Human lineages, including anatomically modern and archaic humans such as Neanderthals and Denisovans, show notable morphological and behavioral differences from nonhuman African apes like chimpanzees and gorillas. As regulatory changes are thought to be a major driver of phenotypic divergence, we sought to identify such regulatory changes along the lineage leading to humans since the split from chimpanzees. Given that DNA methylation is the best proxy for gene expression in ancient samples, we compared methylation maps across modern humans and nonhuman African great apes, alongside DNA methylation reconstructed from ancient DNA of anatomically modern humans (AMHs) and archaic humans.
In past work we detected differentially methylated regions (DMRs) across human linages, separating modern humans, Neanderthals and Denisovans. Here, we extend this work and detect DMRs separating all human lineages from nonhuman African apes. To this end, we experimentally generated whole-genome DNA methylation maps from bones of a gorilla, a chimpanzee, and six present-day humans, and supplemented these with reconstructed methylation profiles from a Neanderthal, a Denisovan, and 28 high-coverage AMH samples. Applying stringent and conservative filtering criteria, we identified over 430 DMRs distinguishing humans from nonhuman African apes, as well as hundreds that show chimpanzee-specific methylation. Together, this constitutes the most comprehensive resource on changes in DNA methylation across apes. These DMRs tend to be associated with bone remodeling and blood pressure control.
Notably, humans predominantly show hypermethylation relative to the other African apes. This pattern aligns with prior findings of increased methylation in DMRs separating modern and archaic humans, suggesting that traits we recognize as distinctly modern human represent a continuation of evolutionary processes initiated much earlier in human evolution.