Trisomy is a most common genetic abnormality in our species, occurring in at least 3-4 percent of all clinically recognized pregnancies. Despite this high incidence and obvious clinical importance, the causes of human nondisjunction remain unclear. In this proposal, we outline a series of cytogenetic and molecular experiments to study the genesis of trisomy in humans. In one set of studies, we will analyze exchange patterns in trisomy-generating meioses; this will allow us to examine the effects of altered recombination on nondisjunction of different chromosomes and nondisjunction involving women of different ages, and to determine whether genome-wide alterations in recombination are a feature of nondisjunctional meioses. Secondly, we propose to investigate the effect of putative environmental agents on trisomic spontaneous abortions; in particular, we will focus on factors recently suggested to play a role in the genesis of trisomy 21. Finally, we intend to develop mouse models of human nondisjunction, utilizing situations in which pairing and recombination is disturbed (inversion heterozygotes) or abolished (minichromosome-carrying homozygotes); if successful, this approach would yield the first useful animal models of human meiotic nondisjunction. These studies parallel those proposed by Dr. Stephanie Sherman in the companion IRPG application. Indeed, with the exception of the murine studies of the present application and the analysis of birth defects in Dr. Sherman's application, the questions and methodological approaches are nearly identical. By combining a large, population-based analysis of trisomy 21 with analyses of other autosomal and sex chromosome trisomies, we intend to characterize the genesis of the most common and clinically important human chromosome abnormalities.
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