Great ape mutation spectra vary across the phylogeny and the genome due to distinct mutational processes that evolve at different rates

All heritable variation begins with mistakes in the transmission of DNA from parents to children. Different DNA motifs can have different mutation rates, and these rates can evolve over time: the spectrum of mutability of three-base-pair motifs has evolved rapidly during great ape diversification, contradicting the fixed molecular clock model. The relative mutation rates of three-base-pair motifs differ significantly among great ape lineages, implying that multiple unknown modifiers of DNA replication fidelity have arisen and fixed on each branch of the ape phylogeny. Such mutator alleles might directly modify DNA replication or repair, or might instead act indirectly by modifying traits like reproduction or chromatin structure. Certain mechanisms of action are expected to create mutations in specific regions of the genome, meaning that the spatial distribution of lineage-specific mutations is informative about their causality.

To harness this source of information, we measured mutation spectra of several functional compartments (such as late-replicating regions) whose attributes are known or suspected to affect their mutation rates. Using genetic diversity from 88 great apes, we find that most functional compartments are imprinted by localized mutational signatures but that these signatures explain very little of the mutational divergence between species. Rather, compartment-specific signatures layer with species-specific signatures to create mutational portraits that reflect both lineage and function. Our results suggest that cis-acting mutational modifiers are highly conserved between species and rapid mutation spectrum evolution is driven primarily by trans-acting modifiers.