The evolution and diversity of mutation, molecular fidelity, and genome structure

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Project Summary Abstract Mutation is the source of all evolutionary novelty and diversity shaping both the structure and sequence of genomes. Over evolutionary timescales changes to genome structure and content are associated with vast phenotypic changes between and within species. Throughout the lifetime of an organism individual cells accumulate somatic mutations that can also confer selective advantages. Our lab is interested in how mutations emerge and how these changes to genome sequence and structure are maintained and acted on by selection. We seek to understand at both the cellular and organismal level how cell-type, genotype, selective pressures, and evolutionary histories influence the structure and sequence of the genome. Ultimately, our research will further our understanding of the mechanisms underlying why specific cell types are more susceptible to disease as well as how genome structure influences phenotypic diversity within and between species. Patterns of somatic mutation have been extensively studied in the context of cancer tumor genomes in which clonal expansions amplify the signals of mutation to detectable levels. Far less is understood however about how “normal” cells accumulate mutations through time and how these dynamics are influenced by factors such as cell type and genotype. Furthermore, somatic mutations have proven challenging to identify due to the comparably high error rate of standard sequencing approaches. We propose to use novel genomic methods to investigate how different forms of somatic mutation accumulate and how somatic mutational processes are impacted by inherited genetic variation. In addition to discerning the contexts in which individual cells accumulate mutations, we propose to determine how genome structures have evolved in the context of different evolutionary histories, selective pressures, and life history strategies. While the size and structure of eukaryotic genomes varies tremendously spanning three orders of magnitude in vertebrates, the evolutionary and mechanistic bases of this variation remain unknown. We propose to study the evolution of genome architectures in the explosive adaptive radiation of rockfish to understand how extreme variation in lifespan can impact mutational processes and genetic diversity. We further propose to study how the structures of human and chimpanzee genomes have been shaped by local adaptations and the forces of selection. Identifying signatures of selection and adaption at structurally variable (SV) loci has been challenging in part due the tendency of SVs to emerge in complex repetitive regions of the genome. We propose to use long-read based genomics approaches and novel computational methods to assess these loci. Ultimately, our research will further our understanding of mutation, diversity, and genome structural diversity both within and between species as well as among the individual cells of organisms.