Beyond the reproductive tract: The future of Y chromosome research

超越生殖道：Y 染色体研究的未来

• 批准号: 8825055
• 负责人: Maximilian Muenke
• 金额: $ 48.76万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-18 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825055
• 关键词: Affect; Biological Process; Biology; Blood; Cells; ChIP-seq; Chromosome abnormality; Chromosomes, Human, Y; Clinical; Clinical Research; Complex; Defect; Disease; Ensure; Epigenetic Process; Etiology; Evaluation; Exhibits; Failure; Female; Future; Gender; Gene Expression Regulation; Genes; Genome; Genomics; Genotype; Health; Hereditary Disease; Histones; Homologous Gene; Human; Human Biology; Human Genetics; Individual; Institute of Medicine (U.S.); Knowledge; Laboratories; Lead; Light; Link; Lysine; Maps; Medicine; Molecular; Noonan Syndrome; Patients; Pattern; Phenotype; Physiological; Play; Positioning Attribute; Predisposition; Prevalence; Production; RNA Splicing; Recruitment Activity; Recurrence; Regulator Genes; Reporting; Reproduction; Research; Resources; Role; Severities; Sex Bias; Sex Characteristics; Skin; Spermatogenesis; Structure; Testing; Testis; Transcript; Turner' s Syndrome; United States National Academy of Sciences; United States National Institutes of Health; Y Chromosome; base; body system; chromatin modification; defined contribution; design; dosage; epigenetic profiling; experience; genome-wide; human disease; insight; male; molecular phenotype; patient oriented; pressure; public health relevance; reproductive; research clinical testing; sex; sex determination; sperm cell; transcription factor; transcriptome sequencing; treatment strategy

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.

描述（由申请人提供）：该提案的目的旨在揭示人类 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。我们正在进行的对多个哺乳动物 Y 染色体的基因组研究揭示了一组广泛表达、剂量敏感的调节基因，这些基因保守在 Y 染色体上。由于许多广泛表达的基因可能具有重要且广泛的生物学功能，因此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、易感性或严重程度的疾病。历史上，缺失图谱研究仅关注 Y 染色体的睾丸特异性基因，这些基因参与性别决定和精子产生。我们将通过研究约 75 名 Y 染色体异常患者（影响一个或多个基因），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。我们将采用多种方法来评估患者的表型： 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，包括身体、生殖、内分泌和放射学检查。我们将表征患者的表型异常，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系统的方式进行，从而能够识别以前被忽视的表型。 2. 在 Page 实验室中，将使用 RNA-seq 和 ChIP-seq 组合的全基因组方法来表征同一组患者的细胞和分子表型。我们将在具有完整 Y 染色体的对照中进行类似的分析，以识别可能与 Y 染色体缺陷相关的染色质修饰、转录水平或剪接效率的扰动。 通过对 Y 染色体异常个体在分子、细胞、解剖和生理水平上进行全面的表型表征，我们可以开始了解 Y 连锁基因对基本生物过程的贡献以及性别之间的根本差异。最终，这些见解可能会导致人们对特纳综合征表型的病因学和疾病性别偏见的根本原因有更深入的了解。