Segregation of homologous chromosomes at the first meiotic division is dependent on the placement of genetic exchanges along the length of the chromosomes. In most organisms, including humans, absent or mis-located exchanges dramatically increase the likelihood of nondisjunction. Despite the importance of this process, we remain remarkably ignorant of the mechanisms through which the sites of exchange are chosen and the overall level of recombination is controlled in meiocytes. In the proposed studies we will combine molecular and cytological approaches to investigate the biology of human meiotic recombination. Our studies will focus on the human male, assessing the manner in which homologous chromosomes initiate and complete the process of synapsis and characterizing recombination in normal males. These studies will allow us to test hypotheses about inter-individual and inter-chromosomal variation, the importance of the synaptonemal complex in mediating recombination levels, and the nature of cross-over interference and to ask directly whether some individuals may be predisposed to meiotic nondisjunction. In related studies, we will use the power of mouse genetics to identify the gene(s) that control the level of recombination in mammals. In a final set of studies, we will conduct meiotic studies of infertile men. We will utilize the meiotic data obtained and the clinical findings to categorize these individuals, focusing subsequent mutation detection studies on that subset of infertile male most likely to include individuals with mutations in meiotic genes. The combined data from these studies will not only provide answers to basic questions about meiotic recombination in the human, but may well lead to the identification of the first recombination-dependent causes of human infertility.
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