This proposal has four major goals: 1. We shall conduct extensive computer simulations to evaluate existing statistical methods, and new ones we have proposed, for studying the accuracy and efficiency of multi-point linkage analysis. We shall analyze multi-locus human linkage data by various methods and compare the results. These studies will shed light on the conditions under which multi-point gene maps can be constructed and the most efficient method for doing so 2. We have proposed new methods for studying gene-centromere and gene-gene linkage from ovarian teratomas, trisomies and triploids. We plan to extend these methods for multi-point mapping and to analyze teratoma/trisomy data for constructing multi-point gene maps. These studies will clarify the process of recombination in germ cells and elucidate the nature of interference on human chromosomes. 3. We evaluate existing statistical techniques and propose new tests for detecting nonallelic heterogeneity in human genetic disease through linkage studies. We will analyze family data on Mendelian disorders and expect to discover greater heterogeneity than possible before. Since part of this heterogeneity may be due to population variability in recombination, we will evaluate this by analyzing linkage data on DNA polymorphisms, protein and blood group loci. DNA polymorphisms in human Beta-globin and growth hormone clusters will also be used to estimate recombination at the molecular level and study its variation with physical distance. Using computer simulations, we shall critically examine the assumptions made in these analyses. These studies will elucidate the degree and nature of linkage heterogeneity in general and nonallelic heterogeneity in particular. 4. We will determine the degree of allelic heterogeneity (number of different mutant alleles) that can be maintained under different selection schemes, migration, recurrent mutation, inter-allelic gene conversion, and population growth and bottlenecks. By analyzing data on Beta-globin mutations and linked DNA polymorphisms we wish to delineate heterogeneity and determine probable mechanisms of origin of specific mutations. We hope to test the hypothesis that the high frequency of certain B-globin mutations in human populations is due to multiple origins.
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