Advancements in recombinant DNA technology have nurtured the growth of linkage analysis into a powerful methodology for human genetic research. Genetic linkage maps of all the chromosomes have been developed using hundreds of cloned genes and anonymous DNA sequences. Such maps further increase the power of linkage analysis to define disease gene location. However, their current utility is limited by rather low resolution and inconsistent spacing of loci. The goal of this proposal is to generate genetic linkage maps of human chromosomes 21 and 22 with a sex-averaged resolution of 1 cM. Data will be generated on 100 sibships containing over 1400 potentially informative meioses. Initial maps with resolutions slightly less than 10 cM already exist and will serve as the backbone for the high resolution maps. Probes will be obtained from all sources, including cosmid libraries. By comparison with physical mapping results (generated under separate proposals), a directed cloning strategy may be used to fill under-represented regions. Efficient methodologies for error checking and analysis of the data will significantly reduce the amount of computer time necessary. The resulting fine-structure maps will be five to ten times as precise as current maps. They will substantially increase the efficiency with which any disease gene residing on these two chromosomes can be localized, and will provide excellent starting points for direct cloning of the disease gene locus. Statistical analysis of the data will help answer questions concerning variation in recombination by sex, age, ethnic background, and familial clustering. It will also aid in the determination of appropriate parameters for interference. Prenatal and presymptomatic diagnosis of disease will be possible with accuracy almost totally dependant on the pedigree structure and clinical diagnosis, not on the markers tested. Finally, these maps will allow informative comparisons between physical and genetic maps, providing new insights into chromosome structure and organization, and facilitating the eventual sequencing of chromosomes 21 and 22.
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