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: 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
• 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

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 该培训和研究应用的目的是确定新型的非编码机制 使用一系列统计和功能基因组学策略与发育障碍（DDS）相关。 大约30-40％的DD可以通过罕见的从头蛋白质截短或结构变体来解释 （SV；大于50个碱基对的基因组改变）在强烈进化约束的基因中。什么 目前未知，代表遗传结构研究中的主要空隙，是罕见的贡献 对DDS的非编码遗传变异。有少数病原长期位置的例子 效果（LRPE）是由导致DD的非编码SV引起的，我们的小组和其他人的初步工作 提出，三维（3D）基因组结构的破坏称为拓扑相关域 （TAD）可能是在这些基因座观察到的强烈调节作用的原因。系统地评估 SVS，TAD中断和DDS风险之间的关系：（1）通过The Necking Cantifuts LRPE基因座定义 识别不耐受的TAD对破坏和建立模型以预测非编码SV的致病性； （2） 确定TAD破坏对基因表达的影响； （3）阐明了附加的诊断值 鉴定DDS中的致病性LRP。拟议的应用程序还将制定广泛的研究计划 对于切尔西·洛瑟（Chelsea Lowther）博士而言，他的目标是成为一名独立研究者。 Lowther博士是计算 在染色体微阵列和整个SV的识别和解释方面训练和解释的基因组学家 现在试图获得高级统计建模和功能方面的新专业知识的基因组测序数据 基因组学检查3D染色质破坏作为疾病机制的影响。迈克尔·泰克斯基（Michael Talkowski）博士 是马萨诸塞州综合医院基因组医学中心主任 哈佛医学院和广大研究所，将担任主要导师，而Erez Lieberman博士 - 艾登（Aiden），分子和人类遗传学副教授，基因组中心主任 贝勒医学院的建筑将担任联合和亲密合作者。博士。 Talkowski Lieberman-aiden是统计，计算和功能基因组学领域的世界领导者，以及 基因组组织和核功能。 Mentalship团队还包括潜水员的基因组专业知识 诊断和变体解释（Heidi Rehm博士），基因组进化和监管（Katie Pollard博士）， 与神经发育和神经精神疾病相关的SVS的功能注释（Douglas博士 Ruderfer），以及与人畸形相关的疾病的非编码机制（Stefan Mundlos博士）。 这个杰出的心态团队和培训计划将有助于洛瑟博士向独立过渡 并将强烈支持她成为基因组医学领域的领导者的轨迹。