Grant: Discovery Grants Program - Individual

Genome variation is critical for phenotypic diversity, fitness and evolution yet our knowledge of the mechanisms responsible for new mutations is limited. Mutations occur over a lifespan in all cell types, but life is dynamic, cell populations are large and diverse, a genome is large, and mutations are rare. Mutation research is challenging. My NSERC-funded research seeks to understand how new mutations arise in mice. My core trainees [2PhD, 4MSc, 5HBSc] and I will examine the number, type and spacing of new mutations across the mouse genome to infer mutational mechanisms. We are intrigued by hotspots, clustering, recurrence, tissue-specificity and developmental timing of mutations. Mechanisms underlying these spatial and temporal phenomena are understudied but new study designs, technology and analytical tools offer new capabilities. Parent-progeny [mouse family] studies permit detection of mutations newly inherited and acquired with development. Recent reports find mutations that are too many, too close, biased in type, and specific to a tissue type or developmental stage. Properties of these non-random phenomena offer mechanistic clues. My long-term vision is to understand the origins of inherited germline and acquired somatic de novo mutations [DNMs]. In the next five years, we will use mouse family study designs, leading-edge genome sequencing technologies and variant calling bioinformatics with new analytical tools for the highest resolution and sensitivity in the analysis of the greatest spectrum of mutation types. Objectives: We will use Parent-Progeny studies and whole genome sequencing of mouse tissues to analyze features of new mutations and infer mutational mechanisms. We will examine: 1] mutations that arise in progeny of parents of 1] crosses of two inbred mouse strains and 2] crosses of outbred mice. Gametes of inbred and outbred mouse genetic backgrounds are hypothesized to differ in the number and spatial distribution of new mutations. 3] We will use new ultra-deep and error-corrected sequencing to profile the number and nature of new mutations in a panel of different tissues of inbred and outbred mice. Genome variation within tissues is hypothesized to reflect tissue-specific biology. Novelty and Significance: We will discover the distinctives of mutagenesis in gametes and other cell types and the factors affecting mutation spacing and timing. Our results are relevant to understanding genetic variation, phenotypic diversity, and genome evolution. Outcomes include new computational, statistical and data visualization tools for analysis of mutation landscapes. Our data will provide a baseline profile of inherited and acquired mutations as a reference applied in comparisons with mouse models of compromised DNA replication and repair to further insight into mechanisms of genome maintenance. Our experimental approach can be applied to biomonitoring and study of mutational mechanisms associated with environmental mutagens.