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It is known that a percentage of transgenic insertions result in an identifiable phenotype unrelated to the actual transgene used. This is the result of a genomic rearrangement, usually a relatively small deletion and/or inversion, that accompanies the transgene insertion. This application is designed to exploit this finding and systematically identify and characterize mice carrying insertional mutations in genes affecting sex determination and/or fertility. The investigators will use a novel transgenic insertional mutagenesis scheme based on the rescue of albinism in the inbred FVB/N strain by the introduction a tyrosinase minigene into the genome. In their experience, gained from a small scale mutagenesis program using this method, 10-15% of insertions resulted in new identifiable mutations, of which 10-15% involve reproductive fitness, including spermatogenesis, oogenesis, sex determination, and parturition. This approach offers many advantages over phenotype-driven schemes employing chemical mutagenesis for the identification of reproductive mutants. The entire screening process, including distinguishing homozygotes from heterozygotes, can be achieved by simple visual inspection of coat color. It uses a single inbred strain throughout, eliminating any confounding genetic background effects. Unlike ENU mutagenesis, it does not require the use of complicated local inversions or balancer chromosomes to help maintain sterile mutants. Finally, one of its most attractive features is that the mutation is tagged by the transgene. This allows cytogenetic mapping and fast molecular analysis of the disrupted locus.

Given the previous productive nature of this novel program with respect to producing reproductive mutants, and the availability of the mouse genome sequence in the public domain, the investigators propose to examine a greater number of transgenic mice in a systematic way. Not only will reproductive mutants be identified and phenotyped in detail, but their cytogenetic map position will be obtained, flanking sequences generated, and the exact position of the mutation in the mouse genome determined. Drs. Colin Bishop and Paul Overbeek have had considerable experience in the past in analyzing transgenic insertion mutants exhibiting a variety of reproductive phenotypes. Working together with Dr. Dolores Lamb, an acknowledged expert in the field of male reproductive biology, and Dr. Martin Matzuk, an expert in the field of female reproduction, the investigators feel that that the proposed program will be very productive. Designed as a national resource, this program should provide researchers in the field of reproductive genetics a unique and highly detailed database and access to novel strains of mice. It will also be highly complementary to other mutagenesis programs using different strategies.

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