989 112260991 tatagggggtttgaaaagcttggacgaatccctgggaatctaaaaagcca chrl2 98459151 98459153 ggctggagtgcaatggcgccatctcggctcactgcaacctgcacctcctg chrlO 29621261 29621263 ATTCTGTACCCAAGGACACTCACACGGTCTGTGAGCCTGCTCTGAGCTAG chrlO 29621473 29621475 TGGGAAACAGGGGCTACCCCGCAGCGGGCCAAGCCCAAGGTGCAGAGGGA chr5 114319704 114319706 ATGTAATATAACACAATTG CTCCTCG CTTCTAAATCAAACACTGTAAG AT chr7 131430361 131430363 AATTCTGATTTACTTTTCTTACCCCGGGAAAGTATGTGTAAGTGGCCTTC chr3 197677415 197677417 TCGTTACATAACAAGAGCCAAGCGCGGGGATGTGTCCCTTTCGGAGACAG chr2 120605793 120605795 cacacacacactcacacacTCATCCGGCAGCTATGAGCTTagcagggaga chr7 6139824 6139826 CG CTCCCTTTCCTCCCACACAG GCCGCAGTGCCCGGAGGCTG CCATCTTC chrl 10969247 10969249 CCTGGGGGCTTGCTTTGCAGCCACCGAGATGCAGAGCATGGAGGGAAGCA chrl7 65271215 65271217 GGCGAGGCTGACTGAAACCCAGCACGAGGGAAAAACAAAGTGGTGGGAAA chrl 967238 967240 CAG G AAGTTG CCG CTG G GTATG G CCGCCTG GTCCACAG CAATCCCTCTGT chrlO 16642323 16642325 TCCAGAGAAGCTGTAGAAAAACAACGTGCTGCTCTGCGGAGACCCACAGA chrlO 59688157 59688159 caggtgca a ca agtctttgcccacggattctgcca a accatgca cttgg chrl8 11832622 11832624 cgtaatcccagcactttgggaggccgaggtgggctaatcacctgaggtca chrl6 57792334 57792336 CGTGATTATTTGGTCACTCTCTGGCGCCTCTGCTAGACTCTCTTGTCTCT chrl 19706305 19706307 TAGAATGCCCCCGGTTTTCAAGACCGACAAAAGAAACTGAGATTTAAACA chr5 128254452 128254454 agttacgtaacttgtccaaggagacggaattgaaattcaggtctgactga chr22 44940707 44940709 GCACCTGCTTCCCCACCTAGAAGGCGAAGGGGCCGAAGGAAGAGGCAGAC chrl7 32274223 32274225 CATGGCAGAGGGTGAAGGGTGAGACGAGGCGTCTGGCCATCAGGTAGACA chrlO 31693750 31693752 TTGAGGCAGATGGTGGGATTGGGGCGGGAGTGTGCAGAAAGAAGTTTCAG chrl4 75188760 75188762 AAGTATTAATAACCTTTCTAAAGACGCACTTCTCCAACATTTGGTGTTTC chr3 16908451 16908453 gatcccatacgtttcaatggttgacgtgtctcttttttcttttaatgtaC chr21 29572229 29572231 GAACCTGAGTGTACATCCCTCTGACGCTTTCTGACAGCTTACCATCCTCG chrl8 25563957 25563959 G G AG AAACCAGTGTCATCTCGTACCG CTG GTCTG CTTTAG G AG AAG CTG G chrl5 92438644 92438646 CCAGCAGGCACTCTGGGGCCAGAGCGGCGGGCAGGCTGTGTTTCAGTGGA chr8 115421230 115421232 actcccaatctcaagtgatctgcccgcctcggcctcccaaagtgctggga chr8 32310673 32310675 GGAACAAAGAAAAGAGAATGAGCACGGGAATAAAAGTAAATAATAATCAT chrl3 103013028 103013030 CCCCAACTTACACAG CACCCCATTCG CACAGTATATTTTACTTAAG ATTA chrlO 32910294 32910296 AATACGTAAAATAGAACCAACAGTCGTCAACATCCTTCTCCTTACAATGG chr3 32506316 32506318 ccgttaggttcgtgcaagagtaatcgcggttttggccattactttaaatg chr3 179540277 179540279 ATT ATG AAAACTG CTTCTTG ATACCGTTTAATGTCATTTG G CTATTACCG chrl2 30974808 30974810 CGGTGATGACCTACACTGAGGAACCGCACGGCAGGCGAAGGGGAGGGACA chrl2 30974784 30974786 ATG G GTAAAGTTGTGTCACTCATCCG GTG ATG ACCTACACTG AG G AACCG chr2 127840596 127840598 tgggattacaggtatgggccaccgcgcccggccTCATGCTTCTTTATGTG chrlO 33204102 33204104 AATATTTTACAGTTTTTGGCATTACGTTTCACTTTACAAGACTTGAGATA chrl 3504172 3504174 GGAGGGGGCTGGCGCCGGGCTTCTCGCTCTCTCCAGCCCAGGCCATGGTC chrl4 91277631 91277633 TCAGAGCTCTGCCGTGAAACCCAGCGTGAGATCCTAGCCCTGTAAGTCAG chrl 234145180 234145182 TGATACCAGTTTTGAAGTTTTTACCGCACTGTCCCGCTGTGAGTGGTACT chrl4 68494555 68494557 CACTAAGTTTCACCATCAGTG AG G CGTCAGTCTAG ATG G G CACTTTCTTT chrl l 114964283 114964285 taatggaatttttttttctcttgccgatttgtttgagttcttgcagattc chrlO 127347399 127347401 GGCCTTGGCAGCCCGGAGACGGCCCGTGGGGCTCAGCCGTGGGAGACAGA chrl8 73923596 73923598 CC l I I I G G AAAT ACCT AAAG AAG CCG tgggga ga a ct ca gtgggcccttg chrlO 34313459 34313461 TCTG ATTTAAG ACTTG CATTAAG G CG G CTTTTGTAGTTCATATACTCCAT chrlO 34361129 34361131 TGAGCTCCTCCTCCTCAGCAATCCCGCCCATGACCAAGATTTCCACCATC chr8 56445225 56445227 ACAGTTTG AACTCTTTCCTGTCTACG GTTATTTCG CCTTCCTCTCCCCGT chr21 28103489 28103491 tgaggcagaagaatcgcttaaacccgggaggcggaggttgcagtgagctg chr21 28103489 28103491 tgaggcagaagaatcgcttaaacccgggaggcggaggttgcagtgagctg chr8 141800471 141800473 G G AAAATAAG ACG CCTCTG AG G GCCGTG CCTTC ATCAG CG CCTG CAG G CT chr8 64773383 64773385 CTCATATCTTTACAG CTTCAG G ATCG CAG ATAAATG G G ATATTCCCTATC chr6 155123808 155123810 AGGAGTGAGCGGCCGGGAG CCTTTCG CCTCCAGTGTCTTCG CTG G ACCTT chrlO 34752396 34752398 AATAACTTATTCAAGTCAG CATGTCGTG CAG ACATCACTACCAATTTG G C chr4 54655713 54655715 attcctggatctaaggagatttagcgtgtctcaaggttgggctgggagat chrl 166161182 166161184 ttttttttttttgaaacagactctcgctctgtcagccaggctggagtgtg chr5 169244217 169244219 ATGCTCACTCACAGGAGATACAAGCGCGCTGAAGGCTGCGCCCACTCACC chr7 154750541 154750543 CCCACGGCGGGGGCGCTCCCTGGGCGATGCTCACGGAGAGTGGGAGGGCG chrl6 85290977 85290979 AGTGCCCGTTCTCAGTGTCAGAGCCGTAGCAGACAGACATGGGAGGGGGC chrl5 70265944 70265946 TCTTCTATATTCCTCCTCTCTTCTCG CTCG CTG AAAACTCCCTGCAG AG G chr22 30737962 30737964 cctgacctcgtgatccacccggctcggcctcccaaagtgctgggattaca chrl 7048907 7048909 GACTTCTGAGACTCTAAGATGAGCCGTCAACCTGTGTTGCAAATCTCCTC chr6 106520270 106520272 ACACTCTCATTGCACAG CAG AG CTCG CG G CAAAATCTG G CCCACAAGTCA chrl l 107988501 107988503 gctactacttcgccttccccactacgctagtttttacTacacaatgaaaa chr2 222470101 222470103 cacagggaggggaacatcacacaccggggcctgtcagcggggtggggggc chr22 35114720 35114722 CAG G CTG G G GTCCAG ATCTCTGCCCG CCTCCACCCAAG ATGTG CTCAG CG chr4 25237957 25237959 gtcccagttaataCAAATCAGGAGCGCTTAGCTCCTGTTAGAGAGCCTAA chrl8 24273998 24274000 tataatcccagcacattgagaggccgaggcaggcagatcacttgaggtca chr20 34196362 34196364 aattttttgtatttttagtagagacggggtttcactgtgttagccaggat chr21 40771526 40771528 CGCACCTACACGGGGGAAGGCTTCCGGACCAGGTTTCTGCAAAGAGCACT chr2 231390519 231390521 TCTCCTG CTCTTCATG AAG AAGTCCG CAG ACCTTAG G G AAG AG CTAG G G G chrlO 387726 387728 GACTCCTTTGTGGACAGACACGGCCGGGGGGACCTCACTTACTGTCAGGA chrlO 3927130 3927132 CCCTCTG ACG G CAGTCAG CAAAG ACG CCTCCCTG ACCTG G CG GTGTGTCT chrl7 29056566 29056568 CCTCCCCATTCACAACTACTTTCTCGCTCCCAGAAGGTTGATCAGATATT chr3 46301401 46301403 CATCAATAGTGTGGCCTGGGGCtacgtctacgacctgaccacttaacacc chrl7 68274037 68274039 CCAACATCACTACCAGACGGTGTCCGAAACGATTGCTCAGGACTGTGGCG chrl 12306466 12306468 TGCTTGCCGCCACTGATGTTATGACGTCTGTGATGATTAGGAAcaaggcc chrl l 131679120 131679122 GGGCTGGAATCCCCTCTAGGCCACCGTCGTTTGCTCCATGATCTGCTCAC chr7 27822880 27822882 tctctccaaggtttttaatttactcgtatgttttcttgtaagggctttat chrl 23309318 23309320 ATCATTTTCACTAAAACTAAAGTCCGCAGTGCAATTGACGCCACAGTACT chrlO 43864232 43864234 CCCGGCCCCAGCATGCTCCTCAGCCGCCTGCTCTCCAGTGTGCCCTTGCC chrl6 76458256 76458258 ttgtaaataatactacaataaatacgtgaatgcaggcatcttttttggtc chrlO 43864498 43864500 CAGGGTGGACTTagagaggcagagcgtgctgcaggcagggtctgtgtttg chr3 79368010 79368012 gcaggaatgcagtggtatgatctccgctcactgcaacctccgcctcctgg chrlO 44279927 44279929 CCATCTTAGTCTTTTCAATG G CAG CGTATTATTGCATAG ATTATG CCATA chrlO 44280044 44280046 tgcaaacaagactgtgacatatttcgtgtatattcatctttatatacccc chrl7 72666182 72666184 ctacgttttgtgatccCTAAACAACGAGGGTATTGTGGGTTCTCTAGATT chr3 72321259 72321261 tagctccctggggagtgttactctcgcgatgaaagtagaagccaaagagg chr7 43884803 43884805 gctatgatggccaccactgtactccggcttgagtgatggagtgagacAAA

> chr3 56203330 56203332 CTATTTGTAGAAGCTGAAGGAGACCGGATTTTTCGTCCACTTTTGTAGTT chr7 133830213 133830215 TTCCTTTTTTTTCCACAAACATTTCGGAATTTGTTGTCCCCTTGGTCATT chrl6 24895739 24895741 TCCTTGAAACGTGTCCACCAAGCCCGGTTTGTGTCACTGCTAATGCAGTT chrlO 45073172 45073174 TCTTGTTG G CAG CTG CCATCTGTCCG G CAATTCTGTCCAG ATCTCTCTCT chrl9 47365708 47365710 ACAGACTTCTCTGAGCTTCCTTCTCGCTCTCTGGCTGTCACATGAGCTGC chrl 21413174 21413176 G AG CCCCATACCCTGTG CTCTTACCG GTACTG GTG GTTTCCTCCTGTTCA chr3 194247515 194247517 CTGCTTGCGCAAATTTCAAAGGAACGGATACTGGGtatcttccaggtact chrl l 1081483 1081485 TGGGGGGACACTCACCACGGGCACCGGGAGCTGGGGGGACACTCACCACG chr7 132646113 132646115 AGTGGCAATCCATTAAGTGATCTACGGTATTATTCTGATCTTTCTCTGTC chrl3 101565625 101565627 TACAGGTTATGAGAAAAGGGGCCTCGTAGCCAAAGTTTTGCAAATTCTAA chrlO 4731819 4731821 tgctcatatctgtgctcagccatccgtagttttctccactatggcttgtg chrlS 39188740 39188742 CCTCATTACTTTATATAACATGGTCGGTATAACTTCTTTCTGAACTATGA chr5 38383233 38383235 AAACAAAAACAGATATTTCTTCAGCGTTCTTTGGCGTTTATAACATTTTA chrlO 48593680 48593682 tgggcaagatagagtgggacaccacgctactcagaacagcatacaattta chr21 46606384 46606386 CAACTGTGCTCTGTGCCCCTTCCTCGCTCAGATGTTGGAGGGACCATTCC chr4 137538611 137538613 TACAGTTTCCATCAGCAAGGAAAACGCTTTTTAGAAAAAGAGATCTAATA chrl 118257426 118257428 TTCCTGGGATTTTTGTCCATTCCTCGCTAGTCTTCAGAAAGGCTGTAAGT chrlO 49290181 49290183 gacatttggtcaatgtgtctctagcgtcttttaatcaatagatctcacct chr5 17043558 17043560 agcttttcccacctaccgtctccccgatagcacatcatagcaactccacc chr3 80420694 80420696 CGTCCTGCCCAGAATGTAAATATTCGTGTGACTTGTAAAagttgtgtgtg chrl6 86651909 86651911 ggccagagcccagacaagtcactgcgtggcttccagcctcagtgtcttca chr22 29146128 29146130 GCTCCACACCCCACCACCTGGCACCGTTAGGTTTCAGATCTCCCGTGTGG chr4 3642975 3642977 ATGACACAGCCAGGCCTGGCAGCCCGTCCTTCAGGCCGGGTGGTCTCCTG chrlO 116043885 116043887 cggtgtcccacacaaatgtcgtctcgaattgtaatctccatgtgtcaagg chrl4 99943176 99943178 GCAGGGAGGCCATCTGTCATTCTGCGGGTGTTTGTTTGGGGGATTTTGTA chr7 149875303 149875305 TCTGTGCAGTGCCTTTCCACAACACGTCTGCATTAAGATGGAGCAATATT chrlS 47595163 47595165 AGACTGAGCCTTTCTCTGCCGCTTCGCAGGACTAAGTGCTTGTTGTTGGG chr6 4789352 4789354 ctcccaaggtgctgagattgcagacgtgacctgccgcgcctggcTGCTCC chr9 129632189 129632191 Aggccaggcacatgggctcacacccgtaatcccagcactttgggaggcca chr2 232574302 232574304 CATGGCCTGGTGAACAGCAGCGGCCGCTGATCGGACGCTCCCCCTCTGTC chr3 105471988 105471990 agcctctggtaaccaccattctaccgtctatttctgtaagatcaactttt chrll 109332508 109332510 caatttgggaacttatgtagaatacgtataattatcctcatcaaataacc chr22 44827980 44827982 gtccagtatggtagccagtgctcgcgtgcggctagtgcagatgctgaatt chr5 145529393 145529395 CTCATTTTTCTTGGGTTGTTAAGACGGCATGAGAACAATCAGACCAGGAT chr9 119121913 119121915 CATTTCTACATTGTGTCCCTAGTACGGGTTTATGAAGGGATGATTCCCCT chr3 99932654 99932656 tgtaatgccaacactttgggaggccgaggcaggcggattacccgaggtca chr3 76628994 76628996 GAAGGTATACTAAGCATAATATAGCGTCACTTTTGTAGAACTGGtgttgt chr2 184141527 184141529 tcttgcggcttttggctaccatatcgttcatcatgaatataaacatttcc chrl2 91645989 91645991 CCTCTGTTAAGAGCATGTTGTGTCCGGTATTTGTCTCATTATTTTCAAAT chr6 3482654 3482656 TGGCAGACACAGCGGGCCGTCCTGCGTGCCCACACGTGGTGCCATCAGCG chr5 38403906 38403908 TGCATCCAGGTATAAATCTGGCATCGACAGGTTGAATTTTCAGTTGACAG chrlO 59279057 59279059 TATTCTAGAAATCTATTTCTAAATCGCACCTGCAGCAGGAACATATTTCA chrlO 59279103 59279105 TTCATGTCACCCCTGGAGTGGCACCGTGTTCTATAAagtattactgaacc chr2 113217808 113217810 GCTCCCTGGGGCTGGCCTGGCTGACGGCAGCTGCCAAGGGGATGCCGCAC chrlO 102758820 102758822 tggttgacaaggtgaagcaggtcacgtgcttacaggatagggggcccttc chr6 168301762 168301764 TCTGCCTGCCCAGCCCActcactgcggcaagccctgaataaacaaccttt chr7 135147918 135147920 GGCTCTTTAAATCAGTTGGTTTGCCGGCTACAGTGTAGGTAAAGAGTATG chr20 36541033 36541035 GTGGTTCCTTCAACCCCGCTCTGGCGGGCGACCGCTGATGTGGACAGAGC chr6 152859420 152859422 ACTCAAATCGAAACCAGATGTAAACGGAGCCAAAACAAGTGCAACCGCAA chrll 10175924 10175926 cctgaatgactactgggtgcataacgaaatgaaggcagaaataaagatgt chr2 219281611 219281613 TCCCCTGCTGTGCCTGCTTTCCCCCGCCAAGTGTCAGAGTGTCAGTCTCT chr2 47026330 47026332 GCAGCCTTAGGGCCACCGACAAGCCGAGCCAGTGGCCCCACTGATCTTAG chr2 232011938 232011940 tgttaggactacaggcgtgagccacgatgcccagccATTGTTTGTTCATT chrll 34299545 34299547 TGCAGGCTGCTGGAGGTGGCAGCTCGGCCCATCCTGCTCCATTAGGAGCC chr6 148967681 148967683 TCCTTGCCGGCCACCCCTCCCCTCGGAGGCCCTTCCCTGCACACCGCATG chr9 132223939 132223941 cccccagcctcattgcagacctcacgggtggaacttctttcagccctagg chr4 165204068 165204070 AAGAGCTTGGTGGTCTTAGGTAGCCGCTCCTAATCCTTAGTGTCCTTCAC chr22 37986002 37986004 AGTTTTCCTCGACGCCACCCCCGGCGCTGCCAACCCTCCTCCCCCCGCCT chrlO 97760005 97760007 GCTGGACAGACCTCGGCCTCCCCTCGAAGACACCTCAATTCACAGACTCT chr6 163403779 163403781 G ATTTGTGTG G CTTACTAAGTG AACG G CAG CTCAGTG CTGTG ATG GTG AT chr22 21937291 21937293 ACCATGAACGCGAGGGCTTATGCACGCAGGAGGTCACAGAAAGACAGGTT chrl2 113149751 113149753 CCTGCTGGTGGCTGCCTTCTGGGCCGAGCTGAGCAGGCTTCCACACCACG chrl 9182245 9182247 GACGCGTCTCTCCAGCCCGGGATCCGGGGAGCTGGGCTGTCCCCAGACCG chr2 18993220 18993222 tgtctgaatgagaaaagtttcaatcgaggtcctgacaggtgtgtgaccct chr6 139408933 139408935 TTTGATTTAGAGAAGACCCATCGTCGGAAAAGCCCTCGTGGGAACGTGGA chr7 4242663 4242665 G GCTTTCCCAG GGTGCCCCAGCAT CGG GGtggaggaggcttctctccctc chrl4 101365577 101365579 CTG G CCAG G AATGTTGCTACTCTACG CAGAGGGCGG CATCCAG G CTCCTA chrl2 1324180 1324182 AATATAGTGGGTTTAAAACGTATCCGTCTATTCTGGATTTGCTTTTGCTC chrlO 67835472 67835474 taggaggccgaggtaggcagatcacgaggtcaagagatgaagaccatcct chr20 60750600 60750602 CAAGGCCATGATTTATTTCTTGGGCGTGTAGTTTTCTCCCGAGGCCTCTG chrl2 49708105 49708107 GAACGCTGTTCTGGGCTCAGTCGGCGGCTGGgtcgttgacatttgcggtg chr4 27041550 27041552 taaatattgatgaatttattttctcgacctcttcctcctcccacttccaa chr4 27041550 27041552 taaatattgatgaatttattttctcgacctcttcctcctcccacttccaa chrl5 94591665 94591667 GAGGAGAGGAGATACTTCCTTTTACGAGTTAtatactgtgactccttgag chrl4 24799228 24799230 agetea ctca cccctgcaggagga cgtta a tctattcata agga a tcca c chrlO 69494838 69494840 TGTTACAGTGAGCTGGGctgcccacgctcctgcccccgccccttcccact chrlO 69494743 69494745 TTGTCTGGCTCTTCAGTCTGGCACCGGAGCCGAGAATGCCCCCTTCGTCC chr3 157872750 157872752 ACTCCTTCCACTATTCCCTGTG G CCG CCG CGTCAAG G G G AG AAACCTG AC chrl9 12882294 12882296 cagcctcccgagtagctgggatcacgggcacatgccactatgcccagcta chrlO 71364493 71364495 TATTCCTTG G AAAACAG CATG G CACG G G AATCAG AG AG AG AAAG G AACCA chr6 71257145 71257147 gatacctaggatagtctcccaaggcgtttcaaaactgaaagaaagatgag

> chrl 156440052 156440054 GTCTGAGGTGTGAAAGGTCACTTACGATCCTGACCTGCATTCTTCTCGGG chr6 7137767 7137769 GGATGGGAGATGAGAGTCATTTCACGGCCGCCTAGCTCCTCCTCTTCCTC chrl2 122161069 122161071 ttttctttata a a atagcaagtctcggatatgcctttttttttttttttt chrl5 27014884 27014886 gatattgaagtctcctactattatcgtgttgctgtctagttgtctcttca chr2 218323778 218323780 TGCAGGAGCCAGGGCTGGGAAGACCGTCCCTGTCCGGGGGTGAGGTCAGC chrl 109687772 109687774 TTCGGGTTGTGGCGGGCCGAGGGGCGGGGTCGCAGCAAGGCCCCGCCTGT chr7 92278330 92278332 aagctgggccagcctctgctgtctcgtagtcagggctgttaggtgtaatc chrlO 72022372 72022374 agcctgagcaacagagtgagactccgtctcaaaaacaaacaaaaaaaaaG chr9 109719145 109719147 TGATTGAGCCTGGAAATTAGATATCGAGGAACAAAAACAATAAAACTCTG chrl3 106713795 106713797 ATAAATAGATTTCCTCCTCTTGGGCGACTTGAATATTCCCCATTGTGTGT chr7 66199154 66199156 ccctgggtcccggctcctggctcccgtgccctgCTGGCCTTCTTTGACAA chrl7 21375315 21375317 CCTG CAG ATCACTCTG CTCTG AG CCG CCAGCAATCTG G GTG CG G G CCAG A chr6 110105517 110105519 TG G G CCAG CTTCTG CCATTCTCG CCG CCTGTCATG AG GTG CTCTTG GCAC chr7 154916613 154916615 CCCAG CAAG AACAG G G G ACG CCTACGTAAG AG G AAAG CTGTCCTG G G CG C chr9 73193094 73193096 aattttagaccatttaaaaaatatcgcacaatcttctgggactgttttct chr9 73193094 73193096 aattttagaccatttaaaaaatatcgcacaatcttctgggactgttttct chrlO 75999872 75999874 ATTGTATGCGGGAGTACTTTATTTCGATATTTTCTTTGTCTGATTATACA chr6 103266434 103266436 tgattacagagacgaaactgtcaccgaattctgctTTCCTCAGCAATTCA chrl7 28837720 28837722 gggtggagtgccatggcatgagctcggctcatta cca cctcca cctcctg chr6 125991533 125991535 ttgccagggttggtctcagactcccggtctcaagttatctctttgcctcg chr3 170045189 170045191 GTGCTGTTGTGGGCCTTTGTCACTCGAGTTGTCAGTCTAGGTGTGTGTGT chr7 51640974 51640976 gccttggaaccaggccctttaccccgaacattctgaatctcatgatagcc chr5 172844168 172844170 TTGTGGTACCCACACAGCCATAGACGTCAAACACCAGTCTGTGGTAAGGG chrl 9826671 9826673 AG AGTG AGTCCAG CTTG AAAGTCTCG G AAACG G G G G AACCAGTAAACTCA chr3 50620837 50620839 CTTG G AG AG G GTGTATG G G CCAGG CG GTCCTCCAGTGTCTG CTTCTCCTG chrl2 108910438 108910440 ATCATCCAGTAG CGTCTG ACCAG CCG G AAG G CAAAAG AG ACAAG CAAAAG chr20 62819512 62819514 CCAGCCCAGTGGAGTCGGAAGTCCCGCCAGCCCTCCTTGCTTGTCCAGGA chrlO 79401789 79401791 GAGCACAAGGCCGACCCCACCGTGCGTCCAGCTGAGAGGCTCTGGCTGGA chr3 114746010 114746012 TTG G AATG AACACTG GG CCTATG G CGTAAAAG CATCTCCCTG CCCCTTGT chrl6 87013194 87013196 GGGCAGCCAGAGGGCGAGCCCACACGCTGCCCTCCAGCTGCTGAGGCAGG chrlO 80094872 80094874 TTCTTCAAAAGGAGATTTGTGCTCCGAATCCCCAGTAAACATTTGAAAAC chrlO 107085835 107085837 GTAGACAATGAGCATTTTGTATTACGCCGAGGCAACTGCATTGAAGACAC chr2 239574925 239574927 CTG G G G G CTTG ACTTGG AATG CG CCG CG GGTCAAACG CTG CCAGG CCTG G chr21 45469473 45469475 CCTGTGAGACTCCACTTTGGAGCACGTGGTGGGAGTCCCCCAGCGGTGAA chrl l 67303456 67303458 GGGCCCGGCCGCCCTGAGAAGCTCCGCGGGCCCGGCTGGGCGAGTGTCTG chrl l 67303525 67303527 CGAGGAGGTGCCAGGCCCGGGTGGCGCCGTCCGTCCTTCCTGGTCCTGCG chrl 203109470 203109472 aatggtgctgggaaaactggctaacgatatgcagaagaatgaaactggat chr4 113707038 113707040 TACAAGGTAAAGGCTGGCCACGTGCGAGAATTGAAATGTAGCAGAAAAAA chrlO 85659210 85659212 ATG CATAAATGTG CACACCTGTTCCG GCCTG G GTGTGTTCATGTAAG AGT chrlO 85659210 85659212 ATG CATAAATGTG CACACCTGTTCCG GCCTG G GTGTGTTCATGTAAG AGT chrl2 92221841 92221843 AAGAGATGTAGTTATGTGCCAAGACGTGGAATTATGAAATCAGAGCTTGA chrl7 79140535 79140537 ctgtaaagctcacgatggcccaggcggtgacagtccctggttttgcagac chrlO 101242383 101242385 GGGTGTCAGGGGTGGTATTGTCGGCGCACAAATGCTCAACTTTATGTACT chrlO 101242343 101242345 CGCAAGCCTGCCAAGGAGCCGGAGCGCTGTGCCGCGTGGAGGGTGTCAGG chrlO 87534082 87534084 tttttttttttggagacagagtctcgctctatcccccaggctggagtgca chrl8 10232472 10232474 CTATCGAAATAACTTCTGAGACACCGTATTTTCTCTCCTCCTGTTTCTTT chr7 7273541 7273543 CTCGAAAATGTTGGGGCCTGCACCCGACATCTCAGCCTTCCTCCCTCCTT chrlO 87727342 87727344 CCCGTCTCTGCAGAGGATAAGACACGGCTGGAAGGGTGCAGCAAGTTTGT chrlO 88086877 88086879 GGCCCTCAGCACAAGGAGCTGCTACGTGCATTTGGGCAACACCTTCCTGC chrl4 24156171 24156173 atggctggagcctggaaagcaaggcgggaatggcaggtggtcagagagaa chrl3 27337317 27337319 AG CATAACTCAG CACAG AGTCCAG CG ACAG CACCAG G G ACACCACTTG CA chrl l 119840345 119840347 G CTG CAG AAG GG ATCAAAAG ATTACG AG CCATCAAAG ACTACAAATTTAG chr21 6136224 6136226 AG G AAG G CCTTG G CGTTTCAAG GTCG G CCTCCACTTTCACTTTC I I I I I A chr2 204110026 204110028 G ACATTTTATCCAAAAG CACATTTCG G CCAG G CTTCCTCTCCTG CAG ACT chr3 109565120 109565122 ttttttttttttttggtggagtctcgctctgttgcccaggctggactgca chr3 168027547 168027549 TTTTAAACCAGCTCATCACATACACGTACACCATGGTTTACAGTTAAAAA chr7 139542065 139542067 CGGAGGGAGCCCTGGATTGGACTACGCAGAGTTGGGGACGAATTCCACTG chr4 183611170 183611172 tgtaatcctagcactttgggaggccgaggcagggggatcacttgaggtca chrl l 66652726 66652728 TCAGATACAAAATTGGGTTGGTTTcgggcgtggtggcgcatgtcgtagtc chrlO 91397464 91397466 taaagataataatatagtcaaattcggaatactgtaatactgtaatgggg chrl 28866361 28866363 ttggccaccaaaaagaggaaatagcgtgtgcggaggcatggggatgttta chr7 101062908 101062910 atgttgaaatgttatccccgatgtcggtagtggggcctagtggcactgag chr2 219888095 219888097 GCAGATTAATCATTTCTGATTTGGCGGCACATAGACCAATAagtgtacat chrlO 92661601 92661603 tcttttattaccctcttgatcttccgcctatttgttttattagtaaaagt chrl5 70867831 70867833 accacaatgcctgcaatCTTGTCACGCATTTCTTTGAGATGAGTATTGGG chrl3 103801301 103801303 gcggagcttgcagtgagccgagatcgcgccactgcactccagcctgggcg chr21 29391039 29391041 AGTCTCTCTCCTCTGCCCTTCCTGCGCACATCATCTGCCTCCTTTTAGTA chrlO 935305 935307 CAGACGCTGCGCTGCTCTGGAAGTCGAGGGCGGCATTCTTTTGGAGCCTG chr3 159753818 159753820 TACT CCAG CTTAGTGATTCCTTCCCGTTACTCCAATGTGTTAAGCTTCTT chrl4 53390381 53390383 cacgttacaaggcatgttccaacccgagggcctctgcacttgctgttcct chrlO 9585562 9585564 ATTTG G AG ATATCTG AACAAG G AACGTCTAG ACTTCATATCTCTAAATTT chr3 164753534 164753536 TAGAATTTACTGTGTTATCTTCTACGTGAGCTTGTATCAGTCTTGTGCCT chr4 67939385 67939387 agagataatttgacttcctcttttcgtatttggatgcattttccttcttt chrl 192538779 192538781 AACCAAAAAAG AAAAATG G G AAG G CG ATTGTCCTCTCCTCCCAG G CAG G G chr3 23272516 23272518 gagcagacgccaaggccgaggaggcgctgagagcgagcgagggccgccag chrlO 96825742 96825744 cgggaggcggagcttgcagtgagccgagattgcatcgctgcactccagcc chr9 25755075 25755077 TAG CTTAAATCTCTAATG G GTTTACG G G GTAAAATTACAG CAG GTATGCA chrlS 7202739 7202741 ATTG AATAATG ATTAATAATAATACG G CTTAAAATACTG CAATG ATAATC chr3 30391151 30391153 CTTTG CATCATCTCAG G AATCAACCG CATAAG ATCATG CCATTACTATCC chr22 48824678 48824680 CTTTCTG CATAG AC AAACACCACGCG CAATG GG ACCGTTG G CACGTCCG C chr2 96895479 96895481 CCCCTCTG G AG G G AATGTG ACCTG CGTAAGTCCAG GTGTCTACAGTTAG C chr2 201872813 201872815 GTAAAACAGATAATAGAGACATTCCGGGAATAGTTAGCTAACTAAGCTGT chr3 76549448 76549450 TTCCTGAGTCAATGCCCAGTGCAACGGCAGGGAGGAAACCATTAACTCTC chrl l 35009415 35009417 ga acta tgttt AATG GTATCG G CG G CA I I I I I I G G AAATTAAAGTTAA chr20 51811855 51811857 GGAGAGATTTTAAACTTCTTTTCTCGCTCAGACGCTCAAGTAAACAAATG chr2 108173836 108173838 TAG ATTAATGTTTTCTCAATATAACG GGGATGGGGGG AATTG G AAAGTTT chrl3 45911860 45911862 TTCCCTGAAGAGTCCAGACTAACACGACTCCACACTGACGAGTGGTGGTT chr5 113181090 113181092 GAGACCAACACATCTCTATGTGAACGATGACACTTATTAAAGATAACCTA chr5 110767118 110767120 AAATTGTGCACTCATTCTTGTCTACGTATTTTCAAACTTGTTCCCTTTTA chr5 57399190 57399192 ACGATGACATTTTTAAAAAAAATACGCATCCATCTATATCCTCCGTTGAC chrl9 35086102 35086104 catgaagacattatttatagacaccggaatttgaattttacatgattttc chr3 192578970 192578972 AAAATACCAATTGAAGACCTCCCACGCTGCCTTGGTTTGTAAAATGTCTA chr5 67976871 67976873 CCAACAAAGACATCCGTGAATTATCGTCACAGCCCACCGTGCCAGCTTTC chr22 50192404 50192406 AGTCTGTGGGGAGCTGTGATGCCTCGGGGCAGCCCCCTCGTGTGGCTGCC chr22 29151957 29151959 ggggaggtggaggttgccgtgagccgagattgtgccattgcactccagcc chr9 95546440 95546442 tgctgaagccgcctgacataggcacgccttctccaggacccgctGTAAGT chrl 174451522 174451524 atttccactccagagataaggaaacgaaagaaaaatgattattcgtcagt chrl 174451522 174451524 atttccactccagagataaggaaacgaaagaaaaatgattattcgtcagt chrl l 113363879 113363881 CTATAAAGATACTAGCTATCTGCACGAATAGTTATCATGAAGCTCGGGAA chrl l 113445794 113445796 tgtgctctccatgaatcctcatcacgtctccatttcccaggagacggaag chr6 109981771 109981773 TAGTGGGTTTGGAAAACAAGTATCCGAGGATGTCCGAAAACATATCTTCC chr6 109977550 109977552 tgtaataacagcactttgggaggccgaggcgggtggatcacacgaggtca chr22 24433075 24433077 TGTG G G GTAAG G G GTG G CACTTTCCG CAGG G CTCG CCCTCTG CAG ATG GT chrl l 113400998 113401000 G GG AAG CAG G ATCCTCCCATCTCACGTCTTG G G CTCTTGG CTCCTTACCT chrl8 7671182 7671184 GTGCTGTTTTTCATTCCCCACCCCCGATTCAGAGAGACAGGTAATTATAT chrl l 113408265 113408267 CTGGAGGCTTCCTTTCCATCCTGTCGTCAAGAGCAAGAGACCATCGTCAG chrl l 113469191 113469193 AccctgcctccctcctgctcctgccgccctccctccTGCTCCCACTGCTT chrl l 113468577 113468579 tgtttgttttttgagatggagtctcgttctgccacccaggttggagtgca chr8 56441389 56441391 AAGCGCTTCAGGAAACCTCCATACCGTTTCTGGTAGTCCATCCACCACTC chrl l 113468826 113468828 ctcccaaagggatgggattacaggcgtgagccaccgcgtctggcTAATCA chr22 24437360 24437362 ATGGTCAATGTTTGGGGTCTAAGACGGCAAGATGTGAGTGTGTTGGTCAC chr22 24425972 24425974 GCCGGTGAGGGGTGTGTGCTGGAGCGGGGAACCCGGGAGGGAGGGTGTTA chr22 24440446 24440448 a ctta acgga agaggatgctggggcgaggtggcaggaa atga ctggtcca chrl l 113433434 113433436 TAGAGACCTAGGCTGGGGGATACCCGTTAGTGGAAGCCCAGGGAGTGGCC chrl l 113433544 113433546 ATACCCCATTTGCCCCTTCTCCCCCG G CATG G G G AG CCTCCCTG G AACCT chrl l 113444137 113444139 caacctccgcctcccgggttcaagcgattctactgcctcagcctccagaa chr22 24425754 24425756 TGGCAATGACTGCCTCATGGGCAACGCGATGTGCTGGAGATTTCAGTGCT chr22 24436014 24436016 CTCTTGGCCTGCATTGTGGCCAGGCGGATGTTCTGACCCTCCTGTTACTC chr22 24437763 24437765 ACACG G G ACTTTCTTTG CAG AGTACG GTG G AAG ACTCCCCTTGTGG GTTC chr22 24434989 24434991 G GAG CGGTCATG AGCAGCCTGTCTCG CAG AGCCTGCACCAG GTGG CTGTC chr6 109981907 109981909 ATTCATGTTG ACTTAATACATTGTCGCTG G CCAG ATCTTGTAGTAAAATG chr8 56439745 56439747 ATGTG G ATGTCCTGTG AG CCCTG G CG G G G CTGTACAG AG AG AACAAACTG chr6 109824080 109824082 acctcttgctaaggatgtcagacacggagctgcatttcaacaaggccttt chr8 56444235 56444237 GATTAAAAGTCAGTCATATTAATTCGCTAACTCACATAATTTAAGTAAAT chr22 24433423 24433425 TGGCCATGCCCATCATGGGCTCCTCGGTGTACATCACGGTGGAGCTGGCC chr22 24433241 24433243 CTCTGTG AAAAAGCCCTTG G AG AG CG CCCCAG CAG G G CTG CACTTG G CTC chrl l 113460726 113460728 G G ACTCCTGTG G CTGTG ACGTTACCGTG G AG ACAG G GTGTG G G G AG ATG C chr22 24434088 24434090 TCCCAGTGACCCACGTGCTGCCAGCGGGTGTGTCTGGGCCATTCCTCACA chr22 24425705 24425707 TTACAG ATCCCCAAATATG CCCTG CGTCG CG ATG GAG GAG G G CAATCAAT chr22 24427448 24427450 CAG G ACTCCTG G G CTCTGTGTCCG CG G GG CCATCTAG AAACACTCCCTTG chrl l 113469614 113469616 agggttactctgaggcaggaggatcgtttgaagccaggagttcaagacca chr6 109977690 109977692 ctggggaggctgaggcaggagaatcgctagaacccaggagacagaggttg chrl l 113470470 113470472 CCAGGTCTGCCTGACTTCCCTTACCGCCCTCTGTCTGGAAGCAAGCTGAC chr22 24425229 24425231 ATGGTGGAGGGTTCTGTGGAGCACCGCGGGCCTGGGAAGCTGTTGCGGGG chrl l 113951238 113951240 cagtctccacctcctgggttcaagcgattcttgtgtctcagcctcctgag chrl l 113951190 113951192 cactctgtcgcccaggctggagtgcggtggtgcgatcttggctcactgca chrl l 114062290 114062292 ctaattttgtattttttgtagagacggggcttctccatgttggtcaggct chrl l 114066467 114066469 GACCAGATAGATGTATCATCTTTCCGGATGTGAATTATTTCGGCTGTGTG chrl l 114062488 114062490 TACATACAATAACTTTGAGGCTTCCGTGGGTAGAAATGACCCAAGTTAGT chrl l 114064208 114064210 ACACTATG G G CG AG AG G AG AGTG CCG AG CAG GTG CCACCCCCAG CTG AG G chrl l 114067705 114067707 taggtgtgtgccaccctgctgggccGAGAATGTGCTTTTGACTGAGGGTG chrl l 114064532 114064534 AGAGCAGTGCAGCGTGTGTGGGGTCGAGCTTCCTGATAACGAGGCTGTGG chrl l 114069492 114069494 AGAGGCTTTGTGGAGCCAGCTGTACGGTGCATGAGCTTTGTGGCTAAGAT chrl l 114069680 114069682 ACTCTTGGTTTTCTTTCATCATCCCGTCCAGAACCTCTGATGTCAAACTA chr4 152888059 152888061 TGTATAGTATGAGACTGAATATTACGTATTTCCAACCCATTTTTTGAACA chr3 59955536 59955538 ttatatccctagctcccacttctccgctggttgtcagactcaaatatcaa chr9 111786816 111786818 ccttctgttagaagaagatgccaacgaggactttcatagctagaaagaag chr4 30170558 30170560 TTACTTGGACTGACTTACTCTCTGCGTGTATATCCAGAACATCTTACAGT chrl l 117725325 117725327 G G ACTCCCAG AAG CT CAG AGTG CACG ACTTATGTTCACCTG CCGTCCATC chr5 83553431 83553433 TG CTACAAATACTTTG CCCATCG ACG CACATG G G ATG CAG CTG AACG G G A chr4 37629013 37629015 CTAACCTTCCCAG ATCTAG AGTACCG CTCTCTG G G CAGTG GTG G CCAAAA chr5 56589734 56589736 G ACATCCAG G ACCAG AG ATG CCCTCG CTCG G AAG CAAGCACCCATATCGC chr4 8576626 8576628 tcttttctttcttagatggaatctcgctctgttgcccaggctggagtaca chrl l 117914441 117914443 TTGCAGTCCACCACCCCGTCACAGCGAACAGCGTGCTTGGGACAGCTCTC chr20 36872375 36872377 GAAACCAGCAGGGGCCGAGCCTGCCGGCCCTGGAGCACAGGGTGACTGAC chrl l 118609944 118609946 TCCCGGCTCCCCCTCTCCTCGGGCCGCCCATCTCTCCTCTCTTCCGCCTT chr5 140543089 140543091 gcctgggtgacaagaacgagacttcgtctcaaaaaaaaaaaaaaaaaaGA chrl l 123025323 123025325 attattctccagtaaaaaggaacccggtctacttaaacagatagctgatt chrl l 126134274 126134276 ATTCCTG AGTG AAG ACAGTCAGCCCG G CTTTG CATCTG ACCCG AG CCCCC chrl8 48841418 48841420 CCTAG G G CAG CG CCCTCGTG G CCCCG G CTCAG CCCAGCTCCTCTAG G G AA chrl l 126871107 126871109 G AAATACAGTCCAAATG G ACTCTTCG G AATCAGTTCATCCCTCAAACAG C chrl5 92109249 92109251 a a ggga a a ggcatttga a cccgggcga a ggct ccagtgtctgtcttttta chrl l 127587360 127587362 AGCTAGAGATAAATAGCCCAAGTACGGAGGCAGACATGCAATAAATAAGT chr9 90939328 90939330 AACCACTTATTATTACCCAACTCACGAGCGATGTGAATCACTCCATGGCA chrl l 127690429 127690431 TCTTCCCTTGAATAAGAAAGCGTACGGCACCCATCTATCCAAGGTACATG chrl l 127690394 127690396 TGATTTTTCTCAAAGTAATTGAGACGCTTACTGTTTCTTCCCTTGAATAA chr7 8783649 8783651 GTCAGAGTTAGTTTAGTTATATGCCGTGCTAAGGAGTTTATATTTTATCC chrl5 95990733 95990735 ATAAG AAG G CCCG GG ACTCCCGTG CGTCCAGTAG ACCTG CTCTG CT ATG G chrl l 128402186 128402188 tctgaccagcacagaatatagcagcggcatcattaccttgttctagttct chrl 242442381 242442383 CATGTGCCTCAAGATTTCCATCTACGTGCAGCATCCAGGTATTACGTCCA chr9 136035347 136035349 tcctgtgacgcactgagaaggttccgctgctgtgaattgcagctgaaatg chrl3 107840158 107840160 ATTCTTTAGTCAGTTAAATG CAGTCG G CTGTGTACCTAACTCTATACATG chr7 8976868 8976870 CATTAACAG CAGTAAAG CACTCATCGTATAAATAG G G AAATG GGTGTG AT chrl l 131233613 131233615 GAT AT CACACAAGtattgagtgctcgctgtatgta a agttctgtgctagg chrl l 73319282 73319284 tcaccatgttggccaggatggtctcgatttcttgacctcgtgatccgcct

> chrl l 13922642 13922644 AAAGTATG CAG AG AATTAG AATAG CG CTCTCTTAATGTC I I I I I I TG GTT chrl l 10626357 10626359 G C G CTTCCCCAG CTCG CTCTCCACG G G G CCAGG CTG AGG G CTGTTCAG G chrl l 1507802 1507804 AG ACCCTG CCTCTCTGTC ACTCTG CG CTCTCCCCACCCCCAG CTTC ACAG chrl l 15508856 15508858 aagttctagggtacatgtgcacaacgtgcaggtttgttacatatgtatac chrl4 32587882 32587884 CCAGGGGTGTGTGAAACCAGGTAACGTGATATTATAAGTAGTATTTACAT chrl l 15706202 15706204 ttcctttttctgtccataaatattcgaccatgtggagtagctctgaacct chrl l 97297420 97297422 TCCATGTTGAATAATAATAAGTAGCGACCATTGAAGGATGGGTAAGGATT chrl l 16344746 16344748 AATCCTTGTGGAAATGGTCAATTTCGATGTGACTTTACTTTGTTTTATtt chr4 53840582 53840584 aaattttggaagttggaaaatacacggatgaatagttactgattagtagg chrl l 16934508 16934510 CAAAACCCAGAGTAGCTTCCAAGTCGCTTTTTAAAAAATGGCTACATCAA chrl2 68919665 68919667 ATG G CCAAGTCCAACTAAAAAGTTCGTCAAG G CTAG AATGTG ACATTTCC chrl l 2237529 2237531 gattccaggcgtgagccgccacgccggccctctttgaatttagagcaaca chrl l 2237733 2237735 gggatgtggtgttagatggggtgccgtAggtgaatggtgactggttggtg chrl8 28484687 28484689 ttaccgaatataaacaacagacagcgaaaataaattggaaaaaaatgagc chrl l 23611038 23611040 AAACAACAGCCATTAATTAGAAGGCGTCCTCAGTATCTCAAATAAATCTG chrl2 2842964 2842966 gtatcccaccttccttgtcatagccgttcatgccttcagagatctttcca chrl 219915507 219915509 CCTGAGTTTTGTTAAGACTTTGTCCGTGGTCACTCAGACAGCTATCCAAA chrl 99844148 99844150 ATT AAA I I I I AAAAT AAAAT ACCACG CAAACtgtgtca gaga eta ctagt chrl l 27405472 27405474 aaaagactcctaaatctatacccacgatacactattctataatctatgcc chrl l 28552792 28552794 AATTAGTTGTTCTTGTTAATGTG G CG G CCACCTG CTTCTCTTGCATCCCT chrl l 28552666 28552668 cccatgactgttcatttgtaaatgcgaatggaaatttacacactgcggag chrl4 88890190 88890192 ATG G CAGTTTTATATTTTAG CAAACG G G AATTGTG GG G AAGTAACAGTTA chrl l 28552687 28552689 atgcgaatggaaatttacacactgcggagttggtatgaagattgtgacta chr6 87948947 87948949 GTG G GTG G AACAAAATCTCCAATG CG G G AAAAG CGTCCTG AG GTTG ACAC chrl l 30683884 30683886 TATCCTAAAACAGGTCAATCACCACGAAAGAGAAAAaaggtggagggaaa chr9 99824708 99824710 TTTTCGGTCCCTGTTCCCACTCTTCGAGCTGCGCCCACCCCGGGCAAAGG chrl4 56817138 56817140 tgtgtgcgtgtgcgtgtgcgcgcgcgcgtgtctctgtgtctgcgtgtgtg chrl l 31820115 31820117 GCACGAGCCGCTCTCCATTTGTCCCGGGCAAGGAGGCTGGGAGGGAGGGA chrl l 31820310 31820312 CTTGGAGGAAGCTGGGCAGGGCCCCGTGTGGTGCCCAGCCTACGAGGTCC

> > chr6 53816078 53816080 TAATAG AAAGTTTTACTTTTATAACGTG AG CTCTTTTG G CAAACG CATG A

> chrl9 16287615 16287617 TTCTTAATTAAATAAATAG ATGTCCG G ACCTCTCTG G G AAG G G ACTTG G A chr5 116864787 116864789 GGTAGAAATAACCAAAAAAGAGCCCGCTACTAGAAAGCAAATAACTGAGT

> chrl5 57463798 57463800 TTTCAGACCTCTCACCTCTTCATACGTGTAGAGTGACTTGCTCCTGCTTT chrl5 34572508 34572510 tctctaagacacacagctggtgagcggatcgaagtgcaaatcttatttac chr2 4416771 4416773 TG ATCATATACTG CAG CAC ATTTTCG GTATTTG CATTTTTATCTCACTAA chrl l 35418357 35418359 CTTGTCCCAAACCACACGTTTTCCCGCCTCCCGGGAAGCACCCAAATCTC chr4 84492457 84492459 CACTTCAAGTCCGGGgggcgggagcgcagtgtagatccagggggtgggca chrl 242442709 242442711 ACTTAAAAACCCGATTAAGTAAATCGACACTCCATACAAAGAAGAGACGC chrl 242442419 242442421 GTATTACGTCCACTTTATCCATGGCGGCACTGTTACATAAATGGGATTAT chr2 4713113 4713115 taacatttaataattaaaggacttcgaaatgtctataaaattggcagctt chr3 152058781 152058783 tccacaactgctttccacagtggtcgaactaatttacattcccaccaata chr5 100877542 100877544 ATGACAATAGGTCATTGAAGATCTCGTGTCCACAATGAAGTGACTGGTTT chrl7 51374368 51374370 ATG G AG AAATTGCACAAG CCTTGTCG GTGGGTACCCG ATG CCCAGTAACG chrl 109931193 109931195 AACACATTCATCTG CATATCTG CTCGTATTG G G CAG AAAGTG G CCAAACA chrl l 41004019 41004021 GTCAAGGACAAAGAGAAGACAAAACGGCCCAGTGGATAGAAAACAGGAAG chr7 100986780 100986782 AGAAAAATGCAGCTCCTGGCATCTCGGAGATTGACAGATGGGACAAGAGG chr7 100986599 100986601 GTCTACCCCTG CACCCCGG CCTTCCGTCTTG GTCCAG CTCCTAG CCTCTC

