RT Journal Article SR Electronic T1 Timing and causes of the evolution of the germline mutation spectrum in humans JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.06.17.496622 DO 10.1101/2022.06.17.496622 A1 Ziyue Gao A1 Yulin Zhang A1 Molly Przeworski A1 Priya Moorjani YR 2022 UL http://biorxiv.org/content/early/2022/06/18/2022.06.17.496622.abstract AB Recent studies have suggested that the human germline mutation rate and spectrum evolve rapidly. When and why these changes occurred remains unclear, however. We develop a framework to characterize temporal changes in polymorphisms within and between human populations, while controlling for the effects of selection and biased gene conversion. Applying this approach to high-coverage, whole genome sequences from the 1000 Genomes Project, we detect significant changes in the mutation spectrum of alleles of different ages, notably two independent changes that arose after the split of the ancestors of African and non-African populations. We also find that the mutation spectrum differs significantly between populations sampled in and outside of Africa at old polymorphisms that predate the out-of-Africa migration; this seemingly contradictory observation is likely due to mutation rate differences in remote ancestors that contributed to varying degrees to the ancestry of contemporary human populations. Importantly, by relating the mutation spectrum of polymorphisms to the parental age effects on de novo mutations, we show that plausible changes in the age of reproduction over time cannot explain the joint patterns observed for different mutation types. Thus, other factors–– genetic modifiers or environmental exposures––must have had a non-negligible impact on the human mutation landscape.Competing Interest StatementThe authors have declared no competing interest.