GENETIC CONTROL OF MEIOTIC CHROMOSOME SEGREGATION

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Errors during meiotic cell division are a leading cause of mental retardation and pregnancy failure in our species. Research over the past decade has demonstrated that the vast majority of meiotic errors are maternal in origin and that the incidence of these errors is strongly correlated with maternal age. The mechanism(s) of error, however, and the manner in which age influences the process of meiotic chromosome segregation remain unknown. The proposed research approaches this problem by focusing on an essential feature of meiotic chromosomes that mediates chromosome segregation at the first meiotic division; reciprocal exchange (recombination) events between homologous chromosomes. Our understanding of the high meiotic error rate in our species has been hampered by the lack of a suitable animal model. The advent of gene targeting technology, however, has provided a means of creating mutations in specific gene. Targeted disruption of genes involved in DNA mismatch repair has resulted in the first mammalian mutants that show a reduction in recombination levels. We will utilize these mutants as well as naturally occurring murine variants to understand the role of recombination in meiotic chromosome segregation. These studies will provide valuable insight to the control of the normal female meiotic process and will allow us to test hypotheses about the mechanism of meiotic errors in the human female.