Mechanisms of meiotic and mitotic recombination

ABSTRACT Recombination is both a means to avoid genome instability and to process that generates genome instability. In meiosis, DNA double-strand breaks are repaired into crossovers that are essential for accurate segregation of homologous chromosomes; defects in this process result in sterility or aneuploidy, the major cause of pregnancy loss and trisomy. Conversely, in mitotically proliferating cells double-strand breaks are a dangerous class of DNA damage. Repair of breaks in this context is done without making crossovers; formation of crossovers in mitotic cells can lead to chromosome rearrangements and tumorigenesis. Research in my laboratory focuses on mechanisms that promote crossovers in meiotic cells and non- crossover outcomes of repair in mitotic cells. We have made important contributions to understand these problems for 20 years, during which time I have trained numerous scientists who are active in research and research-related careers. This proposal sketches out both continued and new directions that will drive the field forward. These include investigations of how large gaps are repaired (important for designing Cas9 fragment integration experiments and Cas9-based gene drive systems) and how meiotic crossovers are patterned (important for proper segregation of chromosomes into gametes). We use a combination of genetics, primarily using Drosophila as a model organism, genomics, biochemistry, cell biology, evolutionary biology, and mathematical modeling.