WGEN MUTATION · Understanding mutation using genome-wide sequence-based approaches

Mutation is the ultimate source of all genetic variation and as such propels the many biological processes that depend on such variation. These include such medically relevant processes as the development of antibiotic resistance, adaptation of pathogens and commensal bacteria to their hosts, and cancer development. Despite the importance of mutation we currently know very little about the dynamics of how the mutational process affects patterns of genomic variation. I propose here to creatively utilize new sequencing technologies, and the resulting ability to obtain extremely large quantities of genomic sequence data to, in a manner never before possible, study mutation, and variation in mutation at a genome-wide level. The work proposed here will address some of the most pressing open questions regarding mutation, and how it shapes patterns of genomic variation: I will use genome-wide, unbiased approaches to quantify overall mutation rates, and elucidate the ways in which differences in the relative rates of different types of mutations bias the patterns of genomic variation generated by mutation. I will reveal how the overall rates of mutation, and the biases introduced by mutation vary, be it between different bacterial lineages, within bacterial populations, in response to changes in bacterial growth, or in the case of somatic mutation in mammals, with age. In addition to shedding much light on what is one of the major forces of evolution, the results of this project will have clear implications for, among other things, our ability to elucidate function from data of genomic variation, our understanding of medically relevant bacterial adaptations, and our understanding of cancer development, and the relationship between cancer and aging.