The objectives of this research are the development and genetic characterization of sets of recombinant inbred (RI) strains of mice, which were derived from the crosses of pairs of inbred (progenitor) strains. These RI strains will be used to genetically analyze numerous differences between the progenitors, including lymphoma susceptibility. The strains will be typed with respect to genetic polymorphisms, especially restriction fragment length DNA polymorphisms, which will serve as genetic markers for identifying loci influencing lymphoma incidence. The genes responsible or differences in lymphoma incidence and latency among 25 AKXD RI strains, derived from the cross of AKR/J and DBA/2J will be further defined. Mouse strains congenic to the high lymphoma AKR/J strain vill be developed which differ from AKR/J with respect to chromosome segments thought to be important for lymphoma susceptibility. Additional RI strains derived from NZB/BlNJ x 129/J and C57L/J x PL/J crosses will be further inbred. The locations of several proto-oncogenes on the cytological and linkage maps will be further defined using RI strains, congenic strains, and stocks with chromosomal aberrations. Freeze- preservation of embryos will be employed to assure the long-term survival of these strains. An inbred strain (HEV) is being developed that possesses multiple ecotropic (MuLV) proviruses. This stock has been selected to carry all ten of the proviruses that were present in its inbred progenitors. These proviruses, which can be identified uniquely in a single Southern blot, will serve as genetic markers when the MEV stock is crossed to mutant-bearing stocks that typically carry no more than one provirus. By typing the F2 progeny from such a cross one can rapidly test for linksage between the new mutation and any of the segregating proviruses. Occasionally germlayer cells are infected by the virus resultlng in the reinsertion of the proviral genome into a new chromosomal location. These reinsertions will be incorporated into the stock as additional genetic markers. One such reinsertion is associated with sterility in homozygous males. A major goal of this research is to clone and analyze the disrupted gene to determine the biochemical basis for the defect in spermiogenesis.
