In this renewal, Project 4 will shift its emphasis slightly from linkage mapping and careful phenotypic characterization tools development (e.g., via time-series data reduction and analysis) to association and linkage disequilibrium analysis; careful analytically-based physiological assessment of candidate polymorphisms and haplotypes; rat and human genome comparison analysis; and microarray expression analysis. They will focus on the development of analysis tools to extract information from maps of markers used in linkage and association analysis, assess the significance of multiple haplotypes in genomic regions likely to harbor trait-influencing alleles, consider the ultimate physiologic significance of genomic variation via their novel """"""""physiological profiling"""""""" methods, exploit novel bioinformatics tools to more adequately characterize regions of homology between the rat and human genomes, and assess potential clustering and differential expression of genes. The relationship of Project 4 to Projects 2, 1, and 3 is thus quite substantial. In Project 2, they conduct linkage disequilibrium studies to facilitate narrowing genomic regions harboring trait-relevant loci. In Project 1, novel haplotype analysis methods will be developed to study African Americans from Milwaukee in a case/control setting to maximize the power of association studies. In Project 3, they will study congenic rats derived from consomic inbred strains of normotensive Brown Norway and hypertensive Dahl salt-sensitive rats. Microarray expression analysis of the rat models will provide differentially expressed genes and related (clustered) gene expression. Such information will be integrated with the association and linkage disequilibrium results and with homology information to support our cross-organism approach.
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