Second, we studied how sequence variants between the two alleles of the same individual can lead to allelic biases in histone modifications, DNA methylation, and transcript levels. We reconstructed chromosome-spanning haplotypes for ESCs, four ESC-derived cell lines71 and 20 tissue samples60, and we resolved allele-specific activity and structure for each. We found widespread allelic bias in both transcript levels and epigenomic marks for each epigenome. For example, 24% of all testable genes that contain exonic variants demonstrate allelic transcription in one or more ESC or ESC-derived cell lineages, and the majority of these genes also exhibit allelic epigenomic modifications in promoters (71%) and Hi-C-linked enhancers (69%)71. Similarly, as many as 11% of the testable enhancers display allelic bias in histone modification H3K27ac in the 20 tissue samples with allele-resolved transcription and chromatin states60. Allelic histone acetylation at enhancers is highly specific to individual genotypes, and often occurs near sequence variants that alter transcription factor binding, suggesting cis-acting sequence drivers60,71.
