Extremely Rare Polymorphisms in Saccharomyces cerevisiae Allow Inference of the Mutational Spectrum

Abstract

The characterization of mutational spectra is usually carried out in one of three ways–by direct observation through mutation accumulation (MA) experiments, through parent-offspring sequencing, or by indirect inference from sequence data. Direct observations of spontaneous mutations with MA experiments are limited, given (i) the rarity of spontaneous mutations, (ii) applicability only to laboratory model species with short generation times, and (iii) the possibility that mutational spectra under lab conditions might be different from those observed in nature. Trio sequencing is an elegant solution, but it is not applicable in all organisms. Indirect inference, usually from divergence data, faces no such technical limitations, but rely upon critical assumptions regarding the strength of natural selection that are likely to be violated. Ideally, new mutational events would be directly observed before the biased filter of selection, and without the technical limitations common to lab experiments. One approach is to identify very young mutations from population sequencing data. Here we do so by leveraging two characteristics common to all new mutations—new mutations are necessarily rare in the population, and absent in the genomes of immediate relatives. From 132 clinical yeast strains, we were able to identify 1,425 putatively new mutations and show that they exhibit extremely low signatures of selection, as well as display a mutational spectrum that is similar to that identified by a large scale MA experiment. We verify that population sequencing data are a potential wealth of information for inferring mutational spectra, and should be considered for analysis where MA experiments are infeasible or especially tedious.

Cytosine methylation affects the mutability of neighbouring nucleotides in human, Arabidopsis, and rice

“…Here, we use data on rare polymorphisms in human, A. thaliana, and rice to quantify the mutational effect methylation has on adjacent bases. Rare SNPs constitute a better proxy for mutational processes than common SNPs or substitutions as the latter more strongly reflect longer-term selection and gene conversion (Rahbari et al 2016;Zhu et al 2017). Controlling for sequence context and chromatin state, and considering a range of potential confounders, we find, in contrast to previous results, that methylation is associated with reduced SNP incidence at CpG-neighbouring sites in human.…”

Population genomics reveals evolution and variation ofSaccharomyces cerevisiaein the human and insects gut

“…The long lasting association of S. cerevisiae with human activities (3150 BC) (Cavalieri et al ., ; Fay and Benavides, ; Legras et al ., ; Goddard et al ., ; Liti, ) has led to the idea that its wide use in fermentation has caused its domestication. Few studies have examined the population biology of S. cerevisiae , its genetic variation and evolution (Fay and Benavides, ; Aa et al ., ; Ezov et al ., ; Ruderfer et al ., ; Legras et al ., ; Zhu et al ., ; Almeida et al ., ; Zhu et al ., ). However, whole genome analysis classified S. cerevisiae strains accordingly to the isolation source (Oak, Wine/European or West African) and the type of human activity from which they derived (Dunn et al ., ), suggesting that the population structure of this yeast consists of a few isolated lineages and mosaicism (Liti et al ., ; Liti, ).…”

Deep sequencing of natural and experimental populations of Drosophila melanogaster reveals biases in the spectrum of new mutations

“…Two such alternative approaches include mutation accumulation (MA) experiments in model organisms (Halligan and Keightley 2009) and a more recently proposed method in which very rare polymorphisms in natural populations are used as a proxy for new mutations (Messer 2009;Aggarwala and Voight 2016;Zhu et al 2017). These approaches have complementary strengths and weaknesses.…”