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

三维基因组组织的破坏作为人类发育障碍疾病的非编码机制

• 批准号: 10705583
• 负责人: Chelsea Lowther
• 金额: $ 13.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705583
• 关键词: 3-Dimensional; Address; Advisory Committees; Appointment; Architecture; Balanced Chromosomal Translocation; Base Pairing; Catalogs; Cell Line; Characteristics; Chromatin; Chromatin Structure; Chromosome abnormality; Collaborations; Collection; Complex; Cytogenetics; DNA Sequence Alteration; Data; Data Set; Diagnosis; Diagnostic; Disease; Evolution; Fellowship; Gene Expression; Gene Targeting; General Hospitals; Genes; Genetic Variation; Genome; Genomic approach; Genomic medicine; Goals; Human; Human Genetics; Individual; International; Learning; Massachusetts; Medicine; Mentors; Mentorship; Methods; Modeling; Molecular; Molecular Conformation; Molecular Genetics; Mutation; Nuclear; Pathogenicity; Pattern; Perinatal mortality demographics; Postdoctoral Fellow; Prevalence; Protein Truncation; RNA analysis; Regulation; Research; Research Personnel; Risk; Sampling; Statistical Methods; Statistical Models; Structure; Technology; Training; Training Programs; Untranslated RNA; Variant; Work; career; case control; cohort; college; comparison control; developmental disease; diagnostic value; exome sequencing; fetal; functional genomics; gene discovery; genetic architecture; genome sequencing; genome-wide; human disease; improved; malformation; medical schools; mid-career faculty; model building; neuropsychiatry; novel; population based; post-doctoral training; postnatal period; prenatal; programs; transcriptome sequencing; transcriptomics; whole genome

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.

摘要 这种训练和研究应用的目的是识别疾病的新的非编码机制 使用一套统计和功能基因组学策略与发育障碍(DDS)相关。 大约30%-40%的DDS可以用一种罕见的从头蛋白截断变体或结构变体来解释 (SV；大于50个碱基对的基因组改变)处于强烈进化约束下的基因。什么 目前尚不为人所知，并代表了遗传体系结构研究中的一个重大空白，是罕见的贡献 DDS的非编码遗传变异。有几个致病的远程体位的例子 非编码SVS导致DDS的影响(LRPE)，以及我们团队和其他人的初步工作有 表明破坏被称为拓扑相关结构域的三维(3D)基因组结构 (TADS)可能是在这些基因座观察到的强烈调控效应的原因。要系统地评估 SVS、TAD干扰与DDS风险之间的关系我们将：(1)通过以下方式定义新的候选LRPE基因座 鉴定对干扰不耐受的TADS并建立模型预测非编码SVS的致病性；(2) 确定TAD干扰对基因表达的影响；以及(3)阐明TAD干扰对基因表达的附加诊断价值 DDS中致病LRPE的鉴定。拟议中的申请还将开发一个广泛的研究计划 对于切尔西·洛瑟博士来说，他的目标是成为一名独立的调查员。洛瑟博士是一名计算机师 受过从染色体微阵列和全基因组中鉴定和解释SVS的基因组学家的培训 基因组测序数据，现在寻求获得高级统计建模和功能方面的新专业知识 基因组学研究3D染色质破坏作为疾病机制的影响。迈克尔·塔科夫斯基博士 是马萨诸塞州总医院基因组医学中心的主任，预约在 哈佛医学院和布罗德研究所，并将担任主要导师，而埃雷兹·利伯曼博士- 艾登，分子和人类遗传学副教授，基因组中心主任 贝勒医学院建筑学教授将担任共同导师和密切合作者。Talkowski博士 和利伯曼-艾登是统计、计算和功能基因组学以及 基因组组织和核功能。导师团队还包括基因组方面的不同专业知识。 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SVS的功能注释(道格拉斯博士 以及与人类畸形相关的疾病的非编码机制(斯特凡·蒙德洛斯博士)。 这一优秀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先者的轨迹。