GENETIC ASPECTS OF VIRAL ONCOGENESIS IN WILD MOUSE SPECIES

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Inbred strains of mice and wild mouse species differ in their susceptibility to retroviruses and retrovirus-induced diseases. These differences have been attributed to various mouse chromosomal genes including endogenous retroviral sequences, mouse cellular genes which facilitate or restrict virus replication, and proto-oncogenes disrupted by viral insertion. We have been using standard classical genetics to identify and map genes involved in this resistance. In one series of experiments, we determined the genetic map location of the resistance gene Rmcf. In the same study, we also identified an additional resistance gene for the leukemogenic MCF viruses in the wild mouse species M. castaneus. We mapped this gene to Chr 1 and suggest that it may be an allelic variant of the gene encoding the cell surface receptor for this subgroup of viruses. In an expanded series of genetic crosses with this wild mouse, we identified two additional factors which contribute to this resistance in M. castaneus, and we are following inheritance of Rmcf in serial backcrosses to M. castaneus which lacks endogenous MCF viruses. These experiments should help determine whether Rmcf represents an endogenous provirus, expression of which blocks viral cell surface receptors, and should characterize the genetic factors responsible for resistance in M. castaneus. In other studies, we contributed to the cloning and characterization of the murine homolog of the leukemia-associated PML gene. We also determined the genetic map location for the tumor specific mammary virus integration site Int6 and in the process demonstrated that this integration site is distinct from other chromosomal genes involved in tumorigenesis. Finally, we identified specific insertion sites initially termed Dis1 and Dis2 for the murine AIDS virus in its infected target B cell. Genetic mapping suggested that Dis1 may be identical to Sfpi1, an insertion site previously identified in erythroleukemias induced by Friend virus. The second site, Dis2, mapped to Chr 11, and appears to harbor a novel gene involved in B-cell proliferation.