The evolutionary and genomic drivers of mutation spectra

Project summary: The evolutionary and genomic drivers of mutation spectra. Patterns of spontaneous mutation vary widely, but there is currently no consensus as to how selection and drift shape this variation. Our goal is to explain diverse mutation patterns, connecting evolutionary causes and consequences with molecular mechanisms. Mutation rates are predicted to be higher in cases where selection had less opportunity to act over evolutionary time, but there is no consensus as to whether this hypothesis is supported by existing evidence. We will test this idea using a novel framework that leverages variation within and among yeast species. Yeast can grow asexually as either haploids or diploids, but species differ in which cell type predominates. We predict that mutation rates will be higher in cells of the rare type in any given species, because selection has had little opportunity to act on mutator alleles specific to that cell type. We will test for ploidy-specific mutation patterns in multiple yeast species that have either haploid- or diploid-dominant life cycles, and test candidate molecular mechanisms for these differences. This project is expected to confirm a controversial hypothesis for the evolution of mutation rates while avoiding previous limitations. Sex is a major dimension of biological variation that can affect mutation patterns, both with regards to differences between males and females as well as the presence or absence of recombination. There is evidence that spontaneous mutations are more likely to arise in the germline of males than females, but the reasons for this bias are still debated. Many existing measures of sex biased mutation come with important limitations, and many organisms also have a sex bias in recombination, potentially confounding the interpretation of sex differences. To disentangle the influence of sex versus recombination we will use a fruit fly strain that lacks meiotic DNA double strand breaks to manipulate the presence of recombination. We will also use crossing techniques to maintain chromosomes with male- or female-exclusive transmission. Allowing mutations to accumulate in these strains and then sequencing their genomes we will provide a unique and powerful perspective on the respective roles of parental sex and recombination in the mutation process. We will further explore the interaction between sex and mutation by measuring how mutations affect reproductive traits. In fruit flies, we will explore the impact of aneuploidy on males and females to understand levels of observed karyotype variation under mutation-selection balance. Yeast are largely asexual, but there is evidence that sexual selection can operate in this system. We will characterize genetic variation for mating- type specific reproductive performance, using genomic data to identify causal alleles. By converting mutant strains between mating types and ploidy states we will be able to infer genetic trade-offs between sexual and asexual performance, informing models for the evolution of sex and anisogamy. These projects will deepen our understanding of how sex and recombination co-evolve with the mutation process.