> chr3 151377932 151377934 TGTGTGTCTCATACATCAAAGTTTCGCTTTGGAGTTTCTGTTATAACTGT chr20 35502853 35502855 TGTTTTAG AG CATCTG CCCATG G CCGTCCAG G AG CG AG AGCAG AAG CTG A chrl l 46385139 46385141 G CCTACCTG G C AGTG CCG ATGTTCCG ATACTG G CACAG CAG CAG GTG CCG chrl l 46398710 46398712 aggatgttcttgatctcctgatctcgtgatctgcccacctcagcctccca chrl l 46441679 46441681 tgaagcaccactgtactatgtattcgacagctcacatctagagttttcta chr6 136943473 136943475 ggcatggtggctcatgcctataatcgcagcactttgagaggctgaggtgg chr6 136924776 136924778 ACGTGTTTTAATG AG AG G CCTCCCCGTTTTATTCTTTG AG G AGTG G G G AA chr9 42278765 42278767 TTCATAAATTTGTCTGACTCCTAACGAGAGTACCTTGTCAAGGGTAATAT chr20 54696328 54696330 agtgagaaggcagctgtctgcaagcgaaggagagagccctcgccaagaac chr8 129464046 129464048 CATCAACTTTAAAAAAAACTTTAGCGGTAAAAATGGCATAAACTGTCTTA chrl l 28779431 28779433 TAAAATAAAGGTTTTTCTTGGTTACGTCTTTGTAAGTGAATATTAAAAAG chr2 6286826 6286828 AGATATTTAAATAGGAGGCCTTGCCGAATCCCTGAATAATGCTCAGGTAG chrl l 59759948 59759950 actgaaCCTTAACATACCAATCTGCGCTTCACTGAGATTCTGTCTTTCTC chr2 109542029 109542031 tctatgtgaaagggctttaaaaGTCGGAGGGAGTACGTACCAGGATTAAC chr7 101657486 101657488 TTTG CC CAG CAG ATG AG GTACAG CG AG G ATG CTCATG ATATCTCC G AA chrl l 61298862 61298864 TTCCCACCGGATCACTGAGAGAAACGTGGTCCCAGACATTGGCCCACCAA chrl l 61601245 61601247 gtggatcacctgaggtcgggaggccgaggcgggcagatcacctgaggtca chrl l 118210650 118210652 AAG ATGTCCCCCATCAAGTGTACG CG GTTCTG G AAG CG CCCAATAG G CAC chrl9 9944860 9944862 agccgggccaacatgatgaaaccccgtctctactaaaaatacaaaaatta chr5 150140043 150140045 TTTCAGGGGACTTTCCGCTGGTGACGTGGAACCCCAGGAGGTGGCAAGGA chrl l 62918189 62918191 TCAGAATCTGGCCTCCTTTGTGTGCGCGGCAGTGTCTGTCGTATATCTGT chrl l 62918024 62918026 tgcaaccaggatttggatccaggccgtctgcctccgagaccaacctcttg chrl l 62918154 62918156 TTGAATCAGTTAACGATGAGCAATCGGTCCTTCTTTCAGAATCTGGCCTC chrl l 62918143 62918145 CAAGCCCAACTTTGAATCAGTTAACGATGAGCAATCGGTCCTTCTTTCAG chrl l 62918204 62918206 CTTTGTGTGCGCGGCAGTGTCTGTCGTATATCTGTGTGATGTGTGATAAC chrl l 62920510 62920512 G ATATAGG ACTG AG ACCCACCCTG CG G G AG CCCAAG ATACTAG AAACATA chrl l 6333181 6333183 acagtagtaagcctttcatgtgtacgaattaaattaatcctcacaatgac chrl8 58846286 58846288 TTGCAGTCTTTAATGAGGCATTGGCGCGTGTTTGAAGAGCAAGGGAGGGC chrl l 64070739 64070741 AG CAAAACAG CTG CCTG CTCCTCCCG CTG CAATAAAAATG G ATTTATTTG chrl l 64635621 64635623 CCACCCCAGGGAGAAGTTGGCAGGCGGGTGCCTGGGTGAGAGCCTGTGCA chrl l 64638406 64638408 CCAGCACCGCGGCTGCCTCCGGAGCGCAGAAGGCTGGGGTTCGGGAGACC chrl l 64638061 64638063 AGGCGAAGCAGCCAGGAAACATGGCGGTGAAGGCACAAAGACAGACCAGG chrl l 64638423 64638425 TCCGGAGCGCAGAAGGCTGGGGTTCGGGAGACCGCGGGGCTGGGAGGCGT chrl l 64638030 64638032 ACCCAGCGTAGAGAGGCAGACCCCCGACAGGAGGCGAAGCAGCCAGGAAA chrl l 64638487 64638489 CCCTCCCCAGCCGCGCTCCGGAGGCGCCTTCAGCCTCTCACCCCGGCAAG chrl l 64638130 64638132 GGACTGGCCAAGCGTGGGACAGGGCGCACGCGTCCCCGCCCCCGAGGCCC chrl l 64638446 64638448 TCGGGAGACCGCGGGGCTGGGAGGCGTGGCTTCCGCCAGGCCCCTCCCCA chrl l 64638134 64638136 TGGCCAAGCGTGGGACAGGGCGCACGCGTCCCCGCCCCCGAGGCCCGCGG chrl l 64638208 64638210 CTCCCCTGGGATTTATCACCCAGCCGTTCTCACACTGCTGCCAGTTTATT chrl l 64638476 64638478 TTCCGCCAGGCCCCTCCCCAGCCGCGCTCCGGAGGCGCCTTCAGCCTCTC chr6 91513599 91513601 aattttcttagccccaacttcagccgttgtagtgggaattatttatgtac chr3 171894906 171894908 TTG AG G ACAATTTAC AAATTG G CTCG ACTCTG G AG AAAACTTTTG AAG AA chrl l 66316168 66316170 GGCAGCTGTAGCCTTGTGGCCCACCGGGCTCACACTGCTGCTCGCACGGA chrl4 101216074 101216076 CACCCTGAGACATTTGGAAGATGTCGTATTTACCTAACACGCAGTCCTTC chr7 94840949 94840951 tggcagtcaacttttgtctggacccggagacagattcctggagcttacta chrl l 66652738 66652740 TTGGGTTGGTTTcgggcgtggtggcgcatgtcgtagtctcagctactaca chr9 38042823 38042825 TTCTCACTATCCCCACCAAATGTCCG CCCCAG G CCAG GCCAG G CTCTG G G chrl l 66905384 66905386 ACCGG CTGTCCTCGTCTCCAAG G G CG G ACTCCAAG CTG ACTCTGTTCAG G chrl l 131327076 131327078 AG ATCCACTG G CTCTTG CATTCCTCG G G CCTCTG GTGG AAAG CAAATAAA chr5 168880153 168880155 AAGAGACAGCGTGAGAGAGAGATACGAGCCTAAACCCTCACATTGGACTA chr2 42221994 42221996 agcgatttgcctgcctggtcccaacgtgctgggattacaggtgtgagcct chrlS 31612779 31612781 tcataaccaatttcccatgtttctcgtactctttacaatcattttcattt chr22 27488317 27488319 GACCGCAGTGTTTATTGACACACGCGTCTGCTCCCTTGCCCAGCGCCCCG chrl4 103132495 103132497 TG G CAGTG G ACTTG G CCTCCG GGCCGGCAG ACAG G CTCTCCTG G CTCCTG chrl l 70828694 70828696 ggcctggctgcctgccctggctggcgagcgctgggaggctgAGACGGGGA chrl l 70828942 70828944 AAGTTTCTG AG CCAATCACTGCTCCG GCG CTG CTG CCTCTG CG G CCTG CC chrl l 70828959 70828961 ACTGCTCCGGCGCTGCTGCCTCTGCGGCCTGCCATGGTGTGGGGAGAGCC chrl l 70828726 70828728 gggaggctgAGACGGGGATGCCACCGTGTCCGTATTGGTGTGTACAGGGA chr7 6988371 6988373 CCTGCCGGATGtgttgtagttgaacgagttagagaaaatgccacactttg chr7 6988400 6988402 tagagaaaatgccacactttgagacgaattaagagtctgttcatttagcc chrl 232767359 232767361 CCCTGTACTGTTGTAAAGTGCCAACGCATAACCAGGCAGCAATAACAGTT chrl5 88486678 88486680 ctga aa ctgtgatgtttca ttgcccggtgtgca cagca agtca ata tgcc chrl l 73636196 73636198 tcaccattttggtcaggctggtctcgaactcctgacctcaggtgatccac chr7 31007402 31007404 tggtatctgcctcgtgaggtgacacgagaatccgcttagataaccctccc chrl l 75832244 75832246 agttcaattctgatgctatttacccggagttatgacctacaagttaaggg chrl2 122228141 122228143 GCTTCTGATTATTTTGCTCGTTGCCGTAGTTTTTAGTTCAAGACTGTTTT chr4 120659773 120659775 AGAGTCAACTAAAGTCGCATTTGGCGTGCTTATTTTGATGCTTGCCCAGA chrl l 76480559 76480561 tgtgactttattaattcagccatgcggccaaggtatccttagaccagtga chr5 15851430 15851432 AAG CCTTGTTCTTCTCTTCTTGTCCG CCAACAG G CTAG AACTCATTTTAT chr3 196757788 196757790 TCTTCTGGTCAGGAAGATGATCTGCGATAAATACCGAGAATACTCGCGTT chrl4 61690962 61690964 aaagaggtaggctttgttactgttcgtggtgtcagaggctaaaatttcct chrl5 42159095 42159097 TGCTTCTGTGTGGGTATGGCCAGTCGGGACGTGGCGCCACACACTGCTCC chr7 105637154 105637156 TTG G G G ATG G CAATTCCATCTG ACCG CGTCCTCCTG AATG CCTG AG G CTG chr3 180283387 180283389 AG AATTCTG GAG ACTG ACTTAG AG CG CTG G CTTTG CCCCAG G ATCAG G G C chr8 62391722 62391724 TTTTGAAATATAATTTACAGATCACGATGGATAATAAGAAACGTTATCTA chr6 134809530 134809532 GTCAATTTTAACTGTTTCCCACTACGTGACTCAAAATAAATCAAAGTGTT chr4 52055928 52055930 TCCCTAG CATCTACTG CATAGTG G CGTCTCCATAAAATTTCTTG AG AGTA chr6 108804924 108804926 gaacagcttagctcagtcctgtttcggagtctctcagaaggctgcaatca chrl9 29879973 29879975 AACTTTGGAAAGGGTTTTGATTACCGAATGCCAGGCTCTCTTTCAGTCGG chrl 17411021 17411023 AGACTCCAAGGGTGTGCAGAGCCCCGAGAAAAAGGTGCATTCACCATCCA chrl6 6529078 6529080 AAAACAAAAAAACTTCTTGTAAACCGCCCCCAAATTCTAGCTGCCACCTT chrl 191351740 191351742 actaaatttaattttattgtataacgatgttatattttgacacataactt chrl l 70552247 70552249 tgcctgcgaacaaacgcacacaggcgagCAGACAGAGTGGGCCT CTCCTG chrl l 8334015 8334017 GGCCTGCATGGCAGGATGGGTTGCCGGTCAGTCTGCCTGAAGGCGGCAGT chrl l 89375694 89375696 AATATTATCTGCAAAAACCACCCACGATTTAACTATATACTACTGAAGGC chr2 127132369 127132371 ATCCGAAGGTGAGTGGTATTTAAACGTATGATGAGGGTAAGATTTGATTT chrl l 94158916 94158918 gatagctcttattattttgagatacgtgccatcaatacgtaatttattga chr20 62225257 62225259 TGGTGCCCAGAAAAGCTGATGGTGCGCCCAGGTGCTGTCCCCGCAGTGCT chrl l 94800334 94800336 G GTG ATTATCAACTG CAG ACGTTTCGTG CG G CTTTTCAAAATTCAATAGT chrl l 94800276 94800278 GTGAGAACAGATGTGGCCGTCCTGCGGTACCAGCCACCCCCTGAGTATGG chr5 89474124 89474126 tgggattacaggcgtgagccaccacgactggccCAAGTTTTTAATAATTT chrl l 99359783 99359785 gagcctctgaaatcgagcaagttacgtgcttctgaaatgcagtagtacga chr4 150828760 150828762 TTCTAAAAAAGCAAAAACTAATTACGTATTCTACAGAATGTACTGAGTGG chr4 150828760 150828762 TTCTAAAAAAGCAAAAACTAATTACGTATTCTACAGAATGTACTGAGTGG chrl2 104666538 104666540 ttgcaactcgtttgcctctgtctgcgtgttgaattctagagggtgcgatg chrl2 104666490 104666492 AGATAGGACTATCCAATTTCCTTCCGTTGTTCTTGGGACTCTGTGTTttt chrl4 68569744 68569746 G GAG CCG ACAGCACCACG GG CTCTCGGGTTTG CCATG G AACCG GGCCTG A chrl 9529013 9529015 gtcaatatgactaaagcgcAGAGCCGGCACTCTCTGGATGTTCGCTAGGG chr21 16589675 16589677 TTGCTCAAATAACTACAGAGTATGCGTGGAAATATTTGCTGTCTGAATAG chrl3 112970862 112970864 TG AATGTCGTG CGAGCCGGGCGCTCG GTGTG GG CCATCGTCTCATCTG GA chrl9 55485668 55485670 CTTATGTTCTCACCAG GTGCACGACGCCAG CTCCCTTCTG GGGGGCCGGG chr7 90709817 90709819 CATCCCCCTCTCTTG GTTGTAGTACG G CCGTACCATTTCAG CTTG CTAGT chr21 33824631 33824633 GTGTATACTGGGCTCTTACATGTGCGGCTCCGTGTACTCGGAGCTGCTCT chr4 149008859 149008861 AATGCTGTGCTCTGGATGCAATAGCGCATGCCTGAGTGAGGAGAGGCAAA chrl2 111199420 111199422 TGCCCACAAACattatccccattgcgcagattaggaaacagactcaggcg chr7 102107431 102107433 cacatgcctgtaatcccagctactcgggaggctgaggcaggagaattgct chrl2 111363167 111363169 GCGGCCAGCACGTAGGTGCGCGCCCGGGTCCCCGCAAAGCGCACAGCGAA chrl2 111363249 111363251 CAGTGCAGCCCTCCAGGATGATGACGCCCACGGGCTCACGGCTGGCAGCG chrl2 116980578 116980580 CCAAATCCATTTCATTG CTAG GTCCG CAGTATG ATAACACTTG ACCTTTC chrl5 58958301 58958303 cggttcactgcaacctccacctcccggcttcaagtgattatcctgcctca chrl2 117087702 117087704 TAACCACCATGTGCTttagctgggcgtgctggtgcacgtctgtcatccca chr6 37713585 37713587 TCATTTCTCCCCTGG ATTATG CAG CG G CTTCCTG CTTCCAG CCCACACAT chr9 131063253 131063255 TG CG G G ACCCTG CACCCCACTG G CCG CCATG CTGTCCCTCCATTCTCGTT chr22 19354500 19354502 ACATG G CCTGG G CCCTGTAG CTAG CG AG CAATG CCAG GCCTCTACCTG CC chrl2 119340812 119340814 G GTTTTTGTTAAAG GTG ACGTCAG CG CTC AGTG ATCTCTCTG G CCTCTAA chrl 197451335 197451337 GGCCAGGTGGAAAAATGACATTTGCGAATTTTAGTTGAGCAAAGTGTAGT chr4 38077991 38077993 GAAGCGGGATGAAAGCAGACCAGACGCTAGAGTCCACTTTCAAGTCCGAT chrl4 61417278 61417280 CCCAATTG CTTTACCACATAG AACCGTCATTACTTTCCCTCTTTTTGG CG chrl2 121507866 121507868 tctacaaaaaaattaaaaattagccgagcatggtggcatgcacctgtagt chr9 109388040 109388042 gagtagcacagcgaggctggggagcgggggtggactccagccagctgcac chr7 5834355 5834357 a ggcgtga gccactgtgcccagccCGATG CCTTGTAAATTT ATATCTG AC chrl7 2266557 2266559 GCGTTTGCAGCATGGCTTATGTCACGTCTCAACCCCAGAAAGATGAAGAG chrl4 84090996 84090998 caggcttgaggttgtccgctccttcggcttggcttctccctgctgtctca chrl5 96288168 96288170 gcattgcagaactggccagatgcacgatggctcgtatttttgccgtcttc chrl2 125905569 125905571 AAGAATGAAGCCTTGAGATACAGACGGAAGAGGCTCCTTTTAATAAAGAT chr2 36127495 36127497 cggctaaaatattctttgattctGCGCTCCCATTCTTGGGGTATGTTTTA chrl2 127115077 127115079 TTTCTTTCTG CCAGTGTGTGAATG CGTG G AG ACACACACACACAATTG AC chr8 29052797 29052799 ACAACTGCTGTGGATTTTCTGCCTCGCTCCATCTCTCCTATGTATAATGA chr4 150185691 150185693 agcgtcattgtactccagcctgggcgacagagtgagatttcatctcaaaa chr4 150185669 150185671 ggaggttgcagtgagctgagatagcgtcattgtactccagcctgggcgac chr2 236121881 236121883 gaggcctctctcacggctggtagacggccgccctctccctatgttctcac chr2 79929386 79929388 taaaagaaaaaaagggacgtattccgaaactgtatgtatgaccacaggga chrl 27249955 27249957 GTCACGATTTTCCTTCTGATCTTGCGTTTCAAACCTAACAGGTGATAAAG chr9 136323313 136323315 ggactccctaggatttactggggacggccgatttgccctcctcatcctgt chr9 134111490 134111492 ttggccacagactgaaagctgcaccgtcggctttcctacttttgaggttt chrl2 131102283 131102285 GATTAATGGGAGTAGCTCTTGGCCCGTCGGTCTGCAGGTGGAGATGTTTG chr9 68830859 68830861 GCTTAATATAAGCAGGTGTTCACTCGCTTCCCTGCACAGCTCAGCCAACC chr5 148966479 148966481 CAAAG G CCCTTAAG CTGTGTCCAACG CTG CCCTG CG G AAG CCCAG G CG CC chr6 146685764 146685766 TGCAATACAGACCTCTCATATGGTCGTATATGCGACATTTACACCTCTTT chrl2 17254791 17254793 taacagaatatcctaaaactttggcgttaaaaacataaatatttattctc chr7 69099312 69099314 CCAAAACTTAAATTGTGCATTCCCCGGTCTTGGAGAAGCGCTGGGAGAAG chr7 69099312 69099314 CCAAAACTTAAATTGTG CATTCCCCG GTCTTGG AG AAG CG CTG G G AG AAG chr20 60889288 60889290 CTAAATGTCCTCTCTGAAATTGCCCGATAATTCACTCTTTATGCAGCTCT chrl2 2081518 2081520 cgggaggtggagcttgcagtgagccgagatcgcgccactgcactccagcc chr8 118694978 118694980 ctttatcccattgtcttggctattcgtacttctcttccttttaggtaagc chr8 118694978 118694980 ctttatcccattgtcttggctattcgtacttctcttccttttaggtaagc chrl2 79364491 79364493 TCAAAGGAAGTCAAAAGACCATACCGGCTGACAGCCTTTTTAAATTACTA

> chrl2 2465968 2465970 TTTTTTAAAACATTCTTACTGATACGATGAATATTGACTTAAAAATTGCT chrl6 75322268 75322270 TCCCAGATATCACCAACACTATTTCGGATCTGTGTTTTTAAAGCACTTGG chrl6 75322268 75322270 TCCCAGATATCACCAACACTATTTCGGATCTGTGTTTTTAAAGCACTTGG chrl2 30766914 30766916 gctttgcagaggacccagctaaaccgtgccaggctgctacatttgtggta chrl3 103071728 103071730 AATTCCTGTAAATCCATG ACCTTG CG GTG G CTG ATT ATATT ATTG CTGTC chrl3 27517013 27517015 TACAGTTTTCCAATCAAAGAGGCACGAATAGGTTATTCCCTCCCCAATCC chrl5 73421182 73421184 caca ataatagctcgctgca acctcga actcctgggctca agcga ccctc chrl9 8066187 8066189 CCGGCCGGAGCTCCAGGATGCGCTCGGCCCGGCCCAGGTGTGAGAGGTTC chrl2 4387265 4387267 tttgtcaaaacccgtagaactgtacgacacaaagagtagaccctaatgca chr22 48824652 48824654 TCCTTTCTCCTTGATTTACAAATACGCTTTCTGCATAGACAAACACCACG chr4 7551934 7551936 AG AATAATTACATG G GTAATTGTGTGTCGTAATCG G CAG CGTTG CCTG CT chrl 38418368 38418370 caagtttatacggatatcactgaacgtaacccagcaccacagggttcact chrl2 47947292 47947294 GCCTGGGAAGCCAGCACAGTGTCCCGTCCCCACCACCAACCACCTGATAG chrl2 48788525 48788527 G GG CATCCCTCCCTCTG CCCAG G CCG GTTCCTCTCCCCTAAATG G AATCT chrl7 48831635 48831637 TCTAGGCAGGAGGAAAGACGGTGTCGTGACCTGCCTCTACAGTTAATCCA chrl2 53274354 53274356 tgaatggagtgcaggagaaaagaccgggtaatcaggctgctatagtattc chrl2 53274417 53274419 gtgggctgaactgaagcagctgcacgagggatggaatgcagtggatcggt chr4 53508148 53508150 G GAG GG AGCCGTGG CTGTG AGGCTCG CACAG CCGTCTGG ACAG CCATCTT chr5 30772245 30772247 tatcctacacaccataaggtaaggcgagaatatagatatagcttgaggaa chr2 159188769 159188771 CAAG CCTCTTCTG GTCCTCATG ATCGTATTG CCTCG CATATCCCCAG CTC chrl8 74833726 74833728 acagaggtttaagatcttgtttatcgtttgaaagttcactctggctgact chr2 238327106 238327108 TTCTCTCCCTTCAGATCCTTCTCTCGTTTCCCATATCTGAGCCCTCCATT chr2 233170602 233170604 GGAGCAGAAGGTCTTCCTACACTTCGGTAAGAGCAGCAACCCCggctggg chr8 65188438 65188440 CAG ATG GTTGTCACAAACTG CATACG G CAATTG AG AATTAGTGTACAAG C chr7 151652356 151652358 ctgaagcagatctgagaattccaccgaattcttctaacccagacatgaaa chrl2 70443965 70443967 GAAATTTTATTGCTTTCTCACTTACGTTTCCTTCCCTGGTAGTACCATAA chr5 78701917 78701919 TAACAACACTAAG ATTG G GTACATCG CCAAG AG CTCCCAACATTTCTAG A chr8 9901380 9901382 TTTTACAG G AG G GCAG CACATCAG CG AAG G GTACAG CAACCTCTG AAG G A chrl7 45240201 45240203 gagagaatggcaagtgactgctgacgcctgtggggtttctttttgggctg chr8 61697578 61697580 acttcagaccaactggctataaatcggagttcccaacaccccctcctcca chr5 24856145 24856147 gcaatcatctcttatattgtctatcgcctatatagaaaaggaaGTCCTGA chr6 143432179 143432181 CTTGGTAGAGCATAGAGCTGGTAACGTTCATTGAATAAAAACTCCAACAG chrl6 1633341 1633343 G CCG CAG ACACCCCCTG CCCACCACG CAG CTAG CTTCTCCACTG AAG AAC chr3 47422872 47422874 CCCACAACAACCACATCCAACCTCCG CATGTG GTTCTTGTCTG GTCTG CA chrl9 49913135 49913137 AGGGAAAGGATGGCGGGGGAGAGGCGCCGTCCACGCGGGAGGAAAGGCCT chrl2 77308440 77308442 CACAAAACCAATATTTTTCAAATTCGATTAATTATATTTGATGCTAAACC chr3 122908926 122908928 TG CTAAAG GAG CAG G CAG AACTCTCG CCTGTTTTGTCG CCTTTG GTGTAC chrl2 78560885 78560887 GATGGTGTTCACTTATGCAGGGGACGCAGATGAAACGGCATGGTGGAGGT chr7 52571138 52571140 AACTGAATAACGAGACAGCTAAAGCGAAGTTATCTGTGTGGGCAGTCATT chrl2 88450938 88450940 AGTTTTACGAACTCATCAAAGATCCGTAAGCAATTTATATAGGAACTTCA chrl2 88451104 88451106 AGTATTCTGAAGTTGGCAGGGTATCGAGGACTCAGAGTTCAATACTTGAA chrl7 78665984 78665986 TATTCCTCAAAGCCGTCCCTGTGGCGTGCtgataacctatcgggtcacat chr7 2954193 2954195 TAGAAAGCCTTCCTCCCGGGACCCCGGGTGACCCGGTGCAGCCACCTCAG chrl2 91615051 91615053 aacaggcacttaaaatattagttACGTCTTCCCAATAACAGTGAAATAAA chr2 22575886 22575888 ACTATGATACACCCTGCAATTGTACGTGAGTGACAGGCAGCTTAGAGAGC chrl5 58712954 58712956 CGAGGACTGAGAGAAAACAAATTTCGAACAAAAATCCTGCATCCCACAAT chr2 122162513 122162515 CTG CG CACTAAAG ACTTAG CATCCCG G G AATTTATTCTCAACATTAATG G chrl2 93894724 93894726 AGGCCCACAGCCCCCGCCAGCTGCCGGCCCGTGGTATTTGGGGACGGCTG chrl2 93894744 93894746 CTGCCGGCCCGTGGTATTTGGGGACGGCTGTTGCTCAGAGACACCTGGGA chrl2 93894790 93894792 GGGAATAGGCCGGGGCCGAGATGGCGCTGAGCACTCGGTCTCCCCTTCAG chrl2 93894714 93894716 AGTTCCACAGAGGCCCACAGCCCCCGCCAGCTGCCGGCCCGTGGTATTTG chrl2 94695777 94695779 GTTGTCCTCCAACTAATCCATTGCCGGACTTTTTCCAAATGCACACTTAC chr9 127496263 127496265 G AACACCTG CCCATCTG CCCCAG CCG CCTGTGTGTGCCCTG CACACTGTC chrl2 95356097 95356099 GATTGGGTTTTGACTTCGTAAATTCGAAAGTCTGAATAAACATTTTGGAG chrl2 129703529 129703531 ATGGTCCACGATGCACAGAATGAACGAAGTAAAACTCATTATCCTCTCAT chr9 114804274 114804276 agtagcagtgagtaaaaaagaccccgtgccttccttcaccgagcttcccg chr7 69099326 69099328 GTGCATTCCCCGGTCTTGGAGAAGCGCTGGGAGAAGGATGTTTACCATAC chrl5 48140618 48140620 G ATTAATG AACGTTCCCCCTCCCCCG CCCTG CCAAAG CCCACTAAATTAA chrl3 104738052 104738054 GTGGCGGGGTGTTAAAGCCATCCACGAGCAGAGATCGCCGGTAACACATC chr3 123653613 123653615 TCTGAAGGCCCAGAGAGGGTTCAGCGGGCTGATGGCAGGGAACAAGGGAG chr20 7866427 7866429 ATGACTTCATTCAGGGCTACGGCTCGCGCATGGAAAGTGCTGGTAAAAAA chrl8 57139112 57139114 G ACCTCCAACGTTCATTGCCCTTTCGTG AACTTGTCAAG G AGTCCTTG G C chr3 150556578 150556580 tatgataatgacatctagtttttgcgttggaatgttgtggcatgaaagat chr3 134660205 134660207 G CATGTTCAATTCCTGTGG CCTG CCG GTCCCCTCCCCACAG G G CTCTG CT chr5 95503240 95503242 GTG ACAATCCCTAACTTCTACGTTCG G AATCTATATG GG G ATCTAG GTCA chrl9 38221003 38221005 TCAGG AAG ATTCTCCCAG ACACTCCG AG G CACCCACACACCCACAG AAAG chr2 86421142 86421144 CCTATTCTGTG AGTCCTG CAAG AACG ATAATG AAG G CTTG GTG CTCAGCC chr3 13191245 13191247 ACTAAACTCATCTTTCTGCATCCTCGCTGGGCTGTCCGCCCGATTCCTCA chr8 27662591 27662593 aggcaaatctatatccagggcaagcgtctattctggtaaaaatattgccc chrl3 24242600 24242602 CTCATCGTAAAATGGGGGTAATTACGTCTTCTTTGCTTCTTTGAAAATAT chr2 239420572 239420574 GGGGGGTTGGGTCAATGACACATACGTGACTTGATTCGCTGGGAGGAAAC chr4 89379269 89379271 GTTTCTCCTCAGCTGTACAGCAAACGCAAGCTTGAAACCATCCAGTGGCC chr2 100923151 100923153 AGACTCCGCAACATCTTGCTGCCACGCCTGCAGTTAGTGTGTGATGTGAG chrl4 72738631 72738633 GGGCAGCATTTCCAAAGGCAAGGTCggggaatcaggagaggctggtcaga chrl7 11326585 11326587 TG ACATG G CACCATATTTG GCCAG CG CCTCAACCTTCCG AATCCTAG ACC chr7 54795471 54795473 TATGTTTTGTCAAGCCATCACAGACGGATGTGCATTTTCTTCCCGAGAAC chrl3 27238208 27238210 cctccagccaaccatcatactgatcggaaagcacaatgttacagcgctgt chrl5 100032792 100032794 tgggaaagctacttaatgactaagcgtctcgaagtcttcatctgtaaaat chrl6 56871247 56871249 CTTGTGCTCCCTCCATCCCTGCGCCGTGGCCTTTGTCCACCTGGTCCACC chr6 37684799 37684801 AAGAAAAGTGAATTCAGGTCTTGCCGTGGCACAGAACTTCAGCTTGCCTT chr9 126414292 126414294 CATGTATTTAGCTGGAGCCGTCATCGCTGGCAGTGCGTGCTTGCTGACCT chr2 170158816 170158818 TTCCCCAACCCTGATAGTCTCTGGCGATCTCTTGGTGATCTCACCTCTCA chr3 126774624 126774626 ccaccgacagggaaggcctcaccacgcttgggtggtagtcagagctccac chrl3 33724973 33724975 TTAG AAAGTAG CAAACCAG G CATTCG G G G CCTTG CTGG G G CTG GCCATG C chr2 211228268 211228270 tccacacaagaaagcaccttcatacgaactaaaaatcaggtgagcaatca chr7 17586547 17586549 TTGACGGGGGTCAGAAGTCCAAGTCGATGGTGACTTGGCTGCAATGAGAT chr5 58754333 58754335 TG ATTGTG GTCTG G ATATCATTGTCG G AAG G G CACG CTCCTTACTTTG G G chrl3 35695164 35695166 CTCTGAATCTCCCCCATGCCTCTCCGCTTCTTCTCTCTCCACGCCCTATG chrl6 87957932 87957934 AG CTCTTGTGTCG GTG G G AG CTG G CG GTG G GTCCCTG AG CAG AGTG CTG C chrl3 41465311 41465313 GTTTTAACCAGGAAGGCTGTTCCCCGTGACCTCAGGGGCCACATCCTGCT chrl6 86757258 86757260 TCCTTCCTGTCTCTGTGGAGCCCCCGCCGCTCACTGTCCTTCCCTCTCAC chrl3 44573330 44573332 CCAACTAAGGAGGGCTCCGCTGCACGCCTGGCATCTTCAATTTGGCTTCC chr3 112000443 112000445 TCCTCCTTTG AAAGTCTAG AATCACGTCCTCATCACGTCACATCATTCCC chrl3 45223370 45223372 CGTG CACCCCTTATG AG G CTAATACG AACAAG AAATACATAAAATTAATT chr2 236442644 236442646 cctcaggtctcggtcactggaaaacgatgctttgcagaattatgtgggtg chr8 80345362 80345364 agattctggatattagtcctttgtcggatgtacagattgtgaagattttc chrl3 93413326 93413328 ATTG CAG G GTTTAATAATC AATATCG CTGCAACTG AGTCTATTTAAAAAT chr20 5670261 5670263 GTGTTGCAACAGAAGCACTCAAGACGCAACAGTGAAATTCACTAGCAGAA chrl3 73026371 73026373 TATTTCTAATACTGCAATCAGAGTCGTAATGTGTCTCTTTTACTTTCAGT chrl3 78061219 78061221 cttgaaaacctgccccaggctatgcgcctcccagctgtgaaagagaaagc chr7 149730029 149730031 GCAGCCATTTAGGGTCCACTAGAACGCATGCTGATCGTGGGCTGAGCTGA chr20 55284577 55284579 GGTAGTATATGTAACGGATCTTTGCGATTTTTTATGAATATAATATAAAT chrl3 92046041 92046043 ggagaatggcttgaacccgggaggcggcagttgcagtgacccaagatcgc chrl3 98404428 98404430 CTGAGCCCCAACTTAGATATCAGACGCTAGTGAGTCCTGCCTATTCAGGA chrlS 61832637 61832639 atttgttagaagaGGATTATGGAACGCTTTGGTTGATAAAGAAAGAGGAA chrl4 100572028 100572030 GTGTTGGCCTGAACGAATGCAGTGCGTCTTAATCCCCAGCCAGAGGCACC chrl9 38470895 38470897 GAAGGATCCTAGAGGTGGCTGGGACGGGGCAGTACTGCAGAGTGGACGCA chrl5 77976043 77976045 GCATCCTCCCATCCCATCTCTAGCCATGGATGGGGCCTGTGCCTGGACGA chr3 140501227 140501229 ATAATTAAGTTCCTG AAATTCCATCG CTTCCTCATTAAG CTAAG G G ATAA chrl4 104963567 104963569 cttctggccaggcgcggtggctcacgcctgtaatcccaacactttgggag chrl 210626571 210626573 GTCTG CTG G GGTTTTG G CAGTTG CCG CTTCGTCTATTCCTTG CTGTG G GT chr9 35350760 35350762 ACCATTGTCCTTTCTCCAAGTGAACGGTTGCCATCACTCAACAAAGGGAA chrl4 28309117 28309119 ttgatcccacttgtttaaaatttccgttgaaagtgccgctcttgtctgca chrl 61973801 61973803 TTCCTAAAATTACATTTG G CTTTTCG CAATGCTGTTTTCAAAATTAAAG C chrl4 31488551 31488553 TTTAAAAG GTTAATAAACTTGTTTCG G GTGTTAATTCCCTTCTCGTATTG chrl4 36524667 36524669 TGGGGGGTGGGGCG CCAAGTCATCCG AG CGCG G CTTCTG CTTCTCCCTTT chrl4 36524389 36524391 GCGCTGCTCCGCAACCCCAAGATCCGAGGAATGCCTCCGGGGGATGATTT chr2 8811580 8811582 aacgttcacagaacattagacaatcggttgtatctaaaacacagcatata chr3 22857045 22857047 CCTAAATATCTTGGAGAAAACTGACGAGAAAACTGGAGATGCACTCTGTT chr3 188051674 188051676 ctcccaaagtgctgggattacaggcgtgagccaccgcgcccACCCCAAGG chrl4 52941165 52941167 aaactattgatacaaacacatgaacgaagctaacatgtattatgctaagt chr6 65498438 65498440 CAAATTTATTTCCACATGTAAATGCGAGGAAACAAATTACATTTGCATTG chrlS 31578184 31578186 aatgcaGGTGGGAAAAGAAGGACACGATCAGTGGATGGAACAAGGAGCAC chr9 89240725 89240727 ggtaaaagatgtaaacagacatttcgctgaagaggacatacagatggcaa chr8 118707989 118707991 TGTAG CATCTCATTTTCACAGTG G CG GTTGTTACTGTTAATAATTG AATC chr3 197800521 197800523 gatgattccaagtactggaaagaacgtggagcagtggagacactcatacg chrl4 58598388 58598390 CATTGTAATTTTGGAGGTGGGAGGCGAGGGTGGGAGGAGAAATGGGAATG chr7 67453619 67453621 TGCTTCTATCTAACCTCCCTGCGCCGTGAAAAGCTGCTTATATACCAGCA chrl6 85452156 85452158 TGAAACGAATGGGAGTGCTGAAGCCGTTTGCCACCCTGGCCTGCATCGGG chrl4 62814638 62814640 tctactaaaaatacaaaaatta gccgggtgtggtggca ggca cctgt a gt chrl6 3255898 3255900 gaggatcacttgaggtcaggagttcgagaccagcctggccaacatggtga chrl7 75002178 75002180 CTCCGGGAGAAGCGGGAACGCAGGCGTACCATCCACACCTTCCCCTGCCT chr21 31599647 31599649 CCCACTATGTTCCACG ATCCAAACCG AAATG CTG G AAG GTAAATATATTT chrl4 65594301 65594303 tttggtctgcctggctccacccctcgcaggagggagcatgcaagtgagtg chr22 47035212 47035214 TCTGCTGCCAGGGACCCCCACCcccgcctgcctccggggcctgcctggcc chr5 162977137 162977139 ATCAAAACACATTACCAG CACCAG CG CTTCTATCACACATCTTTG CAAGT chr2 230465348 230465350 ggaagttgaggctgcagtgagttacgattgtgccactgcactctagcctg chrl4 72746410 72746412 CATTCTGGGAGCCAGGTGCAGCCCCGGCTGTTCAGACTCAGAAGAGGATT chrl4 72746337 72746339 GTTACCACTGACTCCAGGGCACTCCGACGGCCTCTTCATTCACCACCCGC chr9 121699909 121699911 GTTTGGCCGAGACCGGGCGCTGCCCGTGGTGAGGGGAAGGGTGAACATCT chr3 158094973 158094975 CCCGCAAGGCCTGCGCACTGAATACGGCCCAAATCCTGTTCAGTGGTCTT chrl9 13804816 13804818 ATTCCACCTGAGCGGAAACATCCGCGAGCCAGGGAGTCCTGGAGAGCCCG chrl6 90002798 90002800 CG G G CACTG CTGTCTGTG CTGTAG CG GTCTGTG CACCCTG CAG G G ACACG chrl4 91028417 91028419 atttgtagaggcaaggtcttcctacgttgcccaggctggtctcaaatcct chrl6 79856776 79856778 catctgggtcgcactctccctcaccgcttcctttggctgtggcgagaggg chr7 114399231 114399233 agtgattctcctgactcagcctcccgagtagctgtgattacaggcacctg chr7 131603062 131603064 CCTGTG CG G ATG G AG AG ACAAACACG CCAACACATG CCTAG ACAAACAGT chr2 90095397 90095399 atgtaaggtagaatttttatgatacggctccgttgactggaggaacacca chr7 40828899 40828901 GCGGTTTGGACCGCATGACTTTAGCGGTTTGGGGGCATGACTTTAGTTGT chrl4 99239938 99239940 CCAATAAAAAG AACATAAAG AAAACG G AGTG CCCAG CAAG G AG GTTATTG chrl4 99239873 99239875 AACAGAAGGAGGAAGGCTGAGCTGCGAGAATCCCGGAGAATTAAGAATGA chrl4 99240729 99240731 CATCTCCTAACACACTAG CG GTG ACGTG CAGTG CGTG CACAACAAAATGT chrl4 99240690 99240692 GCCACCTTCTTACTTATTTTTTGACGTGAAATCCGTTTTCATCTCCTAAC chrl4 99245037 99245039 GGTAAACTTTTAATCGGCTACAGGCGAACAGTATACAGTTTTATTTCCAG chrl4 99244159 99244161 CCAAACATACAGGGAGAAATCACGCGTAATTCTGATCACTGTTGAGCCGT chrl4 99244383 99244385 ACTGCAG AG ACCTAG G ATG G G G CCCGTCAAACACACACACACATAATTAG chrl4 99261349 99261351 ATGTGTCCCTCCTTAGAACTGTATCGATAATGGAAGAAATAAAAGGAGAA chrl4 99265134 99265136 CCG CAAAGTG ACAAAG CATACTCACG G CAG CTG G ATG ACACAG ACATTCA chrl4 99245125 99245127 GAGCTTTGTGGTGGACAGGCTGGGCGTCCAACCACTGCTTTTCTGGGCCT chrl4 99258195 99258197 cCCTGGCTGCTGACAGCATGAGGTCGTGATgtgtctctcaaagtttccag chrl4 99253114 99253116 cataacccaaaaaggaggtgcagacgaggaaacggaggccaagaaaagtg chrl4 99254307 99254309 AATTACTCTCCAGAATGACTATCCCGAGGAAACAGCTGATATGGGGTCCC chrl4 99259778 99259780 AAAATG G GTTTG AAG ACAATG CC ACGTAATTAATTTACCAATTTATTTTA chrl4 99259851 99259853 AAAATGTAATCACAACCTTCCCACCG AACAG AG GTTCTAG G G AAG ACTG G chrl4 99261299 99261301 CTG G CAG G CAG ATACCAAGCTAG G CGTGTAG G GTG CCTG CATATGTGTG C chrl4 99265442 99265444 TGGGAGATGAAGGAGAGTCTCCAACGGACAAGAACCTGACCCCCTCCCAT chrl5 101045497 101045499 TTCTAACTTTTAAG G CAATCG CGTCGTGTCAACG G G CCAAG AATAATAAA chrl5 101045494 101045496 CTATTCTAACTTTTAAGGCAATCGCGTCGTGTCAACGGGCCAAGAATAAT chrl5 101709644 101709646 gatgttcctatagtcatcaccacccggcagcagatggctgcttgtgcatt chrl 244087973 244087975 gcagaatatataacccagcttcctcgcccccgaccagggacctagcctgt chrl5 27598866 27598868 CTGTGTCTG G GTG AG CAG AG G G CCCG AAACAATCAG G CAG G CCTG ACCAG chr2 131406273 131406275 gcttacaaatttttatcagtgaatcgtattccattgggtccatgtaatgg chr6 60830914 60830916 tgagtcaggagaatggtatgaacccgggaggtggagcttgcagtgagcca chrl5 39667040 39667042 TCCTTACTATCACAAG ACAGTG G G CG CTGTG AAAAG ATG GCCTAGTG GTT chr8 8575133 8575135 CTTGTAGTCTCTGCCTCAGTTCTCCGGTGCTAAATGGTTGTTCTTCTCAG chrl5 39961524 39961526 CACAG CATTG G G CAG CACAG ACCTCG AGTTAG G G GTTTGTG GTTTTCATG chrl5 40579060 40579062 CATATGGAGCAGAAGTAGTGTAGGCGGGGAAAGCAATTGTGTTTATATTC chr6 137290533 137290535 atccccagtccgaatgcactttttcgtctgtcttctctcagcacctgttt chr20 9493674 9493676 AAGAAATAGAAACAACAAAAGTCCCGAATAATCTAAAATAAGGTACTCTT chrl5 42506523 42506525 agtgccagagttacaggcatgagccgctgtgcctagccAATAGACTTCTT chrl5 51015399 51015401 atctaatctagacgtgtttttcatcgcagatattacatttttcatctcta chr7 146691141 146691143 TAACTACTTTAACCAAACAATTTCCGCCATTTTCTTAATATTTCCATTGG chr3 47689722 47689724 AATAACAGATACAGGACTTGATTACGATTCTTGTCTCCTGAGTTTTGCTA chr3 47689722 47689724 AATAACAGATACAGGACTTGATTACGATTCTTGTCTCCTGAGTTTTGCTA chrl5 60850769 60850771 CTGGTGCAGCATCCTCCCAGCCCACGTCTTCCCTGCTGATCACTTTAAGA chr5 74397232 74397234 gcccacagacatgttttatttgcccgtgtcgtatatcttaacaattgaga chr5 74397237 74397239 cagacatgttttatttgcccgtgtcgtatatcttaacaattgagaaattt chrl5 64673973 64673975 CGCAATGGCCGGGGTAGAGGCAAACGCATGCGTCCCAACAGTAATACACC chr5 1554827 1554829 CCTGGTGGAAACCAGCCGTGTGGCCGAGGGCAGGCGCGTGCCGGGAAGTG chr5 89120992 89120994 TATGTTACACTGCAAAGCATGAGACGGGTTCAATGGAGCGAGTCTGAGCA chr2 169415560 169415562 ACCAGCTTTCAAAAACCATTATTCCGTCCTTGACTATCACTTGAATACAT chrl5 73787074 73787076 AATAATTCACTAG CG G CTGTTTACCG CAG CCCTC CAGTG CCAG G CTTTG G chrl5 73787063 73787065 ACTTGGCAAATAATAATTCACTAGCGGCTGTTTACCGCAGCCCTCCAGTG chr6 118577805 118577807 ttctagaattcttctctagtctcacggaaaaatggtttagaaaatggaag chrl5 98347522 98347524 AATACAACCAG CCACGGTTAG GCCCG G AG ATC AACAAG G ACACCCAAG CA chrl5 75706213 75706215 TGCTCTTAGGTGGGAACGGAAGTTCGTCTCCTCTCCCCAGCCCCCTCTGT chrl5 75706205 75706207 GAAGGGGCTGCTCTTAGGTGGGAACGGAAGTTCGTCTCCTCTCCCCAGCC chrl5 78344315 78344317 ctctactaaaaatacaaaattagccgggcgtggtggcatatgcctgtaat chrlS 78344288 78344290 agcctgatcaatatggagaaaccccgtctctactaaaaatacaaaattag chr4 578126 578128 GAGAGTGCAGATTTTAGAACCTCGCGAACGGTCCTGTATCTCCTGCACGA chr4 8868232 8868234 CTCCGTG CCG G CCG CCG G G CCACG CG CCG CCAG CTCCG CTG CCTCCCG CT chr5 151520158 151520160 CAAATCTTCTGAGAAATGATATCCCGAATGCCAGGCAGCTGGACCCATAA chrl5 84784380 84784382 G CTCCAACCCCGTG CCCCTCTATG CG CCAAATCTCAG CCCGCCTG CG G AC chrl5 86311581 86311583 TG AATTAAG ATTCCAACCAAAACCCG GGTTTTCTCCGG GG CTTCCTATTT chr3 62807299 62807301 tttgagacgtagttttgctcttgtcgcccaggctggagggcactggcgtg chrl5 90065084 90065086 CAGATGCACCCTGACCCCCCAGGCCGAGGTTTCCTTCTATCTGATCCCTT chr2 161621740 161621742 G G AACTG AAAGTACATTG AATCCACG CTG ATTTG CTTACTTAAG G G ATTA chr3 197606574 197606576 CAGGTTTTGCTACAAAATGAACTACGTTTGGTAACTCACAGGGCACCTCC chrl5 90946906 90946908 AGAAGGACAGCATCCGCATCCGGGCGCTAGTGGTGAGACGGTGGGCCTGG chr21 37606568 37606570 AG G AAAATCAG G ACG AAATACACACG ATGTCCCAG G GTTTGTTTCACCAA

