View Program - 2022 Population, Evolutionary, and Quantitative Genetics Conference

The distribution of fitness effects (DFE) of new mutations is a key parameter in molecular evolution. The DFE has been explored across different species and across different genes within a species. Recent work has compared the DFE for sites with different levels of conservation across a multispecies alignment finding that the more conserved a site, the more likely mutations occurring at this site are deleterious. In this work, we compare the DFE of sites with different mutation rates in humans based on their 3mer sequence context. For each of the 64 mutation types, we compute their mutation rate using de novo mutations from trio data and their DFE using the distribution of allele frequencies of synonymous and non-synonymous mutations occurring at the same sequence context. We correlate the mutation rate and the mean selective effect of the 64 mutations, compute the unweighted DFE (that is an artificial DFE where all sites have the same mutation rate) and compare it with the observed DFE under the germline and somatic mutation spectra. Our work highlights the importance of mutation bias across sites to explain the observed DFE in humans and the unappreciated tumorogenic role of the somatic mutation spectrum.

The relationship between the distribution of fitness effects and the distribution of mutation rates