Abstract
DNA is a remarkably precise medium for copying and storing biological information. This high fidelity results from the action of hundreds of genes involved in replication, proofreading, and damage repair. Evolutionary theory suggests that in such a system, selection has limited ability to remove genetic variants that change mutation rates by small amounts or in specific sequence contexts. Consistent with this, using SNV variation as a proxy for mutational input, we report here that mutational spectra differ substantially among species, human continental groups and even some closely related populations. Close examination of one signal, an increased TCC→TTC mutation rate in Europeans, indicates a burst of mutations from about 15,000 to 2000 years ago, perhaps due to the appearance, drift, and ultimate elimination of a genetic modifier of mutation rate. Our results suggest that mutation rates can evolve markedly over short evolutionary timescales and suggest the possibility of mapping mutational modifiers.
Highlights
Germline mutations provide the raw material for evolution and generate genetic load and inherited disease
While the precise roles of most of the relevant genes have not been fully elucidated, research on somatic mutations in cancer has shown that defects in particular genes can lead to increased mutation rates within very specific sequence contexts (Alexandrov et al, 2013; Helleday et al, 2014)
We show that mutation spectrum change is much more widespread than these initial studies suggested: the TCC!TTC rate increase in Europeans was unusually dramatic, smaller scale changes are so commonplace that almost every great ape species and human continental group has its own distinctive mutational spectrum
Summary
Germline mutations provide the raw material for evolution and generate genetic load and inherited disease. Due to the combined action of hundreds of genes, mutation rates are extremely low–in humans, about one point mutation per 100 MB or about 60 genome-wide per generation (Kong et al, 2012; Segurel et al, 2014). Mutations in the proofreading exonuclease domain of DNA polymerase cause TCT!TAT and TCG!TTG mutations on the leading DNA strand (Shinbrot et al, 2014). Mutational shifts of this kind have been referred to as ‘mutational signatures’. Specific signatures may be caused by nongenetic factors such as chemical mutagens, UV damage, or guanine oxidation (Ohno et al, 2014)
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