Population whole-genome bisulfite sequencing across two tissues highlights the environment as the principal source of human methylome variation

Abstract

BackgroundCpG methylation variation is involved in human trait formation and disease susceptibility. Analyses within populations have been biased towards CpG-dense regions through the application of targeted arrays. We generate whole-genome bisulfite sequencing data for approximately 30 adipose and blood samples from monozygotic and dizygotic twins for the characterization of non-genetic and genetic effects at single-site resolution.ResultsPurely invariable CpGs display a bimodal distribution with enrichment of unmethylated CpGs and depletion of fully methylated CpGs in promoter and enhancer regions. Population-variable CpGs account for approximately 15–20 % of total CpGs per tissue, are enriched in enhancer-associated regions and depleted in promoters, and single nucleotide polymorphisms at CpGs are a frequent confounder of extreme methylation variation. Differential methylation is primarily non-genetic in origin, with non-shared environment accounting for most of the variance. These non-genetic effects are mainly tissue-specific. Tobacco smoking is associated with differential methylation in blood with no evidence of this exposure impacting cell counts. Opposite to non-genetic effects, genetic effects of CpG methylation are shared across tissues and thus limit inter-tissue epigenetic drift. CpH methylation is rare, and shows similar characteristics of variation patterns as CpGs.ConclusionsOur study highlights the utility of low pass whole-genome bisulfite sequencing in identifying methylome variation beyond promoter regions, and suggests that targeting the population dynamic methylome of tissues requires assessment of understudied intergenic CpGs distal to gene promoters to reveal the full extent of inter-individual variation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0856-1) contains supplementary material, which is available to authorized users.

Roadmap for investigating epigenome deregulation and environmental origins of cancer

“…Until very recently, there was a major gap in our understanding of the “normal” epigenome and its normal variability . As the capacity to map the epigenome continues to increase, the catalog of epigenetic variations associated with adverse environmental exposures will undoubtedly expand . The specific research questions highlighted below warrant particular attention in that they remain equivocal or have not been fully addressed.…”

Genome-Wide Epigenetic Studies in Chicken: A Review

“…The methylation of DNA in gene promoters is usually negatively associated with gene expression [18][19][20][21], whereas it may be positively correlated with transcription within the bodies of actively transcribed genes [22]. In human monozygous twins, differential methylation was shown across several tissues, suggesting that the life history of an individual is able to modify the way its genome is expressed through DNA methylation [23]. The characterization of DNA methylation associated with phenotypic variation is documented in several species [13].…”

Saliva as a Blood Alternative for Genome-Wide DNA Methylation Profiling by Methylated DNA Immunoprecipitation (MeDIP) Sequencing

“…This may partly be explained by the lower enrichment observed in the blood samples or differences in cell-type composition, which is known to vary substantially in buffy coat as a function of season, age, and sex [46][47][48]. However, a high correlation, per se, is still expected, even without correction for cell composition and sex, as methylation status at most CpGs is conserved across tissues [49][50][51][52][53]. This is also illustrated in a methylation array based pilot study where, at 70% of CpGs, methylation positively correlated between saliva and blood even when cell composition was uncorrected for [54].…”