As this project enters in its 14th year, the over-all objectives still remain the characterization of the effects of population mixtures on genetic variation, and differentiation of this from that of genetic linkage and past demographic changes. With introduction of newer laboratory and computational methods in genomic studies, it is now widely accepted that mapping of genes and their interactions with environmental/life style risk factors can be successfully conducted using population-based association study designs, with appropriate considerations of evolutionary factors that may affect association of genes at population level. Based on the past work done in this project and by other investigators, we propose to address the issues of effects of population mixtures on: (i) haploblock size and pattern; (ii) strategies for efficient choice of markers and marker densities; and (iii) methods of adjustments for cryptic differences of cases and controls, so as to make the association study designs cost-effective, and less prone to false positive results. Using analytical as well as computer simulations methods based on the theory of coalescence and diffusion models, we will examine the effects of SNP based studies on the inferences of the above issues. Finally, using the anonymous DNA repositories of our study team from five selected populations (two admixed - US African-Americans, and Mexican Mestizo from Nuevo Leon; two cosmopolitans - US Caucasians, and Chinese; and one small isolated population from Adriatic Islands of Croatia), we will generate empirical data on similarities/dissimilarities of the characteristics of haplotype/haploblocks and choice of markers for 2 to 3 selected regions of the genome, using both microsatellite and SNP a series of theoretical and empirical studies to investigate the effects of population admixture of properties of linkage disequilibrium and to develop better strategies for association mapping through LD. markers. Such data, in addition to the analytical and simulation work, will prescribe bounds for parameters under which mixed and/or non-equilibrium populations can be used for complex disease studies. The results of this project will aid (a) in developing strategies of mapping genes using repeat as well as SNP markers in populations of different mixture histories, and (b) in understanding the history and global spread of mutations underlying complex phenotypes.
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