Characterizing the genetic etiology of delayed puberty with integrative genomic techniques

特发性促性腺激素减退症(IHH)和Kallmann综合征(KS)是罕见的先天性 阻止患者进入青春期并导致成年后不育的不孕症，从而导致 这对受影响儿童的身体和心理都造成了沉重的负担。促性腺激素释放不足 激素(GnRH)是由GnRH神经元分泌的激素，是IHH和KS的原因。尽管做出了以前的努力 通过家系分析和研究确定IHH/KS的原因变异，以探索其功能 尽管GnRH神经元调节失调，但IHH/KS的遗传病因仍在很大程度上尚未解释。要解决这个问题 挑战，我将(1)定义完整的基因组变异谱，从单核苷酸变异 (SNV)到大结构变异(SV)，从最大IHH/KS队列的全基因组测序(WGS) 在全球范围内组装，并使用已经建立的编码和非编码变体进行联合关联 识别风险基因和调控元件的统计方法；(2)检查功能丧失的影响 不育相关基因突变对GnRH神经元转录组失调的影响；以及(3)检查 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。 计划中的研究包括对三个基因组中的基因组变异进行统计建模和解释 从促性腺激素释放激素神经元RNA序列中获得转录组失调以深入了解糖尿病的遗传病因学 罕见的先天性不孕症。为了确保该项目的成功，该中心主任迈克尔·塔科夫斯基博士 基因组医学(CGM)在麻省总医院(MGH)、哈佛医学院(HMS)和布罗德 研究所，将担任主要导师。斯蒂芬妮·塞米纳拉博士，生殖内分泌学家和教授 MGH和HMS的医学系主任，以及Bide SV团队的助理教授兼负责人Harison Brand将 作为联合导师提供额外的指导。Talkowski博士和Seminara博士是计算领域的世界领先者 遗传学和生殖生物学，布兰德博士领导了许多解释疾病基因组中SVS的研究 最近通过K99/R00成功地过渡到MGH和HMS的独立研究人员 获奖。除了他们的互补领导，咨询委员会成员组成的团队在不同的职业生涯 Stages将在整个项目中提供科学反馈和职业发展建议。丰富的…… 可通过CGM、MGH和博德研究所获得的资源、工具以及科学和临床专业知识 形成一个高度协作的环境，这是支持我向独立过渡的理想位置。 这项研究将扩展我的专业知识，包括尖端技术，并提供学习机会 关于与先天性和体质不孕症相关的表型，如何应用统计学 方法确定因果基因组座位，以及如何解释转录组活性的偏差。有了这些 技能，我将能够从功能上描述影响生殖障碍的基因变异，并- 准备推出我自己的高绩效和创新性的独立研究项目。

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.