MALE GERM CELL-AFFECTING GENES ON MOUSE CHROMOSOME 17

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Numerous genes that affect spermatogenesis have been mapped to mouse chromosome 17. The overall goal of the proposed project is to isolate these genes by molecular cloning and to elucidate the mechanisms by which their mutations cause male sterility or sperm dysfunction. Since no information is available on their gene products, the following two cloning strategies will be used: (i) isolation of chromosome 17-derived genomic clones either at random or from the vicinity of HpaII tiny fragment (HTF) islands that exist in association with genes, and (ii) isolation of chromosome 17-encoded cDNA clones that are differentially expressed between normal and sterile mouse testes. The chromosome 17-derived genomic clones isolated from the vicinity of HTF islands will be screened for the presence of testicular transcripts, whereas the clones isolated at random will be regionally localized to identify those clones that map in the vicinity of known male germ cell-affecting loci. The clones that map close enough to such loci will be used to construct "regional" genomic libraries, which will then be screened for the presence of testicular transcripts. In our preliminary studies, the use of the first cloning strategy has resulted in the isolation of a novel testis-specific gene that apparently does not correspond to any of the known male germ cell- affecting loci located on chromosome 17. This gene, the protein products of which contain putative "zinc finger" motifs, will also be characterized in detail in this proposal. It is likely that the mouse genes we will isolate and characterize here have their human counterparts. Some forms of human male infertility may be accounted. for by their mutations. In this sense, the proposed project has direct clinical relevance and should provide us with basic knowledge that should lead to better diagnosis and treatment of human male infertility.