> chr7 71592009 71592011 CTTCTCTTG C AAAG ATG CCAAG G G CG CAG ATG G AG CTGTCCGTCTGTCAG chrl 41767337 41767339 CAAAG CAG ATACAG CTCCCCCAACCG CTAG AG CTCTG GTTTCATG GCG G G chrlS 92971963 92971965 TCATAATTACTTTCTCAAAAAAAACGCTTAGTTTCTCTAGGTGCTTTTCA chrl6 71746304 71746306 a tta caggcgtgagcca cca cgcccggccT CCCACTT CTT AACT AAAT AA chrl6 71746300 71746302 tgggattacaggcgtgagccaccacgcccggccTCCCACTTCTTAACTAA chr7 150451230 150451232 TGCGGAGCCTCGGAGACTGTGGGACGCCGTGGGACCCCATGGGACACGAC chrl7 21405634 21405636 CAGGCCCTGCCCTCCCCTGCGGGACGCTGTGGGCCAGCCCGGCCTGTTGG chr6 158528243 158528245 ggtgaggctgtgga a a atagga acgctttta ca ctgttggtggga atgt chr20 43564715 43564717 ACTGATATGTACCACACAGAGACACGCTGAAACACATCCATATGCACACC chr3 112508351 112508353 gcactagcacttcatcctgctactcgggtaagtcaagcaggctctggtag chrl7 8310790 8310792 AG G G GG G G GTGTCCG GTTG G G AG G CG G ATCTG ATTCCTGTTTCCTG CCCC chrl6 21514377 21514379 AG CATTG CTTG AATTTCC AGTACACG CTG CCAAGTCTTCATCAAG CAATA chrl6 21514493 21514495 CTGGTTCCTCTCATCTTTATGACCCGTGAAAAGCGCACCAACACGAAGAC chrl 83627211 83627213 G GTCACAG GTCATCAAATCAGTC ACG CAATG CCAC ATAAAGTAG CAG G CT chr8 140608236 140608238 G GATGTTACACTTGGCAC I I I I I ACG CTG CCATTCTG CCTTCTCTCCCCT chr5 8773657 8773659 cccatcgtctcagcccaaaatctccgtaagctgataaacaacttcagcaa chr2 82392549 82392551 gttgcgtgggctggagtgcagtgacgtgatcttggctcactgcaacctct chrl6 29674272 29674274 CCCAGGCAAGCCGTACAGGCTCTGCGTTGGCCTTGGAGAGAACCGCCGAC chrl6 29674291 29674293 CTCTGCGTTGGCCTTGGAGAGAACCGCCGACTCCCCCGAGTTGCCTGAGC chrl6 3473308 3473310 aaggaaccaggtttaatggactcacggttgtacatggctggggaggcctc chr22 46346927 46346929 TAG CAACAAGTTCTCAAG GG CGTG CG GTTCAG GCAG ACTTTCAACGTG CT chr20 52979500 52979502 GTCCAAGGGTATCAGACTGAGGTCCGTTCAAAGACATTATATACATACAC chr20 52979806 52979808 TTCAG G AG G CACAG CAAG ATAATCCG ATTATTAATATATCAGTATTATTT chr8 58117688 58117690 gtcattgttaagagttaatatgttcgtatttgcaaaatgccttagagtgg chrl6 49521066 49521068 TCAGGTCAAGTGTGGCCCACAGCTCGAGATAGGTGGGATCGAAGCAAGAT chr9 29444070 29444072 aggcttttcaatagatgatgctgccgcatatgaatatctacatacagaag chr9 29444070 29444072 aggcttttcaatagatgatgctgccgcatatgaatatctacatacagaag chr8 143213111 143213113 GGGAAACAACAGTCCCTGGCCTGGCGCCTGGAGCTGGGGACCAGTGTGAG chrl 45049761 45049763 tgggaggcagaggttgcagtgagccgagatcgcagtactgcactccagcc chrl6 73092631 73092633 ATAG ACG CCTTCATAG AATCAAG CCGAGCGCGAACG CCGTGTCTG GG G CT chr2 22449630 22449632 caaaacaaactcatctatttattgcggcgcaattgtacattggcacaacc chr7 45198338 45198340 aGTaatagtagatctgaatggtgccggtattaaagaaatcgaattaataa chr7 45198353 45198355 gaatggtgccggtattaaagaaatcgaattaataaaaagttttcctagaa chrl8 79206904 79206906 TGTGAATAATGAACAATCATTTGACGGTTTTGTTTTCTTTTTGTCTCCCT chrlS 58144488 58144490 cccaccaagccccacctccaacaccggggattattgtcaacatgagattt chr21 46510096 46510098 ttcattaaggcatattgactcacacgatcacaaggtgaggtcccacagta chrl 207434747 207434749 TACCCTGGGATCACATTATTGGCACGAAAATAACGTAAGGTCAGAAAAAT chrl6 84090291 84090293 GCTGGGATTCAGTGGCAAATGTTTCGCATCTCACGCTGCTTAAGTTTAGC chr3 15391356 15391358 ccagcccttctgtatcaatggcagcgggggagatgtgatctagccaatct chrl7 5786789 5786791 G GTAAAG CCAAG GTCCAG AAG AAG CG AG CAG CAGTTG ACTG CCTCAG G CA chr2 236825115 236825117 CCTCTTG CCAG G CCTCATG CTGTCCG G G CCACCTG G AACTCCCTTCCCAA chr9 136512504 136512506 CAGTTG GG G GAACATCCCCCTCCCCG CTCAG CCCAAACAG AG G G CTCCTT chr9 136512314 136512316 ACCGCAGGCGTGGGACCTCCAGCCCGGCTGCCTGGCCCAGGCAGGCCCTC chrl 8094575 8094577 TCCTG CTG CTTG G CCTTATTTCCACG G G CTGTCCATGTCAG CATG G AAGT chr5 44117981 44117983 ggtccaggaggcttttgaggtgatcgggcagtgtcagtcttcagctgcta chr8 13310666 13310668 catttaaagagtcttttgaaaTCACGCCATTCTGCAATATTGTTAGCCAG chrl6 89747287 89747289 TGTCTATGGTGTTTTCCTGTCTGTCGGCTGTCACGTGCCAACTGAGAGCT chr4 12022338 12022340 GCCACTGTAAAAGGGCAATGGGCCCGTAACAAGAAGAGTCGACACTGGTA chrl 20369180 20369182 CTTAG G CCCCAG CTG GGTGTTG G ACG CCAGTG CTG AG G G CG G CCCTGCAT chrl7 17603475 17603477 GTCTCAG CAAGTGTCCG AGACTG ACG G AG G GG CAAG CTGTCATCCCAG CC chrl7 17603475 17603477 GTCTCAG CAAGTGTCCG AGACTG ACG GAG G GG CAAG CTGTCATCCCAG CC chrl7 19539205 19539207 attgcagggataagccaccgtgcccggccCAGTCTGGCAATTTCTGTCAT chrl7 19539300 19539302 GACAGCAGCTGCTGAGACATCTAGCGGAACAGGCCTTTGTCCAGAATTGG chrl7 20077590 20077592 agcgattctcctgcctcagcctctcgagtagttgggattataggcacccg chr20 10663952 10663954 TGTTTAG AG AAAAGTCCACAG AAG CG ATACTTACG AACG GTGTCATTACT chrl7 2019280 2019282 TCCCTGGAGGCTCCGTTCCCGTTTCGCCAGCTATTTTGCTGCCTCGGCCA chrl7 2019254 2019256 CTGCGTGGAGGTCCTGGCTTCTGCCGTCCCTGGAGGCTCCGTTCCCGTTT chrl7 28273746 28273748 tgcactccagcctgggtgacagagcgagactctgtctcaaaaaacaaaaa chr5 50998391 50998393 AAAACAATGACATAATAAACACTCCGATCTATGATAATTGATTTCAGATC chr3 150033642 150033644 ctcgggaggctgaggcaggagaatcgcttgaacccaggaggcggaggttg chrl7 31593826 31593828 G GCCTCGCCTCTCACACCAG G CCTCG CCTCTCTCTCCCCACCTG CCTTG G chrl7 32037054 32037056 ggctagagtgcagtggtgccatatcggctcactgcaacctctacctcctg chr9 22851312 22851314 tcttgaacttttatgttatggagacggcttattttcttaaaactcatgaa chrl7 39612775 39612777 GTGAGGGCTGGCACGGGTGATATGCGGCTGCGTGCCTTGTGGTGCCATGG chrl9 11490901 11490903 tgctcacgggtgtccctgactcagcggaaggcagctcagtctctccagtg chr3 130566788 130566790 CCACAGATTTCCATGAAATGAAGACGTTCCTGTCAGAGGTGGTAGGGATG chr3 31409610 31409612 ttgaacattttatataattggaatcgtacaatatgtggtcttttttcatg chrl7 45173004 45173006 G CCTCACTTCCCTG GTGTGGGCGGCGG CG AATCTTCCTGCTGCCTACGTG chr7 19111176 19111178 TGGCCAGGTTCTTTGAGAGACTCCCGATCCTTAGTCTCCCACTTCAGGCC chrl7 49578654 49578656 AGAGGACCCTGAGCGTGATGACCACGAGGGCCAGCCCCGGCCCCGGGTGC chrl7 49580573 49580575 AAACTTGAGCAAACACCCTGGGCTCGGTGCTGGAGGAGGGCGTAGCATCT chrl 88186554 88186556 aatccatcccccaatcttgctctccggaggattgatttgaagtaaactat chrl7 58691449 58691451 tgggaggccgaggcaggcggatcacgaggtcaggagttcgagaccagcct chrl7 6264478 6264480 aaaatcacgtgtccctggataggacgtcaggggaagaattcagcgtcatt chrl 25729798 25729800 gttgggattacaggcatgagcccccgtgcctggccaggcatcccattttc chrl7 63117426 63117428 TCAACCAATCTAATGAAAAGAACTCGTCTGTGTAATCTCTTGAAATCATT chrl7 63117237 63117239 TCCGTG AATCATTC ACTCTGTTAACG CTGCG CCATTAG AAACCTAAG AAC chrl7 69499387 69499389 cttcttcacaca ca ctgtgtcaa tcgagtctctta atga cctgcggagat chrl 30120569 30120571 TG G CATTTG GTAATG CCAATG AAACG CAG ACCCTG AGGTTG G CACCAG CG chrl7 74762858 74762860 ggcgtgagcca cctca cccggccCCG AGTT AGGC l I I I AG ACT CGTGCAT chr8 102754235 102754237 AGAGAAGTTGAGCTGGTGGCTCCTCGGATGGGAGTCAGCCCCAGGCCTTT chrl7 75231876 75231878 TTTG ATTACTG CCCCG AG CTG G G CCG AGTCTCCCTG G AGCTG CAC ATTG A chrl7 75231866 75231868 G GTCG ATTACTTTG ATTACTG CCCCG AG CTG G GCCG AGTCTCCCTG GAG C chrl7 76145456 76145458 AGCCGGCACGGAAGGAGCAGGATGCGTGTCACCTGAGACTCCGATGACGG chrl7 76145510 76145512 AGCCACAGCACTCGTGTGTGAGAACGGAGAGAAGCAGGTGCTGACAGGTG chrl7 78458835 78458837 AGCATGGAGGCTAAGGACACCAAGCGGCTCCCGGCACCATCTGGCCCCTG chrl7 78458957 78458959 GTATTGACTGGCAGCGCGAGCAAGCGGCTCTGGTGTTTCGCAGGGACGGG chrl7 81246152 81246154 CTTG G G CTTCATG CG AG G GTCCCCCGTCTCTG CTCCTG G CCCTGCCACG A chrl 155009422 155009424 CAG G G CAG ACCCTG G CACCTTGTG CG GTCTCCTCAGG CCCTAAG G GG AG C chrl7 81839462 81839464 CCCTTG AAACGTTCCATCAG AAG CCG G CCGTCAG CAGTCGTG CCTG CTCC chrl7 81839517 81839519 GGGCGAAGCGTG CTGTTCATG CAG CGTG ACGTCAG AG CCAAACCTGTCTT chrl8 28743520 28743522 GACAGATCATACGGCCACCTTGATCGAGAAAGTGTTTATTATAAAATGAT chr9 75657076 75657078 AAGAATGCCTGCTCTGAAACTCTTCGTAAAATTTCTCTGCATTGTTATAA chr6 80711323 80711325 TGGGCATATTTGGTGGTAATCCAGCGTCTGCCAAAGGCACATGCCCAGGG chrl8 29252619 29252621 a a ga AACAATAC I I I I I I I ATG CCCG CCAATTTATG AACATATTAATTAG chrl8 3015949 3015951 ATGCCTGTGCTCAGTGGCTTTCAACGTCTCAACCAGCAAGGTCCACAGTG chr6 159116933 159116935 ATTCCAAATCTAGGAAATGCAAGTCGGTTTCCTTCAGAGGAGTTGGGAGA chrl8 31668223 31668225 acacaggcacagaaaaccaaataccgcatgttctcacttgtaagtgggag chrl8 31668044 31668046 ctggagacagaggttgcagtgagccgagactgcgccactgcactccagcc chrl8 42840569 42840571 aagctggagtgcaatgctcagtctcggctcactgcatcctctgcctccca chrl8 42840523 42840525 ttaacttttttattttttcaaagacggagttttgctcttgatgcccaagc chrlS 48220327 48220329 ACTTTATTGG G G CTG CAGTG CCAG CG CTG GCACCTTG G ATG G G AG CCTTG chr2 122112932 122112934 TCGCATTTAATATTTGTGCCTAGACGCACCCGTTCCTGCTGGAGGGTTTT chrl8 54620704 54620706 ggcctccca a aggcctggga tea tcggtgtgagcta etgea aetga ccTT chr6 118695678 118695680 tttgcaTTTTGTCTTATAGCTGTTCGTCTATTTCTAGTTAATAAACATAT chrl8 55335150 55335152 GGGAAACCTGTCCTTAATTTATCCCGTCGTGTGTAGATTTGGCAAGGATC chrl8 55316591 55316593 CATCACTTATTCTCAAGCCTCCATCGTGGTACTACAATTTAGTAGAAACA chrl8 55401620 55401622 AAAAAAATTAACTTCAGTTTCACCCG AG G G AAGTATTCCCCACAAACG G A chrlS 55402070 55402072 G CACTCACATTCCAAAG ATGTTTCCGTTG CG CTG G AATG G CTGTAAATTT chrl8 55337856 55337858 TCTCATCTGTTTACCTTTTTCATCCGACGTCCGATGGCCATGTACATACA chrlS 55337859 55337861 CATCTGTTTACCTTTTTCATCCGACGTCCGATGGCCATGTACATACACAC chrl8 55347406 55347408 AGAGGGACAGGCTTCCCCCCGACACGCTGTGCTTGTCCTGTAGACCCTGC chrlS 55347692 55347694 GAAGTCCAGTCTCTGTACCACAGGCGTGTCACAAATAATACCTGATGATG chrl8 55401726 55401728 GCTTTCACAAGTTAAGGGGCCTCACGCTTACTCAGCAGAGGAAATCTTTG chrl8 55401962 55401964 TCAGAAACCAGACCCACAGGAACACGGTCTTCTGCAGGAACTGAGAGCTT chrl8 55401962 55401964 TCAGAAACCAGACCCACAGGAACACGGTCTTCTGCAGGAACTGAGAGCTT chrl8 55863146 55863148 AACCACAGTGAATCCTTCCAGAAACGGCGTCGTATCTAAATTGGGTTGCA chrlS 55863341 55863343 G CTTCG CAAATAAATCCATTTTCACGTACTCG AGTCGTATAACAG AAAAT chrl8 55863406 55863408 ATTGTTAAATTAAAG GTTG CAG CCCATATTCAAAAG CCCATCCGCAAG CT chrlS 55863209 55863211 TGTGTGACCATTTATCTTTCATTTCGGGAGTCGTAGTTAGCTCTTAACCA chrl8 62551668 62551670 CTG AGTG AGTG G ATCTG GAGGTGACGGTGGAG GTCAG CGTTTG GTTTTG G chrlS 62551681 62551683 TCTGGAGGTGACGGTGGAGGTCAGCGTTTGGTTTTGGCAGTCGTGGCACT chr8 57356053 57356055 AGGCAGAGCCTGCTCACTTTGGGACGTGCCCTTGAATATGTCCCTTTGTG chr2 4416732 4416734 gagccttgcctttctcCTTTAATACGTCTCTTTTGAAACTGATCATATAC chrl8 48111878 48111880 caatttcggaccctgaaattattacgtacattctcttccagccagcaatt chrl8 7466797 7466799 ttattttgtgcattctgtttgtctcgattttctAATTGCTAATTCAAAAA chrl8 75281388 75281390 TGAGGAGGAGGGTGCTGGAGAGGGCGGTGGGGTGTCATTTTGTTTGCACA chr5 54475097 54475099 TG G CCTCACAAAG AGTTATCACAACGTCCCTG CATTG CGTG G G CTTCAAC chr9 120498228 120498230 ggccttcccagcctccatacttagcgatggccccctagtgccactttctc chrl8 75629703 75629705 caaggaggagcaagtcacatcttacgtggatggcagcaggcaaacagctt chrl9 1071474 1071476 TGCCGCGCGCCTGGCCTGGCCGTGCGCACCTGGGCATCCCTGCGCTGCGC chrl9 1071020 1071022 CAGCTAGGAGGGGACCCACATGGACGGTGCCACCCCGACACTTCCCGGGC chrl9 13002919 13002921 TTCCTG G CACAG ATCGG G CAAG AG CG G G G ATCTGTCTGTCCCCACCTG AA chrl9 13002694 13002696 TTGCCACCACTACCGATGTGGCTGCGCCAGCCAGGGAGGGGAGGCGGGTA chrl9 13027038 13027040 G GTTTG GG G GTG CTTTCAGCACTG CGTCAG G AATGTAATCTAG ACTAG AG chrl9 13027452 13027454 TG G CTTG CAG AAG G CTCG G AG CCTCG AG CTTACCAGTGTG G CCATCAG AT chrl9 13002909 13002911 AGTG CCAG CCTTCCTG G CACAG ATCG G GCAAG AG CG G G G ATCTGTCTGTC chrl9 13002733 13002735 GGAGGCGGGTAGCGGGCACTGCGGCGCTCTGCAGCCAATCGGAAGCCGGG chrl9 13027645 13027647 TCCCTG G CCTCTTTTATTTTAGG CCG AATTCTTG ACTG CTG CCAGTGTG G chrl9 13027708 13027710 TGAAAAGTATGTGAGGAAGCAGACCGTTTCCTGGCCAGAAGAAAGGCCCC chrl9 19493336 19493338 GTGAAGCACTCTGTGCAGAAAGGCCGCCTGCACTGTGGGCGCAGGGGATG chrl 28675626 28675628 ccaggaggcagaagttgcagtgagcggagatcccgccactgcactccagc chrl9 30071556 30071558 CAGTCCATGCCCGCACCGCCTCCGCGTCCTCCCGGGCTCCCCGTGGAGGG chrl9 30071371 30071373 TG CTAG AG G G G AG G G AG G G G ATCTCGTG CCCCCG ATCTG GCACCGGGGTG chrl9 31596154 31596156 GAAGGACCTTCTATGCAATTTCCTCGTGTCTGTGAGAGGAACCAAGACAA chr8 87977499 87977501 tggaaagcgggtaaaagtagaaatcgcaaaccacttaagttgttggaggc chrl9 31959202 31959204 CATCACCAAGTCCCTGTCTCAATCCG G G ATG CACAG ACGCTCCTG G G GTG chrl9 32327361 32327363 GTCTAAAAATCTG G AG ATATTTCACG CATTTG G G GTG G GTCTCAG ATAG G chr6 34036167 34036169 GGCGCAGCGAGCAGGTGCCAAGGTCGGGCTCAGCGATCATGAGGAAGGTG chrl9 33408728 33408730 ACTGCTCTG GGAGGCGCTCGG CTTCG G G G G AATTCTACG CTG G G CTCATG chrl9 33408838 33408840 TTATTATTTACCG AACG CAGTAG GCG CTCG G CAG ATCAATTTCAATACAA chrl 15765576 15765578 AATTTAATACCCTCAAGCAGAGCACGGGGATCTTGGGGTTCAGTCTCCCT chrl9 39052997 39052999 GCGACACCGCCTGCCCCAGTTCCACGTGAGGTtgtaaagcactgatgctg chrl9 45018947 45018949 ccagattacaggcgtgagccaccgcgctcggctgaaagctagtgcctttc chrl9 45019029 45019031 ctgctgtgtctctcattctgtctccgcacagccaaacatacacacacaca chrl9 46604657 46604659 TGTTCCTAGCTTCTGGAACCTCTCCGTAGAATACTGCAAATTCACATAAT chrl 66534669 66534671 AGCTTGCAGAGCAAATAAGTTGGGCGAGAAGATAAGGTTTTCTGTTCTGG chrl9 46731732 46731734 cctcccacaacgacactgacacgccgcacaggctcagcctctttctcagc chr5 74294397 74294399 TTTCTCG CCTTCTTCCTATG ATG ACG AAG CTTG CCACCTCCTCTTCTCAC chrl9 53965266 53965268 gcttcccattgtagttctgatttccggcttcttctgagctggcggaagat chrl9 53965120 53965122 aggtcacctagctgagaaaggggccgagccaagagcagaactcgaatctC chr6 96873290 96873292 ATG AGTTATATG AAG ATGGTATG ACG CTATATACACAAG GTATG ATGTTA chrl9 53976301 53976303 caggaggtgga ggttgca gtga gccga ga ttgtgcca ctgca ctcca a a c chr2 27738485 27738487 TATCTCCCACCACCCGACATGCTCCGGCCGCCAGCTCTGGTCTGACCGAC chr2 27738545 27738547 AAGAACTCCAAGCAGCCCCCTATTCGTACTGTTTTCCTCAGTGAACTCCC chr2 27738489 27738491 TCCCACCACCCG ACATG CTCCG G CCG CCAGCTCTG GTCTG ACCG ACG CTT chrl9 8066130 8066132 CTTGCTCGTTTCCGCGGACGATGACGTAGCGGATCCGGCCCTCTAGACCC chrl9 8180812 8180814 TATATggccaggagtggtggctcacgcctgtaatcccagcactttgcgag chr4 36635749 36635751 agataaaaatttctgttctcaaggcgctaaagtacagtaagatagtgaag chrl9 940774 940776 GGTGCCGGCGTCTTCCTGGGCCTCCGGGAGCCCCGGCTGCACGTGAGCCG chrl9 940858 940860 G GTCCTCCCCACCG G GG CAG CG CCCG CCTCATCAAAG CCACTGTG G CTG C chrl9 941030 941032 CTG G CCCCT G cgcca ccgcctggccgt cgggt ca ccgccgcggggt ca cc chrl9 941149 941151 CG CCCCATG CTTTCTAATAACACACG CGG CAG CCCG AGGGAGCGGTGCCC chrl9 941242 941244 GGCGTGGTGAGCCGCCGTGGCGTGCGTGCGAGTGTGCACGCTGGGGCTGT chrl9 941271 941273 GAGTGTGCACGCTGGGGCTGTGGCCGGGCGGCTCGTGGGTCCTGTCTCGT chrl9 941208 941210 GAGTGTCCCCGCGTGGTGCCTGGGCGGGGGAATGGGCGTGGTGAGCCGCC chrl9 941471 941473 GTCCCCAGCCAGCACCACGGTGTTCGTTTAGGTCTCTGTGTGCCGAGTGA chr2 1939158 1939160 CACTCAGACGGCCACCCTGTGCCACGCAGGATGGGCGCGGGAGTCACACT chrl 107575614 107575616 TTACTGGGGCACTACTGTTAGAGTCGGTGCACATAAAAACACCCCTATGA chrl 109323018 109323020 CCATTCTG ACACACG G ATG ACTTGCGTAG CCG CAG AAACTGTTCTTTGTA chr2 43149699 43149701 AATGGT AT CAG AACCAT GCGCGCGTG CACgtgtgtgtgtgtgt ctgtgtg chr7 605238 605240 ggatgatgtcactgaggTCCTTCCCGCTGACTCCGCAGGGGCTCGGGCCT chrl 110508162 110508164 GCTCCTGGGCGGGGCTGGGGAGGCCGGCCTTGTCACAGGCAGGAGGGGCC chrl 114587732 114587734 AACTGACCTTTAACTCCACTTTTCCGAAGCTCTCGGTCCTGGATGAATCC chrl 114587798 114587800 TCCATGAAGAGATCCAGGAAGTGGCGTACACTTCGGGAGGTGTGGGACTT chrl 47930687 47930689 CTCCTCTTCAAG G ATCCCTTATCCCG AG AAAG AACATCTCAAG CCTGTG A chrl 15437470 15437472 ctgga a tgcagtgtggcacgatca cggctca ctgcagcctcga a ctcctg chr5 175033106 175033108 CTG G G G ATG G CAG AATAG GGGAGCCGGGG CAG CTG CCAG G CCTG G CCCTG chr2 85447333 85447335 G GG G ATTG AG G CTGG CTACAG G ACCG G CTCCTCCAGTTCTG G CCAAG G AC chrl 16921554 16921556 ATTCTTAGCTAACCATGTGACTCCCGTTCTGGGCCAGAAAGATGGTCACA chr8 58768196 58768198 ATG CTACTCAATATGCTCTGTAG CCG GGTTCATG CAACCTCTAGTATG G C chr4 667460 667462 Atgtgtgatgtgcgcgagtgcacgcgtgtgctgtgcttgcatgatgtgtg chrl 17535924 17535926 tccagcctccgtggactcacagtccgggggggagacatggggcaaacatg chrl 17535615 17535617 ATTCTCTCTTTCCCAGGTCAGCAGCGGAGACAAGGAGGACAGACTCCTGA chr22 50658490 50658492 gagtgcggtggcatgatctcggctcgttacaacctccgcctcctgggttc chr3 113651082 113651084 TATGATTGACACATTAAATGTTTACGCATGAAGAGAATCTGGAATTTTAC chr21 29917226 29917228 TTATTTTTCACAAAAGACAGGCACCGCAAAACAGACAAACGTTAAAATAT chrl 20748527 20748529 tgggaggccgaggccggcagatcacgaggtaaggagattgagatcatctt chr5 151512421 151512423 AGGTGCCTTTCGGGCCTCAGACCACGGCAGTTCTCTGGGACCACAAGGGA chr5 151512485 151512487 TGTCAACCATCAG G CG AATG G AAG CGTCCATCTCCTCCACCAG G ATG G AG chr2 227315087 227315089 tggctcactgcaacctctgcttcccgggttcacgccattctcctgcctca chr2 227315087 227315089 tggctcactgcaacctctgcttcccgggttcacgccattctcctgcctca chr2 198143307 198143309 ttca ca ctcctgaga a tcta atgtcgctgctgatgtga caggagtgggag chr8 5575147 5575149 gactacaggcatgcaccgccacaccgagctaatttttttttgtattttta chrl 223535050 223535052 ttgcatctcttctcagcaactccccgtgcaaacactgagcctgacatgta chr20 49882081 49882083 GGGCACTGAACAAGCCTCTGCTACCGGCCCCTCCCATCATCATTTAAGCA chr5 43282460 43282462 gtagttctgtcgcaggaagcatggcgttactacaggatcccacagagctg chr5 43282446 43282448 catcgggagtctgagtagttctgtcgcaggaagcatggcgttactacagg chrl 241329400 241329402 GTACAATAGTC AGTTG GTTG CTTACG G AGTTTAAAATTTCCAAATG CTTT chr2 148147429 148147431 taatttttgtatttttagtagagacgaggtttcaccatgttggccaggct chrl 244054019 244054021 G AACAG CG ACATTGTTACAG CCCCCG CTTTCG CTCTCCTG CTTG AATTCA chrl 244054025 244054027 CGACATTGTTACAGCCCCCGCTTTCGCTCTCCTGCTTGAATTCATGTATG chrl 244054001 244054003 AAGAGACATTGTTCATCTGAACAGCGACATTGTTACAGCCCCCGCTTTCG chrl 244054334 244054336 GCCCAGCAAAAGGGACTTGGCGGCCGAGCCTGGGAACATGTGGATGCGAT chrl 244054088 244054090 GTTCAAAGACTTGCCCATTGAAGACGTGCTAGCAGCTGCCAGTTATCTCC chrl 244054487 244054489 TTTGTCCCAGAGGTCTGTCACCTCCGTGAGGGATTCGGCAGATGTTGACT chrl 244054213 244054215 AGGAAGAAGATGCTTCAAGTTGTTCGGACAAAGTCGAGAGTCTCTCCGAT chrl 244054412 244054414 GGCTGGCGGAGAGGCAGAGCCACACGCCACAGCAGCTGGAAAAACAGTAG chrl 25968446 25968448 ataagggaagaggtgtgagaggttcgaggagaaaaaaggtgtgaaatagt chr3 18064875 18064877 ACAGGTGATAATTggaggtagcaacgcctgtttgcctgccttttagtaat chrl 213899571 213899573 CTGGGTCAGACCTGGATAAACTTGCGGTTTCCTTCCTTCGTGCTCTCTGG chr4 87865311 87865313 ACTGGTAAAGGAAGAAATTAGAACCGTAAGGACTAAATTTTCCCCAAAGT chrl 30127035 30127037 ATTCTAAGCTCCACATCTGCACAGCGGGGAGGCCACTTGTCAATAAACTA chrl 30830766 30830768 cgcaaagaggaattgagagtttttcgccaagatctcaaaattgggtcaag chrl 30830843 30830845 GCGTGCTagctagagagctgtgggcgtgatcaggatctgctttagaggta chr6 36775571 36775573 cctggcctggaatattctctcctccgcttccatctttgtgactcactcct chr7 88282441 88282443 a tta tgggagtgagccaccgcccccggcAAACTTTT ATT CTT AAT AGTT G chrl 36226553 36226555 attacaggcgtaagccaccgcgcccggccacgatttattatttttaGAAT chr4 119027422 119027424 G ATCACAG CAG ACCTCACAAG CACCG AG CG CG G CATG CACGTAAGTTCTG chrl 38114428 38114430 G AGTG G AAGTCAG CAGTTTG G CACCGTCTG G CTG G CAGCCTCCACCG G CT chrl 38114479 38114481 CCTTTG G CACTTTATTGG CAAAG GCG GTG ACATTTCTTTCAGTTG G GTG G chrl 43465467 43465469 cctgcccgcaagttttacaggagccggccctTGCGGTTGACCtcaggagt chrl 43465657 43465659 agtccaaacaaaaaacagatggcacgctcaaattaggataattcaggaga chr7 48427116 48427118 G ATCCAGGTG CAG CTCAAG G CCCTCG ATGTCTCCACCCCACCTCATTTCC chr7 150150657 150150659 gcttcctcctttgcttttcggtgtcgtataaacatagttccttttgggtt chrl 55154499 55154501 G G AAAAG ACACAG G AATTGCTTCACG ATCAAACTG G CAAAATATG CAAAA chrl 55154474 55154476 TCTCAGTCTCCCAGCTCTGTAGAACGGAAAAGACACAGGAATTGCTTCAC chrl 58786705 58786707 TTTTCCTTACAATCAGGAGAGTTCCGATTCCTATGCCTTGGAGAAGGGGC chr6 11778228 11778230 AAATTACACTTCCTACACACCATACGCCACTCTGCCTTCTCTTCACAGAC chr5 95820943 95820945 agcctggccaacatggtgaaaccccgtctctactaaaaatacaaaaatta chr5 38457056 38457058 TGTTTTCTGAAACCCTTATGGTATCGGGGTATCTGGGAACTGAAATAGAA chr2 184141131 184141133 GAAATGGTCTAAAAGGAACAAATGCGAGTGGAATTGTTCCAGGTCACTGA chr7 159231032 159231034 TCTGGGCCACCCGAGTGGAGCGGCCGGGTTGGGCCATAAAGAGGCCGTGG chrl 6954346 6954348 AG G G G ATTTACCCTG CAG G AGTAACG CTCCTATTG CTCG AG CTGTTG G G G chrl 6954205 6954207 TTTCTAAATG ACG CCCTG G CTG GTCG CCTG ATG ATTG AGCAG G CCATGGT chr3 88788605 88788607 TCTATG AAAAG G AAAATACAG ATTCG AATTGTGTATTTACTTAAG AAG CA chr9 73863812 73863814 accccagcctcattaacctaccaacgtattgtagttccctttacatcaac chrl 84779343 84779345 cctgactttagagggtgcaagcctcggggttgcctagggcagagcatctc chr8 140729234 140729236 taaaaactgaaaaccaaaaaaacacgcacgcacaaaatcaaaaacaaaaa chrl 82344735 82344737 CAGCACAACTATGAAGGCAAACTTCGTTATTTTGTATAGTTGTGACATTC chr20 53032932 53032934 gctctgtgaaatgtagataataatcgttcatacccatggggttatactgg chr2 192676064 192676066 AAGGTTTTGAAAATATTTTTCTGTCGCCTTCGCACATGGTTAAATGTCAT chrl 86323634 86323636 aactgtcttatttgtttacttgttcgattatttgcctcccacaccagagt chrl 89387906 89387908 agattgtgccattgcactccagcccgggcaacagagcctgggcgacagag chr2 926606 926608 AAGGAGGGACCTCAGAAGGCGGGCCGGAGAGGGGCGGGTCTGATCAAGGT chr8 97191731 97191733 atattgcatattctgacttacaagcgggagctaaacactgggtactcgtg chr20 1400335 1400337 acaggtgagacagctggtcatgtacggccacattgtctgtcatcatttgc chr3 53425664 53425666 ctgtctttcaaggccaattctgaacgtggctgtaatgcagccactgtccg chr20 1837975 1837977 agcaccccaactccatgtctaaaccggagttctccctctggtttctgtga chr20 20699456 20699458 TAGATACTATAGAGTCCATGGAATCGAGAGAGAGTCTGCACTGTTTACAC chr2 64793554 64793556 CCAGGTCTAAGCTATATAGTCATACGTCTTCCAAAAGAACACACAGACAG chr7 159142397 159142399 CCACAGCTGAGTGAGGCGCATTCCCGGGTGAGAATGTCACGGGAGTTCTT chr2 115082751 115082753 taactacagatgcatgagcaatctctctttagatcaactgagaggaacca chr20 23049529 23049531 TTACCCAGGCGCGCCGCGTGCAGGCGCCGGGGAAAGCGCGGGCACTGCGA chr20 23049808 23049810 G GGTTCTCTG G CCG CCCTTG CG CCCG CCCTCG CG CATG GG ATCACCTCG C chr9 81702877 81702879 TATATTTTAAACATCTCAAACAAG CGTTGTG CACATATACACACACATAC chr4 87411016 87411018 ATTTG CTTTG AACTTTATAATCCTCG AATCCG G G AG ACTCAAGTG GTCAA chr20 40692864 40692866 TG CACG CATGG GTG CTGTTG GAG G CGTG CG G G AG G GGTGTGTTCGTG CGT chr20 40692708 40692710 AATAACTCCAGAGAGGCCCGGCGGCGTGTCCTCCCGTACGCCTGGAAACC chr20 43423564 43423566 ACTTGGCTCTGGGTGCAGGCACTCCGCTTCATCCTGAGGACAGGCTGTGG chr8 52485371 52485373 AGGAGGAGCAGATGCTCCCGTTCCCGAGTCCCCCGTCCGCCCGTGTTTCT chr3 29736383 29736385 CAATCCCTTATGTACTAAGCTCTGCGTATTTATGGTACACCATTTTGAGC chr20 5024555 5024557 ttgaatttccctaatgattagtaacgatgaccatctccttatgtgcttgt chr20 57730506 57730508 TGATGAGCACCGCAGCAGTGGCAGCGGCACCGTCCTGTGGCTTCTTTCTC chr20 57730576 57730578 CTG AG ACAG CTAATG CGTGG CCAACGTATCCTAGG AAACCAG G ATGCTTG chr21 21578917 21578919 ATTTTCAAATTAAATTATGTTCTCCGTACCTTAATTTCATGTTGACAAAA chr5 95429494 95429496 G AAATTGG AAATATG AAAGTCTG G CGTTTG ATTATTTGTTG GTAGG CG CC chr21 26832851 26832853 gtgcggatctgctttgtgttcactcgcagaatccagtggtgatggaagga chr21 26832783 26832785 ctgggaggccttcactctatccagcgctggagctgacttactgctgtggg chr21 29221598 29221600 CTAAAG AAAG ATAAG CAACTTG AG CG GTTACTAAATATACCAAG CATG CA chr21 29221717 29221719 TGTGTGGCGCTTTGGGTTTGATGACGCACCTCACTATTTAAGGAATGCTG chr21 34957177 34957179 TAG G G AG AG AAACTCTG ACTTG G CCG ACATCGTG G GTGTGTTAG GTAATA chr2 238282674 238282676 CCCACTGACTGACTTGCCCTtattcgcttagcactgagggctggcactgg chr21 43913788 43913790 ctgctgaatcccgcagggcacagccggccctgcagcagagttatcccatc chr4 11187567 11187569 TAGTACAGTCAAAAGAAAATAGTCCGGAAGTGGACTGAGGGAAAGGTCAA chr21 44074575 44074577 GAGAGGTGTTGCTCATTTAGATCACGATGCATCCACTTTAGTGGCCCTAG chr21 44074712 44074714 TGAAATTGACTCTGTACCCTGAGTCGGGGGACACGAGGGTGGTGCTGAAA chr21 45115350 45115352 TCACAGAGTGAGTGAATGCTGGGCTGCTGTGATGGGAAAGCTGTCTGCTG chr21 45115249 45115251 GTGGTCTGCTTTGGTGCCAGTGACCGTCTGTGAGTCACAGAGTGAGTGAA chr8 22762602 22762604 ATATTGACCCATCTGGTTTCTTCTCGGTCAGGCCTCCAATTCCCATGCCG chr22 19666270 19666272 CAAAAG G CTG CG GTG AAAGTCACCCG GTCCACG G CTGTCTCTG CCACCTG chr22 24425509 24425511 AATCCCAGCCACTACCCCTCCATCCGTGTCCCCTGTTTCCCCAGTGCTGA chr22 24425382 24425384 ATCCCG G CAG ATCCATG G CAG G G G CG CCTC ACAG GCTGGTCCACG G CCAC chr22 24425165 24425167 GGGCACCCTGCCGATACTCCATGACGCGCCAGGGCTGCCCCAGGGTGCCC chr22 24425152 24425154 GGGTTCCCCGGCGGGGCACCCTGCCGATACTCCATGACGCGCCAGGGCTG chr22 24436142 24436144 CTGTTCCTG G CCCG CAG GTCCCTTCG CTTTCCTGTTCCTCAG GG CCCCTG chr22 24436130 24436132 G GG CCCTTCAG G CTGTTCCTG G CCCG CAG GTCCCTTCG CTTTCCTGTTCC chr22 24425431 24425433 CG GTGTCAGTCCCTCCTTGTTCTG CG CTTG C l I I I I G G G GTCTCCCAG CC chr22 24425710 24425712 GATCCCCAAATATGCCCTGCGTCGCGATGGAGGAGGGCAATCAATGGCAA chr22 24440428 24440430 gcaaggcatattacttccacttaacggaagaggatgctggggcgaggtgg chr22 24425816 24425818 ctggtcttgcctcctcgacccactcgctgagcaggttgctgtcccgggga chr22 24426997 24426999 TGCTGCTCTTCTGTGCCCACTCCTCGGATGTGCCGCTGCAGCCCTGGTCT chr22 24427006 24427008 TCTGTGCCCACTCCTCGGATGTGCCGCTGCAGCCCTGGTCTCTGGCATCG chr22 24428719 24428721 ctcttgcgctttgaa attgatttgcga ctcctcttAGCTG AGCCAAT GTT chr22 24428701 24428703 ttcttagccttcatatacctcttgcgctttgaaattgatttgcgactcct chr22 24427299 24427301 TCCTGTCAG CCTCCGG G G CTG CCTCGTCG CACCTG CCCAG G G ACCCAACA chr22 24427299 24427301 TCCTGTCAG CCTCCGG G G CTG CCTCGTCG CACCTG CCCAG G G ACCCAACA chr22 24434476 24434478 G ATTTTCCCAG AG G CTG AATTACTCG GCATG G ATTCCACCTACCCAG G CC chr22 24434350 24434352 CTCCTCAAGTCACCAAG G ACTCATCGTCTTAG AG G CAG CCAGTGTG CTCA chr22 24435262 24435264 GACGGGCAGAGCAGAGTTTAGGTTCGTCCAGTGGCAGCTCAGAACACGGA chr6 110018487 110018489 CAGAGACTGCAGAGGCTTAATGCCCGCAAAACAGGAGCAGGTGTGCTAGA chr22 24439355 24439357 attacaggtgtgagccactgcgcccggccTCCTTGCACCTTCTGAGTGTC chr22 24438626 24438628 GGAGCTCCTGAGAATGGGCTTGTCCGGTTACTGTTtggattcagaactga chr22 24438986 24438988 CCTCCTGTGTGTG CTACCTATAG G CG CCTGTTTG CTACCCGTG AATG AG A chr22 24439144 24439146 gtctcccaggctggagtgcagtggcgcgatcttggctcactgcaagctct chr22 24441113 24441115 TTCGGTTGTGAATCCCTTCATCTACGCCTACCGTATCCGCGAGTTCCGCC chr22 24441159 24441161 CG CCAG ACCTTCCG C AAG ATCATTCG CAG CCACGTCCTG AG G CAG CAAG A chr22 29184668 29184670 AGTCG CTTTTTG AAACCATCAG CTCG AG AAATTAAGG ATTCTGTCAG CGT chr22 29184647 29184649 GAGAGAAGCCAGTCTAAAATCAGTCGCTTTTTGAAACCATCAGCTCGAGA chr22 36763396 36763398 TAATAGTAATCTAAGGACTCGGCTCGGAGTCAGGGATTCAGAGGTAATTT chr22 36763391 36763393 GTCATTAATAGTAATCTAAGGACTCGGCTCGGAGTCAGGGATTCAGAGGT chr22 36763700 36763702 gtctccccacagccctgccaggtgcgtgtcctcattcccgtttcctagac chr22 36763790 36763792 ctgctaagtggcagggccagtgtacgccttaggccatcaaagtccaagcc chr22 49391984 49391986 CAG AG CG ACCCTCCCTG G CCAG G CCG G G CATG AATG G AAG G CATGAG CAT chr2 180445347 180445349 accagtgtggttcttctttatccacggtggatgtacaagctatgataatt chr2 106974041 106974043 GCTATGCATGCTCCATTTACCATCCGTGATAGGATTCTCATAACCAGTTG chr6 33906454 33906456 TCTCG G CTCCTGCTGG CTCCCTG G CG G ATACAGTCCTTCTCTCCAGTGTC chr2 214915957 214915959 AAAATGGAAGATGTAACAGACACTCGAGGGTGAAAATGAGTTAGCCCAGA chr9 91268452 91268454 AGACAtttttttttttttaagagacggagtctcactctgctgcccaggct chr2 121664250 121664252 ACCTAACTTCCCCAGCTCTGCCCTCGCTCATGAACTGTATTTCTCTACAT chr2 121664308 121664310 CACTG CATTG G CATTCTG AGTCATCG GG G ATTAG GTATCCTTCCTG CT AT chr8 63031540 63031542 ATTTAAACCAAAATG G G CAACCATCG CCATCAG G G ACCAAAATG G ATTTA chr4 15944086 15944088 attatagtcgtgagccactgtgctcggtctagctccttctcttataagtg chr6 132713871 132713873 GCTCCTTCCAAAATGTCCAGATTCCGATTCATTAATGCCAAAGCCTCCTC chr4 6854578 6854580 TG AG CGTGTCCTG AAACTTG CCAG CGTCTGTATGTG G CTCG CCACTTTG C chr2 144508216 144508218 CCG AG CCCACAG CCTCCTTGTATACG G G CGTTTGTTCATTGTGTCTCAG G chr2 144507406 144507408 ATATGCACACTAACAGCTCCGTATCGTCTTCTAGTTCTAACCACTACTTC chr2 144509942 144509944 CACAAACTTTCTCTCACAAGAGAACGTGAATACCACCAACCCCTCCCCTA chr2 144512702 144512704 ACCAGCAGCCTACTGGCTCTGCTACGAAGGAAAGCATGTTTCTACCCCAA chr2 159230649 159230651 CAACAG CAG AG CAATCCTCCAAG CCG CAG CTG G CACTGTCCG GCACCAG A chr4 9109274 9109276 AGGATAAAATGATTTATTGATAGCCGTAATTAAAAAGCAATGCCAACAGA chr4 54236780 54236782 catgccactgcactccagcccaggcggcagtgcaagactccatctaaaaa chr6 40888325 40888327 TAAG ATCTCAGTCCTGTG G G GTG CCG CCAAGCAAG G CAGCTG CAAG GGTT chr2 199447280 199447282 GAGTCTCAGCAATGTTAAGGACATCGATTTCATAATTCAGAGGATTGCAG chr2 198316634 198316636 TAAAGTTTATTTG AGCCACCATG ACG G G CCTG ATCCATTCTG ATTTTACA chr2 199449983 199449985 AGTTAAGCATAAAG GTCTCCTACTCG AAACC ATTTTAG GTTATTTCTCTG chr2 199450146 199450148 AGAGACTTTGGGCTGCTAATTTTCCGTTCACAAAATCTAAATTCCCCTTA chr3 113902470 113902472 tcttagttagggtcaccaaacagccgagcaacctcaggcaaatcttttca chr2 203121062 203121064 G AATATG AAGTTAACATG CCTTTACG AATGG AG GTTAG CAAATAACACTG chr2 212524214 212524216 CCAAAATTATAATAATTAAGCTGACGTTCATAATTTCTACCATAATATTG chr2 211590141 211590143 CT AAAAAT AT CCAT AG G G Atga aacgcctttgcaaaattatga ctgtga c chr2 211590198 211590200 gaggtcca a cttaa a cga ctcca tcgtgcctcta acctccaagctgtcct chr2 212520797 212520799 ACTCAACTGTAG AAG AG CAG AAATCG CCCTTG CCATTACTAATATCTTTT chr3 142925609 142925611 tttttttttttgagacaagaatatcgctctgtcacccaggctggagtgca chr2 216827945 216827947 AGTAATTCTTCCGAGGGTCTCTGCCGCCACCTCCTTAGTTTACTTCAGGA chr2 224976082 224976084 GCCTGCCGACCTGCAAGACTCCATCGCTTTATAATGTGAATTAGTTTACA chr6 139254024 139254026 CCTACACCATGATGTGATGAGTTCCGTGACTGCCTAAAGGATGATCTTGA chr2 234438297 234438299 CTCCAGTG AGTG GG G CAAGTG G G G CGTTTCATCCCAACCTTCTG CATAAC chr2 234438247 234438249 CCTGGCAGGCCCGACTAAGACACCCGCTCCAGCTCAGGTGGTTTATGTGG chr2 236680576 236680578 AGTTG ACG ATCTCCACTATTTG CACG GTAACTG CAACCCACTTACTAATT chr3 192822185 192822187 CATAACAGTCCAACAGAAAAAAGGCGGGGTGGGGGTGGGAGGTTGGAATG chr2 172079041 172079043 GCAAAGACTCAGGCCCAGTAGCCCCGTGTTTAACTCCTGGTCACTATCCA chr2 23834892 23834894 acagtgagaccccatctccaaaaacgaaaaatatttttaaaaaattaggc chr2 30689098 30689100 CAG CTTTTCTCCCTG G ATG G AAG CCG AGTG CCTCTG G CCTG GAG CCTGTC chr2 30688941 30688943 CATCAG CACAGTATG CTAG CCATTCG G GTCATTACTG CTAATTATAGCTG chr2 44884032 44884034 TGTCAAGAACTCATTTTAATTGACCGTATTAACAATAAACACAACATAAG chr3 179616279 179616281 TCCTCggccaggcacagtggctcacgcctgtaatcccagcactttgggag chr2 520529 520531 GCTGCAGAGCAAGACACTTTTGAACGTAGGAACGATTCTTCGTTTAAAGA chr2 520537 520539 G CAAG ACACTTTTG AACGTAG G AACG ATTCTTCGTTTAAAG AG CAG G G AG chr5 178604407 178604409 aTATTCTATGTATTATTTTTACATCGCCTTAAGAAAACACTTATGCAAAC chr2 73008587 73008589 CCG G G CCCTG CCTCTCCCAGG CCACGTG CATG G AAG CG G CAGTG CTGTG C chr2 8287404 8287406 GCAGGTGTCCTGGAACATTACAGCCGTCGGAAAATAAAACTTGAGAGGGG chr2 8287256 8287258 CAGATTTATGACGTACACAAACAGCGAGAAGACAAACGTCCCCATTAAAA chr2 42964618 42964620 TTGAGCTGCAGAGCTGGGTGGAGGCGGCTGGAGAGGAGTGTCAGAGGATG chr2 8535196 8535198 AG CAG G G CCTAG GTCCAG G CTG AG CG G GTG AG G G GTG G CCCAGG CCTG G A chr2 88493781 88493783 CAGTATAG G CAGGTG GTTATTTTCCG G G ACAG GTTTATGTTACCTAACAG chr6 121099723 121099725 AATAATATCAACAGAGCAATGATACGATTTCTTAAGACAGATTAACTCAC chr3 10546931 10546933 CCATCAGTG AG CACTG AG CATCTG CG CAATGTCCTCTCTG AGTCAAAAAT chr3 10546902 10546904 tgctgtcccatcctccagaccCTCCGCTGCCATCAGTGAGCACTGAGCAT chr7 47238811 47238813 GTG CTG GTCTCTAG CCAACCACCCCG CACTACAG GTATATAC AG ACTG AC chr7 138996163 138996165 G AG G G AAAATTACCTATTAATTATCG CAGTC I I I I I I I I I I I I G GTGTTT chr3 143082577 143082579 GGACGTCACATTTTTGTAAGAGAGCGAGCGCTAGATCTGAGTTTTGAGGA chr3 143082617 143082619 GTTTTGAGGAGTTCCTTCTACCATCGTGGGACACGGTGAGAGATGAGTGG chr7 93580834 93580836 CAACCCAATTG CTAAATTG G AG G CCG AAAACATATG AAAATGTTG CAG AA chr3 154551207 154551209 AGCAATTAAAAATTAAAATGACTACGATATGTGATATTTTATTTGCTTAT chr3 181704950 181704952 TACAACTTGACACCATTGAGCCCACGGTGCTTGTCAATAATCTGTGAATT chr3 181704894 181704896 TCCTAATCCAG G G CCCAG CG G CTACGTG G GTTG CTG CG G G GTGTTG AAAC chr3 181715790 181715792 TTTGGAGAAGTTGGAATCCGGCAGCGTCTTCCACCCTTGAGTAAAGTACC chr3 181716153 181716155 TG G CCAG CCATTGTAATG CATATACG G ATTATTCACGTG GTAATG AG CAC chr3 181724559 181724561 CTGAACAACAATGTAAATCACAATCGCTTTATTATTTAATAACGTCAAAC chr3 181724058 181724060 CCTTG CCCACCACG G CATCTACCTCG G G GTG CACG CCAG G CTCTG AG AAA chr3 181724236 181724238 AGACAGGCAGAATTCTCAGAGCATCGGAACCAGGGAACTTGCAGGGAACC chr3 181724459 181724461 TTCGGCTGTACTTTTTTAAACGCTCGCATATTGTTTGATTACTAATTCGA chr3 194028101 194028103 aatagagctgggtgcagtggctcacgcctgtaatcccagcactttggaag chr8 88495042 88495044 TTG G AGTTTTATG AG G ACAAATCACG G CTG ATAATTTG AG G CTATCAG GT chr3 41117522 41117524 TGTGGCGCTCTGACCACGCCCAGCCGCCCAGCAGCTCCAGCGAGGAAACA chr7 28632740 28632742 gggaggattttctgtccctcggctcgaaggttagccagcccctgatctca chr3 52140201 52140203 CCG ATGTG CCG G G G AGTCTG G ATACGTGTTCCCAG G CACACTTAG G G GG A chr3 52140116 52140118 TTGGTAAACACACCCAACACGAAACGGCCCTCAACAAGGCCCACAGGGTG chr3 56434152 56434154 TCTGCAACCATGTGAAAAGGTTATCGGAAAATAAGGAAATTACAAGCTGT chr6 89949296 89949298 CTTGTCACTGGGTTTGTTCAATCCCGCTCCTGAGGGGGGTCTGAGACACA chr7 159231136 159231138 TTCTCCAG GTGTG ACTTGGTCG G ACG CG G ATCCCG G CAG CCAGCTG G G G C chr3 73746874 73746876 G GCCGTTG G CGTCTTG CCTCACAACG CACAG G G G ACATG CGTTTTATG AC chr5 50998048 50998050 ATTTTCCTTAAATTCTCTGTGGAACGAGTGGTGACAGAAACAAGTAATAA chr3 164753486 164753488 ATCTCTTAACCCCTCTGTTAAATACG CTTTAATG G CTACATATTGCACTA chr7 1680106 1680108 ttca CCTACCCAGTG G ACATTCTCCG ATG CTG G GCTCCGTG GTCTG G ATA chr7 1675882 1675884 AG G G CTG CATG AAGG GTTG G CCAG CG CTTG G CTCCCTCACTG CCATCTCG chr3 81591988 81591990 CAAGTTTCTCATTTTTGATGCTGTCGTTCTTTAATTTTAAAATATTtaat chr3 81591988 81591990 CAAGTTTCTCATTTTTGATGCTGTCGTTCTTTAATTTTAAAATATTtaat chr3 8596019 8596021 tactagcagcatgtgtgaggaagacgtggggaggtttgttgCATGTACAG chr3 8595802 8595804 ggcacacagcgtgctcatcaatggcgtgggtggcactgtgatgagaaggg chr4 77897104 77897106 ttatgagtcagagtttccctctgtcgcccaggctggagtgcaggggtgca chr4 77897059 77897061 GCATTTAGAAACTAAAAACACTAGCGTGAAATATATCttttttttttatg chr5 17306281 17306283 AAGTCCACTG G CAAACCCGG G AG G CGG G GG CTAGTG ATTATTTTCTAACA chr4 163154908 163154910 aaaaacaaaaaaaaaaaaACAGAGCGAGAGAGGAGAACAAAGAGGAAAAA chr4 3377079 3377081 ggctggagtgcagtggtgtgatcacggctcactgcagccttgattttcTT chr4 3376702 3376704 CTCACAGACTGTGAATTGATTTGCCGGTCCCTTGGAGGGTCATGGCTGGG chr4 3374241 3374243 CAG ACAG CAG G AG CTG CCG AG CTCCG AGTG CTG G G CCAG CTTG CCTTG G G chr4 3374062 3374064 GAGGAAGGCAGCGAGCCCGCTTGGCGAGGCCCTTGAGCACTCAGCACCTT chr4 3374306 3374308 CCTCCG G GTTCCCCTCCTCTCCTCCG ACTCCACTG G CTTTTC ACCACTGT chr4 3374342 3374344 CTTTTCACCACTGTCAGGTCTTCACGGGGGAGGCCTAGGCTGGGCGGGGA chr4 3374416 3374418 CCACG ACAG G CTCG ATTCGTCCCTCG CATG CTGCCCTCCCAG CCTG G CCc chr4 3391658 3391660 G AACTCCTCTCATG CAACCCTAG GCGTG AG AAG CAGTGTCCG CCCTGTTT chr4 3406740 3406742 TCCTCTCAG AG ATG AG G CCCTG CTCG G CCTG G GG G CAG G AGCAACAG AG G chr4 3406740 3406742 TCCTCTCAG AG ATG AG G CCCTG CTCG G CCTG G GG G CAG G AGCAACAG AG G chr4 3384314 3384316 attataggcatctgcttccacgctcggctaatttttatattttagtagag chr4 3382402 3382404 ACAAGCCCAGCCGTGGCCTGGAAGCGACACTGATGATTAGTATATCTGTG chr4 3411467 3411469 TCGTGTTAGGCTGGCCTGCTCTGGCGTCTTGCTCATCTTGTTTGTTCCCC chr4 3411570 3411572 AACAAG ACACCCATAGG CAAGTATCG G CGTG ATATGTCCATTTAG G G AG A chr4 3384176 3384178 TG AT Attattta tttatttta agacggagtctca ctctctca cccaggct chr4 3405668 3405670 accttcttaggaaatctacactgacgtgtttaggggcaaagaggcatgct chr4 3384476 3384478 cTTCCTGTGATATTATTTAGATTGCGACATGATTGTGGATGATTTATTGC chr4 3390227 3390229 CTGACCACCTGCCCCCATCCTGAGCGATGGCCACTGTCAATTTCCTGCCC chr4 3389767 3389769 CAGCAGGAAAGCCGGGGAACTGTGCGGCTCTGGCTTTGGGGGACGGTGGC chr4 3389731 3389733 AGAGCGCCCACCTCCTCCTGCGTACGGCGTCTGTGCCAGCAGGAAAGCCG chr4 3385479 3385481 CTGGGCTGAGTCCTGGGCTTGTCCCGTACCTGCCTGACGGCTCTGCGCCC chr4 3385161 3385163 AAAGCCCCAGTGACCTCCACTTCTCGGGAGTGGCCAGGAGGTACCAGGTT chr4 3385492 3385494 TGGGCTTGTCCCGTACCTGCCTGACGGCTCTGCGCCCTGGGCCCTTCCTG chr4 3385638 3385640 GAGTTCTCGGCCTCCTCCTGGTCACGCTGGCCTTCCGGTACCGCCTGCCA chr4 3385938 3385940 TGGGAGGGCAGTGATGCTGGAGAGCGTGAGGGGCGGCGAGTATGGCCCTG chr4 3385938 3385940 TGGGAGGGCAGTGATGCTGGAGAGCGTGAGGGGCGGCGAGTATGGCCCTG chr4 3389755 3389757 CGGCGTCTGTGCCAGCAGGAAAGCCGGGGAACTGTGCGGCTCTGGCTTTG chr4 3389678 3389680 TGTGACCACCTCACCTTCTGAAGTCGGGGTGTGGAGACTATCGGGGAGCT chr4 3393330 3393332 cccccggctgatctttgcctgcctcgtggggtctcggctgtgcatgcaca chr4 3393340 3393342 atctttgcctgcctcgtggggtctcggctgtgcatgcacagcttagaact chr4 3393693 3393695 TTTCCCGCAGGTTCTGATGCTCTGCGTATTTTGTCTACTATTCTACTGTC chr4 3394128 3394130 CTCTCTGAACGTGGTGCCCTTCCACGGCATTTCATCCGTCTGCTCCTTCA chr4 3410433 3410435 TGTACACAGAACAGGATCGGCCCCCGAGGCTGTTTCTGGTGCAGGGCGTG chr4 3410511 3410513 G CTGTCCAGCCAG CTCTG GTCTTCCGTCTCCCAG CACTG G G CG G G AG GTC chr5 150680117 150680119 AAGAATAGCCAAAACGCAGAGAAACGTGGCATTAGacatagcaacaacga chr4 38356556 38356558 GGGAAAAAATCTCAATTCATAAAGCGGCAGAGCAGACGCATATGCATAGA chr4 39815565 39815567 AG ATG CTG CACCAAG CAG G AACAG CG G AGTCTG CG AG CG CG CCCACCTG C chr8 41246826 41246828 gcagcctactcttgtgccaatcaccgagtttctggcaatcgaaagcggcc chr4 44770533 44770535 cagcctgggcacagagggagactccgtctcaaaataaaaaaagaaattaa chr6 164351123 164351125 G AGTCCTCCACTAAG CTGTTAAAG CG CTAATAG GTTTCTCCAG ACACTG C chr4 54226613 54226615 CCCAAGAGGTTGAAAATTAGAATCCGGGCGCGGGTTGAGATCTGCGCAGA chr4 54226464 54226466 CCCTTTTCTCCCAACTTCTCGGCCCGGCTCAATTCGGGAGTTGGGCCTCC chr4 54226502 54226504 AGTTG G G CCTCCTTCCTCTCG G CTCG CAG CCTCCCCG ACTCCCACTTTG G chr4 54226617 54226619 AGAGGTTGAAAATTAGAATCCGGGCGCGGGTTGAGATCTGCGCAGAGCTG chr5 79842653 79842655 GTATGAGTTTGTCCATCAACTGTGCGTGCAGATCTTTACTCGCATGCATG chr4 7626609 7626611 atttgtgtgtatcatatgtgtgtacgtatttatgtacgaatgcatgtata chr4 7766077 7766079 CTCACTTTGTCTAAATCAAAAGCTCGAGTTCAACTCATGGTTAAATTCAC chr5 10524872 10524874 G ACCTCACTGTCATTG G CCCCATTCG CCG G CAGCTCTG G ACACCAG ATG G chr5 10524764 10524766 CTG CTCGG CCCG GCATCTG CTACCCG G CCCTCCACACCATCTG CG CCCAG chr8 117042553 117042555 TATCTG GTCTG G ACCCAAG G AAG CCG GTG CTGTTTTATTCCTTACATTTA chr5 107099103 107099105 GCATCTATTAAATACAGAGATTACCGGAGATGCTTTTGTTAAGGAAGAAC chr5 113040537 113040539 CCCAG CTG ACCTCAACCATAAG CTCG G CTGTG ATTTAATACCTTCAAAAA chr8 144241354 144241356 AGTGTGCGTGCATGTGTGGCAGTGCGTGCTCTTCCCTGCCCGGGGTAAGT chr5 127066418 127066420 gctactgcattagtttggatgagacgggatggtatggactagaacagaaa chr9 83315819 83315821 TAGGCACGCACACCGGGTACCTTCCGCTCAAGCCTGCTGCTGCCCATGAC chr5 167983052 167983054 ACACTCCCATATGATAGTGCATAGCGAATTCAAGGTCAAATCTAAAGTCA chr9 121830266 121830268 GCAATGATCCAGACcagaggctctcgaactttcgaaactcccagagggct chr5 172860953 172860955 G CTG AG CCAG CCTCG G CTG G AG ACCG G CCCTG G CACTG ACTG CCTG G G GT chr5 172860804 172860806 ggaaggagtccagggtgttagccacgcctgtgtttctttgtgagcacaaa chr5 175442710 175442712 TTG G G G GTCATCTTTCTCTCATACCGG AAAG G G CTG G AG ATAG CCCAATA chr5 175442710 175442712 TTG G G G GTCATCTTTCTCTCATACCGG AAAG G G CTG GAG ATAG CCCAATA chr5 175441994 175441996 GCTCATGATGGCTGGAAAACATCGCGGCCCCATTGTTATTGATACTCACC chr5 175442387 175442389 CTGTG GTG GTCTGG CAATTCTTG G CGTG G ACTG CTG CCCTCTCCAAG GCC chr5 175442086 175442088 CCTAAG AG G GTTG AAAATG CCTTCCG AAAATCAG CATTAAAG G CATAAAT chr5 175442040 175442042 CACCGTCTCTATG G CATTATTCGTCGCAG G G CAAAGTCTGTAG CATCCTA chr5 175692868 175692870 TCTTCTGGCAAGGGTGGTGAGGAACGTGTTTTTTATACTAATGAGTCGCT chr5 175692802 175692804 TAACTATATATAAATACTTAACAACG G AG AG AG CGTG CCAACCCCCCAAC chr5 180155581 180155583 TCTTGTTTCTG ATTG CTCAGG G CCCG G CTTG CAG G CAATCTGTTG G ATG C chr5 180155459 180155461 CTGGCCTTGCCTTCAGGAGGGCAACGCGCTTGGCTGTGAGGGGAGGATTG chr5 36490437 36490439 GTGAGGGAATGGTGCGTTCTCTTTCGATGTTGAGAGTTCTACCTAACTAA chr5 36490583 36490585 gaaatagaactaggaggccaggtgcggtggctcatgcctgtaatcccagc chr5 60340044 60340046 AGATTATAAACCAGCCAAAACCACCGGAGATTATGTCAATGTGCATGTGG chr5 60339877 60339879 TCTGTGTTCTGCATGGATGTGTTCCGAGGCAACTCAGCATGTGCAGTTGG chr5 65126330 65126332 CAATAG GTCTG ACAG CTGTCTCCACG CAGTCTTG CAG CATTCAG CTTCAC chr5 65126379 65126381 CTGGGAATGATTAGCCCGTCCTGACGAAGCTCTTCCCCCACTGAGACACG chr5 6810073 6810075 gcctgaaactgagagatgaaataacGCTAACAAGGGCTTATCGTTCAAGT chr5 6810030 6810032 cttttaggccacctagtctgataccgtgatttacagatgaggagcctgaa chr6 105628390 105628392 GAACAAATGAAACCAATAGACACTCGTGATAGGGAAGTTCTTTCAAAAGA chr6 110439611 110439613 ATCAGAAAAAATAACCAGATGTGCCGTCAGAGCACTTTAATGAGATGGCA chr6 117562504 117562506 GAATGGGTAAATGCTCCAGTACTGCGCACACAGATCAACATAATTGAGAA chr7 2108124 2108126 AGCACTAAAGATTTTCATTATGTACGATAACATTCCCATCAGAAGAGAAC chr6 120951342 120951344 ATGGACAGAGATAGAAAAATGAGACGGTGTGTGCTTCTGACTGGAAAGTA chr6 150204270 150204272 CG AG G ACCAACCTGCCG ACTTTCTCGTCACG G G G G CATTGTTAACAACCA chr6 150204473 150204475 CGATTTTCAGGCATCAGGAGTACACGATTCCCTGGAAGAGACATTTACAT chr7 80057215 80057217 gatatactgggccgggcgcggtggcgcatgcctgtaatccaagcactttg chr6 162547293 162547295 CGTTTATCATCTATATGTCACATACGAAATTAGTTACACTAGCAGCATTT chr6 169961951 169961953 GTGAGGATGCGGCTCCCGGACACCCGAGGGCGCCCTCCTGAGCCTGAGCC chr7 1231081 1231083 ATAGAGACAGAAATTAAATTATGGCGAAAAGTAGTGCTCTTGGCCTCTGA chr6 150893713 150893715 CTCTTAAACTACAG GTAGTCTTACCG GTGTG G GCTG ACCTTCCGGTTATC chr8 10296807 10296809 TGCTTTGCCTCCTCTCCCAGACCCCGccaaggtcatgcacctgcccagca chr6 6907253 6907255 AGTCAGAGCTTCCAGGAGGAGACCCGGTATTCTTCAGCAAAGATGGCCAG chr6 6907404 6907406 TAAAAG G CCCTCTGTTC I I I I I I I CG CTGTATACACTGTG CCCTGTTGTT chr7 101915316 101915318 GAGGCCAGGGCACAGGTTCTCTGGCGCGTTGATTATCGGTTTGTTGCGGG chr7 101915318 101915320 G GCCAG G GCACAG GTTCTCTG G CG CGTTG ATTATCG GTTTGTTG CG G G G A chr8 84031486 84031488 aacctggctgggtgtgcgcacactcggggcagcactgacacgctatcacc chr7 138971636 138971638 AGGGGCTGGGTCCTACCCAGTCAGCGGCTGTCACAACAAAACCCACCCCC chr7 157585009 157585011 AGGGTGACAAAACCTTCGTGATGCCGTCCATGACCAGCTCATGGTGCACC chr7 157585001 157585003 CCCAACGCAGG GTG ACAAAACCTTCGTG ATG CCGTCCATG ACCAG CTCAT chr7 157897945 157897947 CACACTGACTGACGAGTGGCCACACGCCATTCCTCAGAGGAGGCGCGTCC chr7 157898014 157898016 TTAAGTTGTCATGTCAGGGGACAGCGGCCATCGGCGCGGTGCGGGGAGGC chr7 157897966 157897968 ACACG CCATTCCTCAG AG G AG GCGCGTCCGCG CTCTGTGTG CAGTTCATT chr7 157897933 157897935 TTGGCTTCGGTCCACACTGACTGACGAGTGGCCACACGCCATTCCTCAGA chr7 157897972 157897974 CATTCCTCAGAGGAGGCGCGTCCGCGCTCTGTGTGCAGTTCATTAAGTTG chr7 157897964 157897966 CCACACGCCATTCCTCAGAGGAGGCGCGTCCGCGCTCTGTGTGCAGTTCA chr7 1672459 1672461 G G AGTAGTTG CCTGTCTCG G ACCCCG G CATTTG AATATTTTCACCCTAAA chr7 1676417 1676419 GGCTGGGGAGCCTCTGGTGTTCGgcgtgacctgaggtgggtcccttccct chr7 1673021 1673023 GTGATGAGGCCATAAATTTCCAGGCGTGAACCTGGAGCGGATGGTGGCAC chr7 1672933 1672935 TACACGAGGGGGCCGGTGGCGGGGCGGGGGGCAG G ATTAAAAATG CAAGT chr7 1672928 1672930 ATAAATACACGAGGGGGCCGGTGGCGGGGCGGGGGGCAGGATTAAAAATG chr7 1673310 1673312 GTGGTGGAGGG GTCCTATGTCTG G CGTCTGTGTCCTGTTGTGTTG GTTCA chr7 1672799 1672801 CTCCGTGCCAGACTCAGACACCATCGCATTGGAGGAAATTTATGAGCAGA chr7 1678807 1678809 TCTGCGACAGTCTTGGTGACTACCCGGCTTAGCGAGTGAGGGAATATTTG chr7 1677614 1677616 CACGTGTGTGTAGATTAGTGTCTGCGTGAATAGAGGTGTGTGCACACCCT chr7 1676641 1676643 GATGGGGCGCAGGTTCGGTCCCTGCGTCCCTCTGTGCCCTGCTGTGCAAA chr7 1674842 1674844 GGGGACAGAGGAGGCACAGCCGGGCGGGAAACATCCTTCGGCCCGGGCCA chr7 1677528 1677530 ACTGTGCAGGGGTGTGTGTAGGTTCGCGGGTGTGTGCATGTAGATTCGTG chr7 1675096 1675098 TACCGACGGGGACCCGGCAGCCCACGGCGTGGAGGTGAACCAGCTTGTCT chr7 1675099 1675101 CGACGGGGACCCGGCAGCCCACGGCGTGGAGGTGAACCAGCTTGTCTGGG chr8 141800688 141800690 TGGGTTTGCAGATGCACGCAGGCGCGGCTGCCTCGTGCTGCGGCCCAACC chr8 141800485 141800487 CTCTGAGGGCCGTGCCTTCATCAGCGCCTGCAGGCTCTCAGGAGGGGCTG chr8 52246671 52246673 TCACAAAATTGGGGGCTCTGGAAGCGAAAATACGAGAAAGAGTTCTGTAC chr8 52252719 52252721 GCTTTTATGTGCAACAGTGATTTCCGCTAATTTGGCAAGAGAAATCTATA chr8 88495214 88495216 CATGCAGACCggcacagcagctcacgcctgtaatcacagcactttgggag chr8 92942006 92942008 attctacaaacatttaataaagaacgaacactaattttactaaaattatt chr9 114250578 114250580 GGGAGGGCTGGGTCCCCGGATTCACGTTGTTTCTCTTGCTTTCGGGAATG chr9 114250449 114250451 CTGGTGGAGTGAGGGAAGTCAGAACGGTGCCCAGAGAGAGGCAGCGCTCT chr9 114250469 114250471 AGAACGGTGCCCAGAGAGAGGCAGCGCTCTCCCCGGCACAACCCCATGCT chr9 114250397 114250399 TCCCAGGGATGTTGGCAGCGGCCCCGCTGCTTGGCTTCAAAATCAGAACC chr9 122212102 122212104 TCACaagagcagccaatacttatgcggcacttgctgaatgttgaggattt chr9 122224319 122224321 attataggtgtgagccaccacacccggccCATCTGGCATGTTTTATACCA chr9 130919223 130919225 CCACGGAGGCACGCTTTCTTTGCACGATGAACGAAGGAAATGTGAGGGTG chr9 130919131 130919133 TCTCGGGTGCTGAGCCACGGCGGGCGCGGGGCTGGGCCCTGCACGTGCAT chr9 134351726 134351728 TCTGCGGCCCTCTTTAATTAAGGCCGAGATGTAATAACCAATCCGCTGCT chr9 134351622 134351624 GAGGGTGGAGGAGGGTGCCGGCTCCGTTTCAGGCCGGTTTGAGTATTTTT chr9 134420684 134420686 AGATGCCCTGAAGTGAGGGATCCCCGAATCCTATTCACAGTCGTTATTCC chr9 134420593 134420595 GCCGGGCGCTGCGTTTAGGCTGCACGTCTCTGATGAGCAGATGGTTGCTG chr9 73879045 73879047 TATTATGTAATATATCCATATTCCCGATGATCAAGATCTTGCTGGTGTAT chr9 79193716 79193718 TGAGGGCGGCGGCGGGAAGAGCGGCGTACGCCCTGGATGTCGCCACGCGG chr9 79193652 79193654 TGGTGCGGGAAAGGTTTCCAGTTCCGGAAGGCGGTTGCGACATCCCGTGC chr9 93156181 93156183 CCCCGTGTGTGGGACCGCTGCCTGCGCAGAGGGGGCAGCCCAGTGTGGGG chr9 93156160 93156162 CGGAAGCGGCTGAGCGCCCAACCCCGTGTGTGGGACCGCTGCCTGCGCAG

Table 2 Exemplary methylation markers (an exemplary subset of Table 1) chr start end chrlO 120517367 120517369 chrlO 129558734 129558736 chrlO 12981474 12981476 chr5 115106946 115106948 chrlO 85659210 85659212 chr3 23272516 23272518 chrll 113951238 113951240 chrll 114069492 114069494 chrll 15508856 15508858 chr6 87948947 87948949 chrll 61601245 61601247 chrll 6333181 6333183 chrll 64638406 64638408 chrll 64638423 64638425 chrll 64638487 64638489 chrll 64638446 64638448 chrll 64638208 64638210 chr7 94840949 94840951 chr2 42221994 42221996 chrll 70828694 70828696 chrll 70828959 70828961 chrl2 104666538 104666540 chrl2 111199420 111199422 chrl2 111363167 111363169 chr8 118694978 118694980 chr7 17586547 17586549 chrl3 44573330 44573332 chr8 80345362 80345364 chrl3 78061219 78061221 chr20 55284577 55284579 chr9 35350760 35350762 chrl4 91028417 91028419 chrl4 99239938 99239940 chrl4 99240729 99240731 chrl4 99265134 99265136 chrl4 99258195 99258197 chrl4 99254307 99254309 chr6 60830914 60830916 chrl5 40579060 40579062 chrl5 60850769 60850771 chrl5 73787074 73787076 chrl5 75706213 75706215 chrl6 71746304 71746306 chr6 158528243 158528245 chrl6 29674272 29674274 chr20 52979500 52979502 chr7 45198338 45198340 chrl7 17603475 17603477 chrl7 2019280 2019282 chrl7 49578654 49578656 chrl 88186554 88186556 chrl7 78458835 78458837 chrl7 81839462 81839464 chrl8 42840569 42840571 chrl8 55863146 55863148 chrl8 55863406 55863408 chr8 57356053 57356055 chrl9 13002909 13002911 chrl9 31596154 31596156 chr8 87977499 87977501 chrl9 33408728 33408730 chrl 15765576 15765578 chr6 96873290 96873292 chrl9 8180812 8180814 chrl 114587732 114587734 chrl 47930687 47930689 chrl 16921554 16921556 chrl 17535924 17535926 chr21 29917226 29917228 chr2 227315087 227315089 chrl 223535050 223535052 chr5 43282460 43282462 chrl 213899571 213899573 chrl 30127035 30127037 chrl 30830766 30830768 chrl 30830843 30830845 chr6 36775571 36775573 chrl 38114428 38114430 chrl 55154499 55154501 chrl 6954346 6954348 chrl 84779343 84779345 chrl 82344735 82344737 chr2 192676064 192676066 chrl 89387906 89387908 chr3 53425664 53425666 chr7 159142397 159142399 chr20 23049529 23049531 chr20 40692864 40692866 chr20 57730506 57730508 chr21 21578917 21578919 chr21 26832851 26832853 chr21 29221598 29221600 chr21 43913788 43913790 chr21 44074575 44074577 chr21 45115350 45115352 chr22 24425509 24425511 chr22 24425165 24425167 chr22 24436142 24436144 chr22 24425431 24425433 chr22 24440428 24440430 chr22 24426997 24426999 chr22 24428719 24428721 chr22 24427299 24427301 chr22 24434476 24434478 chr22 24435262 24435264 chr22 24439355 24439357 chr22 24438986 24438988 chr22 24441113 24441115 chr22 29184668 29184670 chr22 36763396 36763398 chr22 36763700 36763702 chr22 49391984 49391986 chr2 106974041 106974043 chr2 214915957 214915959 chr8 63031540 63031542 chr2 144508216 144508218 chr2 144509942 144509944 chr2 159230649 159230651 chr4 54236780 54236782 chr2 199449983 199449985 chr3 113902470 113902472 chr3 142925609 142925611 chr2 224976082 224976084 chr2 234438297 234438299 chr2 30689098 30689100 chr2 44884032 44884034 chr2 520529 520531 chr5 178604407 178604409 chr2 42964618 42964620 chr2 88493781 88493783 chr3 10546931 10546933 chr3 143082577 143082579 chr3 181704950 181704952 chr3 181715790 181715792 chr3 181724559 181724561 chr3 181724236 181724238 chr3 41117522 41117524 chr7 159231136 159231138 chr7 1680106 1680108 chr3 81591988 81591990 chr4 3377079 3377081 chr4 3374241 3374243 chr4 3374306 3374308 chr4 3374416 3374418 chr4 3384314 3384316 chr4 3411467 3411469 chr4 3384176 3384178 chr4 3384476 3384478 chr4 3389767 3389769 chr4 3385479 3385481 chr4 3385492 3385494 chr4 3385938 3385940 chr4 3389755 3389757 chr4 3393330 3393332 chr4 3393693 3393695 chr4 3410433 3410435 chr5 150680117 150680119 chr4 54226613 54226615 chr4 54226502 54226504 chr4 7766077 7766079 chr5 10524872 10524874 chr5 113040537 113040539 chr5 127066418 127066420 chr5 167983052 167983054 chr5 172860953 172860955 chr5 175442710 175442712 chr5 175441994 175441996 chr5 175442086 175442088 chr5 180155581 180155583 chr5 60340044 60340046 chr5 65126330 65126332 chr5 6810073 6810075 chr6 105628390 105628392 chr7 2108124 2108126 chr6 150204270 150204272 chr6 169961951 169961953 chr6 150893713 150893715 chr7 101915316 101915318 chr8 84031486 84031488 chr7 157585009 157585011 chr7 157897945 157897947 chr7 157897966 157897968 chr7 157897972 157897974 chr7 1672459 1672461 chr7 1672928 1672930 chr7 1672799 1672801 chr7 1677614 1677616 chr7 1674842 1674844 chr7 1675096 1675098 chr8 141800688 141800690 chr8 52246671 52246673 chr9 114250578 114250580 chr9 114250469 114250471 chr9 122212102 122212104 chr9 130919223 130919225 chr9 134351726 134351728 chr9 134420684 134420686 chr9 73879045 73879047 chr9 79193716 79193718 chr9 93156181 93156183

In some examples, measuring the methylation level (or status, e.g., + or -, or H, L, or N) of at least 30 different methylation markers in the genomic DNA of the biological sample includes hybridizing polynucleotides complementary to polynucleotides attached to a solid support. In some examples, the polynucleotides attached to a solid support include at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 different nucleic acid probe specific for CpG methylation markers provided herein, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, 3000, 4000, 5000 or more different nucleic acid probes. In some examples, the polynucleotides attached to a solid support can determine the methylation status of at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 different CpG methylation markers provided herein, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, 3000, 4000, 5000 or more CpG methylation markers. In some examples the polynucleotides attached to a solid support include at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 of the probes provided in SEQ ID NOS: 1-2415, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, or 2400 of SEQ ID NOS: 1-2415.

