Genome-wide DNA methylation landscape of four Chinese populations and epigenetic variation linked to Tibetan high-altitude adaptation

DNA methylation (DNAm) is one of the major epigenetic mechanisms in humans and is important in diverse cellular processes. The variation of DNAm in the human population is related to both genetic and environmental factors. However, the DNAm profiles have not been investigated in the Chinese population of diverse ethnicities. Here, we performed double-strand bisulfite sequencing (DSBS) for 32 Chinese individuals representing four major ethnic groups including Han Chinese, Tibetan, Zhuang, and Mongolian. We identified a total of 604,649 SNPs and quantified DNAm at more than 14 million CpGs in the population. We found global DNAm-based epigenetic structure is different from the genetic structure of the population, and ethnic difference only partially explains the variation of DNAm. Surprisingly, non-ethnic-specific DNAm variations showed stronger correlation with the global genetic divergence than these ethnic-specific DNAm. Differentially methylated regions (DMRs) among these ethnic groups were found around genes in diverse biological processes. Especially, these DMR-genes between Tibetan and non-Tibetans were enriched around high-altitude genes including EPAS1 and EGLN1, suggesting DNAm alteration plays an important role in high-altitude adaptation. Our results provide the first batch of epigenetic maps for Chinese populations and the first evidence of the association of epigenetic changes with Tibetans’ high-altitude adaptation.