# The evolutionary and genomic drivers of mutation spectra

> **NIH NIH R35** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $375,430

## Abstract

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
asexua...

## Key facts

- **NIH application ID:** 10938177
- **Project number:** 1R35GM154954-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Nathaniel Sharp
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $375,430
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938177

## Citation

> US National Institutes of Health, RePORTER application 10938177, The evolutionary and genomic drivers of mutation spectra (1R35GM154954-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10938177. Licensed CC0.

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