Complex Genetic Architecture of Chromosomal Aberrations in Autism

自闭症染色体畸变的复杂遗传结构

• 批准号: 8913266
• 负责人: MICHAEL E TALKOWSKI
• 金额: $ 24.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8913266
• 关键词: 16p11.2; Accounting; Address; Adult; Architecture; Area; Autistic Disorder; Award; Balanced Chromosomal Translocation; Bypass; Characteristics; Child; Chromosomal Rearrangement; Chromosome Structures; Chromosome abnormality; Chromosomes; Classification; Clinical; Complement; Complex; Cytogenetics; DNA; DNA Sequence Alteration; Data; Data Analyses; Development; Diagnostic; Diagnostic and Statistical Manual of Mental Disorders; Disease; Doctor of Philosophy; Environment; Equilibrium; Event; Excision; Failure; Family; Foundations; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Structures; Genetic Variation; Genetic study; Genome; Genomic Segment; Genomics; Genotype; Goals; Hand; Heritability; Heterogeneity; Human; Human Genetics; Individual; Inherited; Institutes; Investigation; Knowledge; Lead; Lesion; Life; Malignant Neoplasms; Mediating; Medical Genetics; Mental disorders; Mentors; Mentorship; Methods; Modeling; Molecular Genetics; National Research Service Awards; Neurodevelopmental Disorder; Outcome; Parents; Patients; Phenotype; Population; Prevalence; Recurrence; Reporting; Research; Research Design; Research Training; Resolution; Resources; Risk; Science; Scientist; Seminal; Sequence Analysis; Series; Source; Specificity; Staging; Surveys; Syndrome; Techniques; Testing; Time; Training; Transcriptional Regulation; Translocation Breakpoint; Universities; Variant; abstracting; autism spectrum disorder; base; cancer cell; career; chromothripsis; cohort; design; dosage; exome sequencing; genetic risk factor; genetic variant; genome wide association study; human disease; innovation; insight; medical schools; meetings; member; microdeletion; novel; patient population; pleiotropism; predictive modeling; repaired; skills; symposium; transcriptomics

Project Summary / Abstract Significance & Research: Balanced chromosomal rearrangements represent both clinical diagnostic quandaries and exceptional experimental opportunities in human genetics as they offer a unique window into the impact of single locus hemizygosity in human disease. However, their contribution to complex disorders remains largely unquantified as they are not detected by conventional association approaches. Failure to consider BCRs bypasses a powerful complement to conventional association approaches in complex disease as they can directly implicate a causal locus or sequence motif, and may help explain a portion of the missing heritability in disorders such as autism spectrum disorders (ASDs). In this proposal, the candidate will delve into this unexplored genomic space by leveraging novel sequencing techniques innovated during his current NRSA to evaluate the full spectrum chromosomal aberrations that can impact human developmental abnormalities such as ASD, their inheritance, and the mechanism by which they arise. The proposed studies were carefully designed to develop expertise in three primary training domains; mechanism of DNA breakage repair and formation of chromosomal aberrations, clinical genetics and heterogeneous phenotypic presentation, and the molecular genetic consequences of chromosomal abnormalities on gene expression (transcriptomics). These skills are needed to establish expertise required to become a leader in the genomics of human neurodevelopmental abnormalities and chromosomal aberrations. Hypotheses: The aims of this proposal were designed to test the specific hypotheses supported by the preliminary data that: (1) inverted genomic segments represent an underappreciated and profound genetic risk factor mediating human chromosomal aberrations and complex chromosomal rearrangements by aberrant repair of small de novo or inherited local inversions (Aim 1), (2) phenotypic discordance from highly penetrant genetic lesions is mitigated by unrecognized genetic structure (Aim 2), and (3) balanced chromosomal aberrations underlie a meaningful portion of the unexplained genetic etiology of children with autism and no detectable dosage imbalance (Aim 3). Training: All research will be conducted within the Center for Human Genetic Research at MGH, Harvard Medical School, and the Broad Institute under the mentorship of James F. Gusella, Ph.D., an established leader in the field with a prolific record of discovery in human genetics. Training will be carried out in three primary domains with contributing experts in each field, including A) studying the mechanism of DNA break repair and chromosomal rearrangements with James Lupski, Ph.D., external advisory panel member, B) deep training in clinical genetics to understand the diverse phenotypes associated with neurodevelopmental abnormalities with Cynthia Morton, Ph.D., advisory panel member and Director of Cytogenetics at Harvard Medical School, and C) molecular genetics, transcriptomics, and the impact of chromosomal aberrations on gene expression with James Gusella, Ph.D. Director of the Center for Human Genetic Research and a leader in the molecular genetics of human disease and Mark J. Daly, Chief of the Analytical and Translational Genetics Unit of CHGR, expert in computational genomics, and emerging leader in autism genetics research. In addition to research training, the candidate will undertake coursework through Harvard University and MIT, participate in regular seminars and symposia, continue to lead an autism genomics group, and attend annual scientific meetings. Significance: The impact of balanced chromosomal aberrations in autism and other human developmental abnormalities is largely unknown as they remain completely undetectable by most genetic research designs. As the population prevalence of autism continues to increase, estimates at cytogenetic resolution suggest the impact of chromosomal abnormalities in these children is potentially high (estimated at an approximately six- fold increase in the development of autism). These studies will fulfill a vital need in the study of human developmental abnormalities and could provide significant insight into the mechanism by which these events occur and ultimately yield sequence specificity and predictive diagnostics to the patients studied in Aim 3. Overall, the training environment is exceptional, the proposed studies are innovative, the science is timely, the hypotheses address unresolved and important questions in the field that could yield seminal findings in autism genetics, the genomics of chromosomal organization, and the implementation of clinical diagnostics. The mentoring and research skills developed over the course of this award will undoubtedly provide a strong foundation for the candidate to become a successful independent scientist and leader in understanding the genomics underlying human developmental abnormalities. Indeed, the candidate's enthusiasm is very high for the remarkable training and research opportunities afforded in this application.

