BIOCHEMICAL GENETICS OF MALE SEXUAL DETERMINATION

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We plan on continuing our studies of mammalian sex determination and differentiation using mice for experimental observations followed by clinical correlations in patients with sexual ambiguity. The first focus will be on the Y chromosomal gene candidate for sex determination recently cloned by Dr. David Page (Zfy). The DNA sequence of this clone predicts a zinc finger, DNA binding protein with probable regulatory properties. We will test its role in sex determination by expression of it, and its antisense, in transgenic mice in order to look for sex reversal. We have developed what we believe is a novel cloning strategy to clone stretches of DNA that will respond to positive regulatory signals from this protein in yeast. This approach may allow us to identify autosomal or X-linked genes involved in sex determination. We will also study Zfy expression in early embryos and in differentiating gonadal tissues of mice and will search for variation in its structure between tow kinds of mouse Y chromosomes which function differently on the C56BL/6J background. Our efforts to detect transcripts in early mouse embryos will use the polymerase chain reaction which has the potential to detect minute amounts of transcription. We have already demonstrated that Y chromosomal clones are very useful in elucidating problems of sexual ambiguity in patients. In addition, analysi of reorganizations of the Y chromosomes such as those that occur in XX male help us to elucidate chromosomal mechanisms during meiosis. Thus, we believe that our studies of sex determination both increase our understanding of mammalian development and provide clinically useful material to aid patients seen in genetics and endocrine clinics.