Understanding the mechanisms underlying human genetic disorders is a major goal of modern biology. Identification of specific mutations causing inherited diseases will greatly add to our knowledge of the pathophysiology of such disorders. This proposal will develop a detailed understanding of the relationship in humans between genetic distance as measured by recombination frequencies and physical distance as measured by DNA content. These studies will provide both a framework for understanding more about the mechanisms of recombination in humans and a means of rapidly identifying specific mutational origins of inherited disorders as a first step in their eventual treatment or ameliorization. Fifty markers to the long arm of chromosome four will be identified and characterized. Restriction fragment length polymorphisms (RFLPs) for these markers will be used to study linkage disequilibrium. This non-random association of polymorphisms can be used to identify short regions of DNA containing mutations and to estimate recombination rates over defined lengths of DNA. The RFLPs will also be used with family studies to develop a saturated, multipoint genetic linkage map into which genetic disorders can be readily included or excluded. This map will provide insights into recombination frequency differences by sex, age or individual and into the phenomena of interference. A physical position for each of the markers will be assigned by deletion mapping and in situ hybridization. The physical and genetic maps will be compared, their interrelationship measured and algorithms developed to predict the specific distance between a mutation and an easily defined genetically linked marker. This study will help provide a bridge for the current gap between our ability to readily assign a genetic position for inherited disorders and the need to identify the specific mutational origin of those disorders. In the absence of specific biochemical abnormalities the identification of exact causes may provide the only logical approaches to therapy for many common genetic conditions.
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