Cis-regulation and natural selection in the evolution of human DNA methylation.

Lineage-specific selection shapes promoter DNA methylation across entire pathways in human versus chimpanzee cell types, including pathways tied to speech, cognition, and hepatitis C susceptibility.

• Why it matters: It remains unclear how species-specific methylation patterns originate, what they do to transcriptional regulation, and whether methylation differences reflect natural selection rather than neutral drift.
• What they did: The study used a hypothesis-testing framework with DNA methylation from six human and chimpanzee cell types plus fused interspecies hybrid cells to separate cis- from trans-acting methylation divergence genome-wide.
• The result: Methylation divergence was primarily cis-driven, with some links to nearby CpG gains and losses, while rarer trans regions were enriched for TF motifs such as FOXM1; cis-linked methylation showed stronger methylation–expression associations.

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