During the formation of egg and sperm, the homologous recombination-mediated exchange of genetic material between homologs is critical for proper chromosome segregation. Defects in crossing over can have catastrophic consequences ranging from miscarriage to chromosomal abnormalities such as Down and Klinefelter Syndromes. These defects result from absent or aberrantly placed crossovers (COs) and are influenced by chromosome-specific factors that are poorly understood. Identifying the underlying causes responsible for these chromosome-specific effects is a major challenge in the field, in part because CO formation is regulated at multiple steps, and in part because changes in distribution are not detected until they have deleterious consequences. Our goal is to identify factors whose loss predisposes chromosomes to missegregation by influencing how and where COs occur. This work could ultimately lead to preventative measures to avoid meiotic failure. A prior genetic screen in our lab led to the identification and subsequent characterization of factors that are specifically required for CO formation on the X chromosome and not the autosomes, revealing that chromosome-specific factors contribute significantly to meiotic CO formation. In this exploratory grant, we build upon this work and propose to develop fluorescent reporter strains of C. elegans that will allow us to obtain recombination data for multiple chromosomes simultaneously. This tool will provide unprecedented access to chromosome-specific and genomic patterns of CO distribution and allow us to assess whether they change coordinately in response to various stresses and mutations. We will use this tool to screen for new meiotic regulators based on their ability to directly change the recombination landscape. In addition, the fluorescent reporter strains will be provided to the C. elegans community where they will be useful both as mapping strains and in detailed analysis of meiotic mutants and environmental exposures.
During the specialized cell division program that gives rise to egg and sperm, DNA is exchanged between matching chromosome pairs. Defects in these exchanges account for a high proportion of miscarriages and birth defects. The proposed research will lay the foundation for treatment of human reproductive disorders by giving us a tool both to investigate how these exchanges are controlled and to identify factors that play a direct role is this process.