The disclosed methods can be used to diagnose and/or treat one or more diseases/disorders in the subject, based on the brain cells identified. For example, as shown in Table 3, if Sst cells are present, this indicates that the subject may have schizophrenia, and can thus be treated with one or more anitpsychotics, such as one or more of Chlorpromazine (Thorazine), Fluphenazine (Prolixin), Haloperidol (Haldol), Perphenazine (Trilafon), Thioridazine (Mellaril), Thiothixene (Navane), Trifluoperazine (Stelazine), Aripiprazole (Abilify), Aripiprazole lauroxil (Aristada), Asenapine (Saphris), Brexpiprazole (Rexulti), Caripraz.ine (Vraylar), Clozapine (Clozaril), Iloperidone (Fanapt), Lumateperonee (Caplyta), Lurasidone (Latuda), Olanzapine (Zyprexa) , Olanzapine/samidorphan (Lybalvi), Paliperidone (Invega Sustenna), Paliperidone palmitate (Invega Trinza), Quetiapine (Seroquel), Risperidone (Risperdal), and Ziprasidone (Geodon). In some examples, the method further includes administering to the subject an effective amount of a therapeutic agent when a particular type of brain cell is identified (e.g., see Table 3).

In some examples, the method also includes reporting the types of brain cells identified, for example a written or electronic report.

Also provided are kits that can be used with the disclosed methods. In some examples, the kits include nucleic acid probes for detecting at least 30 different methylation markers in Table 1 or 2 or FIGS. 25A-25B, such as at least 30 different probes provided in SEQ ID NOS: 1 to 2415, 1 to 1585, 1586-2385, or 2386-2415. In some examples, the kits include at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 different nucleic acid probes specific for CpG methylation markers provided herein, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, 3000, 4000, 5000 or more different nucleic acid probes. In some examples the kits include at least 20, at least 30, at least 40, at least 50, at least 100, at least 150, at least 200, at least 300, at least 389, at least 500, at least 650, at least 785, at least 800, at least 1000, at least 1585, or at least 2000 of the probes provided in SEQ ID NOS: 1 to 2415, 1 to 1585, 1586-2385, or 2386-2415, such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 350, 385, 400, 500, 600, 700, 785, 800, 900, 1000, 1500, 1585, 2000, or 2400 of SEQ ID NOS: 1 to 2415, 1 to 1585, 1586-2385, or 2386-2415. In some examples, the probes in the kit detect at least the markers provided in Table 1. In some examples, the probes in the kit detect at least the markers provided in FIGS. 25A-25B. In some examples, the probes in the kit detect at least the markers chrl_6954205, chrl_6954346, chrl_15437470, chrl_15765576, chrl_16921554, chrl_17535615, chrl_17535924, chrl_20748527, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_47930687, chrl_55154474, chrl_55154499, chrl_82344735, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_l 14587732, chrl_l 14587798, chrl_200664873, chrl_213899571, chrl_223535050, chrl0_12981474, chrl0_85659210, chrl0_85659210, chrl0_96825742, chrl0_120517367, chrl0_120517552, chrl0_129558734, chrl 1_6333181, chrll_15508856, chrl l_30683884, chrll_61601245, chrll_64638030, chrll_64638061, chrl l_64638130, chrll_64638134, chrl l_64638208, chrll_64638406, chrll_64638423, chrll_64638446, chrl 1_64638476, chrll_64638487, chrl 1_66652738, chrll_70828694, chrll_70828726, chrll_70828942, chrl l_70828959, chrl 1_113951190, chrl l_113951238, chrl 1_114069492, chrl 1_114069680, chrl 1_118210650, chr!2_104666490, chrl2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl2_l 11363249, chrl3_44573330, chrl3_78061219, chrl3_92046041, chrl3_93413326, chrl4_28309117, chrl4_32587882, chrl4_91028417, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99265134, chrl5_39667040, chrl5_40579060, chrl5_60850769, chrl5_73787063, chrl5_73787074, chrl5_75706205, chrl5_75706213, chrl6_29674272, chr!6_29674291 , chrl 6_71746300, chr16_71746304, chrl6_79856776, chrl 7_2019254, chr17_2019280, chrl7_17603475, chrl7_17603475, chrl7_49578654, chrl7_49580573, chrl7_58691449, chrl7_78458835, chrl7_78458957, chrl7_81839462, chrl7_81839517, chrl8_31612779, chrl8_42840523, chrl8_42840569, chrl8_55863146, chrl8_55863209, chrl8_55863341, chrl8_55863406, chrl9_8180812, chrl9_13002733, chrl9_l 3002909, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_33408728, chrl9_33408838, chrl9_39052997, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_4416732, chr2_8535196, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_73008587, chr2_88493781, chr2_ 106974041, chr2_l 15082751, chr2_120543523, chr2_l 44507406, chr2_144508216, chr2_144509942, chr2_144512702, chr2_159230649, chr2_180445347, chr2_l 92676064, chr2_199449983, chr2_199450146, chr2_203121062, chr2_214915957, chr2_216827945, chr2_224976082, chr2_227315087, chr2_227315087, chr2_234438247, chr2_234438297, chr20_l 837975, chr20_23049529, chr20_23049808, chr20_40692708, chr20_40692864, chr20_43564715, chr20_49882081, chr20_52979500, chr20_52979806, chr20_53032932, chr20_55284577, chr20_57730506, chr20_57730576, chr21_21578917, chr21_26832783, chr21_26832851, chr21_29221598, chr21_29221717, chr21_29917226, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr22_24425152, chr22_24425165, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425710, chr22_24425816, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24428701, chr22_24428719, chr22_24434350, chr22_24434476, chr22_24435262, chr22_24436130, chr22_24436142, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_49391984, chr3_10546902, chr3_l 0546931, chr3_23272516, chr3_41117522, chr3_53425664, chr3_73746874, chr3_81591988, chr3_81591988, chr3_l 12000443, chr3_l 13902470, chr3_142925609, chr3_143082577, chr3_143082617, chr3_179616279, chr3_181704894, chr3_l 81704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_181724459, chr3_181724559, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_9109274, chr4_l 1187567, chr4_l 5944086, chr4_36635749, chr4_38356556, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_87865311, chr5_6810030, chr5_6810073, chr5_10524764, chr5_10524872, chr5_43282446, chr5_43282460, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_95429494, chr5_l 13040537, chr5_l 15106946, chr5_l 27066418, chr5_150680117, chr5_167983052, chr5_l 72860804, chr5_172860953, chr5_ 175441994, chr5_175442040, chr5_175442086, chr5_175442387, chr5_l 75442710, chr5_175442710, chr5_178604407, chr5_180155459, chr5_180155581, chr6_33906454, chr6_36775571, chr6_40888325, chr6_60830914, chr6_87948947, chr6_96873290, chr6_ 105628390, chr6_l 10018487, chr6_120951342, chr6_l 21099723, chr6_l 37290533, chr6_l 39254024, chr6_l 50204270, chr6_150204473, chr6_150893713, chr6_158528243, chr6_ 169961951, chr7_1231081, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_1675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_l 7586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_88282441, chr7_94840949, chr7_101915316, chr7_101915318, chr7_l 02107431, chr7_l 38971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_l 57897966, chr7_157897972, chr7_157898014, chr7_159142397, chr7_159231136, chr8_10296807, chr8_52246671, chr8_52252719, chr8_57356053, chr8_63031540, chr8_80345362, chr8_84031486, chr8_87977499, chr8_l 18694978, chr8_l 18694978, chr8_140729234, chr8_141800485, chr8_141800688, chr8_l 44241354, chr9_35350760, chr9_73879045, chr9_79193652, chr9_79193716, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181, chr9_l 14250397, chr9_l 14250449, chr9_ 114250469, chr9_l 14250578, chr9_121830266, chr9_122212102, chr9_122224319, chr9_130919131, chr9_130919223, chr9_134351622, chr9_134351726, chr9_l 34420593, and chr9_l 34420684. In some examples, the probes in the kit detect at least the markers chrl_6954205, chrl_6954346, chrl_7048907, chrl_15437470, chrl_15765576, chrl_16921554, chrl_17411021, chrl_17535615, chrl_17535924, chrl_20748527, chrl_25729798, chrl_27249955, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_38418368, chrl_43465467, chrl_43465657, chrl_45049761, chrl_47930687, chrl_50837887, chrl_55154474, chrl_55154499, chrl_82344735, chrl_83627211, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_107575614, chrl_l 14587732, chrl_l 14587798, chrl_155009422, chrl_174451522, chrl_174451522, chrl_197451335, chrl_200664873, chrl_207434747, chrl_210626571, chrl_213899571, chrl_219915507, chrl_223535050, chrl_241329400, chr 1.244054001, chr 1.244054019, chrl.244054025, chrl_244054088, chrl_244054213, chrl_244054334, chrl_244054412, chrl.244054487, chrlO.387726, chrlO_155O998, chrlO_1599134, chrl0_1599460, chrl0_1610306, chrl0_1626613, chrlO.1679796, chrl0_1680989, chrl0_1682975, chrl0_1713526, chrl0_1721323, chrl0_1723256, chrlO.1723398, chrl0_1724564, chrl0_l 726470, chrl0_1975272, chrl0_3927130, chrl0_12981474, chrlO.33204102, chrl0_34752396, chrl0_44279927, chrl0_44280044, chrl0_59279057, chrl0_59279103, chrl0_71529729, chrl0_80094872, chrl0_85659210, chrl0_85659210, chrl0_87727342, chrl0_91397464, chr 10.92661601, chrl0_96825742, chrl0_107085835, chrl0_120517367, chrlO.l 20517552, chrlO.124961029, chrl0_129558734, chrll.6333181, chrl l_10175924, chrl l_15508856, chrl 1.16344746, chrl 1.28779431, chrll_30683884, chrll_31820115, chrll_31820310, chrl l_46385139, chrl 1.46398710, chrl l_46441679, chrl 1.61601245, chrll_64070739, chrl 1.64635621, chrl l_64638030, chrl 1.646380 1, chrl l_64638130, chrl l_64638134, chrll_64638208, chrll_64638406, chrl 1_64638423, chrl 1.64638446, chrl l_64638476, chrl l_64638487, chrl 1_66652726, chrll_66652738, chrl 1.70828694, chrl 1J70828726, chrl l_70828942, chrl l_70828959, chrll_75832244, chrll_94158916, chrl l_112260989, chrl 1_113363879, chrl 1_113400998, chrl 1_113408265, chrl 1_113433434, chrl 1_113433544, chrl 1_113444137, chrl 1_113445794, chrl 1.113460726, chrl 1_113468577, chrl 1_1 13468826, chrl 1_1 13469191, chrl 1_1 1 469614, chrl 1_11 470470, chrl 1_1 13951 190, chrl 1_113951238, chrl 1.114062290, chrl 1_114062488, chrl 1.114064208, chrl 1.114064532, chrl 1.114066467, chrl 1.114067705, chrl 1.114069492, chrl 1.114069680, chrl 1.117914441, chrl 1.118210650, chrl 1.123025323, chrl 1.127690394, chrl 1.127690429, chrl 1.131233613, chrl2_2081518, chrl2_2842964, chrl2_30766914, chrl2_47947292, chrl2_53274354, chrl2_53274417, chrl2_70443965, chrl2_77308440, chrl2_88450938, chrl2_88451104, chrl 2.92221841, chrl2_93894714, chrl2_93894790, chrl2_94695777, chrl2_95356097, chrl2_98459151, chrl 2.104666490, chrl2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl2_l 11363249, chrl2_l 19340812, chr 12.121507866, chrl2_122161069, chrl2_122228141, chrl2_127115077, chrl2_129703529, chrl3_27238208, chrl3_27517013, chrl3_35695164, chrl3_41465311, chrl3_44573330, chrl3_73025821, chr 13.73026371, chrl3_78061219, chrl 3.92046041, chrl3_93413326, chrl3_98404428, chrl3_l 03071728, chrl3_103801301, chrl3_106713795, chr 14.28309117, chrl4_32587882, chrl4_36524389, chrl4_36524667, chr 14.62814638, chrl4_72746337, chrl4_72746410, chrl4_91028417, chrl4_99239873, chr 14.99239938, chr 14.99240690, chr 14.99240729, chrl4_99244159, chrl4_99244383, chrl4_99245037, chrl4_99245125, chrl4_99253114, chrl4_99254307, chr 14.99258195, chrl4_99259778, chrl4_99259851, chr 14.99261299, chrl4_99261349, chrl4_99265134, chrl4_99265442, chrl4_104963567, chrl5_27014884, chrl 5.39667040, chrl5_40579060, chrl5_60850769, chrl5_61832637, chrl5_64673973, chrl5_70265944, chrl5_70867831, chrl5_73421182, chrl5_73787063, chrl5_73787074, chrl5_75706205, chrl5_75706213, chrl5_84784380, chrl5_98347522, chrl6_3255898, chr!6_3473308, chr!6_21514377, chrl6_21514493, chr 16.29674272, chrl6_29674291, chrl6_49521066, chr!6_71746300, chrl6_71746304, chr 16.73092631, chrl6_79856776, chr 16.84090291, chr!6_85290977, chrl6_86757258, chrl6_87957932, chrl6_89747287, chrl7_2019254, chrl7_2019280, chrl7_6264478, chrl7_8310790, chrl7_17603475, chrl7_17603475, chrl7_19539205, chrl7_19539300, chrl7_29056566, chrl7_29093998, chrl7_31593826, chrl7_32274223, chrl7_49578654, chrl7_49580573, chrl7_51374368, chrl7_58691449, chrl7_62458778, chrl7_68274037, chrl7_74762858, chrl7_75231866, chrl7_75231876, chrl7_78458835, chrl7_78458957, chrl7_79140535, chrl7_81246152, chrl7_81839462, chrl7_81839517, chrl8_7466797, chrl8_7671182, chrl8_22191374, chrl8_24273998, chrl8_28743520, chrl8_31612779, chrl8_31668044, chrl8_31668223, chrl8_42840523, chrl8_42840569, chrl8_48111878, chrl8_55316591, chrl8_55335150, chrl8_55337856, chrl8_55337859, chrl8_55347406, chrl8_55347692, chrl8_55401620, chrl8_55401726, chrl8_55401962, chrl8_55401962, chrl8_55402070, chrl8_55863146, chrl8_55863209, chrl8_55863341, chrl8_55863406, chrl8_58846286, chrl8_75629703, chrl9_940774, chrl9_940858, chr!9_941208, chrl9_941242, chrl9_941271, chrl9_941471, chrl9_4020451, chrl9_80661 0, chr!9_8180812, chr!9_l 1943461, chrl9_l 1943461, chrl9_13002733, chrl9_13002909, chrl9_13027645, chrl9_l 027708, chrl9_29879973, chrl9_30071371, chrl9_30071556, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_32327361, chrl9_33408728, chrl9_33408838, chrl9_35046673, chrl9_39052997, chrl9_5 965120, chrl9_53965266, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_1939158, chr2_4416732, chr2_6286826, chr2_8535196, chr2_8811580, chr2_22449630, chr2_27738485, chr2_27738489, chr2_27738545, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_60479437, chr2_73008587, chr2_79929386, chr2_85447333, chr2_88493781, chr2_96895479, chr2_99699856, chr2_l 00923151, chr2_l 06974041, chr2_l 15082751, chr2_120543523, chr2_127840596, chr2_144507406, chr2_144508216, chr2_144509942, chr2_l 44512702, chr2_148147429, chr2_159230649, chr2_ 169415560, chr2_180445347, chr2_184141131, chr2_l 92676064, chr2_198316634, chr2_199447280, chr2_ 199449983, chr2_199450146, chr2_201872813, chr2_203121062, chr2_211590141, chr2_211590198, chr2_212520797, chr2_212524214, chr2_214915957, chr2_216827945, chr2_219281611, chr2_219888095, chr2_222470101, chr2_224976082, chr2_227315087, chr2_227315087, chr2_231390519, chr2_232574302, chr2_234438247, chr2_234438297, chr2_236121881, chr20_1400335, chr20_l 837975, chr20_5670261, chr20_23049529, chr20_23049808, chr20_34196362, chr20_40692708, chr20_40692864, chr20_43423564, chr20_43564715, chr20_49882081, chr20_52979500, chr20_52979806, chr20_53032932, chr20_54696328, chr20_55284577, chr20_57730506, chr20_57730576, chr20_60889288, chr20_62225257, chr21_21578917, chr21_26832783, chr21_26832851, chr21_28103489, chr21_28103489, chr21_29221598, chr21_29221717, chr21_29917226, chr21_37606568, chr21_40771526, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr21_46510096, chr22_24425152, chr22_24425165, chr22_24425229, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425705, chr22_24425710, chr22_24425754, chr22_24425816, chr22_24425972, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24427448, chr22_24428701, chr22_24428719, chr22_24433075, chr22_24433241, chr22_24433423, chr22_24434088, chr22_24434350, chr22_24434476, chr22_24434989, chr22_24435262, chr22_24436014, chr22_24436130, chr22_24436142, chr22_24437360, chr22_24437763, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24440446, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_29185058, chr22_30737962, chr22_34617159, chr22_34617213, chr22_35114720, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_44940707, chr22_46346927, chr22_48824678, chr22_49391984, chr22_50658490, chr3_8595802, chr3_8596019, chr3_10546902, chr3_l 0546931, chr3_13191245, chr3_15391356, chr3_22857045, chr3_23272516, chr3_30391151, chr3_32506316, chr3_41117522, chr3_46301401, chr3_53425664, chr3_59955536, chr3_70568431, chr3_73746874, chr3_76628994, chr3_81591988, chr3_81591988, chr3_99932654, chr3_105471988, chr3_l 12000443, chr3_ 112508351, chr3_l 13651082, chr3_l 13902470, chr3_122908926, chr3_142925609, chr3_143082577, chr3_143082617, chr3_l 50033642, chr3_154551207, chr3_164753486, chr3_171894906, chr3_179540277, chr3_179616279, chr3_l 81704894, chr3_181704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_l 81724459, chr3_181724559, chr4_578126, chr4_667460, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_8576626, chr4_8868232, chr4_9109274, chr4_11 187567, chr4_13785708, chr4_15944086, chr4_25237957, chr4_30170558, chr4_36635749, chr4_38356556, chr4_39815565, chr4_52055928, chr4_53508148, chr4_53840582, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_77897059, chr4_77897104, chr4_87411016, chr4_87865311, chr4_89379269, chr4_152888059, chr5_1554827, chr5_6810030, chr5_6810073, chr5_l 0524764, chr5_10524872, chr5_30772245, chr5_38403906, chr5_43282446, chr5_43282460, chr5_50998048, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_78701917, chr5_89120992, chr5_95429494, chr5_100877542, chr5_l 07099103, chr5_l 13040537, chr5_l 15106946, chr5_127066418, chr5_140543089, chr5_145529393, chr5_150680117, chr5_151512421, chr5_151512485, chr5_151520158, chr5_167983052, chr5_172860804, chr5_172860953, chr5_175033106, chr5_175441994, chr5_l 75442040, chr5_175442086, chr5_175442387, chr5_175442710, chr5_175442710, chr5_175692802, chr5_l 75692868, chr5_ 178604407, chr5_180155459, chr5_180155581, chr6_3482654, chr6_33906454, chr6_34036167, chr6_36775571, chr6_40888325, chr6_60830914, chr6_87948947, chr6_91513599, chr6_96873290, chr6_105628390, chr6_108804924, chr6_109824080, chr6_109977550, chr6_109977690, chr6_109981771, chr6_109981907, chr6_l 10018487, chr6_l 10439611, chr6_l 17562504, chr6_l 18577805, chr6_l 20951342, chr6_121099723, chr6_l 36924776, chr6_136943473, chr6_137290533, chr6_139254024, chr6_l 50204270, chr6_ 150204473, chr6_150893713, chr6_155123808, chr6_158528243, chr6_162547293, chr6_168301762, chr6_ 169961951, chr7_1231081, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1672933, chr7_1673021, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_1675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_6988371, chr7_6988400, chr7_7273541, chr7_8976868, chr7_l 7586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_54795471, chr7_71592009, chr7_80057215, chr7_88282441, chr7_93580834, chr7_94840949, chr7_101915316, chr7_101915318, chr7_102107431, chr7_135147918, chr7_138971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_l 59142397, chr7_159231032, chr7_159231136, chr8_10296807, chr8_l 3310666, chr8_27662591, chr8_29052797, chr8_41246826, chr8_52246671, chr8_52252719, chr8_52485371, chr8_56439745, chr8_56441389, chr8_56444235, chr8_57356053, chr8_58117688, chr8_58768196, chr8_58986453, chr8_63031540, chr8_64773383, chr8_80345362, chr8_84031486, chr8_87977499, chr8_97191731, chr8_102754235, chr8_l 17042553, chr8_l 18694978, chr8_ 118694978, chr8_122825356, chr8_129464046, chr8_l 40608236, chr8_140729234, chr8_141800471, chr8_141800485, chr8_141800688, chr8_143213111, chr8_l 44241354, chr9_29444070, chr9_29444070, chr9_35350760, chr9_42278765, chr9_73879045, chr9_75657076, chr9_79190169, chr9_79193652, chr9_79193716, chr9_81702877, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181, chr9_109388040, chr9_109719145, chr9_l 11786816, chr9_l 14250397, chr9_l 14250449, chr9_l 14250469, chr9_l 14250578, chr9_119121913, chr9_120498228, chr9_121830266, chr9_122212102, chr9_122224319, chr9_127496263, chr9_130919131, chr9_130919223, chr9_l 34351622, chr9_134351726, chr9_134420593, chr9_134420684, and chr9_l 36323313. In some examples, the probes detect at least chrl0_35445343, chr12_l 17087703, chrl5_101709645, chrl7_39612776, chr1_30l 27036, chrl4_58598194, chrl_25968447, chrl8_55401769, chrl0_30583971, chrl l_41004020, chrll_61298863, chrl2_132525847, chrl7_75231867, chr9_l 22207624, chrl0_l 12991920, chrl0_26124733, chrl3_l 13337880, chrl3_44573331, chrl6_89747288, chrl7_49578655, chrl9_53976302, chrl0_l 12219535, chrl l_99359784, chrl6_52967325, chr4_3374470, chr22_49391985, chr4_38356557, chr5_175435725, chrl_209331007, and chr2_73008588, wherein these refer to human chromosomes. The kits can include other elements, such as syringes to collect a biological sample, sodium bisulfite, one or more restriction enzymes, one or more antibodies, reagents to prepare nuclei from a sample (such as one or more of those provided in Example 11 below), or combinations thereof.

Measuring methylation status

The methylation status of the DNA methylation markers, such as least 30 of those disclosed herein, are assayed. In some examples, the method determines the methylation status of at least the markers provided in Table 1 (also see list in claim 8e). In some examples, the method determines the methylation status of at least the markers provided in Table 2 or FIGS. 25A-25B (chrl_6954346, chrl_15765576, chrl_16921554, chrl_17535924, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_47930687, chrl_55154499, chrl_82344735, chrl_84779343, chrl_88186554, chrl_89387906, chrl_l 14587732, chrl_213899571, chrl_223535050, chrl0_12981474, chrl0_85659210, chrl0_120517367, chrl0_129558734, chrll_6333181, chrl l_15508856, chrl l_61601245, chrll_64638208, chrl l_64638406, chrl l_64638423, chrll_64638446, chrll_64638487, chrl 1 70828694, chrl l_70828959, chrl 1_113951238, chrl 1_114069492, chr!2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl3_44573330, chrl3_78061219, chrl4_91028417, chrl4_99239938, chrl4_99240729, chrl4_99254307, chrl4_99258195, chrl4_99265134, chrl5_40579060, chrl5_60850769, chrl5_73787074, chrl5_75706213, chrl6_29674272, chrl6_71746304, chrl7_2019280, chrl7_17603475, chrl7_49578654, chrl7_78458835, chrl7_81839462, chrl8_42840569, chrl8_55863146, chrl8_55863406, chrl9_8180812, chrl9_13002909, chrl9_31596154, chrl9_33408728, chr2_520529, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_88493781, chr2_106974041, chr2_l 44508216, chr2_144509942, chr2_159230649, chr2_192676064, chr2_199449983, chr2_214915957, chr2_224976082, chr2_227315087, chr2_234438297, chr20_23049529, chr20_40692864, chr20_52979500, chr20_55284577, chr20_57730506, chr21_21578917, chr21_26832851, chr21_29221598, chr21_29917226, chr21_43913788, chr21_44074575, chr21_45115350, chr22_24425165, chr22_24425431, chr22_24425509, chr22_24426997, chr22_24427299, chr22_24428719, chr22_24434476, chr22_24435262, chr22_24436142, chr22_24438986, chr22_24439355, chr22_24440428, chr22_24441113, chr22_29184668, chr22_36763396, chr22_36763700, chr22_49391984, chr3_ 10546931, chr3_23272516, chr3_41117522, chr3_53425664, chr3_81591988, chr3_l 13902470, chr3_ 142925609, chr3_143082577, chr3_l 81704950, chr3_181715790, chr3_l 81724236, chr3_l 81724559, chr4_3374241, chr4_3374306, chr4_3374416, chr4_3377079, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385479, chr4_3385492, chr4_3385938, chr4_3389755, chr4_3389767, chr4_3393330, chr4_3393693, chr4_3410433, chr4_341 1467, chr4_7766077, chr4_54226502, chr4_54226613, chr4_54236780, chr5_6810073, chr5_10524872, chr5_43282460, chr5_60340044, chr5_65126330, chr5_l 13040537, chr5_l 15106946, chr5_127066418, chr5_150680117, chr5_167983052, chr5_172860953, chr5_175441994, chr5_175442086, chr5_175442710, chr5_l 78604407, chr5_180155581, chr6_36775571, chr6_60830914, chr6_87948947, chr6_96873290, chr6_l 05628390, chr6_ 150204270, chr6_150893713, chr6_158528243, chr6_ 169961951, chr7_1672459, chr7_1672799, chr7_ 1672928, chr7_1674842, chr7_1675096, chr7_1677614, chr7_1680106, chr7_2108124, chr7_17586547, chr7_45198338, chr7_94840949, chr7_101915316, chr7_l 57585009, chr7_157897945, chr7_157897966, chr7_157897972, chr7_159142397, chr7_159231136, chr8_52246671, chr8_57356053, chr8_63031540, chr8_80345362, chr8_84031486, chr8_87977499, chr8_l 18694978, chr8_141800688, chr9_35350760, chr9_73879045, chr9_79193716, chr9_93156181, chr9_ 114250469, chr9_l 14250578, chr9_122212102, chr9_l 30919223, chr9_134351726, chr9_134420684). In some examples, the method determines the methylation status of at least the markers chrl_6954205, chrl_6954346, chrl_15437470, chrl_15765576, chrl_16921554, chrl_17535615, chrl_17535924, chrl_20748527, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_47930687, chrl_55154474, chrl_55154499, chrl_82344735, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_l 14587732, chrl_l 14587798, chrl_200664873, chrl_213899571, chrl_223535050, chrl0_12981474, chrl0_85659210, chrl0_85659210, chrl0_96825742, chrl0_120517367, chrl0_120517552, chrl0_129558734, chrl l_6333181, chrll_15508856, chrll_30683884, chrll_61601245, chrl l_64638030, chrll_64638061, chrl l_64638130, chrl l_64638134, chrll_64638208, chrll_64638406, chrl 1_64638423, chrll_64638446, chrl l_64638476, chrl l_64638487, chrll_66652738, chrll_70828694, chrl l_70828726, chrll_70828942, chrl l_70828959, chrll_113951190, chrl 1_113951238, chrl l_l 14069492, chrl 1 114069680, chrl 1_118210650, chrl2_104666490, chrl2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl2_l 11363249, chrl3_44573330, chrl3_78061219, chrl3_92046041, chrl3_93413326, chrl4_28309117, chrl4_32587882, chrl4_91028417, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99265134, chrl5_39667040, chrl5_40579060, chrl5_60850769, chrl5_73787063, chrl5_73787074, chrl5_75706205, chrl5_75706213, chrl6_29674272, chrl6_29674291, chrl6_71746300, chrl6_71746304, chrl6_79856776, chrl7_2019254, chrl7_2019280, chrl7_17603475, chrl7_l 7603475, chrl7_49578654, chrl7_49580573, chrl7_58691449, chrl7_78458835, chrl7_78458957, chrl7_81839462, chrl7_81839517, chrl8_31612779, chrl8_42840523, chrl8_42840569, chrl8_55863146, chrl8_55863209, chrl8_55863341, chr!8_55863406, chrl9_8180812, chrl9_13002733, chrl9_13002909, chrl9_31596154, chrl9_31959202, chr!9_32044115, chrl9_33408728, chrl9_33408838, chrl9_39052997, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_4416732, chr2_8535196, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_73008587, chr2_88493781, chr2_l 06974041, chr2_l 15082751, chr2_120543523, chr2_144507406, chr2_144508216, chr2_144509942, chr2_l 44512702, chr2_159230649, chr2_180445347, chr2_192676064, chr2_199449983, chr2_199450146, chr2_203121062, chr2_214915957, chr2_216827945, chr2_224976082, chr2_227315087, chr2_227315087, chr2_234438247, chr2_234438297, chr20_1837975, chr20_23049529, chr20_23049808, chr20_40692708, chr20_40692864, chr20_43564715, chr20_49882081, chr20_52979500, chr20_52979806, chr20_53032932, chr20_55284577, chr20_57730506, chr20_57730576, chr21_21578917, chr21_26832783, chr21_26832851, chr21_29221598, chr21_29221717, chr21_29917226, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr22_24425152, chr22_24425165, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425710, chr22_24425816, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24428701, chr22_24428719, chr22_24434350, chr22_24434476, chr22_24435262, chr22_24436130, chr22_24436142, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_49391984, chr3_10546902, chr3_l 0546931, chr3_23272516, chr3_41117522, chr3_53425664, chr3_73746874, chr3_81591988, chr3_81591988, chr3_l 12000443, chr3_l 13902470, chr3_142925609, chr3_143082577, chr3_143082617, chr3_179616279, chr3_l 81704894, chr3_181704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_l 81724459, chr3_181724559, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_9109274, chr4_l 1187567, chr4_15944086, chr4_36635749, chr4_38356556, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_87865311, chr5_6810030, chr5_6810073, chr5_10524764, chr5_10524872, chr5_43282446, chr5_43282460, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_95429494, chr5_l 13040537, chr5_l 15106946, chr5_127066418, chr5_150680117, chr5_167983052, chr5_172860804, chr5_172860953, chr5_175441994, chr5_l 75442040, chr5_175442086, chr5_175442387, chr5_175442710, chr5_175442710, chr5_ 178604407, chr5_l 80155459, chr5_180155581, chr6_33906454, chr6_36775571, chr6_40888325, chr6_60830914, chr6_87948947, chr6_96873290, chr6_105628390, chr6_l 10018487, chr6_l 20951342, chr6_121099723, chr6_137290533, chr6_139254024, chr6_150204270, chr6_150204473, chr6_150893713, chr6_158528243, chr6_169961951, chr7_1231081, chr7_l 672459, chr7_1672799, chr7_1672928, chr7_1673310, chr7_1674842, chr7_1675096, chr7_l 675099, chr7_1675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_17586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_88282441, chr7_94840949, chr7_101915316, chr7_101915318, chr7_102107431, chr7_138971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_l 57897933, chr7_157897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_l 59142397, chr7_159231136, chr8_10296807, chr8_52246671, chr8_52252719, chr8_57356053, chr8_63031540, chr8_80345362, chr8_84031486, chr8_87977499, chr8_l 18694978, chr8_l 18694978, chr8_140729234, chr8_141800485, chr8_l 41800688, chr8_144241354, chr9_35350760, chr9_73879045, chr9_79193652, chr9_79193716, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181, chr9_l 14250397, chr9_l 14250449, chr9_l 14250469, chr9_l 14250578, chr9_121830266, chr9_122212102, chr9_l 22224319, chr9_130919131, chr9_l 30919223, chr9_134351622, chr9_134351726, chr9_134420593, and chr9_l 34420684. In some examples, the method determines the methylation status of at least the markers chrl_6954205, chrl_6954346, chrl_7048907, chrl_15437470, chrl_15765576, chrl_16921554, chrl_17411021, chrl_17535615, chrl_17535924, chrl_20748527, chrl_25729798, chrl_27249955, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_38418368, chrl_43465467, chrl_43465657, chrl_45049761, chrl_47930687, chrl_50837887, chrl_55154474, chrl_55154499, chrl_82344735, chrl_83627211, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_107575614, chrl_l 14587732, chrl_l 14587798, chrl_155009422, chrl_174451522, chrl_174451522, chrl_197451335, chrl_200664873, chrl_207434747, chrl_210626571, chrl_213899571, chrl_219915507, chrl_223535050, chrl_241329400, chrl_244054001, chrl_244054019, chrl_244054025, chrl_244054088, chrl_244054213, chrl_244054334, chrl_244054412, chrl_244054487, chrl0_387726, chrl0_1550998, chrl0_1599134, chrl0_l 599460, chrl0_1610306, chrl0_1626613, chrl0_1679796, chrl0_1680989, chrl0_1682975, chrl0_1713526, chrl0_1721323, chrl0_1723256, chrl0_1723398, chrl0_1724564, chrl0_1726470, chrl0_1975272, chrl0_3927130, chrl0_12981474, chrl0_33204102, chrl0_34752396, chrl0_44279927, chrl0_44280044, chrl0_59279057, chrl0_59279103, chrl0_71529729, chrl0_80094872, chrl0_85659210, chrl0_85659210, chrl0_87727342, chrl0_91397464, chrl0_92661601, chr!0_96825742, chrl0_107085835, chrl0_120517367, chr!0_120517552, chrl0_124961029, chr!0_129558734, chrl 1_6333181, chrl l_10175924, chrll_15508856, chrll_16344746, chrl l_28779431, chrll_30683884, chrll_31820115, chrll_31820310, chrll_46385139, chrll_46398710, chrl l_46441679, chrll_61601245, chrl l_64070739, chrll_64635621, chrll_64638030, chrll_64638061, chrl l_64638130, chrll_64638134, chrl l_64638208, chrll_64638406, chrll_64638423, chrll_64638446, chrl 1_64638476, chrl 1_64638487, chrl 1_66652726, chrll_66652738, chrll_70828694, chrll_70828726, chrl l_70828942, chrll_70828959, chrl 1_75832244, chrll_94158916, chrl 1_112260989, chrl 1_113363879, chrl 1_113400998, chrl 1_113408265, chrl 1_113433434, chrl 1_113433544, chrl 1_113444137, chrl 1_113445794, chrl 1_113460726, chrl 1_113468577, chrl 1_113468826, chrl 1_113469191, chrl 1_113469614, chrl 1_113470470, chrll_113951190, chrl 1_113951238, chrl 1_114062290, chrl 1_114062488, chrl 1_114064208, chrl 1_114064532, chrl 1_114066467, chrl 1_114067705, chrl 1_114069492, chrl 1_114069680, chrl 1_117914441, chrl 1_118210650, chrll_123025323, chrll_127690394, chrl l_127690429, chrll_131233613, chrl2_2081518, chrl2_2842964, chr!2_30766914, chrl2_47947292, chrl2_53274354, chrl2_53274417, chrl2_70443965, chr!2_77308440, chrl2_88450938, chrl2_88451104, chrl2_92221841, chrl2_93894714, chrl2_93894790, chrl2_94695777, chrl2_95356097, chrl2_98459151, chrl2_l 04666490, chrl 2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl2_l 11363249, chrl2_l 19340812, chrl2_121507866, chrl2_122161069, chrl2_122228141, chrl2_127115077, chrl2_l 29703529, chrl3_27238208, chrl3_27517013, chrl 3_35695164, chrl 3_4146531 1, chr!3_44573330, chrl 3_73025821 , chr13_73026371 , chrl 3_7806l219, chrl3_92046041, chrl 3_93413326, chrl3_98404428, chrl3_103071728, chrl 3_1O38O1301, chrl3_106713795, chrl4_28309117, chrl4_32587882, chrl4_36524389, chrl4_36524667, chrl4_62814638, chrl4_72746337, chrl4_72746410, chrl4_91028417, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99244159, chrl4_99244383, chrl4_99245037, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99259778, chrl4_99259851, chrl4_99261299, chrl4_99261349, chrl4_99265134, chrl4_99265442, chrl4_104963567, chrl5_27014884, chrl5_39667040, chrl5_40579060, chrl5_60850769, chrl5_61832637, chrl5_64673973, chrl5_70265944, chrl5_70867831, chrl5_73421182, chrl5_73787063, chrl5_73787074, chrl5_75706205, chrl5_75706213, chrl5_84784380, chrl5_98347522, chrl6_3255898, chrl6_3473308, chrl6_21514377, chrl6_21514493, chrl6_29674272, chrl6_29674291, chrl6_49521066, chrl6_71746300, chrl6_71746304, chrl6_73092631, chrl6_79856776, chrl6_84090291, chrl6_85290977, chrl6_86757258, chrl6_87957932, chrl6_89747287, chrl7_2019254, chrl7_2019280, chrl7_6264478, chrl7_8310790, chrl7_17603475, chrl7_17603475, chrl7_19539205, chrl7_19539300, chrl7_29056566, chrl7_29093998, chrl7_31593826, chrl7_32274223, chrl7_49578654, chrl7_49580573, chrl7_51374368, chrl7_58691449, chrl7_62458778, chrl7_68274037, chrl7_74762858, chrl7_75231866, chrl7_75231876, chrl7_78458835, chrl7_78458957, chrl7_79140535, chrl7_81246152, chrl7_81839462, chrl7_81839517, chrl8_7466797, chrl8_7671182, chrl8_22191374, chrl8_24273998, chrl8_28743520, chrl8_31612779, chrl8_31668044, chrl8_31668223, chrl8_42840523, chrl8_42840569, chrl8_48111878, chrl8_55316591, chrl8_55335150, chrl8_55337856, chrl8_55337859, chr!8_55347406, chrl8_55347692, chrl8_55401620, chrl8_55401726, chrl8_55401962, chr!8_55401962, chr!8_55402070, chrl8_55863146, chrl8_55863209, chrl8_55863341, chrl8_55863406, chr!8_58846286, chrl8_75629703, chrl9_940774, chrl9_940858, chrl9_941208, chrl9_941242, chrl9_941271, chrl9_941471, chrl9_4020451, chrl9_8066130, chrl9_8180812, chrl9_11943461, chrl9_l 1943461, chrl9_l 3002733, chrl9_13002909, chrl9_13027645, chrl9_l 3027708, chrl9_29879973, chrl9_30071371, chrl9_30071556, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_32327361, chrl9_33408728, chrl9_33408838, chrl9_35046673, chrl9_39052997, chrl9_53965120, chrl9_53965266, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_1939158, chr2_4416732, chr2_6286826, chr2_8535196, chr2_8811580, chr2_22449630, chr2_27738485, chr2_27738489, chr2_27738545, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_60479437, chr2_73008587, chr2_79929386, chr2_85447333, chr2_88493781, chr2_96895479, chr2_99699856, chr2_100923151, chr2_106974041, chr2_l 15082751, chr2_120543523, chr2_127840596, chr2_144507406, chr2_144508216, chr2_144509942, chr2_144512702, chr2_148147429, chr2_159230649, chr2_169415560, chr2_180445347, chr2_184141131, chr2_192676064, chr2_198316634, chr2_199447280, chr2_ 199449983, chr2_199450146, chr2_201872813, chr2_203121062, chr2_211590141, chr2_211590198, chr2_212520797, chr2_212524214, chr2_214915957, chr2_216827945, chr2_219281611, chr2_219888095, chr2_222470101, chr2_224976082, chr2_227315087, chr2_227315087, chr2_231390519, chr2_232574302, chr2_234438247, chr2_234438297, chr2_236121881, chr20_1400335, chr20_1837975, chr20_5670261, chr20_23049529, chr20_23049808, chr20_34196362, chr20_40692708, chr20_40692864, chr20_43423564, chr20_43564715, chr20_49882081 , chr20_52979500, chr20_52979806, chr20_53032932, chr20_54696328, chr20_55284577, chr20_57730506, chr20_57730576, chr20_60889288, chr20_62225257, chr21_21578917, chr21_26832783, chr21_26832851, chr21_28103489, chr21_28103489, chr21_29221598, chr21_29221717, chr21_29917226, chr21_37606568, chr21_40771526, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr21_46510096, chr22_24425152, chr22_24425165, chr22_24425229, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425705, chr22_24425710, chr22_24425754, chr22_24425816, chr22_24425972, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24427448, chr22_24428701, chr22_24428719, chr22_24433075, chr22_24433241, chr22_24433423, chr22_24434088, chr22_24434350, chr22_24434476, chr22_24434989, chr22_24435262, chr22_24436014, chr22_24436130, chr22_24436142, chr22_24437360, chr22_24437763, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24440446, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_29185058, chr22_30737962, chr22_34617159, chr22_34617213, chr22_35114720, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_44940707, chr22_46346927, chr22_48824678, chr22_49391984, chr22_50658490, chr3_8595802, chr3_8596019, chr3_10546902, chr3_10546931, chr3_13191245, chr3_15391356, chr3_22857045, chr3_23272516, chr3_30391151, chr3_32506316, chr3_41117522, chr3_46301401, chr3_53425664, chr3_59955536, chr3_70568431, chr3_73746874, chr3_76628994, chr3_81591988, chr3_81591988, chr3_99932654, chr3_105471988, chr3_l 12000443, chr3_112508351, chr3_l 13651082, chr3_l 13902470, chr3_ 122908926, chr3_142925609, chr3_l 43082577, chr3_143082617, chr3_ 150033642, chr3_ 154551207, chr3_164753486, chr3_171894906, chr3_179540277, chr3_179616279, chr3_181704894, chr3_181704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_181724459, chr3_181724559, chr4_578126, chr4_667460, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_8576626, chr4_8868232, chr4_9109274, chr4_l 1187567, chr4_13785708, chr4_15944086, chr4_25237957, chr4_30170558, chr4_36635749, chr4_38356556, chr4_39815565, chr4_52055928, chr4_53508148, chr4_53840582, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_77897059, chr4_77897104, chr4_87411016, chr4_87865311, chr4_89379269, chr4_152888059, chr5_1554827, chr5_6810030, chr5_6810073, chr5_10524764, chr5_l 0524872, chr5_30772245, chr5_38403906, chr5_43282446, chr5_43282460, chr5_50998048, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_78701917, chr5_89120992, chr5_95429494, chr5_l 00877542, chr5_107099103, chr5_ 113040537, chr5_l 15106946, chr5_127066418, chr5_140543089, chr5_145529393, chr5_150680117, chr5_151512421, chr5_151512485, chr5_151520158, chr5_167983052, chr5_172860804, chr5_172860953, chr5_l 75033106, chr5_l 75441994, chr5_ 175442040, chr5_l 75442086, chr5_l 75442387, chr5_l 75442710, chr5_175442710, chr5_175692802, chr5_175692868, chr5_ 178604407, chr5_180155459, chr5_180155581, chr6_3482654, chr6_33906454, chr6_34036167, chr6_36775571, chr6_40888325, chr6_60830914, chr6_87948947, chr6_91513599, chr6_96873290, chr6_105628390, chr6_l 08804924, chr6_109824080, chr6_l 09977550, chr6_109977690, chr6_109981771, chr6_109981907, chr6_l 10018487, chr6_l 10439611, chr6_l 17562504, chr6_l 18577805, chr6_120951342, chr6_121099723, chr6_136924776, chr6_136943473, chr6_l 37290533, chr6_l 39254024, chr6_150204270, chr6_150204473, chr6_150893713, chr6_155123808, chr6_l 58528243, chr6_162547293, chr6_168301762, chr6_ 169961951, chr7_1231081, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1672933, chr7_1673021, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_l 675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_6988371, chr7_6988400, chr7_7273541, chr7_8976868, chr7_l 7586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_54795471, chr7_71592009, chr7_80057215, chr7_88282441, chr7_93580834, chr7_94840949, chr7_101915316, chr7_101915318, chr7_102107431, chr7_135147918, chr7_138971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_159142397, chr7_159231032, chr7_159231136, chr8_10296807, chr8_13310666, chr8_27662591, chr8_29052797, chr8_41246826, chr8_52246671, chr8_52252719, chr8_52485371, chr8_56439745, chr8_56441389, chr8_56444235, chr8_57356053, chr8_58117688, chr8_58768196, chr8_58986453, chr8_63031540, chr8_64773383, chr8_80345362, chr8_84031486, chr8_87977499, chr8_97191731, chr8_l 02754235, chr8_l 17042553, chr8_l 18694978, chr8_l 18694978, chr8_122825356, chr8_129464046, chr8_140608236, chr8_140729234, chr8_141800471, chr8_141800485, chr8_141800688, chr8_143213111, chr8_144241354, chr9_29444070, chr9_29444070, chr9_35350760, chr9_42278765, chr9_73879045, chr9_75657076, chr9_79190169, chr9_79193652, chr9_79193716, chr9_81702877, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181, chr9_109388040, chr9_109719145, chr9_l 11786816, chr9_l 14250397, chr9_l 14250449, chr9_l 14250469, chr9_ 114250578, chr9_l 19121913, chr9_120498228, chr9_121830266, chr9_122212102, chr9_ 122224319, chr9_127496263, chr9_130919131, chr9_130919223, chr9_134351622, chr9_134351726, chr9_134420593, chr9_134420684, and chr9_136323313. In one example, an Illumina™ DNA methylation array is used. In another example, a PCR protocol using relevant primers is utilized. Determining the methylation status of a particular DNA methylation marker can include determining whether a particular region in the genome is methylated or not.

DNA methylation status can be determined using any available assay. In one example, a molecular break light assay for DNA adenine methyltransferase activity is used. This assay is based on the specificity of the restriction enzyme Dpnl for fully methylated (adenine methylation) GATC sites in an oligonucleotide labeled with a fluorophore and quencher. The adenine methyltransferase methylates the oligonucleotide making it a substrate for Dpnl. Cutting of the oligonucleotide by Dpnl gives rise to a fluorescence increase, thus indicating that the position is methylated. In one example, methylation-specific polymerase chain reaction (PCR) is used. This method is based on a chemical reaction of sodium bisulfite with DNA that converts unmethylated cytosines of CpG dinucleotides to uracil or UpG, followed by traditional PCR. However, methylated cytosines are not converted in this process, and thus primers are designed to overlap the CpG site of interest, which allows one to determine methylation status as methylated or unmethylated. In one example, whole genome bisulfite sequencing, also known as BS-Seq, is used. This is a genome-wide analysis of DNA methylation based on the sodium bisulfite conversion of genomic DNA, which is then sequenced. The sequences obtained are then re-aligned to the reference genome to determine methylation states of CpG dinucleotides based on mismatches resulting from the conversion of unmethylated cytosines into uracil. In one example, the Hpall tiny fragment Enrichment by Ligation-mediated PCR (HELP) assay is used, which is based on restriction enzymes' differential ability to recognize and cleave methylated and unmethylated CpG DNA sites. In one example, methyl sensitive southern blotting is used, which uses Southern blotting techniques to probe gene-specific differences in methylation using restriction digests. This method can be used to evaluate local methylation near the binding site for the probe. In one example, ChlP-on-chip assay is used. This method uses commercially prepared antibodies to bind to DNA methylation-associated proteins like MeCP2. In one example, restriction landmark genomic scanning is used, which is based upon restriction enzymes' differential recognition of methylated and unmethylated CpG sites. In one example methylated DNA immunoprecipitation (MeDIP) is used. Immunoprecipitation is used to isolate methylated DNA fragments for input into DNA detection methods such as DNA microarrays (MeDIP-chip) or DNA sequencing (MeDIP-seq). In one example, pyrosequencing of bisulfite treated DNA is used. In this method, an amplicon is generated by a normal forward primer but a biatenylated reverse primer to PCR the target methylation marker. A pyrosequencer then analyzes the sample by denaturing the DNA and adding one nucleotide at a time to the mix according to a sequence given by the user. If there is a mismatch, it is recorded and the percentage of DNA for which the mismatch is present is noted. This provides a percentage methylation per CpG island.

In some examples, the genomic DNA to be analyzed is used directly, e.g., hybridized to a complimentary sequence (e.g., a synthetic polynucleotide sequence) that is attached to a solid support (e.g., one disposed within a microarray). In some examples, the genomic DNA to be analyzed is amplified by a PCR process. For example, prior to or concurrent with hybridization to an array, the sample may be amplified by a variety of mechanisms, such as those that employ PCR.- The sample may be amplified on the array.

III. Statistical Analysis

Any statistical approach can be used to relate the methylation status to type of brain cell, can be regressed on the CpG markers using a linear regression model as described herein. Using regression model/analysis tools and methodologies, a number of brain cell type prediction models are contemplated for use with specific genomic DNA samples and/or specific analysis techniques and/or specific individual populations. In one example, an identity transformation method is used, wherein the brain cell is identified using regression of the CpG status. In other examples, the brain cell type is transformed. In some examples, a weighted average of the CpGs is determined.

For example, FIGS. 25A-25B provide a matrix showing the relationship between the methylation status of 5 brain cell types. In FIGS. 25A-25B, H indicates that the group is highly methylated at that position for that cell type, L indicates that the group is lowly methylated at that position for that cell type, N indicates that the group may be methylated or not methylated at that position for that cell type (e.g., methylation status not relevant for determining the identity of that cell type). Thus, one can determine the methylation status for at least 30 of the 200 markers listed in FIGS. 25A-25B, and based on the status (methylated or not) for each marker, determine the type of brain cell present (e.g., ASC cell, CAI cell, etc.).

In one example, a prediction model is trained with the methylation status of at least 30 of the markers listed in FIGS. 25A-25B and applied to new samples.

IV. Treatment

Once the brain cell type(s) is determined, the method can include determining a disease state, administering a treatment [such as a conventional treatment for the disease listed], or both, based on the cell(s) identified, as outlined in Table 3. Other exemplary treatments are provided in Berger et al., Frontiers in Cellular Neurosci., 16:931356, 2022, herein incorporated by reference in its entirety.

For example, a subject identified as having a brain cell type associated with schizophrenia can be administered one or more anitpsychotics, such as one or more of Chlorpromazine (Thorazine), Fluphenazine (Prolixin), Haloperidol (Haldol), Perphenazine (Trilafon), Thioridazine (Mellaril), Thiothixene (Navane), Trifluoperazine (Stelazine), Aripiprazole (Abilify), Aripiprazole lauroxil (Aristada), Asenapine (Saphris), Brexpiprazole (Rexulti), Cariprazine (Vraylar), Clozapine (Clozaril), Iloperidone (Fanapt), Lumateperonee (Caplyta), Lurasidone (Latuda), Olanzapine (Zyprexa) , Olanzapine/samidorphan (Lybalvi), Paliperidone (Invega Sustenna), Paliperidone palmitate (Invega Trinza), Quetiapine (Seroquel), Risperidone (Risperdal), and Ziprasidone (Geodon).

For example, a subject identified as having a brain cell type associated with bipolar disorder can be administered one or more mood-stabilizing drugs, antipsychotic, anti-convulsant, and/or antidepressant, such a lithium, valproate, carbamazepine, lamotrigine, ripiprazole, olanzapine, quetiapine, and/or risperidone.

For example, a subject identified as having a brain cell type associated with insomnia can be administered one or more of cognitive behavior therapy for insomnia, a benzodiazepine, melatonin agonist, and/or orexin receptor antagonist. For example, a subject identified as having a brain cell type associated with neuroticism can be administered one or more of psychotherapy, psychoactive drugs, and/or relaxation exercises, such as deep breathing. In one example, one or more antidepressants, anti-anxiety, and/or antipsychotic drugs is administered.

For example, a subject identified as having a brain cell type associated with ADHD can be administered a stimulant, such as methylphenidate.

Table 3: Exemplary cell types and associated diseases

Example 1 Materials and Methods

This example provides the materials and methods used to generate the data described herein.

Human postmortem tissue specimen screening

These studies were intended to be the first explorations of cellular, transcriptional and epigenomic variation across the human brain using the latest single nucleus methylome (this study), RNA-seq, and ATAC-seq technologies. These methods perform best on tissue of the highest quality, prepared using methods optimized, which involved short postmortem interval (PMI targeting <12 hours), highly consistent tissue slabbing and photo documentation to ensure anatomically precise sampling, freezing with supercooled isopentane to preserve tissue integrity, and proper storage under vacuum in -80C freezers. In addition to low PMI, stringent exclusionary criteria were applied for RNA integrity (RIN, >7.0), infectious diseases, head trauma, intubation, neuropathology and manner of death.

The availability of tissues was a significant challenge given the highly stringent exclusionary criteria. Brain specimens meeting these criteria, and for which whole brain hemispheres could be obtained for the current study, were quite rare and with a heavy male bias. Between 2018-2022 16 donors met these criteria, with only three female donors who ultimately were excluded based on QC or other exclusionary criteria. The three donors passing all exclusionary and QC criteria were all males.

