Somatic epimutations cap genetic determinism in the human diploid chromatin epigenome.

Fiber-seq inferred regulatory elements (FIRE) give a more comprehensive and quantitative view of accessible chromatin across the 6 Gbp diploid human genome, correcting biases in existing catalogs. FIRE enables detection of haplotype-selective chromatin accessibility, revealing imprinted elements without parent-of-origin DNA methylation differences, modules allowing escape from X chromosome inactivation, and disrupted TF binding at the HLA locus in immune cells. The work also shows autosomal somatic chromatin epimutations propagate through clonal expansion as mitotically stable, non-genetic regulatory alterations.