The long-term objective of this research is a determination of the nature, causes, and effects of chromosomal mutations in mammals. Using two natural population rodent systems, we propose to generate data critical to understanding the basic biology and organismal significance of chromosomal fragile sites and to continue our productive research into the details of the meiotic mechanisms which govern the process of chromosomal reorganization in mammals. Although the discovery of the human fragile X syndrome (the second most common chromosomal abnormality among the mentally retarded) has caused chromosomal fragile sites to become a major focus of clinical cytogenetics, next to nothing is known about the basic significance or genetic origin of these critical chromosomal regions. No animal model has been developed for investigations of fragile sites and few non-human species have even been surveyed for the occurrence of fragile sites. Along the initial development of a deer mouse model for studying fragile sites, we propose to test the hypothesis that common fragile sites represent loci at which chromosomal mutations are most likely to occur. We will also examine the degree to which fragile sites are conserved among species of known genetic relationships. Using techniques of somatic and meiotic karyology and electron microscopic analyses of synaptonemal complexes, we further propose to test the hypothesis that the sex heterochromatin of deer mice represents an unrecognized category of chromatin that regularly experiences unequal crossing over and that this phenomenon accounts for the various unusual by asymptomatic sex chromosomal conditions in deer mice. Additionally, in order to better understand the reproductive effects of chromosomal mutations in mammals we will use these same techniques to evaluate the meiotic disruptions and loss of reproductive capacity resulting from multiple chromosomal heterozygosity in hybrid mole rats.
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