Nuclear Organization and Regulation of Meiotic Recombination

2009 new Scholar Award in aging

Loss of reproductive fitness is a hallmark of aging, conserved from yeast to humans. Not only does aging result in fewer progeny, it can also affect ìquality,î as progeny produced late in life may be inviable or otherwise less fit. Women over a certain age are at a higher risk for miscarriages or children with developmental disorders, such as Down and Klinefelterís syndromes. The offspring of older fathers have a higher risk of neurodevelopmental disorders, such as schizophrenia and autism. Little is know about the molecular mechanisms that underlie these phenomena. However, it is likely that the misregulation of events in meiosis contribute.

Meiosis is a specialized cell division in which a diploid cell gives rise to haploid gametes, such as eggs and sperm. To ensure that chromosomes segregate appropriately during meiosis, homologous chromosomes undergo recombination, the exchange of genetic material. We have preliminary evidence that proteins associated with the nuclear envelope regulate meiotic recombination. These proteins often localize chromosomal loci to the periphery of the nucleus, leading us to speculate that the large-scale organization of chromosomes within the nucleus affects recombination. More importantly, defects in these and other proteins at the nuclear envelope have been linked to aging and there is a growing body of literature linking loss of nuclear integrity with aging. Therefore, we believe that a potential explanation for loss of reproductive fitness is misregulation of meiotic recombination in response to aging-induced loss of nuclear integrity. We plan to 1) further characterize the role of nuclear organization in regulating meiotic recombination, 2) assess meiotic recombination in aging animals, as well as in mutants that extend and shorten lifespan, and 3) identify additional factors involved in age-dependent regulation of meiotic recombination. We perform our experiments using the nematode worm C. elegans as a model organism, which provides genetic, biochemical and cytological tools to address the question of how aging affects meiotic recombination and genomic stability.