This proposal has four major goals: First, we shall conduct extensive computer simulations to evaluate existing statistical methods, and new ones we propose, for studying the accuracy and efficiency of multipoint linkage analysis using human family data. Multilocus human linkage data will be analyzed by various methods and the results compared. We shall also study, by further computer simulations, the efficiency of detecting nonallelic heterogeneity in human genetic disease using multipoint linkage data. Finally, we propose and evaluate new methods, for constructing multilocus linkage maps in the mouse using recombinant inbred strains. These studies will elucidate the most efficient methods for map construction, detection of disease heterogeneity and for studying the conservation of linkage. Second, we propose new methods for performing segregation analysis and for estimating the number of different genes that contribute to a multilocus genetic disease. For mapping each of the trait loci, lod score and identity by descent score methods are proposed and will be evaluated. Family data on Rheumatoid Arthritis, Hirschprung disease and Vitiligo will be analyzed. These studies will elucidate the efficiency with which the component genes of a multilocus trait, such as for several autoimmune disorders, may be identified. Third, we propose new methods for studying gene-centromere and gene-gene linkage for ovarian teratomas, trisomies and triploids. We shall extend these methods for multi-point mapping and to analyze teratoma/trisomy data for constructing centromere-based gene maps. These studies will clarify the process of recombination in germ cells, the relationship between disjunction at meiosis I or II and crossing-over, the nature of interference on human chromosomes and heterogeneity in origin of ovarian teratomas. Fourth, we present new methods for assessing the contributions of recurrent mutation and meiotic recombination to the variability of DNA haplotypes. We shall use computer simulations to determine the degree of allelic heterogeneity (number of different mutant alleles) that can be maintained under mutation, recombination and other population genetic mechanisms. By analyzing beta-globin, PKU, cystic fibrosis and LDL-receptor gene mutations and linked DNA polymorphisms we wish to delineate allelic heterogeneity and determine probable mechanisms of origin and maintenance of specific mutations.
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