%0 Journal Article %A Catherine Do %A Emmanuel Dumont %A Martha Salas %A Angelica Castano %A Huthayfa Mujahed %A Leonel Maldonado %A Arunjot Singh %A Govind Bhagat %A Soren Lehman %A Angela M. Christiano %A Subha Madhavan %A Peter L. Nagy %A Peter H.R. Green %A Rena Feinman %A Cornelia Trimble %A Karen Marder %A Lawrence Honig %A Catherine Monk %A Andre Goy %A Kar Chow %A Samuel Goldlust %A George Kaptain %A David Siegel %A Benjamin Tycko %T Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs %D 2019 %R 10.1101/815605 %J bioRxiv %P 815605 %X Background Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing functional regulatory sequence polymorphisms (rSNPs). However, the unique advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified.Results We performed whole genome methyl-seq on diverse normal human cells and tissues from multiple individuals, plus a group of cancers (multiple myeloma, lymphoma, and glioblastoma multiforme). After excluding imprinted regions, the data pinpointed 11,233 high-confidence ASM differentially methylated regions (DMRs), of which 821 contained SNPs in strong linkage disequilibrium or precisely coinciding with GWAS peaks. ASM was increased 5-fold in the cancers, due to widespread allele-specific hypomethylation and focal allele-specific hypermethylation in regions of poised chromatin. Allele-switching at ASM loci was increased in the cancers, but destructive SNPs in specific classes of CTCF and transcription factor (TF) binding motifs correlated strongly with ASM in both normal and cancer cells. Allele-specific binding site occupancies from ChIP-seq data were enriched among ASM loci, but most ASM DMRs lacked such annotations, and some were found in otherwise uninformative “chromatin deserts”.Conclusions ASM is increased in cancers but it is produced by shared underlying mechanisms in normal and neoplastic cells. Dense maps of ASM in normal plus cancer samples, provided here as genome browser tracks, uncover mechanistically informative rSNPs that are difficult to find by other approaches. We show examples of TF binding sites disrupted by these rSNPs that point to altered transcriptional pathways in autoimmune, neuropsychiatric, and neoplastic diseases. %U https://www.biorxiv.org/content/biorxiv/early/2019/11/01/815605.full.pdf