Human postmortem tissue specimen processing

Dc-idcntificd adult postmortem human brain tissue was obtained after receiving permission from the deceased’s next of kin. Tissue collection was performed per the United States Uniform Anatomical Gift Act of 2006, described in the California Health and Safety Code section 7150 (effective 1/1/2008) and other applicable state and federal laws and regulations. In addition, the Western Institutional Review Board reviewed tissue collection procedures and determined that they did not constitute human subjects research requiring institutional review board (IRB) review.

Male donors 18-68 years of age with no known history of neuropsychiatric or neurological conditions were considered for inclusion in the study. Routine serological screening for infectious diseases (HIV, Hepatitis B, and Hepatitis C) was conducted using donor blood samples, and donors testing positive for infectious diseases were excluded from the study. Specimens were screened for RNA quality, and samples with average RNA integrity (RIN) values >7.0 were considered for inclusion in the study. Postmortem brain specimens were processed as previously described (22)(dx.doi.org/10.17504/protocols.io.bf4ajqse). Briefly, coronal brain slabs were cut at 1 cm intervals, photographed, frozen in dry-ice cooled isopentane, and transferred to vacuum-sealed bags for storage at - 80°C until the time of further use. For the dissection of brain regions of interest, photos of tissue slabs were annotated by a neuroanatomist to outline regions to target for dissections. Then, tissue slabs were removed from the -80°C freezer and briefly transferred to -20°C, where they were held for ~ 1-3 hours to allow tissues to equilibrate to -20°C. Tissues were then transferred to a custom temperature-controlled cold table held at - 20°C and the region of interest was removed using standard razor blades or scalpels. Tissue blocks were stored at -80°C in vacuum-sealed bags until later use.

Nuclei isolation and Fluorescence Activated Nuclei Sorting (FANS)

Nucleus isolation was conducted using a standard protocol as previously described (dx.doi.org/10.17504/protocols.io.y6rfzd6). Gating on DAPI and NeuN fluorescence intensity was as described previously (22). NeuN+ and NeuN- nuclei were sorted into separate tubes and were pooled at a defined ratio of 90% NeuN+ and 10% NeuN- nuclei after sorting. Sorted samples were centrifuged, frozen in a solution of IX PBS, 1% BSA, 10% DMSO, and 0.5% RNAsin Plus RNase® inhibitor (Promega, N2611), and stored at -80°C until further processing. The presorted nuclei pellets were defrosted and resuspended in DPBS+1%BSA, centrifuged, resuspended back in 1ml of DPBS, and sorted into 384-well plates. Nuclei from donors H19.30.001 and H19.30.002 were prepared and sorted into 384-well plates. For donor H19.30.004, frozen tissue blocks received from AIBS were processed following procedures previously described (5). Nuclei were labeled for NeuN fluorescence and sorted into 384-well plates as described (7).

Library preparation and Illumina sequencing snmC-seq library preparation. snmC-seq3 libraries were prepared using an updated version of snmC-seq2. In brief, samples underwent bisulfite conversion and were barcoded with random primers. Samples were then pooled through two SPRI cleanups to compress 16 x 384-well plates into 1 x 96-well plates. Pooled samples were then adapted and amplified as previously described. Next, libraries were pooled and cleaned through two more SPRI cleanups. Finally, library concentrations were determined by Qubit and normalized for sequencing. snmC-seq3 and snm3C-seq (see below) libraries generated from human brain tissues were sequenced using an Illumina Novaseq 6000 instrument with S4 flowcells and 150 bp paired-end mode. snm3C-seq library preparation. For some samples from donors H19.30.001 and H19.30.002, presorted nuclei were used. The presorted nuclei pellets were defrosted and resuspended in DPBS+1%BSA, centrifuged, and resuspended back in 1 ml of DPBS. For the remaining samples of donors H19.30.001 and H19.30.002 and all samples from donor H19.30.004, frozen tissue was pulverized using a mortar and pestle. All samples were then immediately crosslinked with 2% formaldehyde in solution for 5 min, quenched with 0.2M Glycine for 5 min, centrifuged and washed with DPBS, and stored at -80°C until ready for further processing. Next, nuclei were conditioned and digested using an Arima kit adapted for snm3C-seq for Ihr at 37°C, and 20 min at 65°C to inactivate enzymes, then ligated for 15min at room temperature. Finally, nuclei were resuspended in 1ml of DPBS+1%BSA, filtered through a 0.2 2pM filter, and sorted similarly to the snmC-seq3 samples.

Donor-specific genomes. gDNA Library prep protocol. Genomic DNA was extracted from ground, frozen tissue using the DNeasy Blood and Tissue Kit (Qiagen, Valencia, CA). One pg of DNA was fragmented with a Covaris S2 (Covaris, Woburn, MA) to 300 bp, followed by end repair (Lucigen) and the addition of a 3’ A base (New England Biolabs). Cytosine-methylated adapters provided by Illumina (Illumina, SanDiego, CA) were ligated to the sonicated DNA at 16°C for 16 hours with T4 DNA ligase (New England Biolabs). Adapter- ligated DNA was isolated by two rounds of purification with AMPure XP beads (Beckman Coulter Genomics, Danvers, MA). The adapter-ligated DNA molecules were enriched by 4 cycles of PCR with the following reaction composition: 25pL of Kapa HiFi Hotstart (KapaBiosystems, Woburn, MA) and 5p 1 TruSeq PCR Primer Mix (Illumina) (50plfinal). The thermocycling parameters were: 95°C 2min, 98°C 30sec, then 4 cycles of 98°C 15 sec, 60°C 30 sec, and 72°C Imin, ending with one 72°C 5 min step. The reaction products were purified using AMPure XP beads. The purified PCR reactions of the adapter-ligation resulted in a library used for subsequent sequencing in Novaseq 6000.

Variant calling from donor genome sequencing. Whole genome sequencing reads were first QCed with the software fastp (v0.20.1) (72). The command line used is “fastp -i input_PE_Rl.fastq.gz -I input_PE_R2.fastq.gz -o output_PE_Rl.fastq.gz -O output_PE_R2.fastq.gz -w 4”. The QCed reads were then mapped to human genome assembly GRCh38 (hg38) via the software BWA (v0.7.17)(73) with the BWA-MEM algorithm with mapping results stored in bam format through the software samtools (vl.l0)(74). Specifically, the command line used for mapping is “bwa mem -t 20 hg38-ref input_PE_Rl.fastq.gz input_PE_R2.fastq.gz | samtools view -Sb - > output.bam”.

The mapped reads were analyzed with the germline short variant discovery workflow of the Genome Analysis Toolkit (GATK, v4.1.8.1)(75). Briefly, duplicated reads were removed from the mapped reads, which then went through a base quality score recalibration step (BQSR) to generate analysis-ready reads. The variant references used in the BQSR step were dbSNP138, Mills and 1000 Genomes gold standard indels, and 1000 Genomes phase 1 SNPs. Next, candidate variants (SNPs+InDels) were called with the HaplotypeCaller of GATK from the analysis-ready reads and further filtered with a variant quality score recalibration step (VQSR) to determine the high-confidence SNPs and InDeis, respectively. The variant references used to recalibrate SNP quality scores were Hapmap 3.3, OMNI 2.5, 1000 Genomes phase 1 and dbSNP138, and of InDeis were Mills and 1000 Genomes gold standard indels and dbSNP138. All the references used in the BQSR and VQSR were downloaded from the GATK resource bundle (ftp : //ftp .broadinstitute .org/b undle/hg 38 ) .

Donor-specific reference genome. For each donor, a high-confidence homozygous SNPs was selected using the function SelectVariants of GATK, and created donor-specific reference genomes by substituting the homozygous SNPs into the hg38 FASTA file using the function FastaAlternateReferenceMaker of GATK

Common homozygous SNPs. By comparing the homozygous SNPs of donors, a list of common SNPs shared among the three donors was constructed.

Mapping and count/feature matrix generation

For sequence read mapping of both snmC-seq3 and snm3C-seq datasets, a custom pipeline (https://github.com/lhqing/cemba_data, version 1.2.1.dev94+gc65el73) was used. The main steps of this pipeline included: 1) Demultiplexing FASTQ files into single-cell; 2) Reads level QC; 3) Mapping; 4) BAM file processing and QC; 5) final molecular profile generation. The details of the five steps were previously described (72). All of the reads were mapped to the donor-specific genomes. After mapping, methylcytosine counts and total cytosine counts were calculated for the two sets of genomic features in each cell. Non-overlapping chromosome lOOkb bins of the hg38 genome (generated by “bedtools makewindows -w 100000”), were used for clustering analysis, and the genes defined by the human GENCODE v33 were used for cluster annotation and integration with datasets. Both CG and CH methylation levels of the features were normalized as previously described (I). The cell-by-feature matrices were generated from normalized methylation levels of each feature set.

Quality control measures

The sequenced cells were filtered based on these metrics: 1) mCCC% < 0.06; 2) global mCG% > 0.5; 3) global mCH% < 0.15; 4) total final reads > 250,000; 5) mapping rate > 0.5. For cells profiled with snm3C-seq, a cell was required to have > 50,000 cis contacts with a distance over 2500bp.

Clustering and annotation of snmC-seq3 data

Clustering analysis. CG- and CH-methylation levels of lOOkb genomic bins were used as input features for clustering. Clustering analysis iteratively was performed using the software package ALLCools (https://github.com/lhqing/ALLCools). In each iteration, the lOOkb bins were first filtered by removing bins with mean total cytosine base calls < 250 or > 3000. Those who overlap with the ENCODE blacklist (76) were also excluded from the clustering analysis. The top 5,000 highly variable features (HVFs) were then selected separately from both CG- and CH-methylation via support vector regression (SVR). Next, applied principle component analysis (PCA) was done to each of the 5,000 features to reduce dimension. The top n principle components (PCs) were selected for each methylation type until there is no significant difference between the distributions of n-th and (ra+7)-th PCs by two-sample Kolmogorov- Smirnov test with the criteria as the adjusted p-values < 0.1. Pre-clustering for each top PC set as performed and the PCs that are enriched in pre-clusters following Ref (77) were selected. Finally, the selected PCs from both CG and CH methylation PCs were concatenated for further analysis. Harmony (78) was used on the selected PCs in order to eliminate individual differences. The Harmonized features were further fed into the consensus clustering procedures previously described (1).

Doublet/debris identification. The read number of each cell in one plate is stable in both snmC- seq3 and snm3C-seq. Therefore a doublet/debris detection strategy based on cell relative reads to its plate was adopted. First, the read number per cell to the mean reads of its plate was normalized. The cells with plate-relative-read numbers> 1.2 or <0.8 were considered doublet/debris candidates. After each iteration of clustering, clusters would be labeled as doublet/debris if the cluster contained over 80% doublet/debris candidates and were eliminated from further analysis.

Cell type annotation. The clusters were manually annotated as major or subtypes according to their hypomethylated genes, which were either canonical brain cell type markers or determined de novo from the current dataset. Each cell type was required to have at least five differentially methylated genes in CG and CH methylation compared to the other cell types, otherwise, it would be merged with the closest cluster. A candidate cell type would be labeled as an outlier if all its cells were from a single donor. In major type level, where possible, cell types were annotated using the nomenclature for known brain cell types previously described in the literature(e.g. (13)); otherwise, cell clusters were annotated according to either the regional composition or distinct marker genes of the cell type. One caveat of the former approach is that cell types annotated using marker genes defined in rodents or non-human primates might not reflect the corresponding gene activity in human cell types. For example, the gene SNCG is lowly expressed in the human major type corresponding to mouse Sncg cells. Nevertheless, using common nomenclature aids in cross-species comparison and existing knowledge transferring.

Clustering and annotation of snm3C-seq data

To annotate cells from snm3C-seq, cells were combined with the annotated snmC-seq3 cells and an iterative clustering analysis was carred out similar to what was described above. The only difference was that batch effects from both individuals and sequencing technologies were corrected using the software Scanorama (79). After each clustering iteration, the cell type annotations were transferred from snmC-seq3 cells to snm3C-seq cells with a K Nearest Neighbor (KNN) classifier.

Robust dendrogram of cell types

A certain number of cells from each cell type was sampled without replacement to compute the average methylome profile for the cell type with genome features of lOOkb-bins of both CG- and CH- methylation. The resampling number is 800 for major types and 500 for subtypes. The average profiles were then used to compute the pairwise correlation distances. This process was repeated 500 times to compute an average pairwise distance matrix, which was then used to construct the final cell-type dendrogram via hierarchical clustering with average linkage.

Determine differentially methylated genes The DMGs pairwise was found between cell subtypes for CG- and CH-methylation separately. To avoid potential bias caused by an imbalance of cell numbers of cell types, cells were downsampled in each cell subtype to no more than 500. All the protein-coding and long non-coding RNA genes (IncRNAs) defined by the human GENCODE v33 were tested for significant methylation decrease (or hypomethylation) using the Wilcoxon rank-sum test. The p-values were adjusted with multitest correction using the Benjamini-Hochberg procedure. The Area Under the Receiver Operating Characteristic curve (AUROC) for the candidate genes was computed. The genes with adjusted p-values<0.001 and AUROC>0.8 were considered pairwise DMGs in CG- and CH- methylation.

Determine differentially methylated regions

Single-cell DNA methylation profiles into the cell type (major type/subtype) profiles were merged according to their cluster annotation in both donor-aggregated and donor-separated ways. Non-common homozygous SNP CpG sites of these methylation profiles were filtered out before further analysis. Then, the DMRfind function of the software MethylPy (vl.4.2; (80) ) was used to determine the mCG DMRs across all cell types of the donor-aggregated profiles. The command line used is “methylpy DMRfind —outputprefix OUTPUT_FILE_NAME -samples SAMPLE-NAMES -mc-type CGN — dmr-max-dist 250 -sigcutoff 0.01 — allc-files MC_FILES”. Successive DMRs were merged if their distance was within 250bp and the Pearson correlation of their mCG fractions across 188 subtypes is greater than 0.8. Each DMR was further screened by evaluating the reproducibility of the methylation pattern across cell types between donor- aggregated and -separated profiles. The evaluation criteria were 1) the Pearson’s correlation coefficient between the mCG fractions across cell types is >0.5, and 2) the mean-absolute-error (MAE) is <0.1.

Each reproducible DMR was then assigned as hypo- or hyper-DMRs in each cell type based on the difference of its mCG fraction from its robust mean. The robust-mean m of each DMR was calculated by averaging the mCG fractions between 25th and 75th percentiles across cell types. The DMRs with mCG fractions greater than m+0.3 were assigned as the hyper-DMRs in each cell type, and lower than m-0.3 were assigned as hypo-DMRs. DMRs containing only 1 CG site or without any hypo- or hypcr-DMR assignment were excluded from further analyses.

Motif enrichment analysis

746 transcription factor binding profiles (motif) from JASPAR2020 (81) were used to perform the motif enrichment analysis. Cell-type-specific hypo-DMRs were first segmented into 500bp bins, and then annotated with each motif by intersecting with the genome locations of the motifs. Motif genome locations were downloaded from http://expdata.cmmt.ubc.ca/JASPAR/downloads/UCSC_tracks/2020/hg38. To test for motif enrichment in the major cell types, hypo-DMRs were used as foreground signals, and the hypo- DMRs of all other major types were used as background. For testing at the cell subtype level, hypo-DMRs in only the other subtypes that belong to the same major type were used as background. The one-sided Fisher exact test was used to calculate the p-values of enrichment of the foreground against the background. Integration among different single-cell datasets Feature matrices for human single-cell DNA methylation, expression and open chromatin.

CG- and CH-cell type marker genes determined from the mC dataset for both major and subtype levels were used as the features for integration analysis. When integrating with scRNA (companion manuscript Siletti et al. (75)) or snATAC datasets (companion manuscript Li et ah), the opposite values of gene body methylation were used since they generally were strongly anti-correlated with gene expression. Both scRNA and snATAC datasets were normalized by the averaged total UMI counts of the featured genes and then transformed by log(x+l ). The neuronal cell types and non-neuronal cell types were integrated separately. CH-methylation was used for neuronal cell types, while CG-methylation was used for non-neuronal cell types. An additional filtering step was applied before integrating non-neuronal cell types, which required the total UMI of the featured genes of each cell to be larger than 3,000 for both scRNA and snATAC datasets.

Feature matrices for human and mouse single-cell DNA methylation. Only homologous genes between human and mouse were used to perform the integration analysis. The list of homologous genes was downloaded from the Mouse Genome Informatics (MGI) database (http://www.informatics.iax.org/homology.shtml). The homologous genes were selected from the same features used when integrating with scRNA and snATAC datasets. Human brain cells from thalamus, midbrain, cerebellum, pons, and entorhinal cortices were excluded since no counterparts exist from the public mouse dataset (7). The mouse dataset was re-annotated in the same way as the human dataset. CG- methylation was used to integrate neuronal and non-neuronal cell types separately.

Method to integrate different single-cell sequencing datasets. After feature matrix generation, a 3-step method analogous to Seurat v3 to project two datasets Y and Y onto the same space: 1) Using canonical correlation analysis (CCA) to capture the shared variance across cells between datasets; 2) finding anchors as 5 mutual nearest neighbors (MNN) between the two datasets; 3) pulling the two datasets into the same space. To allow the scalability, 20,000 cells from each dataset were randomly selected

and

}^_f) as a reference to fit the CCA, and transform the other cells ( _? ,,,, and Y^,,,.) onto the same CC space.

Specifically, the canonical correlation vectors (CCV) of ' _f and

(denoted as

and K,_Sf) are computed by singular value decomposition on their dot product,

where

are computed by

U and V were normalized by dividing the L2-norm of each row, and used to find MNN anchors and score anchors using the same method as Seurat v3. Y and Y were also combined vertically and the PCs of this combined matrix were integrated together using the same method as Seurat v3 through the anchors generated from the previous step. This integration step projects the PCs of one dataset (query) to the PCs of the other dataset (reference) while keeping the PCs of the reference dataset unchanged. The resulting PCs were used for visualization and finding matched clusters between datasets.

3D genome analysis

The 3D genome features were analyzed at both single-cell and pseudobulk levels. For single-cell analysis, scHiCluster (79) was used to impute the contact matrices at lOOkb resolution with pad = 1, 25kb resolution with pad = 1 for contact within 10.05 Mb, lOkb resolution with pad = 2 for contact within 5.05 Mb. To speed up the imputation at lOkb resolution, the convolution and random walk were performed within each 30 Mb sliding window across each chromosome with a step size of 10 Mb. Only the values within the 10 Mb in the center of the sliding window were used as the final result.

For pseudobulk analysis, the cells from each group (major type, subtype, or region) were merged by taking the sum of raw matrices or the average of imputed matrices over cells within the group, and only 1500 cells were selected to use if the group contained more than 1500 cells. A group with merged all cell types used in the compartment analysis and embedding comparison was also used. This group contained 5707 cells in total, generated by randomly selected 200 cells with >=100,000 contacts from each major type, except for L5-ET where only 107 cells were identified and all used in the analysis. The details of methods are described below.

Contact distance distribution analysis

A histogram of contacts for each single cell based on the distance between the two anchors of the contact was generated. The bins were equally divided on the log2 distance scale, with a step size of 0.125, ranging from 2500 bp to 249 Mb (length of the longest chromosome). The i-th bin was the number of contacts with a distance between 2500 3°' ¹--¹ and 2500 K 2^&i2s' ¹ > . In FIGs. 6B and 7A-7K, the short-long ratio was defined as the proportion of contacts in 51st (200k) to 76th (2M) bins divided by the proportion of contacts in 103rd (20M) to 114th (50M) bins.

Compartment analysis

Pseudo-bulk contact matrices of each chromosome at lOOkb resolution were used for compartment analysis. The merged contact maps of the 5707 cells was used an lOOkb bins with abnormal coverage were filtered out. Specifically, the coverage of bin i on chromosome c (denoted as Rc,i) was defined as the sum of the i-th row of the contact matrix of chromosome c. Only the bins with coverage between the 99th percentile of R_c and twice the median of R_c minus the 99th percentile of R_c were kept. Contact matrices were normalized by distance, and Pearson's correlation matrices of the normalized matrices were computed (82). These merged contact maps were used to fit the principal component analysis (PCA) models per chromosome. The first principal components (PCI) were used as compartment scores, and the sign of the model was adjusted to ensure the compartment with higher CpG density had positive scores. The PCI of the merged matrices was visually inspected to ensure the values correspond to the plaid pattern of the correlation matrix rather than chromosome arms. The contact maps of each major type were filtered and converted to the correlation matrices in the same way as described above and were then transformed with the PCA models. Both raw matrices and imputed matrices were used for this analysis. The merged raw matrices were used for fitting the PCA model, and transformed the correlation matrices of raw matrices in each cell type as raw compartment scores. In general, the imputed matrices work better with smaller cell populations, while the raw matrices provide higher resolution when enough cells are merged.

To examine whether the enriched longer-range interactions are inter- or intra- compartment, the contact distance plot was stratified by the difference or summation of compartment scores at the contact anchors. The difference of the scores reflected whether the contact was intra- or inter-compartment, and the larger difference represented inter-compartment. The summation of the scores distinguished whether the contact was AA or BB for intra-compartment contacts, and the large positive summation represents AA interaction whereas the small negative summation represents BB interaction. Note that longer-range contained more inter-compartment interactions than shorter-range in general, so non-neuronal cells which had more longer-range interactions also had more inter-compartment contacts than neurons when counting the raw contact counts. The results are reported in FIGs. 7F-7K used distance normalized contact counts, which reflected a relative proportion of intra- or inter-compartment contacts at each distance. Therefore, these results only suggested that a higher proportion of longer-range contacts in non-neuronal cells were intra-compartment, which did not indicate that there were more intra-compartment contacts in total in non- neuronal cells.

Saddle plots and compartment strengths are computed in the same way as described in (83). Specifically, within each chromosome, all the lOOkb bins were ranked based on compartment scores, and group the bins into 50 equal-interval groups. The distance normalized interaction strength between each pair of bins, or the PCC of mCG or mCH levels between each pair of bins were averaged within each group. The axes are ranked by the compartment score of the cell types so that BB interactions are on the top left and AA interactions are on the bottom right.

Differential compartments (DCs) were identified with dcHiC (84) between all major types or neuronal major types using the raw compartment scores as input. A large proportion (>60%) of bins were identified as differential with a traditional q-value threshold of 0.01. Therefore, only the top DCs with a Z- score transformed Mahalanobis distance >1.960 (97.5 percentile of standard normal distribution were selected.

Identification of domains and differential domain boundaries

Domains and insulation scores were derived with scHiCluster at 25kb resolution. Specifically, domains were identified within each single cell with TopDom (85) on the imputed matrices at 25kb resolution. Insulation scores were computed in each cell group (major type or major type within a brain region) for each bin with the pseudo-bulk imputed matrices (average over single cells) and a window size of 10 bins. The boundary probability of a bin is defined as the proportion of cells having the bin called as a domain boundary among the total number of cells from the group.

The number of domains identified in single cells is correlated with the number of short-range reads which could affect the performance of imputation. To avoid computational artifacts, the cells from each cell type were selected to match the distribution of short-range contacts across cell types and observed the same trend in FIGs. 8D-8E, which suggests these differences between domain numbers and sizes are not completely explained by the different short/long ratios between neurons and non-neurons.

To identify differential domain boundaries between n cell groups, an nx2 contingency table for each 25kb bin was derived, where the values in each row represent the number of cells from the group that has the bin called as a boundary or not as a boundary. The Chi-square statistic and p-value of each bin was computed and used the peaks of the statistics across the genome as differential boundaries. The peaks are defined as a local maximum of Chi-square statistics within FDR <le-3 (Benjamini and Hochberg procedure). If two peaks are within 5 bins of each other, only the higher Chi-Square statistic is kept. The peaks also are required to have a Z-score transformed Chi-square statistic >1.960 (97.5 percentile of standard normal distribution), and differences between maximum and minimum boundary probability >0.05. Identification of chromatin loops and differential loops

Chromatin loops were identified with scHiCluster (79) in each major type, subtype, and major type within each brain region, respectively. Only loop calling between 50 kb and 5 Mb was performed, given that increasing the distance only leads to a limited increase in the number of significant loops. For each single cell, the imputed matrix of each chromosome Q_ceii was log-transformed, and Z-score normalized at each diagonal (result denoted as Eceii) and subtracted a local background between >=30 kb and <=50 kb (result denoted as T_ceii), similar to SnapHiC (S6). A pseudo-bulk level t-statistic was computed to quantify the deviation of E and T from 0 across single cells from the cell group, where larger deviations represent higher enrichment against global (E) or local (T) background. E_Ceii is also shuffled across each diagonal to generate Eshufficceii, and then T_Sh_Uffieccii, to estimate a background of the t-statistics. An empirical FDR can be derived by comparing the t-statistics of observed cells versus shuffled cells. The pixels were required to have an average E >0, fold change > 1.33 against donut and bottom left backgrounds, fold change > 1.2 against horizontal and vertical backgrounds (86), and FDR <0.01 compared to global (E) and local (T) backgrounds. The loop summits were selected from the loop pixels with a breadth-first search algorithm, where loop pixels with the largest E were first, and connected it with all the other loop pixels within 20kb (L0 distance) with smaller E values. The loop pixel with the largest E value in each connected component of loop pixels was defined as a loop summit. The concept of summit was only used during the counting of loop summits, and in all other cases, “loop” was used to represent loop pixels.

To compare the interaction strength of loops between different groups of cells, an analysis of variance (ANOVA) framework was adopted to compute the F statistics for each loop identified in at least one cell group using either Q_ceii(result denoted as FQ) or T_ceii (result denoted as FT). Then, Z-scored FQ and FT across all the loops being tested was computed and selected the ones with FQ and FT > 1.036 (85th percentile of standard normal distribution) as differential loops. The threshold was decided by visually inspecting the contact maps as well as the correlation of interaction and loop anchor CG methylation. Motif enrichment analysis between differential loops and constant loops was carried out after controlling the interaction strength and the enrichment against the local background. A pool of constant loops whose Z- scored FQ and FT < 0 was generated. Then the differential and constant loops were grouped into 100 x 100 groups based on FQ and FT. The same number of loops were selected from each group for differential and constant loops and compared the motif enrichment in the differential loops or constant loops compared to the union of them.

Differential loops were identified in 11 comparisons, including between all major types; between neuronal major types; between neuron, glia (ASC, ODC, OPC), MGC, PC, EC, VLMC; between glial major types; between excitatory neurons (L2/3-IT, L4-IT, L5-IT, L6-IT, L6-IT-Car3, L5/6-NP, L6-CT, L6b, L5- ET, Amy-Exc), inhibitory neurons (Lamp5, Lamp5-Lhx6, Sncg, Vip, Pvalb, Pvalb-ChC, Sst, Chd7), cerebral nucleus neurons (MSN-D1, MSN-D2, Foxp2), and SubCtx-Cplx; between excitatory major types; between inhibitory major types; between cerebral nucleus major types; between intra-telencephalic (IT) major types (L2/3-IT, L4-IT, L5-IT, L6-IT); between Caudal ganglionic eminence (CGE)-derived major types (Lamp5, Lamp5-Lhx6, Sncg, Vip); between Medium spiny neurons major types (MSN-D1, MSN-D2). Aggregate peak analysis (APA) of some of the comparisons is shown in FIG. 10A-10C. For each single loop pixel, the imputed contact map from -lOOkb to +100kb was selected and min-max normalized to the range of 0 to 1, and averaged across all the differential loops that have a folder change of Q and T greater than 1.2 and 1.5, respectively, comparing the average of foreground cell types and the average of background cell types.

Single-cell embedding based on different 3D genome features

Contact based. The imputed contacts at lOOkb resolution with distance >=100kb and <=1 Mb are used as features for singular value decomposition (SVD) dimension reduction. The first 30 principal components were normalized by singular values and L2 norms per cell and then used for t-SNE visualization in FTGs. IF and 3F. To better visualize the heterogeneity of neuronal cells, each of the neuronal cell was downsampled to populations of 1,000 cells and, together with all the neurons to fit the t-SNE, and project back the other non-neuronal cells (87). Higashi (25) and fastHigashi (26) were used in the comparison of embedding in FIGs. 9A-9C. Due to the memory limitation (256G), these tools were run at 500kb resolution rather than lOOkb (same as suggested in the literature and github pages). The donor information was used as a confounding factor in the models to avoid the embedding being driven by donor differences.

Compartment based. Single-cell compartment scores were computed using either the CpG density method or the eigenvector method on raw contact maps or contact maps imputed by scHiCluster or Higashi. CpG method used the CpG density of each lOOkb bins across the genome, and a value for each bin was computed for each single cell as the average of CpG density of other lOOkb bins on the same chromosome, weighted by the interaction strength between the two bins. The eigenvector method used an average of imputed matrices across all single cells to compute the correlation matrices (as described in the compartment analysis) and fit PCA models to transform the correlation matrices of all single cells. Higashi was also used to impute the contact maps after generating the cell embedding as described in “Single-cell embedding based on chromatin contacts”, using either 0 neighbors or 5 neighbors on the embedding space to help imputation. Although using 5 neighbors generated compartments with higher cell type specificity, this method enforced the smoothing of information on the cell embedding, which could artificially augment the difference between imputed matrices when the embedding can separate the cell types well. Therefore, this made it challenging to claim if the separation of cell types is due to the intrinsic heterogeneity of compartments across single cells or due to the smoothing of the embedding and we still show the result with 0 neighbors in FIGs. 9A-9C. SVD on the cell-by-bin compartment score matrix A” — £751’ ^T was performed to derive the cell embedding I?.

Loop based. The loop pixels identified in all major types were combined to make a meta loop list and a binary cell-by-loop matrix was generated where each element indicated whether a contact was detected in the cell at the loop pixel. Latent semantic analysis with log term frequency was applied to the binary matrix (denoted as A) to compute the embedding. Specifically, columns having 1 in more than 5 rows were selected, then the column sum of the matrix

^was computed and kept only the bins with Z-scored

between -2 and 2. The filtered matrix was normalized by dividing the row sum of the matrix to generate a term frequency matrix TF, and further converted to used for singular value decomposition A' =

A cell-by-loop matrix B was generated where each element indicated the imputed contact at each loop pixel in each single cell. This is a dense matrix of 5.7k x 3.2M, which limits the ability of this method to scale up to all cells in this dataset. Eigenvalue decomposition was performed SE =

and the eigenvectors were ranked by the eigenvalues from large to small to derive the cell embedding B.

Domain boundary-based. A binary cell-by-25kb bin matrix was generated where each element indicated whether the bin was identified as a domain boundary in the cell. The same LSI framework was used to obtain the cell embedding.

Clustering benchmark. L2 normalization was applied within each cell on the top dimensions for all embeddings. For t-SNE visualization, the top 25 dimensions were used, except in Higashi and fastHigashi where the top 128 dimensions were used. K-Means was used to perform clustering, and the top 50 dimensions were used, except for Higashi and fastHigashi, 128 dimensions were used, k was enumerated from 3 to 12 and the result with the highest adjusted rand index (ARI) compared to the cluster labels was shown in FIGs. 9A-9C. To benchmark the ability to separate excitatory cell types, L2/3-IT, L4-IT, L5-IT, L6-IT, L6-IT-Car3, L5/6-NP, L6b, L6-CT, and L5-ET were used. For inhibitory cell types, Lamp5-Lhx6, Lamp5, Sncg, Vip, Pvalb-ChC, Pvalb, and Sst were used.

The failure to resolve cell types could be due to biological reasons: 1) the differences of compartments across cell types are small, or 2) the heterogeneity of compartments across cells within the same cell type are huge, or technical reasons: 3) the power of algorithms to identify compartments on singlecell Hi-C data is limited. Based on the other analyses, the differential compartments between neuronal cell types as well as excitatory or inhibitory subtypes that strongly correlate with gene expression could be identified. This suggested that compartment differences exist at the pseudobulk level between finer-scale cell types that cannot be distinguished in compartment-based single-cell embedding. Thus, the single-cell heterogeneity or the computational challenges could be the major determinants. The analysis of chromosome imaging data could help further distinguish the two factors given that they are usually considered the gold standard for chromatin structures and do not need imputation algorithms for compartment calling. A previous study concluded small differences between compartments across single cells (88). Even though how large these differences are relative to the across cell types differences remain elusive and would need the chromosome/genome level chromosome imaging data from complex tissues to resolve. In summary, this result is the combined effect of biological feature specificity and computational limitations for quantifying the features accurately within single cells, and the conclusion is drawn from the best methods to date we can apply and might be challenged by technology and algorithm improvement.

Comparison between differential 3D genome structure and other modalities

Compartment. The raw compartment scores were quantile normalized across cell types. For each lOOkb bin, this normalized score was used to compute its PCC with the ATAC, mCG, and mCH signals at the same lOOkb bin across cell types. The PCC was also computed between the normalized compartment scores with the expression level of genes whose promoters (TSS±2kb) or gene bodies (TSS-2kb to TES+2kb) overlap with the lOOkb bin.

Domain. The boundary probability was defined at the start position of each 25kb bin. The ATAC, mCG, and mCH signals at the upstream and downstream lOkb bin of the boundary were used and the average signal of the two bins was taken to compute PCC with the boundary probability. The PCC between the boundary probabilities with the expression level of genes whose promoters or gene bodies overlap with the two lOkb bins was also calculated.

Loop. The interaction strength was defined for each loop pixel between two lOkb bins. The ATAC, mCG, and mCH signals at the two anchor bins of the loop were used and the average signal of the two bins was taken to compute PCC with the imputed loop strength (Q). The PCC between the loop strength with the expression level of genes whose promoters or gene bodies overlap with the two lOkb bins, or whose gene bodies are between the two lOkb bins was also computed.

Note that the differences between compartment and domain or loop in correlation analyses could be due to the different resolution, given the usage of lOOkb resolution for ATAC and methylation could dilute the signals of regulatory elements. Domain and loop are more comparable given that the quantification of ATAC and methylation signals are at lOkb resolution for the analyses.

Differentially expressed genes (DEGs) and comparison with 3D genome structures

Due to the differences between major type annotation, each RNA cell was assigned a major type label according to the mC cell based on the integration of neuronal cells between scRNA-seq data and snmC-seq data. The non-neuronal cells were labeled according to their original annotation given the clear correspondence between the two annotations. 1000 RNA cells were randomly selected from each major type, where the probability of a neuronal cell being chosen is proportional to the confidence of label transfer from mC cells to that RNA cell. This procedure provides 29k RNA cells in total from the 29 major types used in the3C analysis. For each cluster pair, the p-values were derived with the Wilcoxon rank-sum test, and the fold-change was computed as the ratio between the average expression level across cells in the two clusters. The genes with an absolute value of log2 fold-change greater than 1 and False Discovery Rate (FDR, Benjamini-Hochberg Procedure) values smaller than 0.01 were considered as differentially expressed. The top 100 DEGs with the smallest FDR (BH procedure) were used as top DEGs between the cluster pair and the top results from all possible pairs were concatenated and duplicates were removed to generate a final list of top DEGs. This analysis identified 1099 top DEGs between neuronal major types and 1358 DEGs between all major types on autosomes.

The Pearson Correlation Coefficient (PCC) was then calculated between 3D genome structures and gene expression across neuronal major types. To avoid the bias led by the cutoff selection for differential analysis, the bins and genes were grouped based on the differential statistics and ithe correlation for the bins and genes assigned to each group was investigated (FIGs. 13E-13F, 15E-15F). For the expression level of each DEG, the correlation with the quantile normalized compartment scores of each lOOkb bin, the boundary probability of each position with 25kb sliding interval, or the strength of loops within TSS-5Mb to TES+5Mb region of the gene (Fig. 2, K to N) was also computed. The 3D genome features and genes were shuffled within each major type to calculate null PCC and estimate FDR. For each PCC value (denoted as x) between gene i and 3D genome feature j, a left-side FDR was computed as the ratio between the proportion of shuffled PCC smaller than x and the proportion of observed PCC smaller than x, and a rightside FDR was computed as the ratio between proportion of shuffled PCC greater than x and proportion of observed PCC greater than x. The PCC threshold corresponding to left-side and right-side FDR<0.01 was computed (denoted as tl and tr), and the final PCC threshold for significance was determined as ±(max(abs(tl), abs(tr))).

Cis-rcgulatory elements (CREs) prediction

Based on the pairwise CH-DMGs determined between cell subtypes, a gene was assigned as hypomethylated in one subtype if it is a hypomethylated DMG in at least 40 out of 187 pairs compared with other subtypes. A DMR is assigned to a subtype if it is either CG-hypomethylated in the subtype (see section “Determine differentially methylated regions” above) or its CG-methylation level is below 0.3. A DMR is considered as a candidate cis-regulatory element if it is connected by a differential loop to a gene that is also a DMG in the same subtype. The differential loop connecting the DMR-DMG pair was not reauired to be a loop detected in the subtype of the pair. The reason for this loose criterion is threefold: 1) the strength of the differential loop anti-correlates with the methylation levels (FIG. 6K). If a DMR-DMG pair is connected with a differential loop in one subtype, the loop likely exists in another subtype with the DMR-DMG pair of similar methylation statuses; 2) Cis-regulatory elements are usually pleiotropic (89), the loops detected in subtypes covered by the m3c dataset could be reused in another uncovered if the methylation status of the DMR-DMG pairs is similar. 3) Loops could be missed in detection due to either the limitation of the computation methods or the insufficient coverage in certain subtypes. The DNA looping information transferring among subtypes could cope with such a situation to some extent.

Association between brain disorder risk variants and DMRs across cell types

The GW AS summary statistics were obtained for quantitative traits related to neurological disease and control traits of intelligence (90), educational attainment (91), alcohol usage(92), Alzheimer's Disease (93), bipolar disorder (94), attention deficit hyperactivity disorder (95), neuroticism (96), schizophrenia (97), amyotrophic lateral sclerosis (98), tobacco use disorder (99), insomnia (100), sleep duration, coronary artery disease (101), height, tiredness (102), type 1 diabetes (103), type 2 diabetes (104), allergy (105), birth length (106), and birth weight (107).

The summary statistics were prepped in the standard format for linkage disequilibrium score regression. Next, major-type hypo-DMRs were converted to human genome assembly GRCh37 (hg 19) coordinates using the software LiftOver, and annotated with the 1000 Genomes Project Phase 3 SNPs (108). The superset of the hypo-DMRs was used as the background. Finally, cell-type-specific linkage disequilibrium score regression (https://github.com/bulik/ldsc; (46)) was used to estimate the enrichment coefficient of each annotation for each trait.

Brain regional axes from DNA methylation profiles

Both CG- and CH- highly variable 100kb-bins of one cell type (the same features for clustering analysis) were used to compute a lower dimensional representation with the principle component analysis (PCA). First, a neighbor graph of the cells was constructed in the PCA space. Then, for each cell, a regional identity vector was computed by averaging the location information of this cell and its neighbors. A pairwise Manhattan distance matrix was then constructed from the regional identity vectors to capture relations among brain regions. The principle coordinate analysis (PCoA) was applied to this distance matrix to obtain a lower-dimensional embedding in the regional space as well as preserve relative distances among cells. Thus, the cells were transformed from the methylome space to the regional space.

In the regional space, the trajectory analysis was perfored with the Elastic Principal Graph (EPG) algorithm (109) implemented in STREAM (54). The parameters epg alpha, epg mu, and epg lambda were manually adjusted to ensure the resulting trajectories well represented the distributions of the cells in the regional space. Each cell was assigned a regional index (or pseudotime) range in [0,1] according to its relative position to the trajectory. The cells were then grouped into 20 bins along the trajectories based on their regional index. The mean DNA methylation profiles can be computed for each bin.

Consensus regional axis for cortex and basal ganglia. The mean regional index was first computed for cells from each cortical region in each cell type. Then the average regional indices were calculated by averaging the mean regional indices across the corresponding cell types. Finally, the consensus regional axis was constructed by ranking the average indices.

Regional DMGs. A one-vs-rest strategy was used to calculate region-specific CH-DMGs (rDMGs) within major types from the cortex and basal ganglia. To avoid potential bias caused by an imbalance of cell numbers in different regions, cells in each region were downsampled to no more than 500. Using the Wilcoxon rank-sum test, protein-coding genes and IncRNAs, regions were tested for significant methylation decrease (or hypomethylation). The p-values were adjusted with multitest correction using the Benjamini- Hochberg procedure. The genes with adjusted p-values<T¹⁰ and log2 fold-change < -0.1 were considered rDMGs.

Regional DMRs. Cells from the same brain region were merged for each major type to construct the regional pseudo-bulk methylation profiles. Then the DMRfind function of the software MethylPy was used to determine the candidate rDMRs with the same options as in determining cell-type DMRs. If a candidate rDMR has CG-methylation variation > 0.6 across regions tested, it is considered an rDMR.

Regional enriched motifs of TFs. For simplicity, rDMRs with methylation levels changing monotonically (PCC>0.5 or <-0.5) were selected with the regional axes that were revealed in cortex and basal ganglia (FIGs. 19C,19F), and TF motif enrichment analysis was performed against cell type-specific hypomethylated DMRs. TF motifs with adjusted p-val <le-50 were considered as enriched.

Enrichment analysis on conserved DMRs between human and mouse

Functional enrichment analysis of hcCnsvDMRs. The Genomic Regions Enrichment of Annotations Tool (GREAT) (110) was used to compute the Gene Ontology (GO) term enrichment of hcCnsvDMRS. “Basal+extension” option (5.0 kb upstream, 1.0 kb downstream, and up to 100 kb max extension) was selected for gene association, and “curated regulatory domains” are included in the analysis. Comparison between hcCnsvDMRs and histone modification marks in mouse forebrains.

Replicated peaks of histone modification marks of P0 mouse forebrain were downloaded from the Encode project (6). Particularly, H3K27ac (ENCFF044YBD), H3K27me3 (ENCFF461UUN), H3K4mel (ENCFF467MYU), H3K4me3 (ENCFF066LGF), and H3K9me3 (ENCFF997XJK) were used. The software Genomic Association Tester (GAT; 111 ) was used to compute the enrichment of hcCnsvDMRs in the histone modification marks. Accessibility of hcCnsvDMRs was determined by comparing them with snATAC peaks profiled from P56 mouse brains (2). scMCodc construction

Candidate CpG sites. A pseudo-bulk mCG profile was constructed for each major type and then CpG sites were iteratively selected to distinguish all major types. In each iteration, CpG sites were selected according to the criteria: 1) they are either almost entirely methylated (mCG%>80%) or unmethylated (mCG%<20%) among all the remaining major types; 2) both two methylation statuses are presented among the remaining major types; 3) The CpG sites should have coverage >10 in >80% of the remaining major types. These selected CpG sites were added to the CpG site pool for later scMCode construction. In each iteration, the methylation levels of the selected CpGs in the remaining major types were binarized if they are >80% or <20%. Pairwise distances were computed between binarized methylation status, and the cell types that had a distance <20 to any of the other major types were kept for the next iteration of CpG selection. In total, 221,140 CpG sites were selected as candidates for scMCode construction.

CpG site selection for scMCode. The methylation levels of candidate CpG sites across all the major types were trinary-discretized based on their DNAm fractions (discretized values are -1 for mCG%<20%, 1 for mCG%>80%, and 0 for 20%<mCG%<80%) in major type pseudo bulk level. The CpG sites were further grouped into 38,945 features based on these discretized DNAm status across major types. To prevent scMCode from bias caused by cell type population differences or individual variations of donors, 300 cells were randomly selected from each major type from each donor as the dataset for scMCode construction. In each cell, the methylation state of each feature was either computed by averaging the methylation levels of all the CpG sites belonging to this feature (AverageCpG) or by directly using the methylation level of a randomly picked single CpG site belonging to this feature (RandomCpG). The cell- by-feature matrix was trinary-discretized based on their DNAm fractions (discretized values are -1 for mCG%<50%, 1 for mCG%>50%, and 0 for mCG%=50% or uncovered) in single cell level and then used to train a random forest (RF) model to predict major types. A 4-fold cross-validation scheme was used to prevent overfitting. Finally, the top 800 most important features were selected to construct the scMCode for major types. No difference was observed in predicting performance between AverageCpG and RandomCpG, indicating the robustness of scMCode.

Boost the prediction accuracy with K-Nearest-Neighbor imputation. Approximately 88% single-cell predicting accuracy was achieved directly with the cell-by-feature matrix. Given the limited coverage of single-cell data, the cell-by-feature matrix could be further imputed to improve the prediction accuracy. Within the training dataset, half of the cells were selected and merged into pseudo-cells according to their major types. This process was repeated 20 times, and a pseudo-cell-by-feature matrix was constructed from these pseudo-cells in the same way. A K-Nearest-Neighbor (KNN) imputer was built upon this matrix. The testing dataset was first imputed with the KNN imputer and then fed to the RF model for prediction. The KNN imputation step improved the prediction accuracy to -93%.

Cross-donor tests. The scMCodes for each donor were derived and trained the KNN imputer and RF classifier correspondingly. The single donor scMCodes and models were then applied to the data of other donors to assess the cross-individual robustness. When the training and testing donors are the same (FIG. 24E), a 4-fold cross-validation scheme is used to prevent overfitting and to assess the accuracy.

Example 2 Epigenome-based brain cell type taxonomies

Dissection of 46 brain regions encompassing brain structures of the cerebral cortex (CX, 22 regions), basal forebrain (BF, 2), basal nuclei (BN, 11), hippocampus (HIP, 5), thalamus (THM, 2), midbrain (MB, 1), pons (PN, 1) and cerebellum (CB, 2) was done (FIGs. 1A, 2A). Most regions had three biological replicates from the three adult male donors except two amygdala regions (BM and CEN; two replicates each) (FIG. 2A). Fluorescence-activated nuclei sorting (FANS) was used to isolate 90% NeuN- positive and 10% NeuN-negative cells in each sample (FIG. 2A). DNA methylation (DNAm) was profiled using snmC-seq3 (“mC”)( 10) across all 46 brain regions at the single-cell level. Additionally, snm3C- seq(“m3C”)(3) was utilized to simultaneously examine single-cell DNA methylation and chromatin conformation from 17 brain regions spanning CX, BF, and BN (FIG. IB, 2A). Following rigorous quality control, 378,940 mC and 145,070 m3C nuclei were confirmed suitable for further analysis (FIG. 2B). Each mC cell produced an average of 0.94 million filtered reads, and each m3C cell produced around 2.20 million reads with 406k chromatin contacts. This data quality allowed us to reliably measure DNAm across genomic features (FIG. 2C), identify variable methylation regions, and pinpoint TADs and chromatin loops across different brain cell types.

Through iterative clustering of the mC dataset (see Example 1), nuclei were first divided into three classes: telencephalic excitatory neurons, inhibitory/non-telencephalic neurons, and non-neuronal cells (FIGs. 1C, 1G). These were further divided into 40 major types and 188 subtypes (FIGs. 1G, 3A-3C). The cell types were annotated based on CH-hypomethylated gene markers for neuronal cells and CG- hypomethylated markers for non-neuronal cells (Methods). All major types and subtypes were conserved across donors, though there were minor variations in the proportion of certain cell types (FIGs. 1G, 3C). The robust dendrograms demonstrated similarities between major types and subtypes (FIGs. 1G, 3C). Telencephalic excitatory and inhibitory/non-telencephalic neurons are well-separated from non-neuronal cells, each type forming a specific clade except CB and PKJ, which were grouped with the non-neuronal cell types, likely owing to their similar global CG- and CH-methylation fractions (FIGs. 1H, 4A).

Non-neuronal major types distribute evenly across brain structures, whereas neuronal ones exhibit considerable spatial specificity (FIGs. 1F-1G). Most telencephalic excitatory neurons were grouped by location (FIG. 1G). Hippocampal excitatory neurons were grouped based on their sub-structures (CAI, CA3, & DG). Cortical excitatory neurons were clustered by their cortical layers (like L2/3; L=layer) and projection types (like IT). Basal nuclei excitatory neurons, predominantly from the amygdala, form the Amy-Exc group. Telencephalic inhibitory neurons manifest as eleven major types, primarily from cortical areas (Pvalb, Pvalb-ChC, Sst, Lamp5, Lamp5-Lhx6, Sncg, and Vip) and basal nuclei or basal forebrain (MSN-D1, D2, Foxp2, and Chd7). In the thalamus, one excitatory and two inhibitory major types were identified. One inhibitory major type, THM-MB, shares similar DNA methylation profiles with a small population of midbrain cells. The other inhibitory major type, THM-Inh, is very rare (361 cells or 0.07% of the entire dataset), possibly originating from the habenular nuclei of the thalamus due to dissection contamination (FIG. 3D). Pontine nucleus neurons constitute a unique major type (PN). The cerebellum contained two distinct major types: the rare cell type Purkinje cells (PKJ, 867 cells or 0.17%), and cerebellar granule cells (CB). Lastly, the SubCtx-Cplx major type, found in the basal nuclei and midbrain, was notable for its heterogeneity: its subtypes consisted of both excitatory and inhibitory cells (FIG. ID) and featured highly variable DNAm of the genes of neurotransmitter receptors, transporters, and neuropeptides (FIG. 3E).

The cell types determined from single-nucleus DNAm profiles were corroborated with singlenucleus transcriptome (snRNA-seq) and single-nucleus chromatin accessibility (snATAC-seq) data from the same human brains (Methods; companion manuscripts Siletti et al. (77) and Li et al. (72)). Integrative analysis revealed the strong correspondence between cell types determined using different molecular modalities (FIG. 5A). All epigenome-based cell subtypes correspond well with transcriptome-based clusters (FIG. 5B), though the transcriptome-based clusters were derived from -10 times more cells and from -2 times more brain regions.

Global methylation varied among major types: 77.7%-85.5% for mCG and 0.8%-10.7% for mCH. Non-neuronal and granule cell (DG and CB) major types had the lowest global fractions in both mCG and mCH (FIGs. 1H, 4A), consistent with the previous study in mice (7). Cortical inhibitory neurons have the highest mCG, whereas certain non-telencephalic neurons from the thalamus, midbrain, and pons exhibited the highest mCH (FIGs. 1H, 4A). Cell-type global methylation corresponded with the gene expression of DNAm readers and modifiers (FIG. II, 4B). The expression of MECP2 and DNMT3A, the major mCH reader and writer, were positively correlated with global mCH (Pearson Correlation Coefficient, PCC=0.39 and 0.35) and weakly with mCG (PCC=0.17 and 0.08; FIGs. II, 4B). The DNA methyltransferase DNMT1 had a high positive correlation (PCC=0.63) between its expression and mCG across cell types (FIG. II), matching its role as the major mCG maintainer in mature neurons (13). Intriguingly, an even higher correlation between DNMT1 expression and mCH (PCC=0.72, Fig. II) was observed, though it is thought to have little effect on mCH (14). This implied an unknown relationship between DNMT1 and mCH or some yet-to-be-discovered factor influencing both DNMT1 expression and mCH.

Using the improved scHiCluster(75) for m3C cells, all major types except MSN-D1 and D2 solely were separated through chromatin contacts (FIG. I F). This also highlighted the diversity of chromatin conformation across brain regions (FIG. 3F). To ensure the consistency of annotations between the two datasets, mC and m3C cells were co-clustered iteratively and then transferred by cell type annotations from mC to m3C cells (see Example 1).

Example 3 Differences in contact distance between neurons and non-neurons

To investigate cell-type-specific genome folding at different scales, the proportion of contacts per cell at genome distances was first examined. Neurons displayed enrichment of interactions at a shorter distance (200kb-2Mb), whereas mature oligodendrocytes and non-neural cells were enriched for longer- range contacts (20Mb-50Mb). Astrocyte and oligodendrocyte progenitor cells exhibited enrichment in both ranges (FIGs. 6A-6C, 7A-7B). Within neuronal cells, cortical excitatory and subcortical neurons had more shorter-range interactions than cortical inhibitory cells (p-value< le-300, Wilcoxon rank-sum test; FIGs. 6A- 6B). We observed similar patterns in previous datasets from the mouse (7) and from a different technique (Dip-C (76); FIG. 7C), signifying the conservation of these patterns. The enrichment of shorter-range contacts in neurons was observed across the whole genome, including both neuronal and non-neuronal gene loci (FIG. 7D). The ratio between shorter and longer interactions highly correlated with global gene expression activity of cells (PCC=0.87, FIG. 7E), and aligned with the sizes of nuclei (L5-ET > other cortical excitatory neurons > cortical inhibitory neurons > non-neurons (77)). These results demonstrated that the contact distance spectrum, traditionally associated with cell-cycle phases (18), can also vary based on cell type in non-dividing cells. The relationship between enriched longer-range or shorter-range chromatin interactions and chromatin compartments or domains was next investigated. Chromosome compartments within each major type at 100 kb resolution (FIG. 6D) and domains at 25 kb resolution were identified. Enriched longer-range interactions in non-neurons were predominantly intra-compartment, especially between B compartment regions. Shorter-range interactions in neurons were also enriched within the same compartments (FIGs. 7F- 7G). In total, an enrichment of intra-compartment interactions and a depletion of inter-compartment interactions in non-neurons was observed (FIGs. 7H-7K), indicating a stronger compartment strength. In contrast, the enrichment of short-range interactions in neurons was found to be both intra- and inter-domain (FIGs. 7L-7M).

Example 4 Compartments, domains, and loops in brain cell types

The methylation status of two genome loci would co-vary if they were physically proximate. The co-methylation coefficient matrices, depicting the correlation of methylation between genomic bins across single cells, displayed plaid patterns echoing the compartment structures of chromatin contacts (FIGs. 6E, 8A). This suggested the genome was segregated into local co-methylation domains, which constituted two sets with opposite methylation diversities. A similar coregulation structure was also observed for chromatin accessibility in single-cell ATAC-seq data ( 9), reinforcing evidence for genome compartmentalization. Exploring the linking between DNA methylation and 3D genome architecture, correlations between the strengths of chromatin interactions and the average methylation fractions of their anchors were also associated with chromosome compartments (FIG. 8B), where negative correlations occurred more frequently in the active compartment (p-value<le-300; FIG. 8C).

Domains at 25 kb resolution in single cells were determined and it was found that neurons had more domains (median 4,813) than non-neurons (median 4,308, p-value<le-300) but with smaller average size, resulting in a similar domain-covered genome proportion (FIGs. 8D-8E). The number and size of domains were highly correlated with global gene expression activity (FIG. 8F). The boundary probability of a genomic bin was defined as the frequency it was identified as a domain boundary across cells, which mirrored the insulation scores from the cell-type pseudo-bulk contact maps (FIGs. 6F-6G).

Chromatin loops were delineated at 10 kb resolution in each of the 29 major types (and 119 cell subtypes) with >=100 m3C cells. A median of 524,935 (541,551) loop pixels with 45,140 (59,905) loop summits among major types (subtypes) was detected (FIG. 8G). Of these, 24.3% were interactions between distal DMRs (see later section for systematic description of DMRs) and gene promoters (TSS±2kbp), 38.1% between distal DMRs, and 5.8% between promoters (FIG. 8H).

Example 5

Cell type specificity of 3D genome features Using either compartment scores, domain boundary probabilities, or loop strengths, it is possible to distinguish cell types and determine the hierarchy of their similarities (FIGs. 6H, 9A-9C), indicating cell type specificities of these 3D structures. Particularly, chromosome compartments could distinguish nonneurons, excitatory, inhibitory, and MSN neurons, but had difficulty for finer major types within the excitatory or inhibitory cell classes (FIGs. 9B-9C). In contrast, both chromatin domains and loops distinguished better for finer excitatory and inhibitory major types, and loops performed the best (FIGs. 6H, 9B-9C). This underscores the varying roles of different scales of 3D features in gene regulation across cell type granularities, highlighting that loops could be more specific than domains. The primary goal of these analyses was to contrast compartments, domains, and loops in cell type specificity, but not for cell type clustering. The state-of-the-art of cell clustering on chromatin contacts is still based on the genomic binpairs, as shown previously (75) or by other groups (20, 27) (FIGs. 9B-9C).

Systematic examination on specific 3D structures across all (or neuronal) major types determined 1,188 (1,024) differential compartments (DCs), 2,050 (1,720) differential domain boundaries (DBs), and 173,806 (148,395) differential loops (DLs) (FIG. 10A). Chromatin domains were considered conserved across cell types in general (22-25), whereas they could display certain dynamics across cell types and development (5, 26-28). This data further showed that chromatin domains could vary even between closely- related cell types (FIGs. 6F-6G). DMR-DMR loops showed higher cell-type specificity than promoter-DMR or promoter-promoter loops (FIG. 10B). Evaluating transcription factors (TFs) in differential chromatin looping, the motifs of cell type-specific TFs (like NFIX and NHLH1) were more enriched at anchors of DLs, whereas CTCF, a TF pivotal for chromosome structure, was highly enriched at housekeeping loops (FIG. 10C). This implied CTCF's role is more in structural loops than in cell type-specific promoter-enhancer interactions. Many neuronal TFs (like NEUROG1 and NEUROG2) were enriched at the pan-neuronal loops but not pan-brain-cell loops (FIG. 10C), concordant with their neuron-specific roles.

