Beyond the reproductive tract: The future of Y chromosome research

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DESCRIPTION (provided by applicant): The aims of this proposal are designed to uncover biological functions of the human Y chromosome beyond reproduction, which will have significant implications for human health and disease. Until now, Y chromosome research has focused solely on two functions: sex determination and sperm production. Our ongoing genomic studies of multiple mammalian Y chromosomes have revealed a set of broadly expressed, dosage sensitive regulatory genes that have been conserved on the Y chromosome. Because many of these broadly expressed genes likely have important and widespread biological functions, we hypothesize that the disruption of these genes may contribute to disease, especially Turner syndrome and diseases with sex-biased prevalence, susceptibility, or severity. Historically, deletion-mapping studies have focused solely on the Y chromosome's testis-specific genes, which are involved in sex determination and sperm production. We will perform the first systematic examination of phenotypes associated with disruption of the Y chromosome's broadly expressed genes by studying ~75 patients with Y-chromosome anomalies affecting one or more of these genes. We will evaluate phenotypes of patients using a combination of approaches: 1. At the NIH Clinical Center, patients will undergo a thorough examination of all major organ systems, including physical, reproductive, endocrinologic, and radiologic tests. We will characterize phenotypic abnormalities in patients, detecting patterns that correlate with particular Y-linked gene defects. Bringing patients to the Clinical Center ensures that all testing will be conducted in the most rigorous and systematic manner possible, thus allowing the identification of previously overlooked phenotypes. 2. In the Page lab, the cellular and molecular phenotypes of the same set of patients will be characterized using a combination of whole-genome approaches: RNA-seq and ChIP-seq. We will perform similar analyses in controls with intact Y chromosomes to identify perturbations in chromatin modification, transcript level, or splicing efficiently that may be linked to Y-chromosome defects. Through comprehensive phenotypic characterization, at molecular, cellular, anatomical, and physiological levels, of individuals with Y-chromosome anomalies, we can begin to understand the contribution of Y-linked genes to basic biological processes and fundamental differences between the sexes. Ultimately, these insights could lead to a greater appreciation of the etiology of Turner syndrome phenotypes and the underlying causes of sex biases in disease.