Characterizing the genetic etiology of delayed puberty with integrative genomic techniques

特发性低促性腺激素性腺功能减退症（IHH）和卡尔曼综合征（KS）是罕见的先天性形式， 阻止患者进入青春期并导致成年后不孕的不孕症， 对受影响儿童的身心造成沉重负担。缺乏促性腺激素释放 促性腺激素释放激素（GnRH）神经元分泌的激素是引起IHH和KS的原因。尽管之前的努力 通过系谱分析和研究来确定IHH/KS的因果变异，以探索功能性 由于GnRH神经元的调节异常，IHH/KS的遗传病因仍然很大程度上无法解释。为了解决这个 挑战，我将（1）定义基因组变异的完整谱，从单核苷酸变异 从最大的IHH/KS队列的全基因组测序（WGS）， 在全球范围内组装，并使用已建立的编码和非编码变体进行联合关联 统计学方法识别风险基因和调控元件;（2）检查功能丧失的影响 (LoF)不育相关基因突变对GnRH神经元转录组失调的影响;（3）检测 基因组变异在更广泛的受体质性青春期延迟（CDP）影响的个体中的影响。 计划中的研究包括三个基因组中基因组变异的统计建模和对 GnRH神经元中RNA序列的转录组失调，以深入了解 罕见的先天性不孕症为了确保项目的成功，中心主任迈克尔·塔尔科夫斯基博士 基因组医学（CGM）在马萨诸塞州总医院（MGH），哈佛医学院（HMS）和布罗德 研究所，将担任主要导师。Stephanie Seminara博士，生殖内分泌学家和教授 医学在MGH和HMS，哈里森品牌，助理教授和广泛的SV团队的领导，将 作为共同导师提供额外指导。Talkowski博士和Seminara博士是计算机科学领域的世界领导者 遗传学和生殖生物学，Brand博士领导了许多研究，解释疾病基因组中的SV 最近通过K99/R 00成功地过渡到MGH和HMS的独立研究学院 奖除了他们的互补领导，一个顾问委员会成员在不同的职业 阶段将在整个项目中提供科学反馈和职业发展建议。的丰度 通过CGM、MGH和Broad研究所获得的资源、工具以及科学和临床专业知识 形成一个高度协作的环境，以支持我向独立过渡。 这项研究将扩展我的专业知识，包括尖端技术，并提供学习的机会 关于与先天性和体质性不孕症相关的表型，如何应用统计学 鉴定致病基因座的方法，以及如何解释转录组活性的偏差。与这些 技能，我将能够从功能上描述影响生殖障碍的遗传变异，并能很好地- 能够启动我自己的高性能和创新的独立研究项目。

Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are rare congenital forms of infertility that prevent patients from entering puberty and lead to infertility in their adulthood, thus causing significant burden to affected children both physically and psychologically. The lack of gonadotrophin-releasing hormone (GnRH), the hormone secreted by GnRH neurons, is the cause of IHH and KS. Despite previous efforts to identify causal variants in IHH/KS through pedigree analyses and studies to explore the functional dysregulation in GnRH neurons, the genetic etiology of IHH/KS remains largely unexplained. To address this challenge, I will (1) define a complete spectrum of genomic variants, ranging from single nucleotide variants (SNVs) to large structural variation (SV), from whole genome sequencing (WGS) of the largest IHH/KS cohort assembled worldwide, and perform joint association of coding and non-coding variants using already established statistical methods to identify risk genes and regulatory elements; (2) examine the impact of loss of function (LoF) mutations of infertility associated genes on transcriptome dysregulation in GnRH neurons; and (3) examine the effect of genomic variants in a broader range of individuals affected by constitutional delayed puberty (CDP). The planned research incorporates statistical modeling of genomic variants in trio genomes and interpretation of transcriptome dysregulation from RNA sequences in GnRH neurons to gain insights into the genetic etiology of rare congenital infertility. To ensure success of the project, Dr. Michael Talkowski, Director of the Center for Genomic Medicine (CGM) at Mass General Hospital (MGH), Harvard Medical School (HMS) and the Broad Institute, will serve as the primary mentor. Drs. Stephanie Seminara, reproductive endocrinologist and Professor of Medicine at MGH and HMS, and Harrison Brand, Assistant Professor and Lead of the Broad SV Team, will provide additional guidance as co-mentors. Drs. Talkowski and Seminara are world leaders in computational genetics and reproductive biology, and Dr. Brand has led numerous studies interpreting SVs in disease genomes and recently successfully transitioned to an independent research faculty at MGH and HMS through a K99/R00 award. In addition to their complementary leadership, a team of advisory committee members at various career stages will provide scientific feedback and career development advice throughout the project. The abundance of resources, tools, and scientific and clinical expertise accessible through the CGM, MGH, and the Broad Institute form a highly collaborative environment ideally positioned to support my transition to independence. The research will extend my expertise to include cutting-edge techniques and provide the opportunity to learn about phenotypes associated with congenital and constitutional infertility disorders, how to apply statistical methods to identify causal genomic loci, and how to interpret deviations in transcriptome activity. With these skills, I will be able to functionally characterize genetic variation affecting reproductive disorders and be well- positioned to launch my own high-performing and innovative independent research program.