A COMPLETE GENETIC LINKAGE MAP OF THE HUMAN GENOME

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Our long-term objective is to construct a 5 centiMorgan resolution genetic linkage map of the human genome. This would provide a valuable resource which we intend to make available to interested investigators for mapping and cloning genes responsible for Mendelian disorders. In addition, the availability of a genetic map would facilitate construction of a physical map of the human genome. The specific aims of this project are to 1) fill in gaps in our current map by identifying new polymorphisms from chromosome specific libraries and by incorporating RFLPs identified by other researchers into the existing map, 2) establish the physical end points of the existing linkage groups by in situ hybridization of the most distal markers, and extend the maps to the ends of the chromosomes by incorporating RFLPs known to lie in these regions or by identifying new RFLPs near known distal nonpolymorphic DNA segments, 3) define and develop subsets of RFLP markers ("genome kits") that will provide adequate coverage of each chromosome for efficient future genetic mapping of disease causing agents, 4) define and develop a panel of RFLP markers suited for identification of chromosome deletions through the loss of heterozygosity of RFLP alleles, and 5) covert the CRI-MAP multilocus linkage analysis computer program package into a form for general use, and begin development of programs to test the "simultaneous search" method proposed by Lander and Botstein (1987) for identification of multiple genes implicated in complex or heterogeneous disorders. Development of the map and related resources would 1) identify immediately the chromosomal location of new linkages, 2) enable development of more accurate informative tests for presymptomatic diagnosis of genetic diseases, 3) enable searches for and cloning of disease causing genes to be conducted in a more efficient manner, 4) make it possible to map complex genetic disorders, and 5) allow one to detect and define the limits of chromosomal specific deletions that are characteristic of some neoplastic disorders. In the long-term, the genetic map and related resources will likely prove instrumental in developing a better understanding of the molecular genetic mechanism underlying many diseases, and ultimately improved therapeutic approaches for treatment or cure.