Recent developments have made it feasible to generate index genetic maps for all human chromosomes that are densely covered by easy-to-use, PCR based, high heterozygosity markers and that incorporate large numbers of polymorphic genes. These advances include new techniques to identify highly heterozygous loci, the efficiency of characterizing these in large reference families and the analytic techniques used to incorporate them into linkage maps. In parallel with this, there has been a rapid increase in the number of gene based sequences identified. By making use of powerful procedures to identify DNA sequence variants, particularly in the 3' untranslated regions of cDNAs, it is possible to efficiently integrate potential candidate genes into the evolving genetic maps. At the same time, investigators have become increasingly reliant on family and population studies to provide initial guideposts in positional cloning or candidate gene identification projects. These studies require a new standard of genetic maps to maximize our abilities to continue to use linkage, association, quantitative or loss of heterozygosity approaches in characterizing human inherited disorders. The Cooperative Human Linkage Center will bring together five co- investigators with a breadth of experience and skills who will generate human genetic maps with resolution of 2.5 cM and no gaps greater than 5 cM. The maps will incorporate both high heterozygosity and cDNA markers. These maps will provide a resource to the genetics community to quickly localize disorders of interest to a narrow chromosomal region. The projects will include 1) generation of a collection of genomic and cDNA libraries that are highly enriched for the presence of polymorphic short tandem repeats (STRPs), 2) development of sequence based polymorphisms located in cDNAs, 3) localization of cDNA variants on reference genetic maps and use of cDNA polymorphisms in population-based studies, 4) analysis of anonymous STRPs in reference families and studies of the biology and distribution of STRPs, 5) generation of comprehensive linkage maps and studies of the analytic issues involved in generating high resolution linkage maps. In addition, an Ethical, Legal and Social Issues (ELSI) core will review projects performed through the center and address public policy issues relevant to genetic studies of individuals, families and populations. At completion, we will have 1) obtained a linkage map comprised of markers with heterozygosity > 0.7 at an average interval distance of 2.5 cM; 2) characterized 4,200 STRP/STS (> 1/cM) useful in linkage studies and physical/genetic map integration; 3) provided genetic placement and STSs for over 2,000 polymorphic cDNAs; 4) facilitated the use by the scientific community of index map markers and panels of polymorphic candidate cDNAs; 5) studied the biology of STRPs and analytic issues confronting high resolution linkage map generation; 6) evaluated ELSI and Public Policy issues relevant to studies of DNA variation.
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