Affiliations: 1) University of Pennsylvania, Philadelphia, PA; 2) University of California, Berkeley, CA; 3) Columbia University, New York, NY
Keywords: Comparative genomics & genome evolution
Germline mutations are the source of all heritable variation. Understanding the rate and mechanisms by which mutations occur is of paramount importance for studies of human genetics (to interpret heritable disease prevalence) and evolutionary biology (to date evolutionary events). Over the past decade, there has been a flood of data in genomics––within pedigrees, among populations and across species––that is fundamentally revising our understanding of the process of mutagenesis. In my talk, I will first briefly summarize the key findings from these different datasets and then discuss recent findings investigating differences in mutation rate and spectrum (i.e., proportions of different mutation types) across human populations. To investigate inter-population differences, we developed a framework to compare polymorphisms that arose in different time windows in the past while controlling for the effects of selection and biased gene conversion. Applying this approach to Europeans, Africans and East Asians from 1000 Genomes Project, we uncovered multiple significant differences in the mutation spectrum within and across human populations, including at least two independent changes that occurred after the split of the continental groups. Interestingly, we also found that non-Africans and Africans differ significantly in their mutation spectra even for ancient polymorphisms that predate out-of-Africa migration likely due to mutational differences between the ancestors of modern humans and archaic hominins. By relating the observed variations in polymorphisms to the parental age effects on de novo mutations, we show that plausible estimates of reproduction ages cannot explain the joint patterns observed for different mutation types, implying that changes at the molecular level such as genetic modifiers and varying environments have had a non-negligible impact in shaping the human mutation landscape. The composite nature of mutation rate underscores the challenges of using it as the molecular clock for dating evolutionary events even for recent timescales.