The overall goal of this Project is to identify genes that influence quantitative phenotypes related to lipoproteins, oxidative damage, and obesity. A novel DNA microarray strategy will be applied to selected chromosomal regions demonstrated in projects 9 and 11 to contain QTLs for these phenotypes, for the purpose of identifying candidate genes within those regions. These positional candidate genes will be subjected to structural and functional analyses to determine which of them are actually responsible for genetic control of the phenotypes in question. The genome search uses hypervariable short tandem repeats (STRs) spaced at regular intervals along the chromosomes in conjunction with measured levels of serum lipids and lipoproteins on a basal and two challenge diets; traits related to oxidative stress, inflammation, and endothelial injury; and traits related to adiposity. The target populations include 964 non-inbred pedigreed baboons and an additional 686 baboons that are members of inbred families being produced by a selective breeding strategy.
The specific aims are 2) to complete a fine map of selected chromosomal regions of the 1,650 baboons so that the locations of QTLs can be determined more precisely, 2) to construct a 20 centimorgan map of the inbred baboons for use in the mapping of existing QTLs and in additional genome searches involving novel phenotypes, 3) to identify candidate genes in three chromosomal regions containing QTLs, by utilizing a novel DNA expression array strategy, 4) to determine which of the candidate genes detected in Aim 3 actually influence the respective phenotypes, by conducting statistical functional genomic analyses, and 5) to confirm by functional assays the rcspectivc roles of two selected candidate genes identified in Aim 4 to be associated with one or another phenotype. The results will lead to a better understanding of the genetic basis for heritable differences among risk factors for atherosclerosis, and will enable the devclopment of new drugs or other strategies for reducing risk in individuals with unfavorable phenotypic profiles.
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