Friday, January 3, 2025
1/3/2025
Program Summary Our research is aimed at understanding the molecular and cellular mechanisms underlying the faithful inheritance eukaryotic chromosomes. Our primary focus is on elucidating the events required for the orderly segregation of homologous chromosomes during meiosis, the crucial process by which diploid germ cells generate haploid gametes. These events are of central importance to sexually reproducing organisms, since failure to execute them correctly leads to chromosomal aneuploidy, one of the leading causes of miscarriages and birth defects in humans. During meiotic prophase, chromosomes undergo a dramatic and dynamic program of structural reorganization in preparation for the meiotic divisions. Moreover, chromosome inheritance during meiosis relies on the formation of double-strand DNA breaks (DSBs) and repair of a subset of these DSBs as inter-homolog crossovers (COs). Because the DSBs that serve as the initiating events of meiotic recombination pose a danger to genome integrity, the success of genome inheritance during meiosis requires cells to maintain a balance between the beneficial effects of COs and the potential harmful consequences of the process by which they are generated. A major goal of our research is to understand the mechanisms that operate during meiosis to achieve this crucial balance. An inter-related goal is to understand how meiosis-specific chromosome organization is established, maintained, and remodeled to bring about successful segregation of homologous chromosomes. We are approaching these issues using Caenorhabditis nematodes, simple metazoan organisms that are especially amenable to an integrated application of powerful cytological, genetic, genomic, and biochemical approaches, and in which the events under study are particularly accessible. Our goal under the MIRA program is to pursue a systems-level understanding of meiosis, based on the recognition that multiple distinct aspects of the meiotic program are intimately interconnected, and that robustness of the system is an emergent property of this interconnectedness. Our approach will build on recent technical advances and new discoveries in the well-established C. elegans experimental system, in combination with opportunities afforded by a newly-introduced Caenorhabditis interspecies hybrid model, to interrogate the meiotic program at multiple levels. Planned areas of investigation will include: Elucidating mechanisms that ensure reliable formation of CO- based connections for all chromosome pairs; Exploring how different events and developmental transitions in the meiotic program are temporally and spatially coordinated; Investigating the functional organization of meiosis-specific chromosome structures that promote and regulate meiotic recombination and enable chromosomes to sense and respond to events occurring at distant positions; Pursuing a new approach aimed at understanding the fundamental basis of homolog recognition.
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