Segregation of error-prone chromosomes in meiosis

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DESCRIPTION (provided by applicant): In humans, meiotic chromosome segregation errors result in aneuploidy-based birth defects such as Down's, Klinefelter's, and Turner's Syndromes, cause most spontaneous abortions, and are frequently responsible for infertility. The incidence of conceptuses with inappropriate numbers of chromosomes rises with increased maternal age. Recombination between homologous chromosomes greatly increases the probability that they will segregate properly (away from each other) at meiosis I. It has been proposed that in humans many meiotic chromosome segregation errors occur because of two sequential failures of the meiotic machinery. First, failed or inappropriately placed recombination between homologous chromosomes makes them "error-prone". These error-prone chromosomes probably segregate correctly in most meioses, but failures of a second, undefined, component of the segregation machinery renders cells unable to partition these error-prone chromosomes properly. Increased failures in the second component are thought to be responsible for the increased incidence of trisomic progeny as woman age. One candidate for the second failed mechanism is spindle, or spindle checkpoint, function. Studies of meiotic segregation of error-prone chromosomes in yeast have revealed a two-step failure process with strong similarities to the human situation. In yeast, as in humans, failures in recombination render chromosome pairs error-prone in meiosis, and highly dependent on a second process. This second process requires the conserved spindle checkpoint gene, MAD3 (related to BubR1 in humans). The goal of this project is to examine the mechanisms used to partition error-prone chromosomes in yeast meiosis. The aims are: 1) Determine how MAD3 contributes to the partitioning of non-exchange chromosomes. 2) Test the hypothesis that a centromere-pairing mechanism is used to partition error-prone non-exchange chromosomes in yeast. 3) Identify the genes required for the meiotic centromere pairing observed between non-exchange chromosome pairs. 4) Test the hypothesis that centromere pairing plays a previously unrecognized role in mediating meiosis-specific behavior of all chromosomes. These studies should lead to a better understanding of the mechanistic problems that lead to failed meioses in humans.