Component 2, A. Clark, PI, is an integral part of this Collaborative Research Project grant entitled Modeling DNA Diversity in Reverse Cholesterol Transport involving two other components: population-based genomics and DNA genotyping, (Component 1, E. Boerwinkle, PI) and genotype phenotype studies (Component 3, C. Sing, PI). Although there is a division of labor among components for practical and institutional purposes, the co-investigators and consultants engaged in this project will work as a team to develop resources to address one of the most complex and challenging problems in medicine, how is DNA sequence variation related to variation in human health in the population at large? Component 1 of this Collaborative Research Project grant will generate a large amount of new data on complex patterns of variation in a substantial number of genes. A major objective is to develop methods for analyzing these data to find etiologically relevant aspects of variation. For each of 62 candidate genes, the initial responsibility of Component 2 is to analyze the distribution of single DNA site and haplotype variation in terms of the population processes responsible for that variation. We will develop systematic methods to identify subsets of sites that most fully capture the haplotypic structure of the data and thereby reduce the dimensionality of the variation. These methods will be applied to haplotype and genotype variation in a population-based sample of 2007 African-Americans and 2139 European-Americans from the CARDIA study. Single nucleotide polymorphisms frequency spectra, linkage disequilibrium and the block-wise structure of haplotypes will be quantified and related to expectations of population genetic theory. Novel approaches to genotype-phenotype associations will be pursued, in close collaboration with Component 3, by testing the fit of the neutral site frequency spectrum to data stratified by phenotypic measures.
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