The candidate seeks to broaden his background in population and molecular genetics by pursuing training in genetic epidemiology. His primary interests lie in using techniques from population genetics and the knowledge of a population's history to develop methods for identifying genes underlying complex and chronic diseases. The candidate will seek formal training in epidemiological methods at the Harvard School of Public Health. He will pursue research and informal study with genetic epidemiologist and Cosponsor, Xiping Xu. and statistical geneticist and Cosponsor, Nik Schork. He will also pursue training and collaborate in data analyses with Neil Risch at Stanford University. The research plan focuses on the study of linkage disequilibrium among SNPs and microsatellites in several large (500kb) regions of the autosomes and the X chromosome. Tests of association offer greater power than linkage studies in detecting genes of minor effect. An important question is whether (or in what circumstances) genetic associations with disease can be detected via linkage disequilibrium (LD) between the disease predisposing mutation and nearby markers. The extent of LD in populations will be a major factor in determining the optimal density of SNP markers for gene mapping. Another key question, particularly in mapping efforts which rely only on polymorphisms in expressed genes (cSNPs), concerns the nature, amount, and distribution of variation within genes. The second part of the research plan will collect DNA sequence data from a large number of genes in the diverse set of human DNA samples assembled by the NHGRI. A subset of these genes will be sequenced in a smaller number of chimpanzee, gorilla, and orangutan samples to gain a comparative perspective on the patterns of variation in human genes. Although theoretical and simulation studies are progressing rapidly, little is yet known empirically about the extent and distribution of human variation; and the extent of linkage disequilibrium in populations and how it is influenced by population and molecular genetic factors. This proposal seeks to gather empirical data from actual populations to determine the feasibility and optimal design of various gene-mapping approaches, based in particular on linkage disequilibrium between markers and trait-influencing loci.
