Deciphering the Role of Copy Number Variants in Neuroendocrine Disorders of Infertility

项目摘要 尽管全世界有6-12%的女性和男性患有不孕症，但 控制人类生殖的方法还没有完全确定。在这项研究中，PI将研究基因 特发性低促性腺激素性性腺功能减退症（IHH）是一种罕见的神经内分泌疾病， 促性腺激素释放激素（GnRH）神经元信号传导缺陷，导致青春期延迟， 不孕60%的IHH患者的遗传病因仍然未知。这种缺失的遗传性可以归因于 难以描述的遗传变异，如拷贝数变异（CNVs）， 使用传统的测序技术，如核型和微阵列捕获。近期优势 下一代测序已经允许从外显子组测序（ES）数据中检测较小的CNV。在这 研究中，PI将在大量IHH受试者（1，400名）中利用此类尖端CNV调用算法， 检查CNVs对IHH缺失遗传力的贡献，了解GnRH神经元生物学， 破译罕见和常见生殖疾病的遗传控制。PI将探索以下方面的贡献： 已知和新型IHH基因的CNV，并将利用来自IHH患者和受试者的人类表型 登记到马萨诸塞州总布里格姆生物库（其中来自ES的CNV将被调用），以确定 CNV在人类疾病表达中的后果。主要研究者将完成 Seminara博士、Talkowski博士和Balasubramanian博士的指导。Seminara医生是一个NICHD的PI P50国家生殖和不孕症转化研究中心（NCTRI） 生殖医学（CRM）在马萨诸塞州总医院（MGH），并将提供所有可用的 资源（访问ES和表型数据库），以成功完成他的研究计划， 以及直接指导，以促进她过渡到一个独立的职业生涯作为一个医生科学家。博士 Talkowski是MGH基因组医学中心（CGM）的主任，并开创了新型CNV 方法。在他的指导下，PI将分析IHH、对照和生物库受试者中ES衍生的CNV。博士 Talkowski也是基因组学核心的主任，该核心拥有所有用于功能验证的资源， PI的CNV分析中出现的新基因（IPSc来源的GnRH细胞）。最后，博士。 Balasubramanian是NCTRI-CRM的助理主任，在研究人口方面具有重要的专业知识 人类基因研究的生物库，并将为PI提供重要指导，以成功地 完成她的求婚。此外，候选人将追求正式的课程和定期参与 与生殖内分泌学和遗传学有关的研究会议。该项目将促进 在临床研究和人类遗传学领域的技能发展，并代表了一个全面的 计划确定CNV在罕见遗传性神经内分泌疾病不孕症中的作用，准备PI申请 获得职业发展奖，继续接受培训，成为一名独立的临床调查员。

PROJECT ABSTRACT Despite 6-12% of women and men around the world suffering from infertility, the full ensemble of genes that control human reproduction has not been fully characterized. In this study, the PI will study the genetic background of Idiopathic Hypogonadotropic Hypogonadism (IHH), a rare neuroendocrine disorder caused by defects in Gonadotropin Releasing Hormone (GnRH) neuronal signaling, that leads to delayed puberty and infertility. The genetic etiology in 60% of IHH patients remains unknown. This missing heritability can be attributed to poor characterization of elusive genetic variation such as copy number variants (CNVs) that are hard to capture using traditional sequencing technologies, such as karyotypes and microarrays. Recent advantages in next generation sequencing have allowed detection of smaller CNVs from exome sequencing (ES) data. In this study, the PI will utilize such cutting edge CNV calling algorithms in a large cohort of IHH subjects (1,400) to examine the contribution of CNVs to the missing heritability of IHH, understand the GnRH neuronal biology and decipher the genetic control of rare and common reproductive disorders. The PI will explore the contribution of CNVs to known and novel IHH genes and will utilize human phenotypes from the IHH patients and subjects enrolled to the Mass General Brigham biobank (in whom CNVs from ES will be called) to determine the consequences of CNVs in human disease expression. The PI will complete the proposed work under the mentorship of Dr. Seminara, Dr. Talkowski and Dr. Balasubramanian. Dr. Seminara is the PI of a NICHD- sponsored P50 National Center of Translational Research in Reproduction and Infertility (NCTRI) – Center for Reproductive Medicine (CRM) at the Massachusetts General Hospital (MGH) and will provide all available resources (access to ES and phenotypic databases) for the successful completion of his research proposal as well as direct mentorship to facilitate her transition to an independent career as a physician scientist. Dr. Talkowski is the Director for the Center of Genomic Medicine (CGM) at MGH and has pioneered novel CNV approaches. Under his guidance, the PI will analyze ES derived CNVs in IHH, control and biobank subjects. Dr. Talkowski is also the Director of the Genomics Core that houses all the resources for the functional validation of the novel genes that will emerge from the PI’s CNV analyses (IPSc derived GnRH cells). Finally, Dr. Balasubramanian is the Assistant Director of the NCTRI-CRM with significant expertise in studying population biobanks for human genetic investigations and will provide important guidance to the PI for the successful completion of her proposal. In addition, the candidate will pursue formal coursework and regular engagement in research meetings related to both reproductive endocrinology and genetics. This project will facilitate development of skills in the areas of clinical investigation and human genetics and represents a comprehensive plan to identify the role of CNVs in rare inherited neuroendocrine disorders of infertility, preparing the PI to apply for a career development award to continue her training to become an independent clinical investigator.