GENETIC ANALYSIS OF TK AND HPRT GENE MUTATIONS

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We propose to utilize cytogenetics and molecular genetic techniques to survey the spectrum of mutageneric events that occur at the TK and HPRT loci in mouse L5178Y cells. The purpose of these studies is to determine if the spectrum of genetic abnormalities registered at these loci is a function of the heterozygous/hemizygous nature of the gene loci involved, and to compare the spectrum with the known mutagenic events that occur in humans. This spectrum, for both rare and frequent forms of human cancer, has recently been shown to range from point mutations to loss of large segments of the genome. The demonstration of a similar potential for registering mutagenic damage in in vitro assays is likely to contribute significantly to the understanding of the relationship between in vitro mutagenic potential and human genetic disease. Phase I of this project dealt with the adaptation of recently devised molecular generic technical developments to analysis of mouse L5178Y cells (at the HPRT and TK genes); Phase II will provide a full scale analysis of the hemizygous HPRT gene, and the TK gene in the heterozygous state.