Variation in the molecular clock of primates

Abstract Events in primate evolution are often dated by assuming a “molecular clock”, i.e., a constant rate of substitution per unit time, but the validity of this assumption remains unclear. Among mammals, it is well known that there exists substantial variation in yearly substitution rates. Such variation is to be expected from differences in life-history traits, suggesting that it should also be found among primates. Motivated by these considerations, we analyze whole genomes from ten primate species, including Old World Monkeys (OWMs), New World Monkeys (NWMs) and apes, focusing on putatively neutral autosomal sites and controlling for possible effects of biased gene conversion and methylation at CpG sites. We find that substitution rates are ˜65% higher in lineages leading from the hominoid-NWM ancestor to NWMs than to apes. Within apes, rates are ˜2% higher in chimpanzees and ˜7% higher in the gorilla than in humans. Substitution types subject to biased gene conversion show no more variation among species than those not subject to it. Not all mutation types behave similarly, however: in particular, transitions at CpG sites exhibit a more clock-like behavior than do other types, presumably due to their non-replicative origin. Thus, not only the total rate, but also the mutational spectrum varies among primates. This finding suggests that events in primate evolution are most reliably dated using CpG transitions. Taking this approach, we estimate that the average time to the most recent common ancestor of human and chimpanzee is 12.1 million years and their split time 7.9 million years. Significance statement Much of our understanding of the chronology of human evolution relies on the “molecular clock”, i.e., a constant rate of substitutions per unit time. To evaluate the validity of this assumption, we analyze whole genome sequences from ten primate species. We find that there is substantial variation in the molecular clock between apes and monkeys, and rates even differ within hominoids. Importantly, not all mutation types behave similarly: notably, transitions at CpG sites exhibit a more clock-like behavior than other substitutions, presumably due to their non-replicative origin. Thus, the mutation spectra, and not just the overall substitution rates, are changing across primates. This finding further suggests that events in primate evolution are most reliably dated using CpG transitions.