Mechanisms of mutation and recombination and their evolution in vertebrates

PROJECT SUMMARY Mutation and meiotic recombination are the sources of all genetic variation, the fuel of evolution, and the ultimate cause of heritable diseases and of many cancers. Consequently, their rates and properties are of fundamental interest, as well as key parameters in almost any population or human genetic study. Yet many aspects of these processes remain poorly understood. Notably, despite strong constraints on both mechanisms–how deleterious errors in recombination or abnormal numbers of mutations can be–they evolve rapidly over time and differ markedly across species. My group takes advantage of this variation within humans and between species, using it as a tool to learn about the underlying processes of mutagenesis and meiotic recombination. To this end, we combine mathematical modeling, statistical data analysis, and genomic approaches in humans and a broad range of non-model organisms. Ongoing work is concentrated along two main axes: (1) Elucidating sources of point mutations and causes of differences in germline mutagenesis between human sexes and across amniotes; and (2) Characterizing the strategies used by different vertebrate species to direct meiotic double strand breaks to the genome and understanding their evolution. Ultimately, our goal is to elucidate not only how but also why these fundamental genetic processes differ across individuals and species. Answers to these questions have important implications for human and evolutionary genetics, as well as for cancer biology.