The proposed research is designed to identify, map and characterize gene with large effects on ovarian steroidogenesis. We have found that C57BL/6J and A/J strain mice show 6-fold differences in hormone-induced ovulation rate (ovulating 54 + 2 versus 9 + 1 eggs, respectively), which segregate as though they are controlled by the action of approximately 3 to 4 loci. Our recent work demonstrates that one of these maps to the H-2 region of chromosome 17, while another maps to chromosome 9 near P-450aromatase and P-450scc. C57BL/6J and A/J strain mice also show major differences in ovarian testosterone and estradiol production, 17B-HSD activity, and 6-fold differences in ovarian aromatase activity which segregate as though they are controlled by the action of one locus. Therefore, we plan to identify, map and characterize the genes controlling the major differences in ovarian aromatase activity between A/J and C57BL/6J mice. Specifically, we propose to characterize the nature of the genetic differences in ovarian steroidogenesis by comparing the steroids produced form radiolabeled steroid substrates, steroidogenic enzyme activity, mass of steroidogenic enzyme protein and mRNA of C57BL/6J and A/J strain ovaries. Once we have determined the critical difference in steroidogenic enzyme activity between strains, we will examine crosses and recombinant inbred strains derived from C57BL/6J and A/J to identify and map the gene(s) controlling major differences in ovarian aromatase activity. We then plan to produce Cosmid genomic DNA libraries, from both C57BL/6J and A/J, and isolate and sequence both the high and the low strain alleles mediating the differences in ovarian steroidogenesis and reproductive function. The results of the proposed research promise to enhance the understanding of how genetic differences mediate major differences in ovarian steroidogenesis and function.
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