Example 6 Relationship between genome organization and other molecular modalities

The link between different 3D structural features and other epigenomic modalities (mCG, mCH, and open chromatin) was examined. Across neuronal cell types, both mCG and mCH were anti-correlated with compartment scores, domain boundary probabilities, and loop strength (FIGs. 61, 1 IB, 1 ID, 12C-12D). In contrast, open chromatin signals exhibited positive correlations with these structural features with similar or slightly weaker (absolute) correlations (Figs. 61, 11B, 11D, 12C-12D). These (anti-)correlations indicate orchestration among active compartments, strong domains and loop interactions, as well as open chromatin and methylation depletion corresponding to active chromatin states. Between the differential structural features (DCs, DBs, and DLs) across cell types, DLs had stronger (anti-)correlations with mCG, mCH, and open chromatin compared to DCs and DBs (FIG. 12C), particularly at the loops with high variability across cell types (FIG. 12D). Correlations across all cell types were generally weaker than in neurons alone (FIGs. 61, 11 A-l ID, 12A-12D). The anticorrelation observed between DNAm and 3D genome structures could have resulted from the effect of DNAm on the binding of factors driving genome folding (like CTCF)(29), the recruitment or exclusion of methylation writers or erasers (such as DNMTs and TETs) through high- order structural formation, or shared regulators of both methylation and genome organization (for example, Neurog2 in mouse cortex (30)).

Gene expression was correlated with the 3D genome structures as well, particularly for the cell-type- specific genes (FIG. 6J). A total of 1,099 (1,358) top differentially expressed genes (DEGs)were identified pairwisely across neuronal (all) major types. They exhibited strong positive correlations with all three structural features that overlapped with their gene bodies or promoters (FIGs. 6J, 13A-13F, 14A-14C). For loops, the interaction strengths were more correlated with anchor-overlapped DEGs (on gene bodies or promoters) compared to the anchor-encompassed DEGs (p-value<le-300; FIG. 6J). The increasing variability of gene expression and/or structural signals of bins was linked to higher positive correlations between them, which corroborates the overlap between differential structural signatures and differential gene expression (FIGs. 13E-13F, 15A-15F).

The relative location between 1,099 neuronal DEGs and their correlated chromatin structures (FDR<0.01) at surrounding regions (TSS-5Mb to TES+5Mb) was examined. The correlated compartments were mostly within the gene body (FIG. 6K), and the correlated domain boundaries were highly enriched at TSS and TES (FIG. 6L), indicating the dynamics of gene body compartments and domains associated with gene expression diversity. The loops with positive correlations were enriched within gene bodies, as well as between the TSS/TES and the gene body ± 1 Mb regions (FIG. 6M). Specifically, 48% of the loops within the gene body were correlated with gene expression, among which 98% are positively correlated. In comparison, a much smaller proportion of loops outside the gene body were correlated with expression. A higher proportion of positively correlated loops were observed within the upstream and downstream regions of the DEGs, and between the upstream or downstream and the gene body regions, indicating the regulatory domain of a gene structure.

Among the 1,099 DEGs, 453 (41.2%) had gene bodies overlapped by one or more genomic bins with positively correlated compartment scores, and 591 (53.8%) overlapped by one or more correlated domain boundaries. 1,037 (94.4%) DEGs had TSS- or TES-anchored correlated loops, and 898 (81.8%) had correlated loops within gene bodies. These dynamics of chromatin architecture at different scales in total covered 96.8% of the DEGs (FIG. 6N), again suggesting a strong association between genome structures and gene expression diversity. Collectively, these analyses revealed the cell-type specificity of chromatin architecture and its relationship with other epigenomic and transcriptomic signatures at an unprecedented cell-type resolution in the human brain.

Example 7

Cell-type specific DNA methylation patterns and associated gene regulatory landscapes

To delineate the cell type-specific methylation profiles, 24,455 CH- and 13,096 CG- differentially methylated genes (DMGs; FIG. 16A) and 2,059,466 CG-DMRs (FIG. 17A) across 188 brain cell subtypes were identified. In addition to depicting distinct epigenetic signatures for brain cell identities, these methylation patterns provide critical insight into understanding gene regulatory programs in brain cells, with gene body methylation negatively correlating with gene expression (5, 7, 32), DMRs marking putative cis- regulatory elements (CREs) (4, 5)), and transcription factor (TF) motifs implicating candidate cell-type- specific regulators (32).

The TFs were assigned to specific cell types if they were hypomethylated DMGs (FIG. 16B; Methods) and their motifs were enriched at the hypomethylated DMRs (hypo-DMRs) in the same cell types (Methods). In total, 612 TFs were assigned to major neuronal types and subtypes, where they may participate in shaping and maintaining cell identities. For example, TBR1 was assigned to deep-layer excitatory neurons, particularly L6-CT and L6b (FIG. 17B), and it was noted to play a fate-determining role in the development of corticofugal projection neurons (33). ZNF423 and EBF2 were both assigned to the cerebellar cell types (FIG. 17B). Both of them are crucial for cerebellum development, whereas EBF2 particularly directs the migration of Purkinje cells (34-36).

Analyzing subtypes further highlighted variations in TF utilization. For instance, the TF PBX3, assigned to the MSN-D1 major type prevalent in the striatum, was only hypomethylated in the subtypes from the striosome compartment but not the matrix compartment of the striatum (FIGs. 17B, 16C). This indicates a preference for PBX3 expression in the striosome, corroborating previous observations (37, 38). Further examination of potential binding sites of PBX3 (hypo-DMRs with PBX3 motifs) showed lower average methylation fractions in striosome subtypes (FIG. 17B), showing a compartment- specific regulatory role of this TF in the striatum.

DMGs, DMRs, and differential loops were integrated to pinpoint putative CREs for each cell type (FIG. 17C). A gene was associated with a DMR if its TSS was within 5 Mb of the DMR. Further refinement retains only DMR-DMG pairs overlapping with both anchors of a loop or DL. Pearson correlations between mCG fractions of DMRs and mCH fractions of gene bodies across cell subtypes were calculated to assess the association (FIG. 16D). Enhanced associations were observed particularly for DL- filtered DMRs (FIGs. 17D, 16D), which showed an increased overlap with open chromatin regions as well (FIG. 17E). There were 3.2M potential regulatory DMR/gene pairs between 1,122,919 DMRs and 12,327 genes identified. The methylation fractions of these DMRs, DMGs, and the strengths of their interactions (loops) were (anti-)correlated (FIG. 17F), which could collectively orchestrate specific gene regulatory programs. For instance, the gene SYT1, encoding Synaptotagmin-1 — a synaptic vesicle protein — exhibited lower methylation fractions of both the distal DMRs and the SYT1 gene body in L2/3-IT neurons and stronger interactions between the DMRs and the promoter compared to MSN-D1 neurons (FIG. 17G), leading to a higher expression of SYT1 in L2/3-IT than MSN-D1 (FIG. 17G, 16E). Overall, the integration of CG- and CH-methylation with chromatin conformation reveals distinct cell-type regulatory dynamics.

Numerous non-coding loci linked to brain diseases have been pinpointed by GW AS, with many in enhancer regions (39). DMRs and loops help localize these genetic variants to specific cell-type regulatory elements. Using linkage disequilibrium score regression (LDSC) (40), associations between 20 brain diseases or traits and DMRs or loop-overlapping DMRs in human brain cells were detected (FIGs. 17H, 18A). Schizophrenia, bipolar disorder, and neuroticism risk variants were prominently enriched in hypo- DMRs of excitatory neurons in the cortices and hippocampus, whereas Alzheimer's disease (AD) aligned with microglia (MGC; FIG. 17H; (41 ). Tobacco usage disorder variants associated with the Foxp2 cell type from the basal ganglia (FIG. 17H), an area linked to tobacco addiction (42). Further exploration into disease risk variants revealed diverse impacts on gene regulations. Although many cell types are related to the same diseases, the risk variants to which they are implicated could be diverse. For example, the schizophrenia risk variants rs2789588 was implicated in both L2/3-IT and L6-CT neurons with similar epigenetic features, whereas rsl7194490 was only implicated in L2/3-IT with specific DNA hypomethylation, stronger long- range interaction with the corresponding gene, and higher gene expression compared to L6-CT (FIG. 18B).

Example 8 Regional heterogeneity in cortices and basal ganglia

Beyond cell type diversity, heterogeneity within shared cell types across regions has been noted in the neocortex in both gene expression (43^45) and DNA methylation (1). This extensive epigenomic dataset further explores gene regulation heterogeneity across broader cortical regions and subcortical regions. To discern regional diversity from other cell-type heterogeneities, a workflow was devised to unveil the regional landscape within single-nuclei DNA methylation profiles (FIG. 19A). Integrating these profiles with brain region data, the cells can be mapped to a "regional methylation space" (FIG. 19A), where cells closer together have methylation neighbors from similar brain regions. In this "regional methylation space" (FIG. 19A), trajectories depict regional transitions alongside associated methylome shifts, thereby enhancing our grasp of regional DNA methylation effects.

Cortical excitatory neurons exhibited remarkable regional diversity in methylation, particularly the intratelencephalic -projecting neurons (LX-IT; FIG. 19B). The regional diversity of cortical inhibitory neurons (46) was less studied due to their inconspicuous regional patterns in transcriptome and epigenome (1, 47, 48). This analysis reveals regional distinctions among cortical inhibitory neurons (FIG. 19B). Regional axes of each cortical neuronal cell type were constructed through single-cell trajectory analysis (49). A shared ordering of brain regions on the axes among cortical neurons was observed, from the posterior regions of the brain (like the primary visual cortex VIC) to the anterior lateral regions (like the prefrontal cortex A46 & the middle temporal gyrus MTG) and then to the anterior medial regions (like the anterior cingulate cortex ACC & the lateral entorhinal cortex LEC; FIGs. 19C-19D). Only L6-CT showed an exceptional pattern (FIGs. 19B-19C) from this Posterior-Lateroanterior-Medioanterior (P-LA-MA) trend. Nevertheless, the shared trend allowed for further analysis of a consensus regional axis for cortical neurons (FIG. 19C).

Epigenetic alterations along this axis indicate regional specification of cerebral cortices. For instance, the transcription factor NR2F1 (also known as COUP-TFI) has gradient expression during brain development, which is vital for establishing the caudal-rostral regional specialization in the neocortex (43) and the boundary between the neocortex and the entorhinal cortex (50). This data showed low gene body methylation in VIC (P) and LEC (MA) and high in A46 (LA; FIGs. 19G, 20B), accompanied by a reversed trend of gene expression (FIG. 20A). Two chromatin domains associated with NR2F1 showed interaction strengths changing in the opposite direction (FIG. 19F). In V 1C, the upstream domain interacted more with NR2Fl's promoter and had hypo-methylated DMRs compared to LEC. In contrast, the downstream domain displayed a stronger interaction with NR2Fl's promoter and featured DMRs hypo-methylated in LEC (FIGs. 19F-19G). Two neighbor genes NR2F1-AS1 and FAM172A, encompassed in these two domains respectively, showed concordant expression trends with the domain strengths (FIG. 20A). Such coherent variations in epigenetics and transcription imply regulatory domain switching and alternative CRE usage to activate the same gene in different cortical regions, which needs further investigation.

Systematic examination of regionally differential epigenetic features in cortical neurons determined in total 14,606 (average 2.9k for each major type) regional DMGs (rDMGs), 885.4k (63.2k) regional DMRs (rDMRs), 773k (71.2k) regional differential loops (rDLs) and 1,495 (136) regional differential domain boundaries (rDB; FIG. 20B; Methods). Many rDMGs and rDMRs showed monotonic methylation gradients along the P-LA-MA axis (FIG. 19E, 20C-20D), whereas more complex patterns (such as NR2F1) also existed.

Basal ganglia neurons exhibited remarkable regional diversity as well. An L-D-V axis (lateral to dorsal to ventral) became evident in the basal ganglia (FIG. 19H) with accompanying epigenetic shifts. For instance, moving from NAC through CaB to Pu, the LSAMP gene increased in mCH (FIGs. 19L19J) and decreased in strengths of chromatin domains and loops around (FIG. 19K). This study identified 6,371 rDMGs and 398.8k rDMRs in the four major types of basal ganglia (MSN-D1, MSN-D2, FOXP2 and CHD7; FIG. 20B), and identified 98,276 (50,271) rDLs and 193 (99) rDBs (FIG. 20B) in MSN-D1 and MSN-D2 cells. The majority of rDMGs and rDMRs showed strong (anti-)correlations with the L-D-V axis (FIGs. 20C-20F), highlighting regional variation as a key to basal ganglia within-cell-type heterogeneity. Distinctions in both functions and neural connections between the dorsal (CaB and Pu) and the ventral parts of basal ganglia, particularly its major component striatum, have been noted previously (57, 52). This data and analysis provided the epigenetic basis of the dorsal- ventral differences and refined the regional differences within the dorsal basal ganglia (FIG. 19H).

A considerable amount (427 out of 746) of TF motifs were enriched in rDMRs (FIG. 20G; Methods). Approximately 47% of these TFs are expressed in the corresponding cell types (FIG. 20H), with expression (anti-)correlated with the regional axes (FIG. 201). These findings demonstrate region-specific regulatory mechanisms in the brain and underlying functional diversities.

Example 9 Conservation of brain cell types and DMRs between humans and mice

Brain cell type conservation between primates and rodents was noted in several neocortical regions (77, 53). To assess whether the conservation holds in broader brain regions, the single-nucleus DNA methylation profiles from human and mouse were compared (7), using corresponding regions including the cerebral cortex, basal forebrain, basal nuclei, and hippocampus (Methods). The integration analysis showed three major types defined in human brains were discrepant with mouse brain cells (FIG. 21 A). Mouse L4-IT neurons aligned only to subpopulations of their human counterparts (FIG. 2 IB), confirming a larger heterogeneity in human L4-IT neurons ( 17). The human hippocampal HIP-Miscl neurons were integrated with some mouse cortical IT neurons, and HIP-Misc2 neurons did not match any mouse cell type. The parallel snRNA dataset (77) validated these two human hippocampal cell types (FIGs. 21C, 22B). Although the unmatched cell types will need further investigation, the major type taxonomies were generally conserved across broader brain regions between humans and mice (FIG. 21A, 22A), whereas both global CG- and CH-methylation were consistently higher in humans than in mice for corresponding cell types (FIG. 2 ID, 22C).

To compare the gene regulation between human and mouse brains, liftOver was used to match major-type hypo-DMRs identified within single species (FIG. 2 IE). 40-60% hypo-DMRs across cell types had ortholog sequences in the other species (DMRs are referred to as OrthSeqs). Around half of OrthSeqs had their orthologs also hypo-DMRs in the other species (OrthDMRs). Most (95%) of OrthDMRs were reciprocally matchable (CnsvDMRs; FIG. 21F, 22D). Methylation fractions of CnsvDMRs showed remarkable correlations across cell types between human and mouse (FIG. 21 G-21 H), suggesting functional conservation between species.

The most highly correlated DMRs (hcCnsvDMRs, FIG. 21G) were selected for further study. Functional enrichment analysis of hcCnsvDMRs showed that they were enriched in biological processes related to forebrain development and in cellular components related to dendrites and synapses (FIGs. 22F- 22G; Methods). Comparison to histone modifications in mouse forebrains (4) demonstrated these DMRs were depleted from heterochromatic regions (H3K9me3) as well as enriched in regions of enhancers (H3K27ac & H3K4mel), promoters (H3K4me3), and poised enhancers (H3K27me3; FIG. 22E; Methods). Categorizing the hcCnsvDMRs further into open or closed status based on their chromatin accessibility (2) showed that open DMRs were enriched in enhancers and promoters. In contrast, closed DMRs were particularly enriched in the poised enhancers (FIG. 211), which had probably been active during development.

Methylation conservation between species hints at a strategy for enhancer discovery through comparative epigenetics. For example, INPP5J, a specific gene of Pvalb neurons, had many distal and proximal hcCnsvDMRs overlapping with matched chromatin-accessible regions (FIG. 21J), including two validated as specific enhancers for viral targeting of mouse Pvalb neurons (FIG. 21J; 54).

Example 10

Single-cell methylation barcodes (scMCodes) reliably predict human brain cell Identity

DNA methylation variation in the genomes of cells contains molecular “engrams” representing past and present gene regulatory events (55). Distinct DNA methylation patterns were observed on many CpG sites highly specific to brain cell types (FIG. 23B). Single-cell methylation barcodes (scMCodes) were developed to determine brain cell types at single cell level using the methylation status of selected CpG sites (FIG. 24 A, 23 A; Methods).

First, CpG sites distinguishing brain cell types were selected iteratively (Methods). These sites were further clustered into 39k groups according to their across-cell-type methylation patterns. Next, their celltype predicting power was determined through machine learning models with cross-validation (FIG. 23 A; Methods). 800 groups with a total of 12k CpG sites were selected as the scMCodes (FIGs. 24B-24C) to achieve good predicting power (FIG. 24D) while minimizing feature number (FIG. 23C). These scMCodes achieved -93% accuracy (FIG. 24D).

Cross-donor tests were conducted among the three donors of this study and an external individual (5). The results showed high prediction accuracies (92-96%; FIG. 24E), demonstrating the cross-individual robustness of the scMCode approach. Single-cell sequencing has limited genomic coverage. On average, only -200 CpG sites of scMCodes were detected in each cell (FIG. 24F), which underscores the effectiveness of scMCode in determining human brain cell types using a few hundred select methylation sites.

Discussion

A profound understanding of cellular diversity and distinctive gene regulatory mechanisms in the human brain is pivotal for elucidating brain functions and formulating therapeutics for brain disorders. Here, a comprehensive single-cell DNA methylation and 3D genome structure atlas of human brains with 524,010 deeply sequenced nuclei from 46 distinct brain regions has been assembled, permitting the identification of 188 epigenetically distinct cell types. The extensive profiling of brain regions in this study has allowed for the identification of cell types specific to subcortical regions and compare epigenetic diversity within the same cell type across different brain regions, which considerably expands previous work (3, 5, 56). Additionally, this study makes considerable strides in understanding the 3D genome diversity across brain cell types and regions, facilitated by a 30-fold increase in cell profiling via snm3C-seq. Moreover, the specificity of domains and loops across 29 cell types was determined, pushing the cell type resolution extensively beyond previous studies (28, 57-59).

Single-nucleotide resolution DNAm has proven valuable in predicting epigenetic age (60), tracing cell lineage (61, 62), and diagnosing life-threatening diseases (63, 64). The intricate regulatory information encoded in DNAm has enabled us to distill a set of single-cell methylation barcodes (scMCodes) for reliable cell-type identification. Given that circulating-free DNA (cfDNA) methylation has been recognized as a robust tool for cancer diagnosis (58) and provided promising biomarkers for brain disorders (59), this scMCode method presents itself as a potentially transformative tool for the non-invasive diagnosis of brain disorders. It could aid in pinpointing pathological brain cell types and inform treatment selection, marking a stride forward in precision medicine.

Overall, this multimodal human brain cell atlas enriches the understanding of brain cells with a foundational epigenomic perspective. It offers not only an invaluable resource for exploring cell type diversity, gene regulation complexity, regional variation, and evolutionary conservation within brain cells but also provides the essential elements, such as putative regulatory elements, for the development of innovative genetic tools for cell type-specific targeting.

Example 11 snm3C-seq Nuclei Preparation using Arima-3C Kit

Reagents And Consumables (the claimed kits can include one or more of these)

Reagents

Sucrose: Sigma, S0389

KC1: Sigma, 529552

MgC12: 442611-M

Tris-Cl pH 8.0: Mediatech, 46-031 -CM

Triton X-100: ACROS, 327371000

DTT: Sigma, 43816

Proteinase Inhibitor: Sigma, P8340

Optiprep (60% lodixanol): Sigma, D1556-250ML

DPBS: ThermoFisher 14190144

Hoechst 33342: ThermoFisher 62249

BSA: UltraPure™ BSA (50 mg/mL) (ThermoFisher AM2618)

Glycine: Sigma 50046-250G

Formaldehyde Solution (37%): Sigma, F8775-25ML rCutSmart Buffer 10X: NEB B6004S

Arima-HiC+ Kit: Arima 3C kit 8 reactions (Arima 10113). Contact Arima about the snm3C-seq kit, which is adapted from their HiC Kit.

Antibody

NeuN 488: anti-NeuN-488 clone A60 (Millipore MAB377)

Consumables

FALCON 5mL Tube with Cell-Strainer Cap

Sony 100pm sorting chip

Instruments

Eppendorf centrifuge with bucket rotor for 2mL tubes

BD Influx sorter (plate sorting) Two thermal devices for 2mL tubes (for different temperatures)

Prepare Single Nuclei

Prepare Reagents

NIM (Pre-made)

NIMT (Fresh-made)

Dilutent (Pre-made)

50% lodixanol (Fresh-made)

25% lodixanol (Fresh-made)

Prepare Nuclei

1. Change centrifuge to bucket tube rotor and fast cool to 4°C.

2. Make all buffers on ice (volumes are for preparing two samples):

1. lOmL NIMT (in a 15mL tube)

2. lOmL DPBS (in a 15mL tube, put in RT)

3. 5mL DPBS + 1 % BS A (in a 5mL tube)

4. if doing gradient:

1. 6mL 50% lodixanol (in a 15mL tube)

2. 8 tubes of 500pL 25% lodixanol (in eight 2mL tubes)

3. Remove frozen tissue from -80°C, place on ice.

4. Transfer tissue with 2.4mL NIMT from tube into the large dounce.

5. Use loose pestle A 40 times gently without introducing bubbles.

6. Use tight pestle B 40 times gently without introducing bubbles.

7. Transfer lysed solution into a 5ml or a 15ml tube and keep on ice.

8. If doing NeuN stain: add 6ul of NeuN 488, 12ul if vol is double (1:500 dil). Mix and stain for 15 min on ice, keep solution covered from light.

9. Pipette lysed solution into two 2ml tubes and,

10. Centrifuge at 1000 g for 10 min at 4°C using a swing rotor.

11. Remove supernatant,

12. Using ice cold DPBS, re-suspend with 200|.iL each sample, then add another 800|.iL DPBS in each tube to end up with 1 ml of nuclei solution.

Crosslink

1. From resuspended nuclei at end of step 12 of nuclei prep in 1 ml DPBS (at least 1-2M nuclei), we would have 2 reactions per sample going from this point on.

2. Add 57pL of 37% formaldehyde (to get 2% Formaldehyde in solution) to each tube, mix well by inverting 10 times and incubate at RT for 10 min (5min if you are doing NeuN nuclei pre-staining), with occasional inversion. 3. Add 91.9|iL of Stop Solution 1 (or 2.5M Glycine), mix well by inverting 10 times and incubate at RT for 5 min. with occasional inversion.

4. Place sample on ice and incubate for 5 min.

5. Pellet cells by centrifugation. (5 min at 2500 x G or 10 min 1000 x G at 4°C)

6. Discard supernatant leaving only the cross-linked cell pellet and no residual liquid.

Clean Nuclei and Aliquot

If not doing gradient:

1. Resuspend the pellet in each tube using 200pL DPBS+RNase Inhibitors, combine the pellets of each sample, then add another 600pL DPBS to end up with 1 ml of nuclei solution in a new tube.

If doing gradient:

1. Resuspend each tube using 200pL NIMT, then add another 800pL NIMT.

2. In a 5mL tube, mix the suspension with 1.8 mL of 50% lodixanol (~4ml).

3. Slowly pipette ImL of the suspension onto each 2mL tubes containing 500pL 25% lodixanol preadded. Each sample has four tubes.

• Do this drop wise against the side to layer it on top of the cushion

• The last tube will likely be less than a mL as there are always bubbles from the dounce

5. Centrifuge at 10,000 x g for 20 min at 4°C (in bucket rotor)

6. Remove supernatant very carefully so all debris on top of supernatant doesn’t remain. Re-suspend each pellet in 200u L using ice cold DPBS+RNase Inhibitors and combine the pellets from each tube to end up with 1 ml of nuclei solution in a new tube.

• Can leave a bit of supernatant in each tube to avoid sucking up the pellet.

Nuclei staining:

1. Add Hoechst 33342 (dil: 1: 1000): Dilute the Hoechst 1: 10 (5pL + 45pL DPBS), then add 5pL to

1 mL sample, then incubate on ice for 5 min.

Nuclei count:

2. Take l Oul of the Nuclei suspension in a clean 1.5ml tube

3. Add lOul of Trypan Blue staining solution and mix by pipetting and

4. Count the nuclei concentration using a hemocytometer, or

5. Add lOul of the mix to a Cell Counter Slide

6. Use the automated Bio Rad Cell counter TC_20, limit count should be between 5 and 10, and Nuclei count should be the Total count minus the Live count.

7. Aliquot 500K to IM nuclei into 2ml tubes.

8. Centrifuge at 2,500 x g for 5 min at 4°C (in bucket rotor).

9. Discard supernatant leaving only the cross-linked cell pellet and no residual liquid.

10. Proceed directly to the 3C Enzymatic Protocol section Digestion and Ligation section or freeze samples on dry ice or liquid nitrogen and store at -80°C until ready to proceed (do not storage more than 5 days).

3C Enzymatic section

• The volumes below are for two samples and two reactions per sample, four reactions in total.

3C Nuclei Conditioning: 1. Resuspend one reaction of purified crosslinked nuclei in 20pL of DPBS in a tube or a well of a PCR plate and proceed to the next step.

2. Add 24pL of Conditioning Solution, mix gently by pipetting, and incubate at 62°C for 10 min. If using a thermal cycler, set the lid temperature to 85°C.

3. Add 20pL of Stop Solution 2, mix gently by pipetting, and incubate at 37°C for 15 min. If using a thermal cycler, set the lid temperature to 85 °C. igestion and Ligation Reactions: o Note: some of the next steps require addition of several reagents in the same step. These reagents should be combined into master mixes following the master mix tables.

4. Add 28pL of the master mix for restriction enzyme digestion containing the following reagents:

Digestion Master Mix

5. Mix gently by pipetting and incubate as follows: If using a thermal cycler, set the lid temperature to 85°C. Note that there are sequential incubations at different temperatures.

1. 37 °C for 60 min.

2. 65 °C for 20 min.

3. 25 °C for 5 min.

NOTE** To provide flexibility in the workflow, this incubation can be held overnight at 37°C using a thermal cycler or thermomixer with a heated lid to prevent evaporation.

6. Mix gently by inversion, and then immediately transfer 5pL from each reaction and combine them by sample into a new tube labelled “Digestion QC”. Store the Digestion QC sample at -20°C until later use in the following Quality Control section and proceed to the next step with the remaining sample.

7. Add 82pL of the master mix for ligation containing the following reagents:

Ligation Master Mix

8. Mix gently by pipetting and incubate at RT for 15 min. Note: For sorting, after this last step, keep the samples at 4°C overnight if necessary and staining before sorting.

9. Mix gently by inversion, and then immediately transfer 5pL from each reaction and combine them by sample into a new tube labelled “Ligation QC”. Store the Ligation QC sample at -20°C until later use in a following Quality Control section and proceed to the next step with the remaining sample.

10. Combine the liquid from each sample, add 700pL DPBS+1%BSA to bring to total volume to ImL.

11. Centrifuge at 1,000 x g for 10 min at 4°C (in bucket rotor).

12. Remove supernatant and gently resuspend each sample in 200pL DPBS+1%BSA first and then add 800pL DPBS+1%BSA.

13. Add 5pL 1:10 diluted Hoechst 33342.

14. Add IpL of antibody to enhance labeling.

15. Incubate on ice for 5 min.

16. Filter the cells through cell strainer. 17. Add another 500pL DPBS+1%BSA to wash the tube and cell strainer.

18. Take I O.LI L cell suspension to count nuclei in the cell counter.

FACS Sorting

1. Thaw and spin down appropriate 384-well plates, containing digestion buffer.

2. Transfer the sample and plates to FACS core.

3. Sort single nuclei using BD Influx or other sorters

• Special instructions for sorting depend on the type of tissue sorted:

■ 2N gating for Hoechst stain for general nuclei sort,

■ if NeuN 488 stained: NeuN+ col l-22(~90%), NeuN- col 23-24(~10%) of the 384 plates,

■ 1 drop single mode

4. After sorting, spin down the nuclei.

5. Do pK incubation program on PCR machines to lysis nuclei (20 min at 50°C).

6. Store plates in -20°C before library preparation.

Digestion and Ligation QC

1. Thaw the Digestion QC and Ligation QC aliquots.

2. Add 90pL Elution Buffer to each Digestion QC and Ligation QC aliquot, to bring the total volume to 100 L.

3. Add 17.5|iL of a master mix containing the following reagents:

QC Master Mix

4. Add 10pL of Buffer E, mix gently by pipetting, and incubate as follows. If using a thermal cycler, set the lid temperature to 85°C.

1. 55°C for 30 min.

2. 68°C for 90 min.

3. 25°C for 10 min.

4. Step 2: Do not incubate at 68°C for longer than 90 min. unless doing so using a thermal cycler or thermal mixer with a heated lid.

5. Step 3: To provide flexibility, this incubation can also be held overnight at 4°C, in which case, the sample may turn slightly opaque.

6. Buffer E can NOT be added into QC Master Mix in advance.

5. Add 125 pL of DNA Purification Beads, mix thoroughly, and incubate at RT for 5 min.

6. Place sample against magnet, and incubate until solution is clear.

7. Discard supernatant. While sample is still against magnet, add 300pL of 80% ethanol, and incubate at RT for 1 min.

8. Discard supernatant. While sample is still against magnet, add 300pL of 80% ethanol, and incubate at RT for 1 min. 9. Discard supernatant. While sample is still against magnet, incubate beads at RT for 3 - 5 min to airdry the beads.

10. Remove sample from magnet, resuspend beads thoroughly in 10 .L of Elution Buffer, and incubate at RT for 5 min.

11. Place sample against magnet, incubate until solution is clear, and transfer supernatant to a new tube.

12. Analyze the DNA size of the digested and proximally-ligated DNA. Use gel electrophoresis systems or tapestation HS5000. Exemplary results are below.

Bl, Cl is digestion QC; DI, El is ligation QC

Example 12 snmC-seq3 Beckman i7 Protocol

Bisulfite Conversion

1. Prepare the Zymo CT Conversion Reagent.

Prepare 2 bottles for 1 set of plates (8 regular plates) on the Biomek 17, 3 bottles for 2 sets of plates (16 regular plates) on the Biomek i7, or 6 bottles for 1 set ofmCT plates (8 mCT plates). a. Add 7.9 mL Solubilization Buffer and 3 mL Dilution Buffer to each Conversion Reagent bottle via serological pipette. b. Mix for 10 minutes on rollordrum. c. Add 1.6 mL Reaction Buffer to each Conversion Reagent bottle via serological pipette. d. Mix for an additional 5 minutes on rollordrum.

2. Run the method [BiSulf_8Plate_Conversion_full_201023] on the Biomek i7.

The script will add 6 pL Con version Buffer to each well of each sample plate. Manually change the volume as needed (e.g. 25 pL per well for mCT plates).

One rack of 384 x 30 pL tips is needed per 384-well plate undergoing CT conversion reaction.

3. Enter the number of plates to run (up to 8) and select “Perform BS Conversion” and “Add CT Conversion.”

4. Follow guided setup to prepare Biomek i7 deck and allow method to run to completion. Robot will distribute 6 pL CT to each well.

5. Seal, vortex, and quick spin (500 ref) plates.

6. Repeat steps 2-5 as needed.

7. Incubate plates using [DIRECT] method on PCR machines with 384-well plate block. a. 98 °C for 8 minutes b. 64 °C for 3.5 hours c. Hold at 4 °C for up to 20 hours

- I l l - Random Primer Elution Preparation

Complete this step during the [DIRECT] incubation if going directly from Bisulfite Conversion to Bisulfite Cleanup.

1. Thaw the four RP stock plates (one of each quadrant - approximately 30 minutes).

Keep primer stocks and dilution plates at -20 °C when not in use.

2. Run the method [384TP_Stock96toDilution96_300vol] on the Biomek i7.

This method uses one rack of 96 x 200 L tips and four racks of 96 x 30 pL tips. a. This method prepares four 96-well RP dilution plates from four 96-well RP stock plates. b. This method prepares enough diluted primers for 6 sets of 8 plates, using 298.5 pL nuclease-free water and 1.5 pL RP stock solutions.

3. Seal stock plates and return to -20 °C freezer.

4. Seal, vortex, and spin newly made dilution plates, then return plates to deck positions.

5. Run the method [384RP_Dilution96toDeep384] on the Biomek i7.

This method uses four racks of96 x 200 pL tips. a. This method will prepare one 384-deep well RP elution plate from four 96-well RP dilution plates.

6. Enter 1 or 2 to denote the number of sets of plates that need primers.

7. This method transfers either 50 pL (1 set) or 91 pL (2 sets) of random primer dilution into a 384 deep-well plate.

8. After completion of the method, seal and quick spin (500 ref) deep-well plate, dilution plates, and stock primer plates.

9. Store dilution plates and stock primer plates at -20 °C for up to 1 week. Store deep-well plate at ambient temperature if being used the same day.

Bisulfite Cleanup (Biomek i7)

1. Run the method [Bisul_8Plate_Conversion_Full_201023] on the Biomek i7.

Tips: this method uses one rack of 96 x 30 pL tips ( total) plus seven racks of 384 30 pL tips per plate. For 8 plates, 56 racks of 384 x 30 pL tips are needed; for 16 plates, 112 racks of 384 x 30 pL tips are needed.

2. Enter the number of plates and select “Perform Bisulfite Conversion.”

3. Add Magbeads to the plates. a. Manually prepare the Magbead plate. i. Invert Magbead stock tube repeatedly to ensure homogeneity. ii. Pipette 58 pL Magbead stock to each well of a 96-well plate (avoid bubbles and do not spin). Tap plate to remove bubbles. b. Place Magbead plate on plate skirt at position prompted by the method. Robot will distribute 14 pL beads to each well of a clean 384-well plate. c. Tap down 384-well plate and pipette out any bubbles from the bottom of the wells (do not spin). d. Robot will distribute 1.5 L to each well of sample plates. the free DNA to the Magbeads in the plates. a. Replace the used bead tips with clean 384 x 30 uL tips and add binding buffer to the binding buffer reservoir when prompted by the method. Continue the method. b. Once transfer of binding buffer has concluded, start a 5-minute timer. c. When the timer goes off, move the plates to their corresponding 384-well magnet positions. Continue the method.

Note: if running two sets of plates, cover the binding buffer with an optical seal to avoid evaporation and contamination and move to the right side of the deck. If running one set of plates, pour binding buffer back into the bottle and discard reservoir. d. Robot will remove supernatant and discard in the waste trough. h the beads. a. When prompted by the method, replace the used binding buffer tips with clean 384 x 30 pL tips and add wash buffer to the wash buffer reservoir. Continue the method. b. Robot will add 20 pL M-Wash Buffer to all plates and subsequently remove and discard in the waste trough. M-Desulphonation Buffer to the plates. a. When prompted by the method, replace the used wash buffer tips with clean 384 x 30 pL tips and add desulph buffer to the desulph reservoir. Cover the wash reservoir with an optical seal to avoid evaporation and contamination. Continue the method. b. Robot will add 15 pL M-Desulphonation Buffer to all plates. c. Start a 15-minute timer upon addition of desulph buffer to the first plate.

Note: if running two sets of plates, cover the desulph buffer with an optical seal to avoid evaporation and contamination. If running one set of plates, pour desulph buffer back into the bottle and discard reservoir. d. During the 15-minute incubation, empty the waste trough and cover the bottom with DI water. Return it to the robot. e. When the timer goes off, continue the method. Robot will remove the desulphonation buffer and discard in the waste trough. h the beads. a. When prompted by the method, replace the used desulph buffer tips with 384 x 30 pL tips and uncover/replenish the wash buffer in the wash reservoir. Continue the method. b. Robot will add 20 pL M-Wash Buffer to all plates and subsequently remove and discard in the waste trough. c. Repeat steps 7a-b an additional time.

Note: if running two sets of plates, cover the wash buffer with an optical seal to avoid evaporation and contamination after completion of step 7c. If running one set of plates, pour wash buffer back into the bottle and discard reservoir.

8. Let the plates dry a. Once the washes have completed, check plates to see if there is residual wash buffer. If there is a significant amount of buffer, run the Residual Wash step, changing out the wash tips for clean 384 x 30 .L tips. Otherwise continue the method by entering “false”. b. Wait 5 minutes and check the plates again. When most of the wash buffer has evaporated, continue to elution.

9. Elute the DNA from the beads using the RP elution plate a. Replace the tips on the deck with clean 384 x 30 pL tips and place the unsealed random priming elution plate in the appropriate position. b. Robot will distribute 5.5 pL random primer elution buffer to all plates. c. Once the elution is finished adding, set a 5-minute timer, remove the plates from the deck, and seal carefully. d. DO NOT VORTEX; instead, throw the sealed plates onto the bench 10-15 times, until beads appear to be mixed into elution buffer. Repeat for all plates. e. Quick spin plates for 5s at 200xg f. When the timer goes off, unseal the plates and place them back onto their previous positions on the 384-well magnets. Be sure to preserve the original order of plates.

10. Transfer eluted DNA into clean 384-well plates. a. Label a new 384-well plate for each of the original 384-well plates that underwent the bisulfite cleanup. b. Place the new plates onto the appropriate positions on the deck. c. Verify that each bead plate has a corresponding new plate, then continue the method. d. Robot will transfer elution into the clean 384-well plates e. Once transfer of eluted DNA has concluded, check to ensure successful transfer of elution buffer from bead plates to new plates. Once transfer has been confirmed, seal and spin the new plates. Store at -20 °C until needed for next step.

11. If running two sets of plates, repeat steps 1-10 for next set of 8 plates.

Library Preparation

Random Primed DNA Synthesis

1. Run the method [Bisulf_8 to l_Library Prep Only_200615] on the Biomek i7.

Tips: this method uses one rack, of 96 x 200 pL tips (total), one rack of 96 x 30 pL tips ( total), plus two racks of 384 x 30 pL tips per plate. a. Enter the number of plates (up to 8) and sets of plates (up to 2) and select “Perform Library Construction.”

2. Prepare appropriate volume of Random Priming Master Mix (RP MM) in a 50 niL conical tube. Invert gently to mix.

Random Priming Master Mix Per well 8 plates 16 plates

Nuclease-free H2O 3.45 pL 12420 pL 24840 pL

Enzymatics blue buffer ( 10X) 1.025 pL 3690 pL 7380 pL dNTPs (10 mM each) 0.50 pL 1800 pL 3600 pL

Enzymatics Klenow exo- (50 U/pL) 0.025 pL 90 pL 180 pL

3. Prepare Random Priming Master Mix plate a. Pipette 185 pL RP MM to each well of a 96-well plate, seal, and quick spin (500 ref). b. Place unsealed RP MM plate at position prompted by the method. Robot will distribute 45 pL RP MM to each well of a 384 deep-well plate. c. Repeat steps 4a-b if running 16 plates. d. Seal and quick spin (500 ref) plate, then unseal and place on the deck at position prompted by the method.

4. Denature 8 sample plates at 98 °C for 3 minutes using the method [DN] on the PCR machines with the 384-well plate block. Remove plates from PCR machines and immediately place on ice to prevent rehybridization. Proceed once bottom of each plate is cool to the touch.

5. Add Random Priming Master Mix to the sample plates. a. Quick spin the denatured plates and place on appropriate deck positions. b. Robot will distribute 5 pL RP MM to each sample plate. c. Seal, vortex, and quick spin (500 ref) sample plates. Verify that well volumes look even on the last plate.

6. Incubate plates using [RANDOM] method on PCR machines with 384-well plate block. a. 4 °C for 30 minutes b. 25 °C for 5 minutes c. 37 °C for 60 minutes d. Hold at 4 °C

7. Repeat steps 4-6 for second set of plates (if applicable).

Inactivation of free primers <& dNTPs

8. Prepare appropriate volume of Exo/rSAP Master Mix (E/S MM) in a 15 mL conical tube. Gently invert to mix. Exo/SAP Master Mix Per well 8 plates 16 plates

Nuclease-free H2O 1.15 pL 4140 pL 8280 pL

Enzymatics blue buffer (10X) 0.2 pL 720 pL 1480 pL Exonuclease I (20 U/ pL) 0.1 pL 360 pL 720 pL rSAP (1 U/pL) 0.05 pL 180 pL 360 pL

9. Prepare Exo/Sap Master Mix plate a. For 8 plates, pipette 53 pL E/S MM to each well of a 96-well plate. For 16 plates, pipette 105 pL E/S MM to each well of a 96-well plate. b. Place unsealed E/S MM plate at position prompted by the method along with a clean 384- well plate and one rack of 96 x 30 pL tips c. Robot will distribute 13 pL E/S MM to each well of a 384-well plate. d. Seal and quick spin (500 ref) plate, then unseal and place on the deck at position prompted by the method.

10. Add Exo/Sap Master Mix to sample plates a. Robot will distribute 1.5 pL Master Mix to each sample plate. b. Seal, vortex, and quick spin (500 ref) sample plates.

11. Incubate plates using [EXO] method on PCR machines with 384-well plate block. a. 37 °C for 30 minutes b. Hold at 4 °C

12. Repeat steps 10-11 for second set of plates (if applicable).

13. Either continue to reformat and cleanup or store at -20 °C until needed for next step (no longer than overnight).

Reformat and sample cleanups

1. Thaw (if applicable) and quick spin (500 ref) sample plates.

2. To process one set of plates, run the method [ISet Reformat and Cleanups_200616] on the Biomek i7. To process two sets of plates, run the method [2Set_Reformat and Cleanups_200616] on the Biomek i7.

Note: this protocol will describe the process for running two sets of plates.

Tips: to reformat and cleanup two sets of plates, this method requires 42 racks of 96 x 200 u.L tips ( “EtOH tips ”) and 10 racks of 96 x 30 pL tips ( “elution tips ”).

3. Compress 384-well plates (1-8) into four new 96-well plates (1-4). a. Place four new, labeled 96-well plates onto positions prompted by the method, then place the eight 384-well sample plates (1-8) onto positions prompted by the method. b. Robot will use four racks of 200 piL tips to transfer samples from 384-well plates into 96- well plates. c. After the reformat is complete, discard empty tip racks and check to ensure that the volume in the wells of each of the 96-well plates look even. d. Remove the 384-well plates. the free DNA to the Sera-Mag beads in plates 1-4. a. Place four racks of 200 pL tips onto the prompted positions on the deck. b. Thoroughly mix Sera-Mag beads by repeatedly inverting bottle and pour Sera-Mag beads to the brim of a low-profile 96-well reservoir in the position prompted by the method. c. Robot will transfer 73.6 pL beads into sample plates and pipette up and down to mix. d. Move tip racks directly to the left of their corresponding sample plate for later use. e. Pour remaining Sera-Mag beads back into bottle (keeping the reservoir) and discard empty tip racks. press 384-well plates (9-16) into four new 96-well plates (5-8). a. Place four new, labeled (plate numbers, sample type, and date in yymmdd format) 96-well plates onto positions prompted by the method, then place the eight 384-well sample plates (9-16) onto positions prompted by the method. b. Robot will use four racks of 200 pL tips to transfer samples from 384-well plates into 96- well plates. c. After the reformat is complete, discard empty tip racks and check to ensure that the volume in the wells of each of the 96-well plates look even. d. Remove the 384-well plates and replace with 96-well magnets. ove supernatant from plates 1-4 and add beads to plates 5-8. a. Move the four saved tip racks back to their original positions (preserve order to avoid sample contamination). b. Place four new racks of 200 pL tips onto the remaining tip positions. c. Top off bead reservoir with well-mixed Sera-Mag beads. d. Robot will place plates 1-4 onto magnets. c. Robot will add 73.6 pL beads to plates 5-8 and pipette up and down to mix. f. Robot will remove supernatant from plates 1-4 and discard in waste trough. g. Pour remaining Sera-Mag beads back into bottle (again keeping the reservoir) and discard empty tip racks. h beads in plates 1-4 with 80% EtOH. a. Add a high-profile 96-well reservoir to the position prompted by the method and add approximately 200 mL of 80% EtOH. b. Place eight new racks of 200 pL tips onto the tip positions. c. Robot will add 180 pL of 80% EtOH to plates 1-4 and subsequently remove and discard in the waste trough. d. Robot will repeat previous step with the next four tip racks. e. Robot will move plates 1-4 from magnets onto plate skirts. f. Empty the tip waste and liquid waste. Discard empty tip racks.

8. Remove supernatant and add EtOH to plates 5-8. a. Place eight new 200 pL tip racks on the tip positions. b. Pour another 100 mL of 80% EtOH into EtOH reservoir. c. Robot will remove supernatant from plates 5-8. d. Robot will add 180 pL EtOH to plates 5-8. e. Discard empty tip racks, leave full tip racks on deck.

9. Elute DNA from plates 1-4 and perform second EtOH wash on plates 5-8. a. Place four 30 pL tip racks onto the remaining tip positions. b. Add a low-profile 96-well reservoir to the position prompted by the method and add approximately 50 mL elution buffer (EB). c. Check plates 1-4 to ensure no EtOH drops remain and that beads appear to have “cracked,” which indicates that they are sufficiently dry for the elution step. d. Robot will add 10 pL EB to plates 1-4. Set a 5-minute timer upon completion of transfer. e. Remove plates 1-4 and the corresponding magnets from the deck. Seal plates, vortex until beads no longer remain on the sides of the well, and then quick spin to 100 ref to avoid pelleting beads. When 5-minute timer is completed, place plates on the magnets. f. Replace empty 30 pL tip racks with 200 pL tip racks and continue the method. g. Robot will remove EtOH from plates 5-8 and discard in the waste trough. h. Robot will add 180 pL EtOH to plates 5-8, and subsequently remove and discard in the waste trough. i. Robot will move plates 5-8 from magnets to plate skirts. j. Discard empty tip racks.

10. Elute DNA from plates 5-8. a. Place four 30 pL tip racks onto the remaining tip positions. b. Top off EB reservoir (as needed). c. Wait for beads in plates 5-8 to appear cracked, then continue the method. d. Robot will add 10 pL EB to plates 5-8. Start a 5-minute timer upon completion of transfer. e. Remove plates 5-8 and the corresponding magnets from the deck. f. Seal plates, vortex until beads no longer remain on the sides of the well, and then quick spin to 100 ref. g. When 5-minute timer is completed, place plates on the magnets.

11. Compress plates 1-4 into new 96-well plate. a. Cover EtOH reservoir with plate seal and move out of the way to avoid collision during compression. Dump the waste and tip trash. b. Label a clean 96-well plate with “1-8,” sample type, and date and place on plate skirt position prompted by the method. c. Place three 200 L tip racks onto positions prompted by the method. d. Unseal plates 1-4 and place plates (with magnets) onto the positions prompted by the method. e. Robot will transfer eluted sample from plates 1-4 into a new 96-well plate.

Note: this new plate will contain all samples from original 384-well plates 1-8. Each row of the plate will contain a different plate, (i.e., row A contains plate 1, row B contains plate 2, etc.) f. After the reformat is complete, discard empty tip racks and check to ensure that the volume in the wells of each of the 96-well plates look even.

12. Compress plates 5-8 into new 96-well plate. a. Label a new 96-well plate with “9-16,” sample type, and date and place on plate skirt position prompted by the method.

Unseal plates 5-8 and place plates (with magnets) onto the positions prompted by the method. b. Robot will transfer eluted sample from plates 5-8 into a new 96-well plate.

Note: this new plate will contain all samples from original 384-well plates 9-16. Each row of the plate will contain a different plate, (i.e., row A contains plate 9, row B contains plate 10, etc.) c. After the reformat is complete, discard empty tip racks and check to ensure that the volume in the wells of each of the 96-well plates look even. d. Remove empty plates and magnets, except for one magnet at position prompted by the method.

13. Compress two 96-well plates into single new 96-well plate. a. Label two new 96-well plates with “1-16,” sample name, and date place on plate skirts at positions prompted by the method. b. Robot will compress plate containing original plates 1-8 onto the left half of the new 96- well plate, then will compress plate containing original plates 9-16 onto the right half of the new 96-well plate.

Note: final plate configuration will have six wells per plate (i.e., wells Al- A6 contain plate 1, wells B1-B6 contain plate 2, etc. for the rest of the left half of the plate. Wells A7-A12 contain plate 9, wells B7-B12 contain plate 10, etc. for the rest of the right half of the plate. c. Discard empty tip racks.

14. Perform cleanup on compressed 96-well plate. a. Place three 200 |1L tip racks and two 30 j_iL tip racks onto positions prompted by the method. b. Place EtOH reservoir back onto original position, unseal, and pour another 50 mL of 80% EtOH into reservoir. c. Thoroughly mix Sera-Mag beads by repeatedly inverting bottle and pour beads to the brim of the bead reservoir. d. Robot will add 64 L beads to each well of the sample plate. Start a 5-minute timer. e. When 5-minute timer is complete, continue method. Robot will move plate from plate skirt to magnet. Wait until the beads are settled to continue (approximately 3 minutes). f. Robot will remove supernatant from plate and discard in waste trough. g. Robot will perform two 180 pL EtOH washes on plate and discard in waste trough. h. After second EtOH wash is complete, wait until the beads appear visibly “cracked,” which indicates that they are sufficiently dry for the elution step (approximately 10 minutes). i. Top off EB reservoir and continue method. j. Robot will add 10 pL EB to each well of the sample plate. Set a 5-minute timer. Immediately seal plate, vortex until beads no longer cling to sides of wells, then quick spin to 100 ref. k. After 5-minute timer is complete, unseal plate and place back on plate skirt. Continue method. l. Robot will move plate from skirt onto magnet. m. Verify that the beads have settled on the magnet and continue the method. n. Robot will transfer eluted DNA into clean 96-well final plate. o. Check plate to ensure volume of wells appear even. Seal and quick spin (500 ref). p. Remove all items from deck and discard empty tip racks.

Adaptase addition and SCPCR

1. Prepare appropriate volume of Adaptase mix in a 1.5 mL microcentrifuge tube and keep on ice.

Adaptase Mix Per well 8 plates 16 plates

Elution Buffer (EB) 4.45 pL 239.2 pL 478.2 pL

Buffer G1 2.00 pL 112.5 pL 225.0 pL

Reagent G2 2.00 pL 112.5 pL 225.0 pL

Reagent G3 1.25 pL 70.3 pL 140.6 pL

Enzyme G4 0.50 pL 28.13 pL 56.26 pL

Enzyme G5 0.50 pL 28.13 pL 56.26 pL

2. Run the method [PCR Setup and Cleanup_384primer_200825] on the Biomek i7.

Tips: to add Adaptase mix, KAPA, and PCR primers to sample plate, this method requires one rack of 96 x 200 uL tips per sample plate and two racks of 96 x 30 LIL tips per sample plate.

Note: this protocol will describe the process for running one full 96-well plate.

3. Enter the number of plates to run (1 or 2), select “Pause to Place Index Lab ware on Deck,” select “Consolidated PCR plate contains 2 sets of 8 x 384 well plates” (if true), and enter the quadrant of the PCR primer plate to be used.

4. Denature the 96-well plate at 98 °C for 3 minutes using the method [DN] on a thermocycler. Immediately place on ice to prevent rehybridization. Plate is ready once bottom of plate is cool to the touch.

5. While denatured plate is cooling, pipette appropriate volume of Adaptase mix into a 96-well plate: a. 1 set (8 plates) - 35 pL to first 2 columns b. 2 sets (16 plates) - 46.5 pL to first 3 columns

6. Place cooled sample plate and Adaptase plate onto plate skirts on positions indicated by the method. Place tip racks onto positions indicated by the method.

7. Robot will transfer 10.5 pL Adaptase mix to sample plate.

8. Seal, vortex, and quick spin (500 ref) sample plate.

9. Incubate plate using [TAG] method on PCR machines with 96-well plate block. a. 37 °C for 30 minutes b. 95 °C for 2 minutes c. Hold at 4 °C

10. Pipette appropriate volume of KAPA to a 96-well plate and place on deck. a. 1 set (8 plates) - 80 pL to first 2 columns b. 2 sets (16 plates) - 110 pL to first 3 columns

11. Robot will transfer 25 pL KAPA and 5 pL PCR primers to sample plate.

12. Seal, vortex, and quick spin (500 ref) sample plate.

13. Incubate plate using [SCPCR] method on thermocycler: a. 95 °C for 2 minutes b. 98 °C for 30 seconds c. 98 °C for 15 seconds d. 64 °C for 30 seconds e. 72 °C for 2 minutes f. Repeat steps c through e for a total of 15 cycles g. 72 °C for 5 minutes h. Hold at 4 °C

Final Cleanup

Automated portion affinal cleanup 1. Run the method [FinalPlate BeadCleanup] on the Biomek i7.

Tips: this method requires three 96 x 200 uL tip racks and one 96 x 30 uL tip rack per sample plate.

2. Place three 200 pL tip racks and two 30 pL tip racks onto positions prompted by the method.

3. Place two low-profile 96-well reservoirs and two high-profile 96-well reservoirs onto the deck in prompted positions.

4. Thoroughly mix Sera-Mag beads by repeatedly inverting bottle and pour beads to the brim of the bead reservoir.

5. Robot will add 40 pL beads to the sample plate and mix by pipetting. Upon addition of beads, start a 5 -minute timer.

6. When 5-minute timer is complete, continue method. After robot moves plate from plate skirt to magnet, wait until the beads are settled to continue (approximately 3 minutes).

7. Robot will remove supernatant from plate.

8. Robot will perform two 180 pL EtOH washes on plate.

9. After second EtOH wash is complete and plate has been moved to plate skirt, wait until the beads appear visibly “cracked,” which indicates that they are sufficiently dry for the elution step (approximately 10-15 minutes).

10. Add Elution Buffer to EB reservoir and continue method.

1 1 . Robot will add 20 pL EB to each well of the plate. Start a 5-minute timer. Immediately seal plate, vortex until beads no longer cling to sides of wells, then quick spin to 100 ref.

12. Press OK to end method. Remove all items from deck and discard empty tip racks.

13. After 5-minute timer is complete, place plate onto magnet and unseal.

Manual portion of final cleanup

1. Using a 200 pL 8-channel pipette, compress wells such that samples from each original 384-well plate are contained in a single well. a. Sample from A1-A6 should end up in A6, sample from B1-B6 should end up in B6, etc.

2. Using a P-200 pipette, transfer sample from each well into an individually labeled, 1.5 mL microcentrifuge tube.

3. Add 96 pL Sera-Mag beads to each microcentrifuge tube. Set a 5-minute timer, then vortex and quick spin all tubes.

4. After the 5-minute timer has completed, place each tube onto the DynaMag tube magnet. Allow beads to settle (approximately 3 minutes).

5. Remove and discard supernatant, careful to not disturb the beads.

6. Wash beads with 300 pL EtOH. Remove and discard EtOH.

7. Repeat step 6.

8. Using a P-10 pipette, remove any residual EtOH at the bottom of the tube and discard. 9. Remove tubes from DynaMag tube magnet and allow to dry with lid open until beads are visibly “cracked.”

10. Add 20 pL EB to each tube. Set a 5-minute timer, then vortex and spin all tubes.

11. After 5-minute timer has completed, place each tube onto the DynaMag tube magnet.

12. Transfer 20 pL from each sample tube into a new clean, labeled, 2 mL microcentrifuge tube. Try not to transfer any beads.

Note: It helps to not push the tubes all the way down on the magnet. Slide them in about halfway so the bead pellet stays near the liquid.

13. Go on to DNA quantification and sample pooling.

DNA quantification and sample pooling

Qubit reagent Per sample Volume for 16 x 384-plates

Qubit dsDNA Broad Range Buffer 199 pL 4975 pL

Qubit dsDNA Broad Range Dye 1 pL 25 pL

1. To quantify the DNA in each sample tube, prepare an appropriate volume of Qubit reagent in a 15 mL microcentrifuge tube.

Note: always make enough Qubit buffer for 5-10 extra samples, to ensure that pools can be quantified and that samples can be re-checked, as needed.

1. Label one 0.5 mL Qubit assay tube per sample, and one Qubit assay tube per pool to be created. Label two additional 0.5 mL tubes with “SI” and “S2” for the standards.

3. Transfer 190 pL Qubit reagent to each of the standard tubes, and 199 pL to each of the sample/pool tubes.

4. Transfer 10 pL Standard 1 into tube “SI” and pipette to mix. Transfer 10 pL Standard 2 into tube “S2” and vortex to mix.

5. Transfer 1 pL sample into labeled sample tube and vortex to mix. Repeat for all samples.

6. Follow instructions on Qubit for Broad Range dsDNA quantification of all samples, starting with reading the standards.

7. Create sequencing pool by adding normalized amounts of each tube.

8. Transfer 1 pL of pooled sample(s) into its own labeled Qubit tube and vortex to mix.

9. Follow instructions on Qubit to check the concentration of the pooled sample. Pool is now ready for sequencing.

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42. Liu ct al., Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat. Genet. 51, 237-244 (2019).

43. S. N. Sansom, F. J. Livesey, Gradients in the brain: the control of the development of form and function in the cerebral cortex. Cold Spring Harb. Perspect. Biol. 1, a002519 (2009).

44. Hawrylycz et al., An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 489, 391-399 (2012).

45. Yao et al., A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex. Nature. 598, 103-110 (2021).

46. Krienen et al., Innovations present in the primate interneuron repertoire. Nature. 586, 262-269 (2020).

47. Yao et al., A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation. Cell. 184, 3222-324 Le26 (2021).

48. Tasic et al., Shared and distinct transcriptomic cell types across neocortical areas. Nature. 563, 72-78 (2018).

49. Chen et al., Single-cell trajectories reconstruction, exploration and mapping of omics data with STREAM. Nature Communications. 10 (2019), , doi: 10.1038/s41467-019-09670-4. 50. J. Feng, W.-H. Hsu, D. Patterson, C.-S. Tseng, H.-W. Hsing, Z.-H. Zhuang, Y.-T. Huang, A. Facdo, J. L. Rubenstein, J. Touboul, S.-J. Chou, COUP-TFI specifies the medial entorhinal cortex identity and induces differential cell adhesion to determine the integrity of its boundary with neocortex. Sci Adv. 7 (2021), doi: 10.1126/sciadv.abf6808.

