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Molecular mechanisms of aneuploidy

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In meiosis chromosomes replicate once, then undergo two rounds of segregation to generate haploid meiotic products. The aberrant segregation of chromosomes during meiosis generates products that are aneuploid (have an incorrect number of chromosomes). In humans, meiotic aneuploidy is the leading cause of pregnancy loss, congenital birth defects, and mental retardation. Exposure to environmental agents (pollutants, pesticides, hormone mimetics, etc.) is implicated as a risk factor. However, it is difficult to gauge significant effects in humans and there are no good models for large-scale screening. The goal of this project is to develop and validate a system for high-throughput screening (HTS) of chemical libraries to identify those that cause meiotic aneuploidy (meiotic aneugens). The system is based on the unique biology of the fission yeast Schizosaccharomyces pombe, in which meiosis can be induced in a synchronous fashion and in which meiotic chromosome mis-segregation can be monitored directly. Selectable markers will be configured to allow quantitative analysis of the frequency of meiotic aneuploidy following exposure to chemical agents. Additional features will be incorporated into the system for secondary screening and to permit identification of specific molecular mechanisms by which any given chemical affects meiosis. The system will be validated and calibrated by using mutations that affect meiotic sister chromatid cohesion (e.g., rec8) and meiotic recombination (e.g., rec12), and by testing chemicals known to cause meiotic errors (e.g., bisphenol A, diethanolamine, etc.). Upon validation, the systems will be made available to a molecular libraries screening center network site (NIH Roadmap initiative, RFA-RM-04-017) for HTS screening of potential meiotic aneugens.

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