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 the nematode C. elegans, a simple metazoan organism that is especially amenable to combining powerful cytological, genetic and genomic approaches in a single experimental system, and in which the events under study are particularly accessible. Multiple lines of research are converging on a view of meiotic prophase as a highly integrated biological system that incorporates multiple ?engineering design features? such as positive and negative feedback, self-limiting properties, quality control and fail-safe mechanisms that together promote a robust biological outcome. Our goal under the MIRA program is to elucidate how the different features of the meiotic program work, both individually and as a system, through integrating the use of advanced technologies that enable us to visualize the process (either through microscopic imaging or computational analysis of sequence-based assays) with advantages of the C. elegans system that enable experimental perturbation of the process. Another major long term goal is to understand the fundamental basis of homolog recognition and the nature of the interface between aligned homologous chromosomes. We will interrogate the process of meiosis at multiple different scales: 1) at the level of the DNA repair complexes that assemble at the sites of meiotic recombination; 2) at the level of the meiosis-specific chromosome structures that promote, regulate and respond to meiotic recombination events; 3) at the level of DNA organization at the whole-chromosome scale; and 4) at the level of nucleus-wide responses to signals that report on the status of the chromosomes.
The proposed research will increase our understanding of the basic mechanisms that promote and ensure the faithful inheritance of chromosomes. The work is highly relevant to human health, as errors in chromosome inheritance are one of the leading causes of miscarriages and birth defects and are also a major factor contributing to the development and progression of cancer. Several aspects of our program address how DNA damage is recognized and repaired appropriately, which is important for maintaining intact chromosomes and inhibiting cancer progression. Other aspects will address how key events are coordinated during the meiotic program, how chromosomes are organized in 3D space, and how these features contribute to successful inheritance of genomes.