This proposal posits that the study of rapidly evolving genes involved in speciation will provide significant insights into the human molecular genetics of male infertility. Speciation is the process by which two populations become reproductively isolated. Between recently diverged species, reproductive isolation typically manifests itself in the form of male infertility. Rapidly evolving genes on the X chromosome are primary drivers of this reproductive isolation. My preliminary studies have identified rapidly evolving X-linked genes which are harbored in large, near-perfect, segmental duplications, or amplicons. I hypothesize that these X-ampliconic sequences contain genes critical for spermatogenesis and that the rapid evolution of these sequences within a species can lead to male infertility. I will perform studies in humans and mice to test this hypothesis. In humans, all amplicons of the X chromosome will be accurately sequenced to determine their genomic architecture. Upon resolution of each ampliconic region, I will determine the extent to which X- ampliconic deletions are significantly associated with spermatogenic failure;the most common type of male infertility. To do this I will screen for deletions in a collection of 500 men with spermatogenic failure and 500 men from a control population. To test whether human X-ampliconic genes are expressed in spermatogenic cells, I will perform expression profiling of X-ampliconic genes to provide insight into the molecular pathogenesis of spermatogenic failure. In mice, 12% of the X chromosome is comprised of ampliconic sequences. Two X-ampliconic regions are of particular interest because they represent the most rapidly evolving regions of the X chromosome and have been linked to spermatogenic failure in hybrid mice. Thus, these two X-ampliconic regions represent highly promising candidates to study the spermatogenic functions of X-ampliconic genes. To test whether these two X-ampliconic regions have a role in spermatogenic failure, I will generate independent targeted knockouts of both regions. The knockout of X-ampliconic regions in mice offers opportunities to perform controlled loss-of-function and rescue experiments not feasible in humans. The DNA studies in humans coupled with molecular characterizations of X-ampliconic genes in mice will be essential to advance our understanding of X-ampliconic gene functions in human spermatogenesis and reproduction.

Public Health Relevance

Few genetic factors have been identified to explain the high incidence of spermatogenic failure, which affects 1-2% of all men. Understanding the location and role of X-linked genes in spermatogenic failure will help explain molecular mechanisms of spermatogenesis and important causes of infertility.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Career Transition Award (K99)
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Pediatrics Subcommittee (CHHD)
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Taymans, Susan
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Whitehead Institute for Biomedical Research
United States
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