The primary goals of this project are to develop high-density genetic maps of selected regions of the human X chromosome based on well characterized physical maps and to use these maps to study linkage disequilibrium in three distinct populations. Based on extensive work performed here at the Washington University Genome Center and elsewhere, >80% of the X chromosome is covered by high quality yeast artificial chromosome (YAC) contigs. We propose to utilize this invaluable local resource and expertise to develop genetic maps with markers placed approximately 100 kb apart, using as markers single nucleotide polymorphisms that can be genotyped by the semi-automated oligonucleotide ligation assay (OLA). The use of diallelic markers, which are less mutable, is of crucial importance because the highly informative and useful simple tandem repeat polymorphism (STRP) markers appear to have a high mutation rate which make them disadvantageous for disequilibrium mapping. The regions selected comprised of 20 Mb of the X chromosome between Xq25 and Xq28. These regions contain numerous disease gene loci, including several that are of local interest. The addition of some 200 genetic markers in these regions will aid numerous investigators here and abroad in their search for their genes of interest. Once developed, the allele frequencies of these markers will be determined and they will be used to genotype approximately 100 males in each of three populations, including those of the CEPH pedigree, an isolated population in Finland, and a similarly isolated population in Sardinia. The haplotypes of these individuals will be analyzed to study linkage disequilibrium in terms of population history and chromosomal location. If successful, the approaches developed in this proposal will be applicable to any region of the human genome. Furthermore, the linkage disequilibrium data obtained will shed light on several important questions in population genetics and guide disease gene mapping efforts based on population or disequilibrium studies.