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In view of the many possible embodiments to which the principles of the disclosed invention may be applied, it should be recognized that the illustrated embodiments are only examples of the invention and should not be taken as limiting the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

We claim:

1. A method for identifying a brain cell in a biological sample obtained from a subject, comprising: treating genomic DNA of the biological sample with bisulfite to convert unmethylated cytosines of

CpG dinucleotides to uracil; measuring methylation status of at least 10, at least 20, at least 30, or at least 50 different methylation markers in the genomic DNA of the biological sample; and identifying a brain cell in the biological sample based on the measured methylation status of the at least 30 different methylation markers.

2. The method of claim 1, wherein identifying the brain cell comprises applying a statistical prediction algorithm to the measured methylation status of the different methylation markers.

3. The method of claim 2, wherein applying the statistical prediction algorithm comprises (a) obtaining a linear combination of the methylation marker status of the different methylation markers, and (b) applying a transformation to the linear combination to identify the brain cell in the biological sample.

4. The method of any one of claims 1 to 3, wherein identifying the brain cell in the biological sample comprises determining the type of brain cell, such as determining that the brain cell is a type or subtype listed in Table 3, such as a ASC, Amy-Exc, CAI, HIP-Misc2, CA3, CB, Chd7, DG, Foxp2, HIP-Miscl, L2/3-IT, L4-IT, L5/6-NP, L5-ET, L5-IT, L6-CT, L6-IT, L6-IT-Car3, L6b, Lamp5, Lamp5-Lhx6, MGC, MSN-D1, MSN-D2, ODC, OPC, PKJ, PN, Pvalb, Pvalb-ChC, Sncg, Sst, SubCtx-Cplx. THM-Exc, THM- Inh, THM-MB, VLMC, or Vip brain cell.

5. The method of any one of claims 1 to 4, wherein the biological sample is a blood, urine, feces, saliva, or a brain tissue sample.

6. The method of any one of claims 1 to 5, wherein the subject is a human.

7. The method of any one of claims 1 to 6, wherein the different methylation markers comprise the markers in Table 1, Table 2, or FIGS. 25A-25B.

8. The method of any one of claims 1 to 7, wherein the different methylation markers comprise or consist of a. chrl_6954346, chrl_15765576, chrl_l 6921554, chrl_17535924, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_47930687, chrl_55154499, chrl_82344735, chrl_84779343, chrl_88186554, chrl_89387906, chrl_l 14587732, chrl_213899571, chrl_223535050, chrl0_12981474, chrl0_85659210, chrl0_120517367, chrlO_129558734, chrll_6333181, chrll_15508856, chrll_61601245, chrll_64638208, chrll_64638406, chrll_64638423, chrl 1_64638446, chrl 1_64638487, chrl l_70828694, chrll_70828959, chrl 1_113951238, chrl 1_114069492, chrl2_l 04666538, chrl2_l 11199420, chrl2_l 11363167, chrl3_44573330, chrl3_78061219, chrl4_91028417, chrl4_99239938, chrl4_99240729, chrl4_99254307, chrl4_99258195, chrl4_99265134, chrl5_40579060, chrl5_60850769, chrl5_73787074, chrl5_75706213, chrl6_29674272, chrl6_71746304, chrl7_2019280, chrl7_17603475, chrl7_49578654, chrl7_78458835, chrl 7_81839462, chrl8_42840569, chrl8_55863146, chrl8_55863406, chrl9_8180812, chrl9_13002909, chrl9_31596154, chrl9_33408728, chr2_520529, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_88493781, chr2_106974041, chr2_144508216, chr2_144509942, chr2_159230649, chr2_192676064, chr2_199449983, chr2_214915957, chr2_224976082, chr2_227315087, chr2_234438297, chr20_23049529, chr20_40692864, chr20_52979500, chr20_55284577, chr20_57730506, chr21_21578917, chr21_26832851, chr21_29221598, chr21_29917226, chr21_43913788, chr21_44074575, chr21_45115350, chr22_24425165, chr22_24425431, chr22_24425509, chr22_24426997, chr22_24427299, chr22_24428719, chr22_24434476, chr22_24435262, chr22_24436142, chr22_24438986, chr22_24439355, chr22_24440428, chr22_24441113, chr22_29184668, chr22_36763396, chr22_36763700, chr22_49391984, chr3_l 0546931 , chr3_23272516, chr3_411 17522, chr3_53425664, chr3_81591988, chr3_ 113902470, chr3_l 42925609, chr3_143082577, chr3_l 81704950, chr3_181715790, chr3_181724236, chr3_181724559, chr4_3374241, chr4_3374306, chr4_3374416, chr4_3377079, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385479, chr4_3385492, chr4_3385938, chr4_3389755, chr4_3389767, chr4_3393330, chr4_3393693, chr4_3410433, chr4_3411467, chr4_7766077, chr4_54226502, chr4_54226613, chr4_54236780, chr5_6810073, chr5_10524872, chr5_43282460, chr5_60340044, chr5_65126330, chr5_l 13040537, chr5_l 15106946, chr5_127066418, chr5_150680117, chr5_167983052, chr5_172860953, chr5_175441994, chr5_l 75442086, chr5_175442710, chr5_178604407, chr5_180155581, chr6_36775571, chr6_60830914, chr6_87948947, chr6_96873290, chr6_105628390, chr6_l 50204270, chr6_150893713, chr6_158528243, chr6_ 169961951, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1674842, chr7_1675096, chr7_1677614, chr7_1680106, chr7_2108124, chr7_17586547, chr7_45198338, chr7_94840949, chr7_101915316, chr7_157585009, chr7_157897945, chr7_157897966, chr7_157897972, chr7_159142397, chr7_159231136, chr8_52246671, chr8_57356053, chr8_63031540, chr8_80345362, chr8_84031486, chr8_87977499, chr8_l 18694978, chr8_141800688, chr9_35350760, chr9_73879045, chr9_79193716, chr9_93156181, chr9_l 14250469, chr9_l 14250578, chr9_122212102, chr9_130919223, chr9_134351726, chr9_l 34420684, b. chrl0_35445343, chrl2_l 17087703, chrl5_101709645, chrl7_39612776, chrl_30127036, chrl4_58598194, chrl_25968447, chrl8_55401769, chrl0_30583971, chrl 1_41004020, chrll_61298863, chrl2_l 32525847, chrl7_75231867, chr9_l 22207624, chrl0_l 12991920, chrl0_26124733, chr!3_l 13337880, chrl3_44573331, chrl6_89747288, chrl7_49578655, chr!9_53976302, chr 10_l 12219535, chrll_99359784, chrl6_52967325, chr4_3374470, chr22_49391985, chr4_38356557, chr5_175435725, chrl_209331007, and chr2_73008588, c. chrl_6954205, chrl_6954346, chrl_15437470, chrl_15765576, chrl_16921554, chrl_17535615, chrl_17535924, chrl_20748527, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_47930687, chrl_55154474, chrl_55154499, chrl_82344735, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_l 14587732, chrl_l 14587798, chrl_200664873, chrl_213899571, chrl_223535050, chrl0_12981474, chrl0_85659210, chrl0_85659210, chrl0_96825742, chrl0_120517367, chrl0_120517552, chrl0_129558734, chrl 1_6333181, chrll_15508856, chrl l_30683884, chrll_61601245, chrll_64638030, chrll_64638061, chrl l_64638130, chrll_64638134, chrl l_64638208, chrll_64638406, chrll_64638423, chrll_64638446, chrl 1_64638476, chrll_64638487, chrl 1_66652738, chrl l_70828694, chrll_70828726, chrll_70828942, chrl l_70828959, chrl 1_113951190, chrl 1_113951238, chrl 1_114069492, chrl 1_114069680, chrl 1_118210650, chrl2_104666490, chrl2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl2_l 11363249, chrl3_44573330, chrl3_78061219, chrl3_92046041, chr 13_93413326, chrl4_28309117, chrl4_32587882, chrl4_91028417, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99265134, chrl5_39667040, chrl5_40579060, chr15_60850769, chrl 5_73787063, chr!5_73787074, chrl5_75706205, chr!5_75706213, chr! 6_29674272, chrl6_29674291, chrl6_71746300, chrl6_71746304, chrl6_79856776, chrl7_2019254, chr 17_2019280, chrl7_17603475, chrl7_17603475, chrl7_49578654, chrl7_49580573, chrl7_58691449, chrl7_78458835, chrl7_78458957, chrl7_81839462, chrl7_81839517, chrl8_31612779, chrl8_42840523, chrl8_42840569, chrl8_55863146, chrl8_55863209, chrl8_55863341, chrl8_55863406, chrl9_8180812, chrl9_13002733, chrl9_l 3002909, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_33408728, chrl9_33408838, chrl9_39052997, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_4416732, chr2_8535196, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_73008587, chr2_88493781, chr2_ 106974041, chr2_l 15082751, chr2_120543523, chr2_l 44507406, chr2_144508216, chr2_144509942, chr2_144512702, chr2_159230649, chr2_180445347, chr2_l 92676064, chr2_199449983, chr2_199450146, chr2_203121062, chr2_214915957, chr2_216827945, chr2_224976082, chr2_227315087, chr2_227315087, chr2_234438247, chr2_234438297, chr20_l 837975, chr20_23049529, chr20_23049808, chr20_40692708, chr20_40692864, chr20_43564715, chr20_49882081, chr20_52979500, chr20_52979806, chr20_53032932, chr20_55284577, chr20_57730506, chr20_57730576, chr21_21578917, chr21_26832783, chr21_26832851, chr21_29221598, chr21_29221717, chr21_29917226, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr22_24425152, chr22_24425165, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425710, chr22_24425816, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24428701, chr22_24428719, chr22_24434350, chr22_24434476, chr22_24435262, chr22_24436130, chr22_24436142, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_49391984, chr3_10546902, chr3_10546931, chr3_23272516, chr3_41117522, chr3_53425664, chr3_73746874, chr3_81591988, chr3_81591988, chr3_l 12000443, chr3_l 13902470, chr3_142925609, chr3_143082577, chr3_143082617, chr3_179616279, chr3_181704894, chr3_l 81704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_181724459, chr3_181724559, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_9109274, chr4_l 1187567, chr4_l 5944086, chr4_36635749, chr4_38356556, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_87865311, chr5_6810030, chr5_6810073, chr5_10524764, chr5_10524872, chr5_43282446, chr5_43282460, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_95429494, chr5_ 113040537, chr5_l 15106946, chr5_l 27066418, chr5_150680117, chr5_167983052, chr5_l 72860804, chr5_172860953, chr5_ 175441994, chr5_175442040, chr5_175442086, chr5_175442387, chr5_l 75442710, chr5_175442710, chr5_178604407, chr5_180155459, chr5_180155581, chr6_33906454, chr6_36775571, chr6_40888325, chr6_60830914, chr6_87948947, chr6_96873290, chr6_ 105628390, chr6_l 10018487, chr6_120951342, chr6_121099723, chr6_137290533, chr6_l 39254024, chr6_150204270, chr6_l 50204473, chr6_150893713, chr6_158528243, chr6_ 169961951, chr7_1231081, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_1675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_l 7586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_88282441, chr7_94840949, chr7_101915316, chr7_101915318, chr7_l 02107431, chr7_l 38971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_159142397, chr7_159231136, chr8_10296807, chr8_52246671, chr8_52252719, chr8_57356053, chr8_63031540, chr8_80345362, chr8_84031486, chr8_87977499, chr8_l 18694978, chr8_l 18694978, chr8_140729234, chr8_141800485, chr8_141800688, chr8_l 44241354, chr9_35350760, chr9_73879045, chr9_79193652, chr9_79193716, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181, chr9_l 14250397, chr9_l 14250449, chr9_ 114250469, chr9_l 14250578, chr9_121830266, chr9_122212102, chr9_122224319, chr9_130919131, chr9_130919223, chr9_134351622, chr9_134351726, chr9_l 34420593, chr9_134420684, d. chrl_6954205, chrl_6954346, chrl_7048907, chrl_l 5437470, chrl_15765576, chrl_16921554, chrl_17411021, chrl_17535615, chrl_17535924, chrl_20748527, chrl_25729798, chrl_27249955, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_38418368, chrl_43465467, chrl_43465657, chrl_45049761, chrl_47930687, chrl_50837887, chrl_55154474, chrl_55154499, chrl_82344735, chrl_83627211, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_107575614, chrl_l 14587732, chrl_l 14587798, chrl_155009422, chrl_174451522, chr 1.174451522, chrl.197451335, chrl_200664873, chrl_207434747, chr 1.210626571, chrl.213899571, chrl.219915507, chrl.223535050, chrl_241329400, chrl.244054001, chrl_244054019, chrl.244054025, chrl.244054088, chrl_244054213, chrl_244054334, chrl_244054412, chrl_244054487, chrl0_387726, chrlO.1550998, chrl0_1599134, chrl0_l 599460, chrl0_1610306, chrl0_1626613, chrl0_1679796, chrlO.1680989, chrl0_1682975, chrl0_1713526, chrl0_1721323, chrl0_1723256, chrl0_1723398, chrlO.1724564, chrl0_1726470, chrl0_1975272, chrl0_3927130, chrl0_12981474, chrl0_33204102, chrlO.34752396, chrl0_44279927, chrl0_44280044, chrl0_59279057, chrl0_59279103, chrl0_71529729, chrlO.80094872, chrl0_85659210, chrl0_85659210, chrl0_87727342, chrl0_91397464, chr 10.92661601, chrlO.96825742, chrl0_107085835, chrl0_120517367, chrl0_120517552, chrl0_124961029, chrlO.129558734, chrl 1.6333181, chrll_10175924, chrll_15508856, chrll_16344746, chrl 1.28779431, chrl 1.30683884, chrl l_31820115, chrl 1.31820310, chrll_46385139, chrll_46398710, chrl l_46441679, chrl 1.61601245, chrl l_64070739, chrl 1.64635621, chrll_64638030, chrl 1.64638061, chrl l_64638130, chrl 1.64638134, chrl l_64638208, chrl l_64638406, chrll_64638423, chrll_64638446, chrl 1_64638476, chrl 1J54638487, chrl l_66652726, chrl l_66652738, chrll_70828694, chrll_70828726, chrl l_70828942, chrl l_70828959, chrl l_75832244, chrl l_94158916, chrl 1_112260989, chrl 1_113363879, chrl 1_113400998, chrl 1_113408265, chrl 1_113433434, chrl 1_113433544, chrl 1_113444137, chr! 1_1 13445794, chr! 1.1 13460726, chr! 1_1 13468577, chrl 1_113468826, chrl 1_1 13469191, chrl 1_113469614, chrl 1.113470470, chrll.l 13951190, chrll.113951238, chrl 1.114062290, chrl 1.114062488, chrl 1.114064208, chr 11.114064532, chrl 1.114066467, chrl 1.114067705, chrl 1.114069492, chrl 1.114069680, chrl 1.117914441, chrl 1.118210650, chrl 1.123025323, chrl 1.127690394, chrl 1.127690429, chrll.131233613, chrl2_2081518, chrl2_2842964, chrl2_30766914, chr 12.47947292, chrl2_53274354, chrl2_53274417, chrl2_70443965, chrl2_77308440, chrl2_88450938, chrl2_88451104, chr 12.92221841, chrl2_93894714, chr 12.93894790, chrl2_94695777, chrl2_95356097, chrl2_98459151, chrl2_104666490, chrl2_104666538, chr 12.111199420, chrl2_l 11363167, chrl2_l 11363249, chrl2_l 19340812, chrl2_121507866, chrl2_122161069, chrl2_122228141, chrl2_127115077, chrl2_129703529, chrl3_27238208, chrl3_27517013, chrl3_35695164, chrl3_41465311, chrl3_44573330, chrl3_73025821, chrl3_73026371, chrl3_78061219, chr 13.92046041, chrl 3.93413326, chrl3_98404428, chrl3_103071728, chrl 3.103801301, chrl3_l 06713795, chrl4_28309117, chrl4_32587882, chrl4_36524389, chrl4_36524667, chrl4_62814638, chrl4_72746337, chrl4_72746410, chrl4_91028417, chrl4_99239873, chrl4_99239938, chr 14.99240690, chrl4_99240729, chrl4_99244159, chrl4_99244383, chrl4_99245037, chrl4_99245125, chrl4_99253114, chrl4_99254307, chr 14.99258195, chrl4_99259778, chr 14.99259851, chr 14.99261299, chrl4_99261349, chrl4_99265134, chrl4_99265442, chrl4_104963567, chrl5_27014884, chrl5_39667040, chrl5_40579060, chrl5_60850769, chrl5_61832637, chrl5_64673973, chrl5_70265944, chrl5_70867831, chrl5_73421182, chrl5_73787063, chrl5_73787074, chrl5_75706205, chrl5_75706213, chr!5_84784380, chrl5_98347522, chrl6_3255898, chrl6_3473308, chrl6_21514377, chr 16.21514493, chr!6_29674272, chrl6_29674291, chrl6_49521066, chrl6_71746300, chr 16.71746304, chr 16.73092631, chrl6_79856776, chrl6_84090291, chrl6_85290977, chrl6_86757258, chrl6_87957932, chrl6_89747287, chrl7_2019254, chrl7_2019280, chrl7_6264478, chrl7_8310790, chrl7_17603475, chrl7_17603475, chrl7_19539205, chrl7_19539300, chrl7_29056566, chrl7_29093998, chrl7_31593826, chrl7_32274223, chrl7_49578654, chrl7_49580573, chrl7_51374368, chrl7_58691449, chrl7_62458778, chrl7_68274037, chrl7_74762858, chrl7_75231866, chrl7_75231876, chrl7_78458835, chrl7_78458957, chrl7_79140535, chrl7_81246152, chrl7_81839462, chrl7_81839517, chrl8_7466797, chrl8_7671182, chrl8_22191374, chrl8_24273998, chrl8_28743520, chrl8_31612779, chrl8_31668044, chrl8_31668223, chrl8_42840523, chrl8_42840569, chrl8_48111878, chrl8_55316591, chrl8_55335150, chrl8_55337856, chrl8_55337859, chrl8_55347406, chrl8_55347692, chrl8_55401620, chrl8_55401726, chrl8_55401962, chrl8_55401962, chrl8_55402070, chrl8_55863146, chrl8_55863209, chrl8_55863341, chrl8_55863406, chrl8_58846286, chr!8_75629703, chrl9_940774, chr!9_940858, chrl9_941208, chr!9_941242, chrl9_941271, chr!9_941471, chrl9_4020451, chrl9_8066130, chrl9_8180812, chrl9_l 1943461, chrl9_l 1943461, chrl9_l 002733, chrl9_13002909, chrl9_13027645, chrl9_13027708, chrl9_29879973, chrl9_30071371, chrl9_30071556, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_32327361, chrl9_33408728, chrl9_33408838, chrl9_35046673, chrl9_39052997, chrl9_53965120, chrl9_53965266, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_1939158, chr2_4416732, chr2_6286826, chr2_8535196, chr2_8811580, chr2_22449630, chr2_27738485, chr2_27738489, chr2_27738545, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_60479437, chr2_73008587, chr2_79929386, chr2_85447333, chr2_88493781, chr2_96895479, chr2_99699856, chr2_100923151, chr2_ 106974041, chr2_l 15082751, chr2_120543523, chr2_127840596, chr2_144507406, chr2_l 44508216, chr2_144509942, chr2_144512702, chr2_148147429, chr2_159230649, chr2_169415560, chr2_l 80445347, chr2_184141131, chr2_192676064, chr2_198316634, chr2_199447280, chr2_ 199449983, chr2_l 99450146, chr2_201872813, chr2_203121062, chr2_211590141, chr2_211590198, chr2_212520797, chr2_212524214, chr2_214915957, chr2_216827945, chr2_219281611, chr2_219888095, chr2_222470101, chr2_224976082, chr2_227315087, chr2_227315087, chr2_231390519, chr2_232574302, chr2_234438247, chr2_234438297, chr2_236121881, chr20_1400335, chr20_1837975, chr20_5670261, chr20_23049529, chr20_23049808, chr20_34196362, chr20_40692708, chr20_40692864, chr20_43423564, chr20_43564715, chr20_49882081, chr20_52979500, chr20_52979806, chr20_53032932, chr20_54696328, chr20_55284577, chr20_57730506, chr20_57730576, chr20_60889288, chr20_62225257, chr21_21578917, chr21_26832783, chr21_26832851, chr21_28103489, chr21_28103489, chr21_29221598, chr21_29221717, chr21_29917226, chr21_37606568, chr21_40771526, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr21_46510096, chr22_24425152, chr22_24425165, chr22_24425229, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425705, chr22_24425710, chr22_24425754, chr22_24425816, chr22_24425972, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24427448, chr22_24428701, chr22_24428719, chr22_24433075, chr22_24433241, chr22_24433423, chr22_24434088, chr22_24434350, chr22_24434476, chr22_24434989, chr22_24435262, chr22_24436014, chr22_24436130, chr22_24436142, chr22_24437360, chr22_24437763, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24440446, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_29185058, chr22_30737962, chr22_34617159, chr22_34617213, chr22_35114720, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_44940707, chr22_46346927, chr22_48824678, chr22_49391984, chr22_50658490, chr3_8595802, chr3_8596019, chr3_10546902, chr3_10546931, chr3_13191245, chr3_15391356, chr3_22857045, chr3_23272516, chr3_30391151, chr3_32506316, chr3_41117522, chr3_46301401, chr3_53425664, chr3_59955536, chr3_70568431, chr3_73746874, chr3_76628994, chr3_81591988, chr3_81591988, chr3_99932654, chr3_105471988, chr3_l 12000443, chr3_112508351, chr3_l 13651082, chr3_l 13902470, chr3_ 122908926, chr3_142925609, chr3_l 43082577, chr3_143082617, chr3_150033642, chr3_154551207, chr3_164753486, chr3_171894906, chr3_l 79540277, chr3_179616279, chr3_181704894, chr3_181704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_181724459, chr3_181724559, chr4_578126, chr4_667460, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_8576626, chr4_8868232, chr4_9109274, chr4_l 1 187567, chr4_l 3785708, chr4_l 5944086, chr4_25237957, chr4_30170558, chr4_36635749, chr4_38356556, chr4_39815565, chr4_52055928, chr4_53508148, chr4_53840582, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_77897059, chr4_77897104, chr4_87411016, chr4_87865311, chr4_89379269, chr4_152888059, chr5_1554827, chr5_6810030, chr5_6810073, chr5_10524764, chr5_l 0524872, chr5_30772245, chr5_38403906, chr5_43282446, chr5_43282460, chr5_50998048, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_78701917, chr5_89120992, chr5_95429494, chr5_l 00877542, chr5_107099103, chr5_ 113040537, chr5_l 15106946, chr5_127066418, chr5_140543089, chr5_145529393, chr5_150680117, chr5_151512421, chr5_151512485, chr5_151520158, chr5_167983052, chr5_172860804, chr5_172860953, chr5_l 75033106, chr5_175441994, chr5_175442040, chr5_175442086, chr5_175442387, chr5_175442710, chr5_l 75442710, chr5_175692802, chr5_175692868, chr5_ 178604407, chr5_180155459, chr5_180155581, chr6_3482654, chr6_33906454, chr6_34036167, chr6_36775571, chr6_40888325, chr6_60830914, chr6_87948947, chr6_91513599, chr6_96873290, chr6_105628390, chr6_l 08804924, chr6_109824080, chr6_l 09977550, chr6_109977690, chr6_109981771, chr6_109981907, chr6_l 10018487, chr6_l 10439611, chr6_l 17562504, chr6_l 18577805, chr6_120951342, chr6_121099723, chr6_136924776, chr6_136943473, chr6_137290533, chr6_139254024, chr6_150204270, chr6_150204473, chr6_150893713, chr6_155123808, chr6_l 58528243, chr6_162547293, chr6_168301762, chr6_ 169961951, chr7_1231081, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1672933, chr7_1673021, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_1675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_6988371, chr7_6988400, chr7_7273541, chr7_8976868, chr7_l 7586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_54795471, chr7_71592009, chr7_80057215, chr7_88282441, chr7_93580834, chr7_94840949, chr7_101915316, chr7_101915318, chr7_102107431, chr7_135147918, chr7_138971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_159142397, chr7_159231032, chr7_159231136, chr8_10296807, chr8_13310666, chr8_27662591, chr8_29052797, chr8_41246826, chr8_52246671, chr8_52252719, chr8_52485371, chr8_56439745, chr8_56441389, chr8_56444235, chr8_57356053, chr8_58117688, chr8_58768196, chr8_58986453, chr8_63031540, chr8_64773383, chr8_80345362, chr8_84031486, chr8_87977499, chr8_97191731, chr8_102754235, chr8_l 17042553, chr8_l 18694978, chr8_l 18694978, chr8_122825356, chr8_129464046, chr8_140608236, chr8_140729234, chr8_141800471, chr8_141800485, chr8_141800688, chr8_143213111, chr8_144241354, chr9_29444070, chr9_29444070, chr9_35350760, chr9_42278765, chr9_73879045, chr9_75657076, chr9_79190169, chr9_79193652, chr9_79193716, chr9_81702877, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181, chr9_109388040, chr9_109719145, chr9_l 11786816, chr9_l 14250397, chr9_l 14250449, chr9_l 14250469, chr9_ 114250578, chr9 119121913, chr9_120498228, chr9_121830266, chr9_122212102, chr9_122224319, chr9_127496263, chr9_130919131, chr9_130919223, chr9_134351622, chr9_134351726, chr9_l 34420593, chr9_134420684, chr9_l 36323313, or e. chrl_967238, chrl_3504172, chrl_6954205, chrl_6954346, chrl_7048907, chrl_8094575, chrl_9182245, chrl_9529013, chrl_9826671, chrl_10969247, chrl_12306466, chrl_15437470, chrl_15629316, chrl_15765576, chrl_16921554, chrl_l 7411021, chrl_17535615, chrl_17535924, chrl_19706305, chrl_20369180, chrl_20748527, chrl_21413174, chrl_23309318, chrl_25729798, chrl_25968446, chrl_27249955, chrl_28675626, chrl_28866361, chrl_30120569, chrl_30127035, chrl_30830766, chrl_30830843, chrl_36226553, chrl_36953252, chrl_38114428, chrl_38114479, chrl_38418368, chrl_39994748, chrl_41767337, chrl_43465467, chrl_43465657, chrl_45049761, chrl_47930687, chrl_50837887, chrl_55154474, chrl_55154499, chrl_58551063, chrl_58786705, chrl_61973801, chrl_66250918, chrl_66534669, chrl_82344735, chrl_83627211, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_91197452, chrl_99844148, chrl_99920443, chrl_107575614, chrl_109323018, chrl_109687772, chrl_109931193, chrl_l 10508162, chrl_l 14587732, chrl l 14587798, chrl_l 18257426, chrl_155009422, chrl_156440052, chrl_161837399, chrl_166161182, chrl_174451522, chrl_174451522, chrl_191351740, chrl_192538779, chrl_197451335, chrl_200664873, chrl_203109470, chrl_207434747, chrl_210626571, chrl_213899571, chrl_219915507, chrl_223535050, chrl_224770412, chrl_226712592, chrl_232767359, chrl_234145180, chrl_237556460, chrl_241329400, chrl_242442381, chrl_242442419, chrl_242442709, chrl_244054001, chrl_244054019, chrl_244054025, chrl_244054088, chrl_244054213, chrl_244054334, chrl_244054412, chrl_244054487, chrl_244087973, chrl_247437780, chrl0_387726, chrl0_935305, chrl0_1247497, chrl0_1318744, chrl0_l 357942, chr!0_1360114, chr!0_1372793, chr!0_1394602, chr!0_1403853, chrlO_ 1464103, chr!0_1508066, chr!0_1508075, chr!0_1534652, chrl0_1535173, chr!0_1535179, chrl0_1535208, chrl0_1535214, chrl0_1538728, chrl0_1542987, chrl0_1543090, chrl0_1543258, chrl0_1547036, chrl0_1547973, chrl0_1549841, chrl0_1550998, chrl0_1552016, chrl0_1562547, chrl0_1569401, chrl0_1577668, chrl0_1577694, chrl0_1596439, chrl0_1599134, chrl0_1599460, chrlO_161O3O6, chrl0_1611415, chrl0_1611485, chrl0_1625484, chrlO_l 626613, chrl0_1626656, chrl0_1626669, chrl0_1633241, chrl0_1654938, chrlO_1661OO3, chrl0_1661062, chrl0_1661397, chrlO_1666355, chrl0_1666430, chrl0_1666472, chrl0_1666792, chrl0_1668209, chrl0_1671751, chrl0_1671760, chrl0_1679796, chrlO_l 680977, chrl0_1680989, chrl0_l 682975, chrl0_1686583, chrl0_1686722, chrl0_1694923, chrl0_1710088, chrl0_1711037, chrl0_1711066, chrl0_1712543, chrl0_1713526, chrl0_1717306, chrl0_1717669, chrl0_1721323, chrl0_1722689, chrl0_1722905, chrl0_1723106, chrl0_1723168, chrl0_1723256, chrl0_1723398, chrl0_1724434, chrl0_1724564, chrl0_1724748, chrl0_1724818, chr!0_1725175, chr!0_1726197, chr!0_1726436, chr!0_1726447, chrl0_ 1726470, chrl0_1727111, chr!0_1727408, chr!0_1727713, chr!0_1727852, chr!0_1975272, chr!0_3927130, chrl0_4731819, chrl0_9585562, chrl0_l 1207696, chrl0_ 11207803, chrl0_12981474, chrl0_13892298, chrl0_14558632, chrl0_16642323, chrl0_17143716, chrl0_23513396, chrl0_23513421, chrl0_25083707, chrl0_26124732, chrl0_29369388, chrl0_29621261, chrl0_29621473, chrl0_31693750, chrl0_32910294, chrl0_33204102, chrl0_34313459, chrl0_34361129, chrl0_34752396, chrl0_35511869, chrl0_43864232, chrl0_43864498, chr10_44279927, chrl0_44280044, chr!0_45073172, chrl0_48466468, chr!0_48593680, chr10_49290l 81 , chrl0_59279057, chrl0_59279103, chrl0_59688157, chrl0_67835472, chrl0_69494743, chrl0_69494838, chrl0_71364493, chrl0_71529729, chrl0_72022372, chrl0_73992099, chrl0_75999872, chrl0_79401789, chrl0_80094872, chrl0_85659210, chrl0_85659210, chrl0_87534082, chrl0_87727342, chrl0_88086877, chrl0_91397464, chrl0_92661601, chrl0_96825742, chrl0_97760005, chrl0_100072990, chrl0_100828496, chrl0_101242343, chrl0_101242383, chrl0_102758820, chrl0_106956123, chrl0_107085835, chrl0_108335363, chrl0_108862889, chrl0_l 12992389, chrl0_l 14188109, chrl0_l 14512228, chrl0_114571333, chrl0_l 16043885, chrl0_l 19395824, chrl0_l 19410604, chrl0_l 19413170, chrl0_120517367, chrl0_120517552, chrl0_124961029, chrl0_127347399, chrl0_129558734, chrl0_l 31954864, chrl0_132541497, chrl0_132747207, chrll_1081483, chrll_1507802, chrll_2237529, chrll_2237733, chrl 1_6333181, chrl l_8334015, chrll_9187748, chrll_10175924, chrl l_10626357, chrll_10925589, chrl 1_13922642, chrll_15508856, chrl l_15706202, chrll_15852550, chrl l_15852550, chrll_16344746, chrll_16934508, chrl 1_23611038, chrl l_27405472, chrll_28552666, chrl 1_28552687, chrll_28552792, chrll_28779431, chrll_30683884, chrl 1_31820115, chrll_31820310, chrl 1_34299545, chrll_35009415, chrl 1_35418357, chrll_41004019, chrl l_46385139, chrll_46398710, chrl l_46441679, chrll_59759948, chrl 1_61298862, chrll_61601245, chrl l_62918024, chrll_62918143, chrl l_62918154, chrll_62918189, chrl 1_62918204, chrll_62920510, chrl l_64070739, chrll_64635621, chrl l_64638030, chrll_64638061, chrll_64638130, chrl 1_64638134, chrl l_64638208, chrll_64638406, chrl 1_64638423, chrll_64638446, chrll_64638476, chrll_64638487, chrl 1_66316168, chrll_66652726, chrl l_66652738, chrl l_66905384, chrll_67303456, chrll_67303525, chrl 1 70552247, chrll_70828694, chrl l_70828726, chrl l_70828942, chrll_70828959, chrl 1_73319282, chrl l_73636196, chrll_75832244, chrl l_76480559, chrll_83537579, chrll_89375694, chrll_91494016, chrll_94158916, chrll_94800276, chrl l_94800334, chrll_97297420, chrll_99359783, chrll_105521555, chrl 1 105648919, chrll_107988501, chrll_109332508, chrl 1_112260989, chrl 1_112865051, chrl 1_112865051, chrl 1_113363879, chrl 1_113400998, chrl 1_113408265, chrl 1_113433434, chrl 1_113433544, chrl 1_113444137, chrl 1_113445794, chrl 1_113460726, chrl 1_113468577, chrl 1_113468826, chrl 1_113469191, chrl 1_113469614, chrl 1_113470470, chrl 1_113951190, chrl 1_113951238, chrl 1_114062290, chrl 1_114062488, chrl 1_114064208, chrl 1_114064532, chrl 1_114066467, chrl 1_114067705, chrl 1_114069492, chrl 1_114069680, chrl 1_114964283, chrl 1_117725325, chrl 1_117914441, chrl 1_118210650, chrl 1_118609944, chrl 1_118883931, chrl 1_119840345, chrl l_123025323, chrll_126134274, chrl 1_126871107, chrll_127587360, chrll_127690394, chrl l_127690429, chrll_128402186, chrll_129969666, chrll_131233613, chrl 1_1 1327076, chrl l_131679120, chrl2_1324180, chrl2_2081518, chrl2_2465968, chrl2_2842964, chrl2_4387265, chrl2_17254791, chrl2_30766914, chrl2_30974784, chrl2_30974808, chrl2_32719406, chrl2_47947292, chrl2_48788525, chrl2_49708105, chrl2_53274354, chrl2_53274417, chrl2_68919665, chrl2_70443965, chrl2_77308440, chrl2_78560885, chrl2_79364491, chrl2_88450938, chrl2_88451104, chrl2_91615051, chrl2_91645989, chrl2_92221841, chrl2_93894714, chrl2_93894724, chrl2_93894744, chr!2_93894790, chrl 2_94695777, chr12_95356097, chrl2_98459151, chr12_104666490, chrl2_104666538, chrl2_104858423, chrl2_108910438, chrl2_ll 1199420, chrl2_l 11363167, chrl2_l 11363249, chrl2_l 13149751, chrl2_l 14671951, chrl2_l 16980578, chrl2_l 17087702, chrl2_l 19340812, chrl2_121507866, chrl2_122161069, chrl2_122228141, chrl2_125905569, chrl2_127115077, chrl2_129703529, chrl2_l 31082380, chrl2_131102283, chrl3_24242600, chrl3_27238208, chrl3_27337317, chrl3_27517013, chrl3_33724973, chrl3_35695164, chrl3_41465311, chrl3_44573330, chrl3_45223370, chrl3_45911860, chrl3_73025821, chrl3_73026371, chrl3_73707925, chrl3_73707942, chrl3_78061219, chrl3_92046041, chrl3_93413326, chrl3_98404428, chrl3_101565625, chrl3_103013028, chrl3_103071728, chrl3_103801301, chrl3_104738052, chrl3_106713795, chrl3_107840158, chrl3_l 11944810, chrl3_ 112909258, chrl3_l 12970862, chrl4_24156171, chrl4_24799228, chrl4_28309117, chrl4_31488551, chrl4_32587882, chrl4_36524389, chrl4_36524667, chrl4_45008380, chrl4_52941165, chrl4_53390381, chrl4_55679980, chrl4_56817138, chrl4_58598388, chrl4_61417278, chrl4_61690962, chrl4_62814638, chrl4_65594301, chrl4_68494555, chrl4_68569744, chrl4_72738631, chrl4_72746337, chrl4_72746410, chrl4_75188760, chrl4_76713363, chrl4_84090996, chrl4_86470352, chrl4_88890190, chrl4_91028417, chrl4_91277631, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99244159, chrl4_99244383, chrl4_99245037, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99259778, chrl4_99259851, chrl4_99261299, chrl4_99261349, chrl4_99265134, chrl4_99265442, chrl4_99943176, chrl4_100572028, chrl4_101216074, chrl4_101365577, chrl4_103132495, chrl4_104963567, chr!4_105061228, chrl5_27014884, chrl5_27598866, chrl5_34572508, chr!5_39188740, chr!5_39667040, chrl5_39828226, chrl5_39961524, chrl5_40579060, chrl5_42159095, chr!5_42506523, chrl5_48140618, chrl5_51015399, chrl5_57463798, chrl5_58712954, chrl5_58958301, chrl5_60850769, chrl5_61832637, chrl5_64673973, chrl5_70265944, chrl5_70867831, chrl5_73421182, chrl5_73787063, chrl5_73787074, chrl5_74146200, chrl5_75706205, chrl5_75706213, chrl5_77976043, chrl5_78344288, chrl5_78344315, chrl5_84784380, chrl5_86311581, chrl5_88486678, chrl5_90065084, chrl5_90946906, chrl5_92109249, chrl5_92438644, chrl5_92971963, chrl5_94591665, chrl5_95990733, chrl5_96288168, chrl5_98347522, chrl5_100032792, chrl5_101045494, chrl5_101045497, chrl5_101709644, chrl6_1633341, chrl6_3255898, chrl6_3473308, chrl6_6529078, chrl6_21514377, chrl6_21514493, chrl6_22272849, chrl6_24895739, chrl6_29674272, chrl6_29674291, chrl6_49521066, chrl6_56871247, chrl6_57792334, chrl6_71746300, chrl6_71746304, chrl6_73092631, chrl6_75322268, chrl6_75322268, chrl6_76458256, chrl6_79856776, chrl6_84090291, chrl6_85290977, chrl6_85452156, chrl6_86651909, chr!6_86757258, chrl6_87013194, chrl6_87957932, chrl6_89747287, chrl6_90002798, chr!7_2019254, chr!7_2019280, chr!7_2266557, chr!7_5786789, chr!7_6264478, chr!7_8310790, chrl7_l 1326585, chrl7_17603475, chrl7_17603475, chrl7_19539205, chrl7_19539300, chrl7_20077590, chrl7_21375315, chrl7_21405634, chrl7_28273746, chrl7_28837720, chrl7_29056566, chrl7_29093998, chrl7_31593826, chrl7_32037054, chrl7_32274223, chrl7_39612775, chrl7_45173004, chrl7_45240201, chrl7_48831635, chrl7_49578654, chrl7_49580573, chrl7_51374368, chrl7_58691449, chrl7_61405604, chrl7_62458778, chr17_631 17237, chrl7_631 17426, chrl7_65271215, chrl7_68274037, chr17_69499387, chr! 7_72666182, chrl7_74762858, chrl7_75002178, chrl7_75231866, chrl7_75231876, chrl7_76145456, chrl7_76145510, chrl7_78458835, chrl7_78458957, chrl7_78665984, chrl7_79140535, chrl7_81246152, chrl7_81312889, chrl7_81839462, chrl7_81839517, chrl8_1477011, chrl8_3015949, chrl8_7202739, chrl8_7466797, chrl8_7574188, chrl8_7671182, chrl8_l 0232472, chrl8_l 1832622, chrl8_22191374, chrl8_24273998, chrl8_25563957, chrl8_26965747, chrl8_28484687, chrl8_28743520, chrl8_29252619, chrl8_31578184, chrl8_31612779, chrl8_31668044, chrl8_31668223, chrl8_42840523, chrl8_42840569, chrl8_47595163, chrl8_48111878, chrl8_48220327, chrl8_48841418, chrl8_49660177, chrl8_54620704, chrl8_55316591, chrl8_55335150, chrl8_55337856, chrl8_55337859, chrl8_55347406, chrl8_55347692, chrl8_55401620, chrl8_55401726, chrl8_55401962, chrl8_55401962, chrl8_55402070, chrl8_55863146, chrl8_55863209, chrl8_55863341, chrl8_55863406, chrl8_57139112, chrl8_58144488, chrl8_58846286, chrl8_59627566, chrl8_61244954, chrl8_62551668, chrl8_62551681, chrl8_63087914, chrl8_73923596, chrl8_74833726, chrl8_75281388, chrl8_75629703, chrl8_77087501, chrl8_79206904, chrl9_940774, chrl9_940858, chrl9_941030, chrl9_941149, chrl9_941208, chrl9_941242, chrl9_941271, chrl9_941471, chrl9_1071020, chrl9_1071474, chrl9_4020451, chrl9_8066130, chrl9_8066187, chrl9_8180812, chrl9_9944860, chrl9_l 1066436, chrl9_ 11490901, chrl9_l 1943461, chrl9_l 1943461, chrl9_12882294, chrl9_l 3002694, chrl9_13002733, chrl9_13002909, chrl9_13002919, chrl9_13027038, chrl9_13027452, chrl9_l 3027645, chrl9_13027708, chrl9_13804816, chrl9_16287615, chrl9_19493336, chrl9_29879973, chrl9_30071371, chrl9_30071556, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_32327361, chr!9_33408728, chrl9_33408838, chrl9_35046673, chrl9_35086102, chrl9_38221003, chr!9_38470895, chr!9_39052997, chrl9_45018947, chrl9_45019029, chrl9_45216040, chrl9_46604657, chr!9_46731732, chrl9_47365708, chrl9_49913135, chrl9_51225987, chrl9_53965120, chrl9_53965266, chrl9_53976301, chrl9_55485668, chrl9_58538912, chr2_520529, chr2_520537, chr2_926606, chr2_1939158, chr2_4416732, chr2_4416771, chr2_4713113, chr2_6286826, chr2_8287256, chr2_8287404, chr2_8535196, chr2_8811580, chr2_10557447, chr2_l 0557495, chr2_10557501, chr2_18993220, chr2_22449630, chr2_22575886, chr2_23834892, chr2_27738485, chr2_27738489, chr2_27738545, chr2_30688941, chr2_30689098, chr2_36127495, chr2_42221994, chr2_42964618, chr2_43149699, chr2_44884032, chr2_46460276, chr2_46955071, chr2_47026330, chr2_60479437, chr2_61005128, chr2_64793554, chr2_73008587, chr2_76533399, chr2_79929386, chr2_82392549, chr2_85447333, chr2_86421142, chr2_88493781, chr2_90095397, chr2_96895479, chr2_99699856, chr2_100923151, chr2_106974041, chr2_108173836, chr2_109542029, chr2_l 13217808, chr2_ 115082751, chr2_l 19816994, chr2_120543523, chr2_120605793, chr2_121664250, chr2_121664308, chr2_122112932, chr2_122162513, chr2_127132369, chr2_127840596, chr2_128280247, chr2_131406273, chr2_144507406, chr2_144508216, chr2_144509942, chr2_144512702, chr2_148147429, chr2_156397401, chr2_159188769, chr2_l 59230649, chr2_161621740, chr2_169415560, chr2_170158816, chr2_172079041, chr2_180445347, chr2_184141131, chr2_184141527, chr2_192676064, chr2_198143307, chr2_198316634, chr2_199447280, chr2_l 99449983, chr2_199450146, chr2_201872813, chr2_203121062, chr2_204110026, chr2_204434785, chr2_211228268, chr2_21 1590141 , chr2_211590198, chr2_212520797, chr2_212524214, chr2_214915957, chr2_216827945, chr2_218323778, chr2_219281611, chr2_219888095, chr2_222470101, chr2_224976082, chr2_226970614, chr2_227315087, chr2_227315087, chr2_230465348, chr2_231390519, chr2_232011938, chr2_232574302, chr2_233170602, chr2_234438247, chr2_234438297, chr2_236121881, chr2_236442644, chr2_236680576, chr2_236825115, chr2_238282674, chr2_238327106, chr2_239420572, chr2_239574925, chr2_240622671, chr20_l 400335, chr20_1837975, chr20_5024555, chr20_5670261, chr20_7866427, chr20_9493674, chr20_l 0663952, chr20_17913505, chr20_20699456, chr20_23049529, chr20_23049808, chr20_34196362, chr20_35502853, chr20_36541033, chr20_36872375, chr20_40692708, chr20_40692864, chr20_43423564, chr20_43564715, chr20_48291365, chr20_49882081, chr20_51811855, chr20_52979500, chr20_52979806, chr20_53032932, chr20_54696328, chr20_55284577, chr20_57730506, chr20_57730576, chr20_60750600, chr20_60889288, chr20_62225257, chr20_62819512, chr20_63081946, chr20_63582957, chr21_5068206, chr21_6136224, chr21_14871182, chr21_16589675, chr21_21578917, chr21_26832783, chr21_26832851, chr21_28103489, chr21_28103489, chr21_29221598, chr21_29221717, chr21_29391039, chr21_29572229, chr21_29917226, chr21_31599647, chr21_33824631, chr21_34957177, chr21_37606568, chr21_40771526, chr21_42158069, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr21_45434453, chr21_45469473, chr21_46510096, chr21_46606384, chr21_46622779, chr22_19002217, chr22_l 9354500, chr22_19666270, chr22_21937291, chr22_24425152, chr22_24425165, chr22_24425229, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425705, chr22_24425710, chr22_24425754, chr22_24425816, chr22_24425972, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24427448, chr22_24428701, chr22_24428719, chr22_24433075, chr22_24433241, chr22_24433423, chr22_24434088, chr22_24434350, chr22_24434476, chr22_24434989, chr22_24435262, chr22_24436014, chr22_24436130, chr22_24436142, chr22_24437360, chr22_24437763, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24440446, chr22_24441113, chr22_24441159, chr22_27488317, chr22_29096890, chr22_29146128, chr22_29151957, chr22_29184647, chr22_29184668, chr22_29185058, chr22_30472552, chr22_30737962, chr22_34617159, chr22_34617213, chr22_35114720, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_37986002, chr22_42646574, chr22_44026938, chr22_44827980, chr22_44940707, chr22_46346927, chr22_47035212, chr22_48824652, chr22_48824678, chr22_49391984, chr22_50192404, chr22_50658490, chr3_2528585, chr3_8595802, chr3_8596019, chr3_l 0546902, chr3_l 0546931, chr3_13191245, chr3_15391356, chr3_16908451, chr3_18064875, chr3_22857045, chr3_23272516, chr3_29736383, chr3_30391151, chr3_31409610, chr3_32506316, chr3_41117522, chr3_42733336, chr3_46301401, chr3_47422872, chr3_47689722, chr3_47689722, chr3_50620837, chr3_52140116, chr3_52140201, chr3_53425664, chr3_56203330, chr3_56434152, chr3_59955536, chr3_62807299, chr3_70568431, chr3_72321259, chr3_73746874, chr3_76549448, chr3_76628994, chr3_79368010, chr3_80420694, chr3_81591988, chr3_81591988, chr3_88788605, chr3_99932654, chr3_102334993, chr3_105471988, chr3_107915549, chr3_109565120, chr3_l 12000443, chr3_l 12508351, chr3_l 13651082, chr3_l 13902470, chr3_l 14746010, chr3_l 22908926, chr3_123653613, chr3_126774624, chr3_130566788, chr3_l 34430495, chr3_134660205, chr3_140501227, chr3_142925609, chr3_l 43082577, chr3_143082617, chr3_l 50033642, chr3_l 50556578, chr3_151 77932, chr3_ 152058781, chr3_154551207, chr3_157872750, chr3_158094973, chr3_159753818, chr3_l 64753486, chr3_164753534, chr3_168027547, chr3_170045189, chr3_171894906, chr3_179540277, chr3_l 79616279, chr3_l 80283387, chr3_181704894, chr3_181704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_l 81724236, chr3_181724459, chr3_181724559, chr3_188051674, chr3_192578970, chr3_l 92822185, chr3_194028101, chr3_194247515, chr3_196757788, chr3_197606574, chr3_197677415, chr3_197800521, chr4_578126, chr4_667460, chr4_1245701, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3406740, chr4_3406740, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_3642975, chr4_4169964, chr4_6854578, chr4_7551934, chr4_7626609, chr4_7766077, chr4_8576626, chr4_8868232, chr4_9109274, chr4_l 1187567, chr4_12022338, chr4_l 3785708, chr4_15944086, chr4_25237957, chr4_25602291, chr4_27041550, chr4_27041550, chr4_30170558, chr4_31772049, chr4_36635749, chr4_37629013, chr4_38077991, chr4_38356556, chr4_39815565, chr4_44257363, chr4_44770533, chr4_52055928, chr4_53508148, chr4_53840582, chr4_54041134, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_54655713, chr4_67939385, chr4_77897059, chr4_77897104, chr4_77902675, chr4_84492457, chr4_87411016, chr4_87865311, chr4_88058507, chr4_89379269, chr4_94410831, chr4_l 13707038, chr4_l 17877755, chr4_l 19027422, chr4_120659773, chr4_137538611, chr4_149008859, chr4_150185669, chr4_l 50185691, chr4_150828760, chr4_150828760, chr4_152888059, chr4_163154908, chr4_165204068, chr4_172578855, chr4_183611170, chr5_1554827, chr5_4942229, chr5_6810030, chr5_6810073, chr5_8773657, chr5_10524764, chr5_10524872, chr5_15851430, chr5_17043558, chr5_17306281, chr5_24856145, chr5_30772245, chr5_32631299, chr5_36490437, chr5_36490583, chr5_38383233, chr5_38403906, chr5_38457056, chr5_43282446, chr5_43282460, chr5_44117981, chr5_50998048, chr5_50998391, chr5_54475097, chr5_56589734, chr5_57399190, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_67976871, chr5_74294397, chr5_74397232, chr5_74397237, chr5_78701917, chr5_79842653, chr5_83553431, chr5_89120992, chr5_89474124, chr5_95429494, chr5_95503240, chr5_95820943, chr5_100877542, chr5_107099103, chr5_110767118, chr5_l 13040537, chr5_l 13181090, chr5_l 14319704, chr5_l 15106946, chr5_l 16361553, chr5_l 16864787, chr5_l 27066418, chr5_128254452, chr5_140543089, chr5_145529393, chr5_148966479, chr5_ 150140043, chr5_150680117, chr5_151512421, chr5_151512485, chr5_151520158, chr5_160247828, chr5_160247828, chr5_l 62977137, chr5_ 167264351, chr5_167264377, chr5_167983052, chr5_168880153, chr5_169244217, chr5_l 72844168, chr5_172860804, chr5_172860953, chr5_173793773, chr5_175033106, chr5_175441994, chr5_l 75442040, chr5_175442086, chr5_175442387, chr5_175442710, chr5_175442710, chr5_175692802, chr5_l 75692868, chr5_ 178604407, chr5_180155459, chr5_180155581, chr6_725467, chr6_3482654, chr6_4789352, chr6_5724062, chr6_6907253, chr6_6907404, chr6_7137767, chr6_8839734, chr6_9035118, chr6_l 1778228, chr6_26756234, chr6_33906454, chr6_34036167, chr6_36775571, chr6_37006218, chr6_37684799, chr6_37713585, chr6_40888325, chr6_53816078, chr6_60830914, chr6_65498438, chr6_71257145, chr6_72620288, chr6_80711323, chr6_87948947, chr6_89949296, chr6_91513599, chr6_96873290, chr6_l 03266434, chr6_105628390, chr6_l 06520270, chr6_l 08804924, chr6_109824080, chr6_109977550, chr6_109977690, chr6_109981771, chr6_109981907, chr6_l 10018487, chr6_l 10105517, chr6_l 10439611, chr6_l 17562504, chr6_l 18577805, chr6_l 18695678, chr6_120951342, chr6_l 21099723, chr6_125991533, chr6_l 32713871, chr6_134809530, chr6_136924776, chr6_136943473, chr6_137290533, chr6_139254024, chr6_139408933, chr6_143432179, chr6_ 145694391, chr6_146685764, chr6_l 47500518, chr6_148967681, chr6_150204270, chr6_150204473, chr6_150893713, chr6_152859420, chr6_l 55123808, chr6_158528243, chr6_159116933, chr6_162547293, chr6_163403779, chr6_164351123, chr6_l 65726824, chr6_168301762, chr6_169961951, chr7_605238, chr7_1231081, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1672933, chr7_1673021, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_l 675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_1964753, chr7_1964753, chr7_2108124, chr7_2954193, chr7_4242663, chr7_5244881, chr7_5244971, chr7_5834355, chr7_6139824, chr7_6988371, chr7_6988400, chr7_7273541, chr7_7609460, chr7_8783649, chr7_8976868, chr7_17586547, chr7_19111176, chr7_27822880, chr7_28632740, chr7_31007402, chr7_40828899, chr7_43884803, chr7_45198338, chr7_45198353, chr7_47238811, chr7_48427116, chr7_51640974, chr7_52571138, chr7_54795471, chr7_66199154, chr7_67453619, chr7_69099312, chr7_69099312, chr7_69099326, chr7_71592009, chr7_74183318, chr7_76305544, chr7_77909010, chr7_80057215, chr7_87851757, chr7_88282441, chr7_90709817, chr7_92278330, chr7_93580834, chr7_94840949, chr7_97427528, chr7_100986599, chr7_100986780, chr7_101062908, chr7_101657486, chr7_101915316, chr7_101915318, chr7_ 102107431, chr7_105637154, chr7_106848245, chr7_l 14399231, chr7_l 14428892, chr7_l 14575444, chr7_131430361, chr7_131603062, chr7_132646113, chr7_133830213, chr7_135147918, chr7_138971636, chr7_138996163, chr7_l 39542065, chr7_146691141, chr7_149730029, chr7_149875303, chr7_l 50150657, chr7_ 150451230, chr7_151652356, chr7_154750541, chr7_154916613, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_ 159142397, chr7_159231032, chr7_159231136, chr8_1757845, chr8_3245755, chr8_5575147, chr8_8575133, chr8_9901380, chr8_10296807, chr8_l 3310666, chr8_22243620, chr8_22762602, chr8_27662591, chr8_29052797, chr8_32310673, chr8_41246826, chr8_45729351, chr8_52246671, chr8_52252719, chr8_52485371, chr8_56439745, chr8_56441389, chr8_56444235, chr8_56445225, chr8_57356053, chr8_58117688, chr8_58768196, chr8_58986453, chr8_61697578, chr8_62391722, chr8_63031540, chr8_64773383, chr8_65188438, chr8_66011320, chr8_80345362, chr8_84031486, chr8_85556739, chr8_87977499, chr8_88495042, chr8_88495214, chr8_92942006, chr8_97191731, chr8_ 102754235, chr8_l 15421230, chr8_ 117042553, chr8_l 18694978, chr8_l 18694978, chr8_l 18707989, chr8_122825356, chr8_ 129464046, chr8_140608236, chr8_140729234, chr8_141800471, chr8_l 41800485, chr8_141800688, chr8_!432131 1 1, chr8_144241354, chr8_144242229, chr9_22851 12, chr9_25755075, chr9_29444070, chr9_29444070, chr9_35350760, chr9_38042823, chr9_42278765, chr9_68830859, chr9_73193094, chr9_73193094, chr9_73863812, chr9_73879045, chr9_75657076, chr9_79190169, chr9_79193652, chr9_79193716, chr9_81624163, chr9_81702877, chr9_83315819, chr9_89240725, chr9_90939328, chr9_91222453, chr9_91268452, chr9_93156160, chr9_93156181, chr9_95546440, chr9_99824708, chr9_l 09388040, chr9_109719145, chr9_l 11786816, chr9_ 114250397, chr9_l 14250449, chr9_l 14250469, chr9_l 14250578, chr9_l 14804274, chr9_l 19121913, chr9_120498228, chr9_l 21699909, chr9_121830266, chr9_122212102, chr9_122224319, chr9_ 124441496, chr9_126414292, chr9_l 27496263, chr9_129632189, chr9_130919131, chr9_130919223, chr9_131063253, chr9_132223939, chr9_134111490, chr9_134351622, chr9_134351726, chr9_134420593, chr9_134420684, chr9_135941758, chr9_l 36035347, chr9_136323313, chr9_136512314, chr9_136512504, chr9_137281028, wherein these refer to human genome assembly GRCh38.

9. The method of any one of claims 1 to 8, wherein measuring the methylation level of the different methylation markers in the genomic DNA of the biological sample comprises hybridizing polynucleotides complementary to polynucleotides attached to a solid support.

10. The method of claim 9, wherein the polynucleotides attached to a solid support comprise at least 30 nucleic acid probes, wherein the at least 30 nucleic acid probes comprise at least 30 of SEQ ID NOS: 1 to 2415, 1 to 1585, 1586-2385, or 2386-2415.

11. The method of any one of claims 1 to 10, wherein the method diagnoses one or more diseases in the subject, based on the brain cells identified.

12. The method of any one of claims 1 to 11, further comprising: administering to the subject an effective amount of one or more therapeutic agents when the particular brain cell type is identified as shown in Table 2.

13. The method of any one of claims 1 to 12, further comprising obtaining the biological sample from the subject.

14. The method of any one of claims 1 to 13, further comprising extracting genomic DNA from the biological sample.

15. The method of any one of claims 1 to 14, further comprising selecting the subject, wherein the subject has or is suspected of having a brain disorder.

