Rapid evolution of the human mutation spectrum

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 TCCtrue0false→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.DOI: http://dx.doi.org/10.7554/eLife.24284.001

Ancestral characterization of 1018 cancer cell lines highlights disparities and reveals gene expression and mutational differences

“…55 When not accounting for ancestry, the mutational differences identified across cancers might be ascribed exclusively to differences in tumor type (for example, kidney cancer vs ovarian cancer), whereas our results demonstrate that these differences may be significantly influenced by ancestry (ie, European vs East Asian). Furthermore, these differences agree with recent findings of mutational differences across ancestry, 56,57 and extend such mutational work into a cancer genome context. However, it is important to note that calling somatic mutations is notoriously difficult, and that even though COSMIC somatic calls represent one of the best curated sets to date, somatic mutation call sets are often plagued by high falsepositive rates.…”

Signatures of replication timing, recombination and sex in the spectrum of rare variants on the human X chromosome and autosomes

“…In this respect, we note that a number of recent studies have shown that the mutation spectrum changes slightly across populations (3,(82)(83)(84). These findings have largely been attributed to biochemical modifiers of mutation that alter the relative rates of different mutation types by influencing the biochemical process of error/repair over time.…”

TrackSig: reconstructing evolutionary trajectories of mutations in cancer

“…Another important innovation of TrackSig is the used of CCF as a surrogate for evolutionary timing. Similar ideas have been used in human population genetics, where variant allele frequency to get relative order of mutations along the ancestral lineage 25 . In population genetics, allele frequency is calculated across individuals, while we calculate VAF across cell population within a single sample.…”