Beyond the reproductive tract: The future of Y chromosome research

描述（由申请人提供）：本提案的目的是揭示人类Y染色体在生殖之外的生物学功能，这将对人类健康和疾病产生重大影响。到目前为止，Y染色体的研究只集中在两个功能上：性别决定和精子产生。我们正在进行的多个哺乳动物Y染色体的基因组研究揭示了一组广泛表达的，剂量敏感的调控基因，已被保守的Y染色体上。由于这些广泛表达的基因中的许多可能具有重要和广泛的生物学功能，我们假设这些基因的破坏可能导致疾病，特别是特纳综合征和具有性别偏见的患病率，易感性或严重性的疾病。从历史上看，缺失图谱研究只集中在Y染色体的睾丸特异性基因上，这些基因与性别决定和精子产生有关。我们将通过研究约75例Y染色体异常影响一个或多个这些基因的患者，对与Y染色体广泛表达基因破坏相关的表型进行首次系统检查。我们将使用以下方法的组合来评估患者的表型：1.在NIH临床中心，患者将接受所有主要器官系统的彻底检查，包括体格检查、生殖检查、内分泌检查和放射检查。我们将描述患者的表型异常，检测与特定Y连锁基因缺陷相关的模式。将患者带到临床中心可确保所有测试都以最严格和最系统的方式进行，从而可以识别以前被忽视的表型。2.在Page实验室，同一组患者的细胞和分子表型将使用全基因组方法的组合进行表征：RNA-seq和ChIP-seq。我们将在具有完整Y染色体的对照中进行类似的分析，以鉴定可能与Y染色体缺陷相关的染色质修饰、转录水平或有效剪接的扰动。 通过对Y染色体异常个体在分子、细胞、解剖学和生理学水平上的综合表型表征，我们可以开始了解Y连锁基因对基本生物学过程的贡献和两性之间的根本差异。最终，这些见解可能导致对特纳综合征表型的病因学和疾病中性别偏见的根本原因的更大理解。

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.