16. The method of any one of claims 1 to 15, further comprising reporting the brain cells identified.

17. The method of claim 16, wherein the reporting comprises preparing a written or electronic report.

18. A kit, comprising: nucleic acid probes for detecting at least 30 different methylation markers in Table 1 or 2.

19. The kit of claim 18, wherein the at least 30 different methylation markers comprise or consist of

(a) chrl0_35445343, chrl2_l 17087703, chrl5_101709645, chrl7_39612776, chrl_30127036, chrl4_58598194, chrl_25968447, chrl8_55401769, chrl0_30583971, chrl l_41004020, chrll_61298863, chrl2_l 32525847, chrl7_75231867, chr9_l 22207624, chrl0_l 12991920, chrl0_26124733, chrl3_l 13337880, chrl3_44573331, chrl6_89747288, chrl7_49578655, chrl9_53976302, chrl0_l 12219535, chrll_99359784, chrl6_52967325, chr4_3374470, chr22_49391985, chr4_38356557, chr5_175435725, chrl_209331007, and chr2_73008588, wherein these refer to human chromosomes; b. chrl_6954346, chrl_15765576, chrl_16921554, chrl_17535924, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_47930687, chrl_55154499, chrl_82344735, chrl_84779343, chrl_88186554, chrl_89387906, chrl_l 14587732, chrl_213899571, chrl_223535050, chrl0_12981474, chrl0_85659210, chrl0_120517367, chrl0_129558734, chrl l_6333181, chrll_15508856, chrl l_61601245, chrll_64638208, chrll_64638406, chrll_64638423, chrl 1_64638446, chrll_64638487, chrl l_70828694, chrl l_70828959, chrl 1_113951238, chrl 1_114069492, chr!2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl3_44573330, chrl3_78061219, chrl4_91028417, chrl4_99239938, chrl4_99240729, chrl4_99254307, chrl4_99258195, chrl4_99265134, chrl5_40579060, chrl5_60850769, chrl5_73787074, chrl5_75706213, chrl6_29674272, chrl6_71746304, chrl7_2019280, chrl7_17603475, chrl7_49578654, chrl7_78458835, chrl7_81839462, chrl8_42840569, chrl8_55863146, chrl8_55863406, chrl9_8180812, chrl9_13002909, chrl9_31596154, chrl9_33408728, chr2_520529, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_88493781, chr2_106974041, chr2_144508216, chr2_144509942, chr2_159230649, chr2_192676064, chr2_199449983, chr2_214915957, chr2_224976082, chr2_227315087, chr2_234438297, chr20_23049529, chr20_40692864, chr20_52979500, chr20_55284577, chr20_57730506, chr21_21578917, chr21_26832851, chr21_29221598, chr21_29917226, chr21_43913788, chr21_44074575, chr21_45115350, chr22_24425165, chr22_24425431, chr22_24425509, chr22_24426997, chr22_24427299, chr22_24428719, chr22_24434476, chr22_24435262, chr22_24436142, chr22_24438986, chr22_24439355, chr22_24440428, chr22_24441113, chr22_29184668, chr22_36763396, chr22_36763700, chr22_49391984, chr3_10546931, chr3_23272516, chr3_41117522, chr3_53425664, chr3_81591988, chr3_ 113902470, chr3_142925609, chr3_143082577, chr3_l 81704950, chr3_181715790, chr3_181724236, chr3_181724559, chr4_3374241, chr4_3374306, chr4_3374416, chr4_3377079, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385479, chr4_3385492, chr4_3385938, chr4_3389755, chr4_3389767, chr4_3393330, chr4_3393693, chr4_3410433, chr4_3411467, chr4_7766077, chr4_54226502, chr4_54226613, chr4_54236780, chr5_6810073, chr5_10524872, chr5_43282460, chr5_60340044, chr5_65126330, chr5_l 13040537, chr5_l 15106946, chr5_127066418, chr5_150680117, chr5_167983052, chr5_172860953, chr5_175441994, chr5_l 75442086, chr5_175442710, chr5_178604407, chr5_180155581, chr6_36775571, chr6_60830914, chr6_87948947, chr6_96873290, chr6_l 05628390, chr6_l 50204270, chr6_150893713, chr6_158528243, chr6_ 169961951, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1674842, chr7_1675096, chr7_1677614, chr7_1680106, chr7_2108124, chr7_17586547, chr7_45198338, chr7_94840949, chr7_101915316, chr7_157585009, chr7_157897945, chr7_157897966, chr7_157897972, chr7_159142397, chr7_l 59231136, chr8_52246671, chr8_57356053, chr8_63031540, chr8_80345362, chr8_84031486, chr8_87977499, chr8_l 18694978, chr8_141800688, chr9_35350760, chr9_73879045, chr9_79193716, chr9_93156181, chr9_l 14250469, chr9_l 14250578, chr9_122212102, chr9_130919223, chr9_134351726, chr9_l 34420684, c. chrl_6954205, chrl_6954346, chrl_15437470, chrl_15765576, chrl_16921554, chrl_17535615, chrl_17535924, chrl_20748527, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_47930687, chrl_55154474, chrl_55154499, chrl_82344735, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_l 14587732, chrl_l 14587798, chrl_200664873, chrl_213899571, chrl_223535050, chrl0_12981474, chrl0_85659210, chrl0_85659210, chrl0_96825742, chrl0_120517367, chrl0_120517552, chrl0_129558734, chrl 1_6333181, chrll_15508856, chrl l_30683884, chrll_61601245, chrll_64638030, chrll_64638061, chrl l_64638130, chrll_64638134, chrl l_64638208, chrll_64638406, chrll_64638423, chrll_64638446, chrl 1_64638476, chrll_64638487, chrl l_66652738, chrl l_70828694, chrll_70828726, chrll_70828942, chrl l_70828959, chrl 1_113951190, chrl 1_113951238, chrl 1_114069492, chrl 1_114069680, chrl 1_118210650, chrl2_104666490, chrl2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl2_l 11363249, chrl3_44573330, chrl3_78061219, chrl3_92046041, chrl3_93413326, chrl4_28309117, chrl4_32587882, chrl4_91028417, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99265134, chrl5_39667040, chrl5_40579060, chrl5_60850769, chrl5_73787063, chrl5_73787074, chrl5_75706205, chrl5_75706213, chrl6_29674272, chrl6_29674291, chrl6_71746300, chrl6_71746304, chrl6_79856776, chrl7_2019254, chrl7_2019280, chrl7_l 7603475, chrl7_17603475, chrl7_49578654, chrl7_49580573, chrl7_58691449, chrl7_78458835, chrl7_78458957, chrl7_81839462, chrl7_81839517, chrl8_31612779, chrl8_42840523, chrl8_42840569, chrl8_55863146, chrl8_55863209, chrl8_55863341, chrl8_55863406, chrl9_8180812, chrl9_13002733, chrl9_l 3002909, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_33408728, chrl9_33408838, chr!9_39052997, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_4416732, chr2_8535196, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_448 4032, chr2_73008587, chr2_88493781, chr2_ 106974041, chr2_ 115082751, chr2_120543523, chr2_l 44507406, chr2_144508216, chr2_144509942, chr2_144512702, chr2_159230649, chr2_180445347, chr2_l 92676064, chr2_199449983, chr2_199450146, chr2_203121062, chr2_214915957, chr2_216827945, chr2_224976082, chr2_227315087, chr2_227315087, chr2_234438247, chr2_234438297, chr20_l 837975, chr20_23049529, chr20_23049808, chr20_40692708, chr20_40692864, chr20_43564715, chr20_49882081 , chr20_52979500, chr20_52979806, chr20_53032932, chr20_55284577, chr20_57730506, chr20_57730576, chr21_21578917, chr21_26832783, chr21_26832851, chr21_29221598, chr21_29221717, chr21_29917226, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr22_24425152, chr22_24425165, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425710, chr22_24425816, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24428701, chr22_24428719, chr22_24434350, chr22_24434476, chr22_24435262, chr22_24436130, chr22_24436142, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_49391984, chr3_10546902, chr3_10546931, chr3_23272516, chr3_41117522, chr3_53425664, chr3_73746874, chr3_81591988, chr3_81591988, chr3_l 12000443, chr3_l 13902470, chr3_142925609, chr3_143082577, chr3_143082617, chr3_179616279, chr3_181704894, chr3_l 81704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_181724459, chr3_181724559, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_9109274, chr4_l 1187567, chr4_l 5944086, chr4_36635749, chr4_38356556, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_87865311, chr5_6810030, chr5_6810073, chr5_10524764, chr5_l 0524872, chr5_43282446, chr5_43282460, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_95429494, chr5_l 13040537, chr5_l 15106946, chr5_127066418, chr5_150680117, chr5_167983052, chr5_l 72860804, chr5_172860953, chr5_175441994, chr5_175442040, chr5_175442086, chr5_175442387, chr5_l 75442710, chr5_175442710, chr5_178604407, chr5_180155459, chr5_180155581, chr6_33906454, chr6_36775571, chr6_40888325, chr6_60830914, chr6_87948947, chr6_96873290, chr6_105628390, chr6_l 10018487, chr6_120951342, chr6_121099723, chr6_137290533, chr6_139254024, chr6_150204270, chr6_150204473, chr6_150893713, chr6_158528243, chr6_ 169961951, chr7_1231081, chr7_1672459, chr7_1672799, chr7_1672928, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_1675882, chr7_1676417, chr7_l 676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_l 7586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_88282441, chr7_94840949, chr7_101915316, chr7_101915318, chr7_102107431, chr7_l 38971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_l 57897966, chr7_157897972, chr7_157898014, chr7_159142397, chr7_159231136, chr8_10296807, chr8_52246671, chr8_52252719, chr8_57356053, chr8_63031540, chr8_80345362, chr8_84031486, chr8_87977499, chr8_l 18694978, chr8_l 18694978, chr8_140729234, chr8_141800485, chr8_141800688, chr8_l 44241354, chr9_35350760, chr9_73879045, chr9_79193652, chr9_79193716, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181 , chr9_l 14250397, chr9_l 14250449, chr9_l 14250469, chr9_l 14250578, chr9_121830266, chr9_122212102, chr9_122224319, chr9_130919131, chr9_130919223, chr9_l 34351622, chr9_134351726, chr9_l 34420593, chr9_134420684, d. chrl_6954205, chrl_6954346, chrl_7048907, chrl_l 5437470, chrl_15765576, chrl_16921554, chrl_17411021, chrl_17535615, chrl_17535924, chrl_20748527, chrl_25729798, chrl_27249955, chrl_30127035, chrl_30830766, chrl_30830843, chrl_38114428, chrl_38114479, chrl_38418368, chrl_43465467, chrl_43465657, chrl_45049761, chrl_47930687, chrl_50837887, chrl_55154474, chrl_55154499, chrl_82344735, chrl_83627211, chrl_84779343, chrl_86323634, chrl_88186554, chrl_89387906, chrl_107575614, chrl_l 14587732, chrl_l 14587798, chrl_155009422, chrl_174451522, chrl_174451522, chrl_197451335, chrl_200664873, chrl_207434747, chrl_210626571, chrl_213899571, chrl_219915507, chrl_223535050, chrl_241329400, chrl_244054001, chrl_244054019, chrl_244054025, chrl_244054088, chrl_244054213, chrl_244054334, chrl_244054412, chrl_244054487, chrl0_387726, chrl0_1550998, chrl0_1599134, chrl0_l 599460, chrl0_1610306, chrl0_1626613, chrl0_1679796, chrl0_1680989, chrl0_1682975, chrl0_1713526, chrl0_1721323, chrl0_1723256, chrl0_1723398, chrl0_1724564, chrl0_1726470, chrl0_1975272, chrl0_3927130, chrl0_12981474, chrl0_33204102, chrl0_34752396, chrl0_44279927, chrl0_44280044, chrl0_59279057, chrl0_59279103, chrl0_71529729, chrl0_80094872, chrl0_85659210, chrl0_85659210, chrl0_87727342, chrl0_91397464, chrl0_92661601, chrl0_96825742, chrl0_107085835, chrl0_120517367, chrl0_120517552, chrl0_124961029, chrl0_129558734, chrl l_6333181, chrll_10175924, chrll_15508856, chrll_16344746, chrl l_28779431, chrll_30683884, chrl l_31820115, chrl l_31820310, chrll_46385139, chrll_46398710, chrl l_46441679, chrll_61601245, chrl l_64070739, chrl l_64635621, chrll_64638030, chrll_64638061, chrl l_64638130, chrll_64638134, chrl l_64638208, chrll_64638406, chrll_64638423, chrll_64638446, chrl 1_64638476, chrll_64638487, chrl 1_66652726, chrll_66652738, chrll_70828694, chrll_70828726, chrl l_70828942, chrll_70828959, chrl 1_75832244, chrll_94158916, chrl 1_112260989, chrl 1_113363879, chrl 1_113400998, chrl 1_113408265, chrl 1_113433434, chrl 1_113433544, chrl 1_113444137, chrl 1_113445794, chrl 1_113460726, chrl 1_113468577, chrl 1_113468826, chrl 1_113469191, chrl 1_113469614, chrl 1_113470470, chrll_113951190, chrl 1_113951238, chrl 1_114062290, chrl 1_114062488, chrl 1_114064208, chrl 1_114064532, chrl 1_114066467, chrl 1_114067705, chrl 1_114069492, chrl 1_114069680, chrl 1_117914441, chrl 1_118210650, chrll_123025323, chrll_127690394, chrll_127690429, chrll_131233613, chrl2_2081518, chrl2_2842964, chrl2_30766914, chrl2_47947292, chrl2_53274354, chrl2_53274417, chrl2_70443965, chrl2_77308440, chr!2_88450938, chrl2_88451104, chrl2_92221841, chrl2_93894714, chrl2_93894790, chr!2_94695777, chr!2_95356097, chrl2_98459151, chrl2_l 04666490, chrl2_104666538, chrl2_l 11199420, chrl2_l 11363167, chrl2_l 11363249, chrl2_l 19340812, chrl2_121507866, chrl2_122161069, chrl2_122228141, chrl2_127115077, chrl2_l 29703529, chrl3_27238208, chrl3_27517013, chrl3_35695164, chrl3_41465311, chrl3_44573330, chrl3_73025821, chrl3_73026371, chrl3_78061219, chrl3_92046041, chrl _93413326, chrl3_98404428, chrl3_103071728, chrl 3_103801301, chrl 3_106713795, chr14_28309l 17, chrl 4_32587882, chr!4_36524389, chrl 4_36524667, chrl4_62814638, chrl4_72746337, chrl4_72746410, chrl4_91028417, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99244159, chrl4_99244383, chrl4_99245037, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99259778, chrl4_99259851, chrl4_99261299, chrl4_99261349, chrl4_99265134, chrl4_99265442, chrl4_104963567, chrl5_27014884, chrl5_39667040, chrl5_40579060, chrl5_60850769, chrl5_61832637, chrl5_64673973, chrl5_70265944, chrl5_70867831, chrl5_73421182, chrl5_73787063, chrl5_73787074, chrl5_75706205, chrl5_75706213, chrl5_84784380, chrl5_98347522, chrl6_3255898, chrl6_3473308, chrl6_21514377, chrl6_21514493, chrl6_29674272, chrl6_29674291, chrl6_49521066, chrl6_71746300, chrl6_71746304, chrl6_73092631, chrl6_79856776, chrl6_84090291, chrl6_85290977, chrl6_86757258, chrl6_87957932, chrl6_89747287, chrl7_2019254, chrl7_2019280, chrl7_6264478, chrl7_8310790, chrl7_17603475, chrl7_17603475, chrl7_19539205, chrl7_19539300, chrl7_29056566, chrl7_29093998, chrl7_31593826, chrl7_32274223, chrl7_49578654, chrl7_49580573, chrl7_51374368, chrl7_58691449, chrl7_62458778, chrl7_68274037, chrl7_74762858, chrl7_75231866, chrl7_75231876, chrl7_78458835, chrl7_78458957, chrl7_79140535, chrl7_81246152, chrl7_81839462, chrl7_81839517, chrl8_7466797, chrl8_7671182, chrl8_22191374, chrl8_24273998, chrl8_28743520, chrl8_31612779, chrl8_31668044, chrl8_31668223, chrl8_42840523, chrl8_42840569, chrl8_48111878, chrl8_55316591, chrl8_55335150, chrl8_55337856, chrl8_55337859, chrl8_55347406, chrl8_55347692, chrl8_55401620, chrl8_55401726, chrl8_55401962, chrl8_55401962, chrl8_55402070, chrl8_55863146, chrl8_55863209, chrl8_55863341, chrl8_55863406, chrl8_58846286, chr!8_75629703, chrl9_940774, chr!9_940858, chrl9_941208, chr!9_941242, chrl9_941271, chr!9_941471, chrl9_4020451, chrl9_8066130, chrl9_8180812, chrl9_l 1943461, chrl9_l 1943461, chrl9_l 3002733, chrl9_13002909, chrl9_13027645, chrl9_l 3027708, chrl9_29879973, chrl9_30071371, chrl9_30071556, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_32327361, chrl9_33408728, chrl9_33408838, chrl9_35046673, chrl9_39052997, chrl9_53965120, chrl9_53965266, chrl9_53976301, chr2_520529, chr2_520537, chr2_926606, chr2_1939158, chr2_4416732, chr2_6286826, chr2_8535196, chr2_8811580, chr2_22449630, chr2_27738485, chr2_27738489, chr2_27738545, chr2_30688941, chr2_30689098, chr2_42221994, chr2_42964618, chr2_44884032, chr2_60479437, chr2_73008587, chr2_79929386, chr2_85447333, chr2_88493781, chr2_96895479, chr2_99699856, chr2_100923151, chr2_106974041, chr2_l 15082751, chr2_120543523, chr2_127840596, chr2_144507406, chr2_l 44508216, chr2_144509942, chr2_144512702, chr2_148147429, chr2_159230649, chr2_169415560, chr2_180445347, chr2_184141131, chr2_192676064, chr2_198316634, chr2_199447280, chr2_ 199449983, chr2_199450146, chr2_201872813, chr2_203121062, chr2_211590141, chr2_211590198, chr2_212520797, chr2_212524214, chr2_214915957, chr2_216827945, chr2_219281611, chr2_219888095, chr2_222470101, chr2_2249760 2, chr2_227315087, chr2_227315087, chr2_231390519, chr2_232574302, chr2_234438247, chr2_234438297, chr2_236121881, chr20_1400335, chr20_1837975, chr20_5670261, chr20_23049529, chr20_23049808, chr20_34196362, chr20_40692708, chr20_40692864, chr20_43423564, chr20_43564715, chr20_49882081, chr20_52979500, chr20_52979806, chr20_53032932, chr20_54696328, chr20_55284577, chr20_57730506, chr20_57730576, chr20_60889288, chr20_62225257, chr2l_2l578917, chr21_26832783, chr2l_26832851, chr21_28103489, chr21_28103489, chr21_29221598, chr21_29221717, chr21_29917226, chr21_37606568, chr21_40771526, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr21_46510096, chr22_24425152, chr22_24425165, chr22_24425229, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425705, chr22_24425710, chr22_24425754, chr22_24425816, chr22_24425972, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24427448, chr22_24428701, chr22_24428719, chr22_24433075, chr22_24433241, chr22_24433423, chr22_24434088, chr22_24434350, chr22_24434476, chr22_24434989, chr22_24435262, chr22_24436014, chr22_24436130, chr22_24436142, chr22_24437360, chr22_24437763, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24440446, chr22_24441113, chr22_24441159, chr22_29184647, chr22_29184668, chr22_29185058, chr22_30737962, chr22_34617159, chr22_34617213, chr22_35114720, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_44940707, chr22_46346927, chr22_48824678, chr22_49391984, chr22_50658490, chr3_8595802, chr3_8596019, chr3_10546902, chr3_10546931, chr3_13191245, chr3_15391356, chr3_22857045, chr3_23272516, chr3_30391151, chr3_32506316, chr3_41117522, chr3_46301401, chr3_53425664, chr3_59955536, chr3_70568431, chr3_73746874, chr3_76628994, chr3_81591988, chr3_81591988, chr3_99932654, chr3_105471988, chr3_l 12000443, chr3_112508351, chr3_l 13651082, chr3_l 13902470, chr3_ 122908926, chr3_142925609, chr3_l 43082577, chr3_143082617, chr3_150033642, chr3_154551207, chr3_164753486, chr3_171894906, chr3_l 79540277, chr3_179616279, chr3_181704894, chr3_181704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_181724459, chr3_181724559, chr4_578126, chr4_667460, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_7766077, chr4_8576626, chr4_8868232, chr4_9109274, chr4_l 1187567, chr4_13785708, chr4_15944086, chr4_25237957, chr4_30170558, chr4_36635749, chr4_38356556, chr4_39815565, chr4_52055928, chr4_53508148, chr4_53840582, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_77897059, chr4_77897104, chr4_87411016, chr4_87865311, chr4_89379269, chr4_152888059, chr5_1554827, chr5_6810030, chr5_6810073, chr5_10524764, chr5_10524872, chr5_30772245, chr5_38403906, chr5_43282446, chr5_43282460, chr5_50998048, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_78701917, chr5_89120992, chr5_95429494, chr5_l 00877542, chr5_107099103, chr5_ 113040537, chr5_l 15106946, chr5_127066418, chr5_140543089, chr5_145529393, chr5_150680117, chr5_151512421, chr5_151512485, chr5_151520158, chr5_167983052, chr5_172860804, chr5_172860953, chr5_l 75033106, chr5_175441994, chr5_ 175442040, chr5_175442086, chr5_175442387, chr5_175442710, chr5_l 75442710, chr5_175692802, chr5_175692868, chr5_ 178604407, chr5_180155459, chr5_180155581, chr6_3482654, chr6_33906454, chr6_34036167, chr6_36775571 , chr6_40888325, chr6_60830914, chr6_87948947, chr6_91513599, chr6_96873290, chr6_105628390, chr6_l 08804924, chr6_109824080, chr6_l 09977550, chr6_109977690, chr6_109981771, chr6_109981907, chr6_l 10018487, chr6_l 10439611, chr6_l 17562504, chr6_l 18577805, chr6_120951342, chr6_121099723, chr6_136924776, chr6_136943473, chr6_l 37290533, chr6_l 39254024, chr6_150204270, chr6_150204473, chr6_150893713, chr6_155123808, chr6_l 58528243, chr6_162547293, chr6_168301762, chr6_ 169961951, chr7_1231081, chr7_1672459, chr7_1672799, chr7_ 1672928, chr7_1672933, chr7_1673021, chr7_1673310, chr7_1674842, chr7_1675096, chr7_1675099, chr7_1675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_2108124, chr7_6988371, chr7_6988400, chr7_7273541, chr7_8976868, chr7_l 7586547, chr7_28632740, chr7_45198338, chr7_45198353, chr7_54795471, chr7_71592009, chr7_80057215, chr7_88282441, chr7_93580834, chr7_94840949, chr7_101915316, chr7_101915318, chr7_102107431, chr7_135147918, chr7_138971636, chr7_149730029, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_159142397, chr7_159231032, chr7_159231136, chr8_10296807, chr8_13310666, chr8_27662591, chr8_29052797, chr8_41246826, chr8_52246671, chr8_52252719, chr8_52485371, chr8_56439745, chr8_56441389, chr8_56444235, chr8_57356053, chr8_58117688, chr8_58768196, chr8_58986453, chr8_63031540, chr8_64773383, chr8_80345362, chr8_84031486, chr8_87977499, chr8_97191731, chr8_102754235, chr8_l 17042553, chr8_l 18694978, chr8_l 18694978, chr8_122825356, chr8_129464046, chr8_140608236, chr8_140729234, chr8_141800471, chr8_141800485, chr8_141800688, chr8_143213111, chr8_144241354, chr9_29444070, chr9_29444070, chr9_35350760, chr9_42278765, chr9_73879045, chr9_75657076, chr9_79190169, chr9_79193652, chr9_79193716, chr9_81702877, chr9_83315819, chr9_91268452, chr9_93156160, chr9_93156181, chr9_109388040, chr9_109719145, chr9_ll 1786816, chr9_l 14250397, chr9_l 14250449, chr9_l 14250469, chr9_ 114250578, chr9_l 19121913, chr9_120498228, chr9_121830266, chr9_122212102, chr9_ 122224319, chr9_127496263, chr9_130919131, chr9_130919223, chr9_134351622, chr9_134351726, chr9_134420593, chr9_134420684, chr9_l 36323313, or e. chrl.967238, chrl_3504172, chrl_6954205, chrl.6954346, chrl_7048907, chrl_8094575, chrl.9182245, chrl_9529013, chrl.9826671, chrl_10969247, chrl_12306466, chrl_15437470, chrl.15629316, chrl_15765576, chrl_16921554, chrl.17411021, chrl_17535615, chrl_17535924, chrl.19706305, chrl_20369180, chrl_20748527, chrl_21413174, chrl_23309318, chrl_25729798, chr 1.25968446, chrl_27249955, chrl_28675626, chrl.28866361, chrl_30120569, chrl_30127035, chrl.30830766, chrl.30830843, chrl.36226553, chrl.36953252, chrl_38114428, chrl_38114479, chrl.38418368, chrl_39994748, chrl_41767337, chrl_43465467, chrl_43465657, chrl.45049761, chrl.47930687, chrl_50837887, chrl_55154474, chrl_55154499, chrl.58551063, chrl.58786705, chrl.61973801, chrl.66250918, chr 1.66534669, chrl.82344735, chrl.83627211, chrl.84779343, chrl.86323634, chrl_88186554, chrl_89387906, chrl_91197452, chrl_99844148, chr 1.99920443, chrl_107575614, chrl_109323018, chrl_109687772, chrl_1099 1193, chrl.110508162, chrl.l 14587732, chrl.l 14587798, chrl.l 18257426, chrl .155009422, chrl .156440052, chrl.161837399, chrl.166161 182, chrl.174451522, chr 1.174451522, chrl.191351740, chrl.192538779, chrl.197451335, chrl.200664873, chrl.203109470, chrl.207434747, chr 1.210626571, chrl.213899571, chrl.219915507, chrl.223535050, chrl.224770412, chrl.226712592, chrl.232767359, chrl.234145180, chr 1.237556460, chrl.241329400, chrl.242442381, chr 1.242442419, chrl.242442709, chrl.244054001, chrl.244054019, chrl.244054025, chrl.244054088, chrl.244054213, chrl.244054334, chrl.244054412, chrl.244054487, chrl.244087973, chrl.247437780, chrlO.387726, chrlO.935305, chrlO.l 247497, chrl0_1318744, chr 10.1357942, chrlO.1360114, chrlO.1372793, chr 10.1394602, chrlO.1403853, chrlO.1464103, chrl0_1508066, chrl0_1508075, chrlO.1534652, chrlO.1535173, chrlO.1535179, chrlO.1535208, chrlO.1535214, chrlO.1538728, chrlO.1542987, chrl0_1543090, chrlO.1543258, chrlO.1547036, chrlO.1547973, chrlO.1549841, chrlO.1550998, chrlO.1552016, chrlO.1562547, chrlO.1569401, chrlO.1577668, chrlO.1577694, chrlO.1596439, chrlO.1599134, chrlO.1599460, chrl0_1610306, chrlO.1611415, chrlO.1611485, chrlO.1625484, chrlO.l 626613, chrlO.1626656, chrlO.1626669, chrlO.1633241, chrlO.1654938, chrlO.1661003, chr 10.1661062, chrlO.1661397, chrlO.1666355, chrlO.1666430, chrlO.1666472, chrlO.1666792, chrlO.1668209, chrlO.1671751, chrlO.1671760, chrlO.1679796, chrlO.l 680977, chrlO.1680989, chrlO.l 682975, chrlO.1686583, chrlO.1686722, chrlO.1694923, chrlO.1710088, chrlO.1711037, chr 10.1711066, chrl0_1712543, chrlO.1713526, chrlO.1717306, chrlO.1717669, chrlO.1721323, chrlO.1722689, chrlO.1722905, chrlO.1723106, chrlO.1723168, chrlO.1723256, chrlO.1723398, chrlO.1724434, chrlO.1724564, chrlO.1724748, chrlO.1724818, chrlO.1725175, chrlO.1726197, chrlO.1726436, chrlO.1726447, chr 10.1726470, chrlO.1727111, chrlO.1727408, chrlO.1727713, chrlO.1727852, chrlO.1975272, chrlO.3927130, chrlO.4731819, chrl0_9585562, chrlO_l 1207696, chrl0_ 11207803, chrl0_12981474, chrl0_13892298, chrl0_14558632, chrl0_16642323, chrl0_17143716, chrl0_23513396, chrl0_23513421, chrl0_25083707, chrl0_26124732, chrl0_29369388, chrl0_29621261, chrl0_29621473, chrl0_31693750, chrl0_32910294, chrl0_33204102, chrl0_34313459, chrl0_34361129, chrl0_34752396, chrl0_35511869, chrl0_43864232, chrl0_43864498, chrl0_44279927, chrl0_44280044, chrl0_45073172, chrl0_48466468, chrl0_48593680, chrl0_49290181, chrl0_59279057, chrl0_59279103, chrl0_59688157, chrl0_67835472, chrl0_69494743, chrl0_69494838, chrl0_71364493, chrl0_71529729, chrl0_72022372, chrl0_73992099, chrl0_75999872, chrl0_79401789, chrl0_80094872, chrl0_85659210, chrl0_85659210, chrl0_87534082, chrl0_87727342, chrl0_88086877, chrl0_91397464, chrl0_92661601, chrl0_96825742, chrl0_97760005, chrl0_100072990, chrl0_100828496, chrl0_101242343, chrl0_101242383, chrl0_102758820, chrl0_106956123, chr!0_107085835, chrl0_108335363, chrl0_108862889, chrl0_l 12992389, chrl0_l 14188109, chrl0_l 14512228, chrl0_114571333, chrl0_l 16043885, chrl0_l 19395824, chrl0_l 19410604, chrlOJ 19413170, chrl0_120517367, chrl0_120517552, chrl0_124961029, chrl0_127347399, chrl0_129558734, chrlO_l 31954864, chrl0_132541497, chrl0_132747207, chrl l_1081483, chrll_1507802, chrll_2237529, chrl l_2237733, chrl l_6333181, chrl l_8334015, chrl l_9187748, chrl l_10175924, chrl l_10626357, chrl 1_10925589, chrll_13922642, chrll_15508856, chrl l_15706202, chrl 1_15852550, chrl 1 J 5852550, chrl 1 16344746, chrl 1_16934508, chrl 1_2361 1038, chrl l_27405472, chrl 1_28552666, chrl l_28552687, chrl l_28552792, chrll_28779431, chrll_30683884, chrl l_31820115, chrl l_31820310, chrl 1_34299545, chrll_35009415, chrl 1_35418357, chrll_41004019, chrl 1_46385139, chrll_46398710, chrl 1 46441679, chrll_59759948, chrll_61298862, chrll_61601245, chrl l_62918024, chrll_62918143, chrl 1_62918154, chrll_62918189, chrl 1_62918204, chrll_62920510, chrl l_64070739, chrll_64635621, chrl l_64638030, chrll_64638061, chrll_64638130, chrll_64638134, chrl l_64638208, chrll_64638406, chrl l_64638423, chrll_64638446, chrll_64638476, chrll_64638487, chrl 1_66316168, chrl 1_66652726, chrl 1_66652738, chrll_66905384, chrll_67303456, chrll_67303525, chrl l_70552247, chrll_70828694, chrl l_70828726, chrll_70828942, chrll_70828959, chrl 1_73319282, chrl l_73636196, chrll_75832244, chrl l_76480559, chrll_83537579, chrll_89375694, chrll_91494016, chrl l_94158916, chrll_94800276, chrl l_94800334, chrll_97297420, chrll_99359783, chrll_105521555, chrl 1_105648919, chrll_107988501, chrll_109332508, chrl 1_112260989, chrl 1_112865051, chrl 1_112865051, chrl 1_113363879, chrl 1_113400998, chrl 1_113408265, chrl 1_113433434, chrl 1_113433544, chrl 1_113444137, chrl 1_113445794, chrl 1_113460726, chrl 1_113468577, chrl 1_113468826, chrl 1_113469191, chrl 1_113469614, chrl 1_113470470, chrl 1_113951190, chrl 1_113951238, chrl 1_114062290, chrl 1_114062488, chrl 1_114064208, chrl 1_114064532, chrl 1_114066467, chrl 1_114067705, chrl 1_114069492, chrl 1_114069680, chrl 1_114964283, chrl 1_117725325, chrl 1_117914441, chrl 1_118210650, chrl 1_118609944, chrl 1_118883931, chrl 1_119840345, chrl l_123025323, chrll_126134274, chrl 1_126871107, chrll_127587360, chrll_127690394, chrl l_127690429, chrll_128402186, chrll_129969666, chrll_131233613, chrl 1_131327076, chrl 1J31679120, chrl2_1324180, chrl2_2081518, chrl2_2465968, chrl2_2842964, chrl2_4387265, chrl2_17254791, chrl2_30766914, chrl2_30974784, chrl2_30974808, chr 12_32719406, chrl2_47947292, chrl2_48788525, chrl2_49708105, chrl2_53274354, chrl2_53274417, chrl2_68919665, chrl2_70443965, chrl2_77308440, chrl2_78560885, chrl2_79364491, chrl2_88450938, chrl2_88451104, chrl2_91615051, chrl2_91645989, chr 12_92221841, chrl2_93894714, chrl2_93894724, chrl2_93894744, chrl2_93894790, chrl2_94695777, chrl2_95356097, chrl2_98459151, chrl2_104666490, chrl2_104666538, chrl2_104858423, chrl2_108910438, chrl2_l 11199420, chrl2_111363167, chrl2_l 11363249, chrl2_113149751, chrl2_114671951, chrl2_l 16980578, chrl2_l 17087702, chrl2_l 19340812, chrl2_121507866, chrl2_122161069, chrl2_122228141, chrl2_125905569, chrl2_127115077, chrl2_129703529, chrl2_131082380, chrl2_131102283, chrl3_24242600, chrl3_27238208, chrl3_27337317, chrl3_27517013, chrl3_33724973, chrl3_35695164, chrl3_41465311, chr!3_44573330, chrl3_45223370, chr 13_45911860, chrl3_73025821, chrl3_73026371, chr!3_73707925, chr!3_73707942, chrl3_78061219, chrl3_92046041, chrl3_93413326, chrl3_98404428, chrl3_101565625, chrl3_103013028, chrl3_103071728, chrl3_103801301, chrl3_104738052, chrl3_106713795, chrl3_107840158, chrl3_l 11944810, chrl3_l 12909258, chr 13_112970862, chrl4_24156171, chrl4_24799228, chrl4_28309117, chrl4_31488551, chrl4_32587882, chrl4_36524389, chrl4_36524667, chrl4_45008380, chrl4_52941165, chrl4_53390381, chrl4_55679980, chrl4_56817138, chr14_58598388, chrl4_61417278, chr 14_61690962, chrl4_62814638, chr!4_65594301, chrl 4_68494555, chrl4_68569744, chrl4_72738631, chrl4_72746337, chrl4_72746410, chrl4_75188760, chrl4_76713363, chrl4_84090996, chrl4_86470352, chrl4_88890190, chrl4_91028417, chrl4_91277631, chrl4_99239873, chrl4_99239938, chrl4_99240690, chrl4_99240729, chrl4_99244159, chrl4_99244383, chrl4_99245037, chrl4_99245125, chrl4_99253114, chrl4_99254307, chrl4_99258195, chrl4_99259778, chrl4_99259851, chrl4_99261299, chrl4_99261349, chrl4_99265134, chrl4_99265442, chrl4_99943176, chrl4_100572028, chrl4_101216074, chrl4_101365577, chrl4_103132495, chrl4_104963567, chrl4_105061228, chrl5_27014884, chrl5_27598866, chrl5_34572508, chrl5_39188740, chrl5_39667040, chrl5_39828226, chrl5_39961524, chrl5_40579060, chr 15_42159095, chrl5_42506523, chrl5_48140618, chrl5_51015399, chrl5_57463798, chrl5_58712954, chrl5_58958301, chrl5_60850769, chrl5_61832637, chrl5_64673973, chrl5_70265944, chrl5_70867831, chrl5_73421182, chrl5_73787063, chrl5_73787074, chr 15_74146200, chrl5_75706205, chrl5_75706213, chrl5_77976043, chrl5_78344288, chrl5_78344315, chrl5_84784380, chrl5_86311581, chrl5_88486678, chrl5_90065084, chrl5_90946906, chrl5_92109249, chrl5_92438644, chrl5_92971963, chrl5_94591665, chrl5_95990733, chrl5_96288168, chrl5_98347522, chrl5_100032792, chrl5_101045494, chrl5_101045497, chrl5_101709644, chrl6_1633341, chrl6_3255898, chrl6_3473308, chrl6_6529078, chrl6_21514377, chrl6_21514493, chrl6_22272849, chrl6_24895739, chrl6_29674272, chrl6_29674291, chrl6_49521066, chrl6_56871247, chrl6_57792334, chrl6_71746300, chrl6_71746304, chr 16_73092631, chrl6_75322268, chrl6_75322268, chrl6_76458256, chrl6_79856776, chrl6_84090291, chrl6_85290977, chrl6_85452156, chr 16_86651909, chr!6_86757258, chrl6_87013194, chrl6_87957932, chrl6_89747287, chrl6_90002798, chr!7_2019254, chr 17_2019280, chr!7_2266557, chrl7_5786789, chr!7_6264478, chrl7_8310790, chrl7_l 1326585, chrl7_17603475, chrl7_17603475, chrl7_19539205, chrl7_19539300, chrl7_20077590, chrl7_21375315, chrl7_21405634, chrl7_28273746, chrl7_28837720, chrl7_29056566, chrl7_29093998, chrl7_31593826, chrl7_32037054, chrl7_32274223, chrl7_39612775, chrl7_45173004, chrl7_45240201, chrl7_48831635, chrl7_49578654, chrl7_49580573, chrl7_51374368, chrl7_58691449, chrl7_61405604, chrl7_62458778, chrl7_63117237, chrl7_63117426, chrl7_65271215, chrl7_68274037, chrl7_69499387, chrl7_72666182, chrl7_74762858, chrl7_75002178, chrl7_75231866, chrl7_75231876, chrl7_76145456, chrl7_76145510, chrl7_78458835, chrl7_78458957, chrl7_78665984, chrl7_79140535, chrl7_81246152, chrl7_81312889, chrl7_81839462, chrl7_81839517, chrl8_1477011, chrl8_3015949, chrl8_7202739, chrl8_7466797, chrl8_7574188, chrl8_7671182, chrl8_l 0232472, chrl8_l 1832622, chrl8_22191374, chrl8_24273998, chrl8_25563957, chrl8_26965747, chrl8_28484687, chrl8_28743520, chrl8_29252619, chrl8_31578184, chr!8_31612779, chrl8_31668044, chrl8_31668223, chrl8_42840523, chrl8_42840569, chr!8_47595163, chr!8_48111878, chrl8_48220327, chrl8_48841418, chrl8_49660177, chrl8_54620704, chr!8_55316591, chrl8_55335150, chrl8_55337856, chrl8_55337859, chrl8_55347406, chrl8_55347692, chrl8_55401620, chrl8_55401726, chrl8_55401962, chrl8_55401962, chrl8_55402070, chrl8_55863146, chrl8_55863209, chrl8_55863341, chrl8_55863406, chrl8_57139112, chrl8_58144488, chrl8_58846286, chrl8_59627566, chrl8_61244954, chrl 8_62551668, chrl8_62551681, chrl8_63087914, chrl8_73923596, chrl8_74833726, chrl 8_75281388, chrl 8_75629703, chr!8_77087501 , chrl8_79206904, chr!9_940774, chrl 9_940858, chrl9_941030, chrl9_941149, chrl9_941208, chrl9_941242, chrl9_941271, chrl9_941471, chrl9_1071020, chrl9_1071474, chrl9_4020451, chrl 9_8066130, chrl9_8066187, chrl9_8180812, chrl9_9944860, chrl9_l 1066436, chrl9_ 11490901, chrl9_l 1943461, chrl9_l 1943461, chrl9_12882294, chrl9_l 3002694, chrl9_13002733, chrl9_l 3002909, chrl9_13002919, chrl9_l 3027038, chrl9_13027452, chrl9_l 3027645, chrl9_13027708, chrl9_l 3804816, chrl9_16287615, chrl9_19493336, chrl9_29879973, chrl9_30071371, chrl9_30071556, chrl9_31596154, chrl9_31959202, chrl9_32044115, chrl9_32327361, chrl9_33408728, chrl9_33408838, chrl9_35046673, chrl9_35086102, chrl9_38221003, chrl9_38470895, chrl9_39052997, chrl9_45018947, chrl9_45019029, chrl9_45216040, chrl9_46604657, chrl9_46731732, chrl9_47365708, chrl9_49913135, chrl9_51225987, chrl9_53965120, chrl9_53965266, chrl9_53976301, chrl9_55485668, chrl9_58538912, chr2_520529, chr2_520537, chr2_926606, chr2_1939158, chr2_4416732, chr2_4416771, chr2_4713113, chr2_6286826, chr2_8287256, chr2_8287404, chr2_8535196, chr2_8811580, chr2_10557447, chr2_l 0557495, chr2_10557501, chr2_18993220, chr2_22449630, chr2_22575886, chr2_23834892, chr2_27738485, chr2_27738489, chr2_27738545, chr2_30688941, chr2_30689098, chr2_36127495, chr2_42221994, chr2_42964618, chr2_43149699, chr2_44884032, chr2_46460276, chr2_46955071, chr2_47026330, chr2_60479437, chr2_61005128, chr2_64793554, chr2_73008587, chr2_76533399, chr2_79929386, chr2_82392549, chr2_85447333, chr2_86421142, chr2_88493781, chr2_90095397, chr2_96895479, chr2_99699856, chr2_100923151, chr2_106974041, chr2_108173836, chr2_109542029, chr2_l 13217808, chr2_ 115082751, chr2_l 19816994, chr2_120543523, chr2_120605793, chr2_121664250, chr2_121664308, chr2_122112932, chr2_122162513, chr2_127132369, chr2_127840596, chr2_128280247, chr2_131406273, chr2_144507406, chr2_l 44508216, chr2_144509942, chr2_144512702, chr2_148147429, chr2_156397401, chr2_159188769, chr2_l 59230649, chr2_161621740, chr2_169415560, chr2_170158816, chr2_172079041, chr2_180445347, chr2_184141131, chr2_184141527, chr2_192676064, chr2_198143307, chr2_198316634, chr2_199447280, chr2_199449983, chr2_199450146, chr2_201872813, chr2_203121062, chr2_204110026, chr2_204434785, chr2_211228268, chr2_211590141, chr2_211590198, chr2_212520797, chr2_212524214, chr2_214915957, chr2_216827945, chr2_218323778, chr2_219281611, chr2_219888095, chr2_222470101, chr2_224976082, chr2_226970614, chr2_227315087, chr2_227315087, chr2_230465348, chr2_231390519, chr2_232011938, chr2_232574302, chr2_233170602, chr2_234438247, chr2_234438297, chr2_236121881, chr2_236442644, chr2_236680576, chr2_236825115, chr2_238282674, chr2_238327106, chr2_239420572, chr2_239574925, chr2_240622671, chr20_l 400335, chr20_1837975, chr20_5024555, chr20_5670261, chr20_7866427, chr20_9493674, chr20_10663952, chr20_17913505, chr20_20699456, chr20_23049529, chr20_23049808, chr20_34196362, chr20_35502853, chr20_36541033, chr20_36872375, chr20_40692708, chr20_40692864, chr20_43423564, chr20_43564715, chr20_48291365, chr20_49882081, chr20_51811855, chr20_52979500, chr20_52979806, chr20_53032932, chr20_54696328, chr20_55284577, chr20_57730506, chr20_57730576, chr20_60750600, chr20_60889288, chr20_62225257, chr20_62819512, chr20_63081946, chr20_63582957, chr21_5068206, chr21_6136224, chr21_14871182, chr21_16589675, chr21_21578917, chr21_26832783, chr21_26832851, chr21_28103489, chr21_28103489, chr21_29221598, chr21_29221717, chr21_2939l039, chr21_29572229, chr21_29917226, chr21_31599647, chr21_33824631, chr21_34957177, chr21_37606568, chr21_40771526, chr21_42158069, chr21_43913788, chr21_44074575, chr21_44074712, chr21_45115249, chr21_45115350, chr21_45434453, chr21_45469473, chr21_46510096, chr21_46606384, chr21_46622779, chr22_19002217, chr22_l 9354500, chr22_19666270, chr22_21937291, chr22_24425152, chr22_24425165, chr22_24425229, chr22_24425382, chr22_24425431, chr22_24425509, chr22_24425705, chr22_24425710, chr22_24425754, chr22_24425816, chr22_24425972, chr22_24426997, chr22_24427006, chr22_24427299, chr22_24427299, chr22_24427448, chr22_24428701, chr22_24428719, chr22_24433075, chr22_24433241, chr22_24433423, chr22_24434088, chr22_24434350, chr22_24434476, chr22_24434989, chr22_24435262, chr22_24436014, chr22_24436130, chr22_24436142, chr22_24437360, chr22_24437763, chr22_24438626, chr22_24438986, chr22_24439144, chr22_24439355, chr22_24440428, chr22_24440446, chr22_24441113, chr22_24441159, chr22_27488317, chr22_29096890, chr22_29146128, chr22_29151957, chr22_29184647, chr22_29184668, chr22_29185058, chr22_30472552, chr22_30737962, chr22_34617159, chr22_34617213, chr22_35114720, chr22_36763391, chr22_36763396, chr22_36763700, chr22_36763790, chr22_37986002, chr22_42646574, chr22_44026938, chr22_44827980, chr22_44940707, chr22_46346927, chr22_47035212, chr22_48824652, chr22_48824678, chr22_49391984, chr22_50192404, chr22_50658490, chr3_2528585, chr3_8595802, chr3_8596019, chr3_l 0546902, chr3_l 0546931, chr3_13191245, chr3_15391356, chr3_16908451, chr3_18064875, chr3_22857045, chr3_23272516, chr3_29736383, chr3_30391151, chr3_31409610, chr3_32506316, chr3_41117522, chr3_42733336, chr3_46301401, chr3_47422872, chr3_47689722, chr3_47689722, chr3_50620837, chr3_52140116, chr3_52140201, chr3_53425664, chr3_56203330, chr3_56434152, chr3_59955536, chr3_62807299, chr3_70568431, chr3_72321259, chr3_73746874, chr3_76549448, chr3_76628994, chr3_79368010, chr3_80420694, chr3_81591988, chr3_81591988, chr3_88788605, chr3_99932654, chr3_102334993, chr3_105471988, chr3_107915549, chr3_109565120, chr3_ 112000443, chr3_l 12508351, chr3_l 13651082, chr3_l 13902470, chr3_l 14746010, chr3_l 22908926, chr3_123653613, chr3_126774624, chr3_130566788, chr3_134430495, chr3_134660205, chr3_140501227, chr3_142925609, chr3_143082577, chr3_143082617, chr3_150033642, chr3_150556578, chr3_l 51377932, chr3_152058781, chr3_154551207, chr3_157872750, chr3_158094973, chr3_159753818, chr3_l 64753486, chr3_164753534, chr3_168027547, chr3_170045189, chr3_171894906, chr3_179540277, chr3_179616279, chr3_180283387, chr3_181704894, chr3_181704950, chr3_181715790, chr3_181716153, chr3_181724058, chr3_181724236, chr3_181724459, chr3_181724559, chr3_188051674, chr3_192578970, chr3_l 92822185, chr3_194028101, chr3_194247515, chr3_196757788, chr3_197606574, chr3_197677415, chr3_197800521, chr4_578126, chr4_667460, chr4_1245701, chr4_3374062, chr4_3374241, chr4_3374306, chr4_3374342, chr4_3374416, chr4_3376702, chr4_3377079, chr4_3382402, chr4_3384176, chr4_3384314, chr4_3384476, chr4_3385161, chr4_3385479, chr4_3385492, chr4_3385638, chr4_3385938, chr4_3385938, chr4_3389678, chr4_3389731, chr4_3389755, chr4_3389767, chr4_3390227, chr4_3391658, chr4_3393330, chr4_3393340, chr4_3393693, chr4_3394128, chr4_3405668, chr4_3406740, chr4_3406740, chr4_3410433, chr4_3410511, chr4_3411467, chr4_3411570, chr4_3642975, chr4_4169964, chr4_6854578, chr4_7551934, chr4_7626609, chr4_7766077, chr4_8576626, chr4_8868232, chr4_9109274, chr4_ll 187567, chr4_12022338, chr4_l 3785708, chr4_15944086, chr4_25237957, chr4_25602291, chr4_27041550, chr4_27041550, chr4_30170558, chr4_31772049, chr4_36635749, chr4_37629013, chr4_38077991, chr4_38356556, chr4_39815565, chr4_44257363, chr4_44770533, chr4_52055928, chr4_53508148, chr4_53840582, chr4_54041134, chr4_54226464, chr4_54226502, chr4_54226613, chr4_54226617, chr4_54236780, chr4_54655713, chr4_67939385, chr4_77897059, chr4_77897104, chr4_77902675, chr4_84492457, chr4_87411016, chr4_87865311, chr4_88058507, chr4_89379269, chr4_94410831, chr4_l 13707038, chr4_l 17877755, chr4_l 19027422, chr4_120659773, chr4_137538611, chr4_149008859, chr4_150185669, chr4_l 50185691, chr4_150828760, chr4_150828760, chr4_152888059, chr4_163154908, chr4_165204068, chr4_l 72578855, chr4_183611170, chr5_1554827, chr5_4942229, chr5_6810030, chr5_6810073, chr5_8773657, chr5_10524764, chr5_10524872, chr5_15851430, chr5_17043558, chr5_17306281, chr5_24856145, chr5_30772245, chr5_32631299, chr5_36490437, chr5_36490583, chr5_38383233, chr5_38403906, chr5_38457056, chr5_43282446, chr5_43282460, chr5_44117981, chr5_50998048, chr5_50998391, chr5_54475097, chr5_56589734, chr5_57399190, chr5_58754333, chr5_60339877, chr5_60340044, chr5_65126330, chr5_65126379, chr5_67976871, chr5_74294397, chr5_74397232, chr5_74397237, chr5_78701917, chr5_79842653, chr5_83553431, chr5_89120992, chr5_89474124, chr5_95429494, chr5_95503240, chr5_95820943, chr5_100877542, chr5_107099103, chr5_110767118, chr5_l 13040537, chr5_l 13181090, chr5_l 14319704, chr5_l 15106946, chr5_l 16361553, chr5_l 16864787, chr5_l 27066418, chr5_128254452, chr5_140543089, chr5_145529393, chr5_148966479, chr5_ 150140043, chr5_150680117, chr5_151512421, chr5_151512485, chr5_151520158, chr5_160247828, chr5_160247828, chr5_l 62977137, chr5_167264351, chr5_167264377, chr5_167983052, chr5_168880153, chr5_169244217, chr5_l 72844168, chr5_172860804, chr5_172860953, chr5_173793773, chr5_175033106, chr5_175441994, chr5_l 75442040, chr5_175442086, chr5_175442387, chr5_175442710, chr5_175442710, chr5_175692802, chr5_l 75692868, chr5_ 178604407, chr5_180155459, chr5_180155581, chr6_725467, chr6_3482654, chr6_4789352, chr6_5724062, chr6_6907253, chr6_6907404, chr6_7137767, chr6_8839734, chr6_9035118, chr6_l 1778228, chr6_26756234, chr6_33906454, chr6_34036167, chr6_36775571, chr6_37006218, chr6_37684799, chr6_37713585, chr6_40888325, chr6_53816078, chr6_60830914, chr6_65498438, chr6_71257145, chr6_72620288, chr6_80711323, chr6_87948947, chr6_89949296, chr6_91513599, chr6_96873290, chr6_103266434, chr6_105628390, chr6_l 06520270, chr6_l 08804924, chr6_109824080, chr6_109977550, chr6_109977690, chr6_109981771, chr6_109981907, chr6_l 10018487, chr6_l 10105517, chr6_l 10439611, chr6_l 17562504, chr6_l 18577805, chr6_l 18695678, chr6_120951342, chr6_l 21099723, chr6_125991533, chr6_132713871, chr6_134809530, chr6_136924776, chr6_136943473, chr6_l 37290533, chr6_l 39254024, chr6_139408933, chr6_143432179, chr6_ 145694391, chr6_146685764, chr6_l 47500518, chr6_148967681, chr6_150204270, chr6_150204473, chr6_150893713, chr6_152859420, chr6_l 55123808, chr6_158528243, chr6_159116933, chr6_162547293, chr6_163403779, chr6_164351123, chr6_l 65726824, chr6_168301762, chr6_ 169961951, chr7_605238, chr7_12 1081, chr7_1672459, chr7_1672799, chr7_1672928, chr7_l 672933, chr7_l 673021, chr7_l 673310, chr7_l 674842, chr7_l 675096, chr7_1675099, chr7_1675882, chr7_1676417, chr7_1676641, chr7_1677528, chr7_1677614, chr7_1678807, chr7_1680106, chr7_1964753, chr7_1964753, chr7_2108124, chr7_2954193, chr7_4242663, chr7_5244881 , chr7_5244971, chr7_5834355, chr7_6139824, chr7_6988371, chr7_6988400, chr7_7273541, chr7_7609460, chr7_8783649, chr7_8976868, chr7_l 7586547, chr7_19111176, chr7_27822880, chr7_28632740, chr7_31007402, chr7_40828899, chr7_43884803, chr7_45198338, chr7_45198353, chr7_47238811, chr7_48427116, chr7_51640974, chr7_52571138, chr7_54795471, chr7_66199154, chr7_67453619, chr7_69099312, chr7_69099312, chr7_69099326, chr7_71592009, chr7_74183318, chr7_76305544, chr7_77909010, chr7_80057215, chr7_87851757, chr7_88282441, chr7_90709817, chr7_92278330, chr7_93580834, chr7_94840949, chr7_97427528, chr7_100986599, chr7_100986780, chr7_101062908, chr7_101657486, chr7_101915316, chr7_101915318, chr7_ 102107431, chr7_105637154, chr7_106848245, chr7_l 14399231, chr7_l 14428892, chr7_l 14575444, chr7_131430361, chr7_131603062, chr7_132646113, chr7_133830213, chr7_135147918, chr7_138971636, chr7_138996163, chr7_l 39542065, chr7_146691141, chr7_149730029, chr7_149875303, chr7_l 50150657, chr7_ 150451230, chr7_151652356, chr7_154750541, chr7_154916613, chr7_157585001, chr7_157585009, chr7_157897933, chr7_157897945, chr7_157897964, chr7_157897966, chr7_157897972, chr7_157898014, chr7_ 159142397, chr7_159231032, chr7_159231136, chr8_1757845, chr8_3245755, chr8_5575147, chr8_8575133, chr8_9901380, chr8_10296807, chr8_l 3310666, chr8_22243620, chr8_22762602, chr8_27662591, chr8_29052797, chr8_32310673, chr8_41246826, chr8_45729351, chr8_52246671, chr8_52252719, chr8_52485371, chr8_56439745, chr8_56441389, chr8_56444235, chr8_56445225, chr8_57356053, chr8_58117688, chr8_58768196, chr8_58986453, chr8_61697578, chr8_62391722, chr8_63031540, chr8_64773383, chr8_65188438, chr8_66011320, chr8_80345362, chr8_84031486, chr8_85556739, chr8_87977499, chr8_88495042, chr8_88495214, chr8_92942006, chr8_97191731, chr8_ 102754235, chr8_l 15421230, chr8_ 117042553, chr8_l 18694978, chr8_ 118694978, chr8_l 18707989, chr8_122825356, chr8_129464046, chr8_140608236, chr8_140729234, chr8_141800471, chr8_l 41800485, chr8_141800688, chr8_143213111, chr8_144241354, chr8_ 144242229, chr9_22851312, chr9_25755075, chr9_29444070, chr9_29444070, chr9_35350760, chr9_38042823, chr9_42278765, chr9_68830859, chr9_73193094, chr9_73193094, chr9_73863812, chr9_73879045, chr9_75657076, chr9_79190169, chr9_79193652, chr9_79193716, chr9_81624163, chr9_81702877, chr9_83315819, chr9_89240725, chr9_90939328, chr9_91222453, chr9_91268452, chr9_93156160, chr9_93156181, chr9_95546440, chr9_99824708, chr9_109388040, chr9_109719145, chr9_l 11786816, chr9_ 114250397, chr9_l 14250449, chr9_l 14250469, chr9_l 14250578, chr9_l 14804274, chr9_l 19121913, chr9_120498228, chr9_l 21699909, chr9_121830266, chr9_ 122212102, chr9_122224319, chr9_ 124441496, chr9_126414292, chr9_l 27496263, chr9_129632189, chr9_130919131, chr9_130919223, chr9_131063253, chr9_132223939, chr9_134111490, chr9_134351622, chr9_134351726, chr9_134420593, chr9_134420684, chr9_135941758, chr9_l 36035347, chr9_l 36323313, chr9_1 6512314, chr9_136512504, chr9_137281028.

20. The kit of claim 18 or 19, wherein the nucleic acid prohes comprise or consist of at least 30 of SEQ ID NOS: 1 to 2415, 1 to 1585, 1586-2385, or 2386-2415.

21. The kit of claim 18, 19 or 20, further comprising sodium bisulfite one or more restriction endonucleases, or combinations thereof.