The broad, long-term objective of the present application is to explore the role of genetic defects in human male infertility. In millions of American men who are otherwise healthy, spermatogenesis is qualitatively or quantitatively defective, and infertility results. In the great majority of such otherwise normal men, the cause of the spermatogenesis defect cannot be pinpointed at present. Numerous studies have focused on the possible role of infectious agents, immune processes, varicoceles, chemical insults, or other physiologic or environmental factors. While it has always been formally possible that genetic defects could selectively impair spermatogenesis (without causing disease elsewhere), there has been little direct evidence that this is the case. As a result, though it is widely accepted that genetic variation plays a major role in such common diseases as cancer, heart disease, diabetes, and hypertension, genetic explanations have not featured prominently in the conventional thinking with regard to impaired spermatogenesis. The present application will explore the possibility that genetic abnormalities are a significant cause of spermatogenic defects in otherwise normal men. More specifically, the goal of the present application is to test the hypothesis that deletion of the """"""""Azoospermia Factor"""""""" (AZF) gene on the long arm of the Y chromosome is a frequent cause of severe spermatogenic defects in human males. The AZF gene will be identified by genetic deletion analysis of men with severe spermatogenic defects. The structure, function, and expression of the gene will be examined. The possibility that subtle mutations within the gene cause less severe spermatogenic defects will be explored. The mechanisms by which de novo deletions of the AZF gene occur at high frequency in human populations will be investigated.
