Diet-induced obesity (DIO) is associated with increased incidences of atherosclerosis, diabetes, and hypertension. While identification of genes underlying any complex disease is difficult in humans, these problems will be increased for DIO, where it will be hard to distinguish genes that cause spontaneous obesity from those that cause DIO. In contrast, the tools available for analysis of complex disease in mice, combined with the relative ease of controlling diets, suggest that identification and isolation of genes causing DIO will be possible with mouse models. The long range goal of this project is to isolate and identify genes causing DIO. This proposal is distinguished by its use of existing congenic mouse strains to enable rapid detection and isolation of DIO genes. Congenic mouse strains are derived from inbred mouse strains by a regimen of crossing and selection They are identical to a background strain except for a small chromosomal region derived from a donor strain. The use of existing congenic strains as a rapid approach to positional cloning is generic and the impact on the search for novel genes contributing to other complex diseases could be great. The first objective is to examine the segregation of genes underling DIO in F2 crosses of congenic and background strains. We have identified five strains of congenic mice that exhibit significantly different body lipid percent or adiposity index (sum of fat pad weights divided by carcass weight) than their background strains when both are placed on a high-fat, high-sucrose diet. Each of these strains will be tested for suitability as a resource for positional cloning by examining 100 F2 mice derived from crosses of the congenic and background strains. Identification of two segregating groups, corresponding to congenic and background strain genotypes, will be made by examination of individual phenotypes or combinations of phenotypes. The second objective is to initiate positional cloning of genes underlying diet-induced obesity. The one cross that includes a novel obesity gene and that exhibits the most distinct segregation of obesity traits into two groups will be expanded to include 1000 F2 mice. These mice will be typed for all available PCR markers near the locus. When we identify markers within 1 cM of the gene underlying DIO, then we will isolate linked genomic clones (YAC, BAC, P1 or PAC clones). A contig will be constructed that includes the DIO gene.
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