Disruption of three-dimensional genome organization as a noncoding mechanism of disease in human developmental disorders

摘要 本培训和研究应用程序的目的是确定新的非编码机制的疾病 使用一套统计和功能基因组学策略研究与发育障碍（DDs）相关的基因组学。 大约30-40%的DD可以由罕见的从头蛋白质截短变体或结构变体解释 (SV大于50个碱基对的基因组改变）。什么 是目前未知的，代表了遗传结构研究的一个主要空白，是罕见的贡献， 非编码遗传变异到DDs。已经有一些致病性长距离定位的例子 非编码SV引起的LRPE效应（导致DD），以及我们小组和其他人的初步工作， 这表明，被称为拓扑相关结构域的三维（3D）基因组结构的破坏 （TADs）可能是负责在这些位点观察到的强调控作用。系统地评估 SV、LRPE破坏和DD风险之间的关系，我们将：（1）通过研究LRPE基因， 鉴定不耐受破坏的TADs并建立模型预测非编码SV的致病性;（2） 确定干扰对基因表达的影响;和（3）阐明干扰的附加诊断价值。 鉴定DD中的致病性LRPE。拟议中的申请还将制定一项广泛的研究计划 切尔西洛瑟博士的目标是成为一名独立调查员。洛瑟博士是个计算型的 在染色体微阵列和整个基因组中识别和解释SV方面接受过培训的基因组学家 基因组测序数据谁现在寻求获得先进的统计建模和功能的新的专业知识 基因组学研究3D染色质破坏作为疾病机制的影响。Michael Talkowski博士 是马萨诸塞州总医院基因组医学中心的主任， 哈佛医学院和布罗德研究所，并将担任主要导师，而博士埃雷兹利伯曼- 艾登，分子和人类遗传学副教授，基因组中心主任 贝勒医学院的建筑学教授将担任共同导师和密切合作者。Talkowski博士 和Lieberman-Aiden是统计，计算和功能基因组学以及 基因组结构和核功能。导师团队还包括基因组领域的各种专业知识 诊断和变异解释（海蒂雷姆博士），基因组进化和调控（凯蒂波拉德博士）， 与神经发育和神经精神疾病相关的SV的功能注释（道格拉斯博士 Ruderfer），以及与人类畸形相关的疾病的非编码机制（Stefan Mundlos博士）。 这个杰出的指导团队和培训计划将促进洛瑟博士向独立的过渡 并将有力地支持她成为基因组医学领域的领导者。

Abstract The purpose of this training and research application is to identify novel noncoding mechanisms of disease associated with developmental disorders (DDs) using a suite of statistical and functional genomics strategies. Approximately 30-40% of DDs can be explained by a rare de novo protein-truncating variant or structural variant (SV; genomic alterations larger than 50 base pairs) in genes that are under strong evolutionary constraint. What is currently unknown, and represents a major void in genetic architecture studies, is the contribution of rare noncoding genetic variation to DDs. There have been a handful of examples of pathogenic long-range positional effects (LRPEs) caused by noncoding SVs that result in DDs, and preliminary work by our group and others have suggested that disruption of three-dimensional (3D) genome structures called topologically associated domains (TADs) may be responsible for the strong regulatory effects observed at these loci. To systematically assess the relationship between SVs, TAD disruption, and risk for DDs we will: (1) define novel candidate LRPE loci via the identification of TADs intolerant to disruption and build models to predict the pathogenicity of noncoding SVs; (2) determine the impact of TAD disruption on gene expression; and (3) elucidate the added diagnostic value of identifying pathogenic LRPEs in DDs. The proposed application will also develop an extensive research program for Dr. Chelsea Lowther whose goal it is to become an independent investigator. Dr. Lowther is a computational genomicist trained in the identification and interpretation of SVs from chromosomal microarray and whole genome sequencing data who now seeks to obtain new expertise in advanced statistical modeling and functional genomics to examine the impact of 3D chromatin disruption as a mechanism of disease. Dr. Michael Talkowski is the Director of the Center for Genomic Medicine at Massachusetts General Hospital, with appointments at Harvard Medical School and the Broad Institute, and will serve as the primary mentor, while Dr. Erez Lieberman- Aiden, an Associate Professor in Molecular and Human Genetics and the Director of the Center for Genome Architecture at Baylor College of Medicine, will serve as the co-mentor and close collaborator. Drs. Talkowski and Lieberman-Aiden are world-leaders in statistical, computational, and functional genomics as well as in genome organization and nuclear function. The mentorship team also consists of diverse expertise in genome diagnostics and variant interpretation (Dr. Heidi Rehm), genome evolution and regulation (Dr. Katie Pollard), the functional annotation of SVs associated with neurodevelopmental and neuropsychiatric conditions (Dr. Douglas Ruderfer), and in noncoding mechanisms of disease associated with human malformations (Dr. Stefan Mundlos). This outstanding mentorship team and training program will facilitate Dr. Lowther’s transition to independence and will strongly support her trajectory towards becoming a leader in the field of genomic medicine.