A well-defined genetic map of the mouse genome that establishes gene order in an unambiguous manner and accurately estimates recombinational distances between genes is an important tool for analyzing the molecular basis of mutational lesions and determining the structural genes associated with mutant phenotypes. The application of the genetic map to characterize mouse mutations readily extends to similar concerns in human genetics since close genetic linkages have a high probability of being evolutionarily conserved. The historical construction of gene maps in the mouse has relied extensively upon 2, 3, and 4 factor crosses and the compilation of composite maps that integrate the results of these accumulated recombinational data. These approaches were generally limited by the use of mutant gene markers or limited variability for a set of biochemically defined genes. Our laboratory and others have turned to the use of diverse Mus species as a source of increased genetic variability and, using these resources, it is possible to identify mice that differ from laboratory strains for 100% of the probes analyzed using Southern techniques. We have produced backcrosses of Mus species with laboratory strains that co- segregate for a large number of genes on a chromosome and thus become multilocus linkage testing resources. We have devised methods of using these backcross resources that allow us to map new genes to a previously characterized cross in a highly efficient and cumulative manner. The result of these approaches is the development of multilocus linkage maps that order genes unambiguously and provide highly reliable estimates of map distance. This proposal specifically describes the use of Mus species backcrosses with mice carrying mutant markers for chromosome 5. We propose the development of a linkage testing resource that will span mouse chromosome 5 from the centromere to the most distal marker. Once constructed, this map can be used to analyze genes associated with the W gene complex in mouse associated with the c-kit oncogene. The map will also better define homologous linkages with human chromosome 4q and 7q.
