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

基本信息

批准号：
10427710
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
项目类别：
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/10427710
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 Institutes International Learning Massachusetts Medicine Mentors Mentorship Methods Modeling Molecular Molecular Conformation Molecular Genetics Mutation Nuclear Pathogenicity Pattern Perinatal mortality demographics Prevalence Proteins 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 developmental disease diagnostic value disorder control exome sequencing fetal functional genomics gene discovery genetic architecture genome sequencing genome-wide human disease improved malformation medical schools mid-career faculty neuropsychiatry novel population based post-doctoral training postnatal period programs transcriptome sequencing transcriptomics whole genome

项目摘要

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.

抽象的本次培训和研究应用的目的是确定疾病的新型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（DD）相关。大约 30-40% 的 DD 可以用罕见的从头蛋白质截短变异或结构变异来解释（SV；大于 50 个碱基对的基因组改变）处于强烈进化限制的基因中。目前尚不清楚，并且代表了遗传结构研究中的一个主要空白，是罕见的贡献 DD 的非编码遗传变异已经有一些致病性远程位置的例子。由导致 DD 的非编码 SV 引起的效应（LRPE），以及我们小组和其他人的初步工作表明三维（3D）基因组结构的破坏称为拓扑相关域（TAD）可能是在这些位点观察到的强烈调节作用的原因。 SV、TAD 破坏和 DD 风险之间的关系我们将：（1）通过鉴定不耐受破坏的 TAD 并建立模型来预测非编码 SV 的致病性 (2) 确定 TAD 破坏对基因表达的影响；以及 (3) 阐明 TAD 破坏的附加诊断价值识别 DD 中的致病性 LRPE。拟议的应用还将开发一个广泛的研究计划。对于切尔西·劳瑟博士来说，他的目标是成为一名独立研究者。劳瑟博士是一名计算人员。接受过从染色体微阵列和整体中识别和解释 SV 的基因组学家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 Michael Talkowski 博士利用基因组学来研究 3D 染色质破坏作为疾病机制的影响。是马萨诸塞州总医院基因组医学中心主任，任命于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（Aiden），分子和人类遗传学副教授兼基因组中心主任贝勒医学院的建筑学博士将担任共同导师和密切合作者。和 Lieberman-Aiden 是统计、计算和功能基因组学以及基因组组织和核功能的指导团队还由基因组方面的不同专业知识组成。诊断和变异解释（Heidi Rehm 博士）、基因组进化和调控（Katie Pollard 博士）、与神经发育和神经精神疾病相关的 SV 的功能注释（Douglas 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）。这个出色的导师团队和培训计划将促进 Lowther 博士向独立过渡并将大力支持她成为基因组医学领域的领导者。