项目摘要 /摘要 意义与研究：均衡的染色体重排代表两个临床诊断 难民和人类遗传学中出色的实验机会，因为它们为您提供了独特的窗口 单基因座半加性在人类疾病中的影响。但是，它们对复杂疾病的贡献 由于没有被常规关联方法检测到，因此在很大程度上保持了很大的效果。无法 考虑BCR绕过复杂疾病中常规关联方法的有力补充 因为它们可以直接暗示因果基因座或序列基序，并可能有助于解释缺失的一部分 自闭症谱系障碍（ASD）等疾病的遗传力。在此提案中，候选人将深入研究 通过利用新的测序技术创新，进入这个未开发的基因组空间 NRSA评估可能影响人类发育的全光谱染色体畸变 异常，例如ASD，其继承以及它们出现的机制。提出的研究 经过精心设计，以在三个主要培训领域发展专业知识； DNA断裂机理 染色体畸变，临床遗传学和异质表型的修复和形成 呈现以及染色体异常对基因表达的分子遗传后果 （转录组学）。需要这些技能来建立成为基因组学领导者所需的专业知识 人类神经发育异常和染色体畸变。 假设：该提案的目的旨在测试由 初步数据：（1）倒基因组段代表了一个未被充分认识和深刻的遗传风险 介导人染色体畸变和复杂染色体重排的因子因异常 修复从头开始或继承的局部倒置（AIM 1），（2）表型与高度渗透剂的不一致 通过未识别的遗传结构（AIM 2）和（3）平衡染色体来减轻遗传病变 畸变是自闭症儿童无法解释的遗传病因的有意义的部分 可检测的剂量不平衡（AIM 3）。 培训：所有研究将在哈佛大学的MGH人类遗传研究中心进行 医学院，以及詹姆斯·F·古塞拉（James F. Gusella）博士的指导下的广大研究所 该领域的领导者在人类遗传学中具有多产的发现记录。培训将在三个 在每个领域中具有贡献专家的主要领域，包括a）研究DNA断裂机制 詹姆斯·卢普斯基（James Lupski，Ph.D.）的维修和染色体重排，外部咨询面板成员，b） 临床遗传学的培训以了解与神经发育相关的多种表型 辛西娅·莫顿（Cynthia Morton）博士的异常 医学院和c）分子遗传学，转录组学以及染色体畸变对 詹姆斯·古塞拉（James Gusella）博士的基因表达人类遗传研究中心主任和领导者 在分析和转化的负责人马克·戴利（Mark J. Daly）的分子遗传学中 CHGR的遗传学单位，计算基因组学专家以及自闭症遗传学研究的新兴领导者。 除了研究培训外，候选人还将通过哈佛大学和麻省理工学院进行课程。 参加常规研讨会和研讨会，继续领导自闭症基因组学小组，并参加年度 科学会议。 意义：平衡染色体畸变对自闭症和其他人类发育的影响 异常在很大程度上是未知的，因为大多数遗传研究设计仍然完全无法检测到。 随着自闭症的人口流行率继续增加，细胞遗传学分辨率的估计表明 这些儿童中染色体异常的影响可能很高（估计约为六 自闭症发展的折叠增加）。这些研究将满足人类研究的重要需求 发育异常，可以对这些事件的机制有重大见解 发生并最终对AIM 3中研究的患者产生序列特异性和预测性诊断。 总体而言，培训环境是例外的，拟议的研究具有创新性，科学是及时的， 假设解决了可能在自闭症中产生开创性发现的未解决和重要问题 遗传学，染色体组织的基因组学以及临床诊断的实施。这 在本奖项过程中发展的指导和研究技能无疑将提供强大的 候选人成为一名成功的独立科学家和领导者的基础 人类发育异常的基因组学。确实，候选人的热情非常高 本应用程序提供了非凡的培训和研究机会。