It is proposed to study the androgen-responsive genes of mouse kidney as a model system to investigate naturally occurring polymorphism in eucaryotic gene structure and expression. For this, use will be made of a variety of cDNA clones that have ben isolated and shown to correspond to various androgen-inducible mRNAs from the kidney; initial focus will be on one such clone, pMK908, whose cDNA insert hybridizes to two RNAs, termed the 908 RNAs. It is one purpose of this proposal to characterize at molecular and genetic levels identified variation in the structure and quantity of the 908 RNAs. These studies will include determination of the molecular details of the inter-strain structural difference in the 908 RNAs, linkage analysis of genetic determinants for 908 RNA concentrations, and assay of the 908 gene transcription rate and its perturbation by genetic variation. In order to identify potentially novel variants for 908 gene expression, it is proposed to screen new stocks of wild-derived mice, which represent more divergent gene pools compared to laboratory inbred mice and therefore may be more highly polymorphic. To determine the possible interrelationships among the family of androgen-responsive genes, both laboratory inbred and wild-derived stocks will be screened for polymorphism in structure and expression of the other androgen-response genes for which probes are on hand; results for all the genes will be compared and correlations in variation among the genes will be looked for. An interesting Mus species, Mus caroli, that is resistant to androgen in the kidney, will be analyzed to obtain information concerning the evolution of the androgen response and the genetic factors that may potentiate it. Finally, since comparisons of the detailed genomic structures of these genes and variants thereof will be important in the long term, it is planned to begin the isolation and characterization of corresponding genomic clones. The proposed studies should provide information on the molecular and genetic nature of naturally-occurring mammalian polymorphism, and the mechanisms controlling eucaryotic gene expression.
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