Striking interindividual variability in the Methylome: Comparison of dizygotic vs monozygotic twins

DNA methylation at various cytosine-guanine dinucleotide sites (CpG methylation) is known to be variable and is likely involved in human trait formation and disease susceptibility. Analyses within populations have been biased towards CpG-dense regions––due to the application of targeted arrays. Authors (in article referenced below) performed whole-genome bisulfite sequencing data on ~30 adipose and blood samples from monozygotic and dizygotic twins, in order to compare the characterization of non-genetic vs genetic effects at single-site resolution.

Invariable CpGs displayed a bimodal distribution with enrichment of unmethylated CpGs and depletion of fully methylated CpGs in promoter and enhancer regions. Population-variable CpGs accounted for approximately 1520 % of total CpGs per tissue, were enriched in enhancer-associated regions, and were depleted in promoters, and single-nucleotide variants at CpG sites were a frequent confounder of extreme methylation variation.

Differential methylation was 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 was 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 were shared across tissues and, thus, limited inter-tissue epigenetic drift. CpH methylation (in which “H” denotes A, C or T) was rare, and showed similar characteristics of variation patterns as CpG methylation.

This interesting study underscores the utility of low-pass whole-genome bisulfite sequencing in identifying methylome variation above-and-beyond promoter regions, and suggests that targeting the population dynamic methylome of tissues––requires assessment of understudied intergenic CpGs distal to gene promoter regions, in order to reveal the full extent of inter-individual variation––even between identical twins..!!

 Genome Biol 2015; 16: 290

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