mutation rate and spectrum are selected in yeast

What determines the rate and molecular spectrum of mutation is a fundamental question. The prevailing hypothesis asserts that natural selection against deleterious mutations has pushed mutation rate to the minimum achievable in the presence of genetic drift, or the drift barrier. Here we show that, contrasting this hypothesis, mutation rate substantially exceeds the drift barrier in diverse organisms. Random mutation accumulation (MA) in yeast frequently reduces mutation rate, and deleting the newly discovered mutator gene PSP2 nearly halves mutation rate. These results, along with a comparison between the MA and natural yeast strains, demonstrate that mutation rate is maintained above the drift barrier by stabilizing selection. Similar comparisons show that the mutation spectrum such as the universal AT mutational bias is not intrinsic but has been selectively preserved. These findings blur the separation of mutation from selection as distinct evolutionary forces but open the door to alleviating mutagenesis in various organisms by genome editing.