The overall goal of this Project is to conduct a genome search in pedigreed baboons to identify genes that influence quantitative phenotypes related to atherosclerosis and obesity. The genome search will use hypervariable short tandem repeats (STRs) spaced at regular intervals throughout the baboon chromosomes, as well as polymorphisms in candidate genes involved in metabolic processes related to atherosclerosis and obesity. The genetic markers will be used for variance component analyses to detect linkage with lipoprotein and adiposity-related phenotypes The target population is comprised of 750 non-inbred pedigreed baboons that were measured during the current grant period for serum levels of lipids, lipoproteins, and lipid processing enzymes on a basal diet and two challenge diets. In addition, we have established new breeding groups on the basis of eight distinct lipoproteins phenotypes. These selective breeding groups include related baboons that have been mated to produce inbred progeny. The inbred progeny will have large chromosomal regions that are autozygous (identical-by-descent within an individual), thus enhancing our ability to detect linkage and to determine map locations of loci affecting quantitative phenotypes. After our genome screen detects chromosomal regions that show linkage with quantitative phenotypes, we will type additional closely spaced STR markers for high resolution mapping. We will then consult the human gene to identify positional candidate genes will be subjected to molecular analysis to identify polymorphisms for linkage and association studies. If linkage and association is demonstrated, we will conduct detailed structure/function studies to determine the causative mutations and mechanisms that are responsible for effects on lipoprotein and adiposity-related phenotypes. As an example of molecular strategies that will be used for future structure/function studies of positional candidate genes, we propose experiments that focus on apo(a) alleles in baboons to identify amino acid substitutions that disrupt intracellular and secretion of apo(a).
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