Extensive Variation in Chromatin States Across Humans

The majority of disease-associated variants lie outside protein-coding regions, suggesting a link between variation in regulatory regions and disease predisposition. We studied differences in chromatin states using five histone modifications, cohesin, and CTCF in lymphoblastoid lines from 19 individuals of diverse ancestry. We found extensive signal variation in regulatory regions, which often switch between active and repressed states across individuals. Enhancer activity is particularly diverse among individuals, whereas gene expression remains relatively stable. Chromatin variability shows genetic inheritance in trios, correlates with genetic variation and population divergence, and is associated with disruptions of transcription factor binding motifs. Overall, our results provide insights into chromatin variation among humans. Overall design: To characterize human variation in diverse types of regulatory elements, we studied the chromatin state of lymphoblastoid cell lines (LCLs) derived from 19 individuals: 5 European (CEU), 7 Yoruban (YRI), and 2 Asian individuals from the 1000 Genomes Project (including two mother-father-daughter trios), an additional Caucasian individual), and four individuals from the San population). We used RNA-Seq to measure expression and Chromatin Immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) to map five histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, and H3K27me3) and two general factors (CTCF, and SA1, a subunit of cohesin). We generated 2 replicates per factor.