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: 9100918
• 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/9100918
• 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; 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; genomic data; human disease; innovation; insight; medical schools; meetings; member; microdeletion; novel; patient population; pleiotropism; predictive modeling; repaired; skills; symposium; transcriptome; transcriptomics; translational genetics

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.

项目概要/摘要 意义与研究：平衡染色体重排代表临床诊断 人类遗传学中的困境和特殊的实验机会，因为它们提供了一个独特的窗口 单基因座半合子对人类疾病的影响。然而，它们对复杂疾病的贡献 由于传统的关联方法无法检测到它们，因此在很大程度上仍然是未量化的。未能 考虑 BCR 绕过了复杂疾病中传统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，并且可能有助于解释缺失的一部分 自闭症谱系障碍 (ASD) 等疾病的遗传性。在此提案中，候选人将深入探讨 通过利用他当前期间创新的新颖测序技术进入这个未经探索的基因组空间 NRSA 评估可能影响人类发育的全谱染色体畸变 自闭症谱系障碍 (ASD) 等异常、其遗传及其发生机制。拟议的研究 经过精心设计，旨在培养三个主要培训领域的专业知识； DNA断裂机制 染色体畸变的修复和形成、临床遗传学和异质表型 染色体异常对基因表达的分子遗传学影响 （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：本提案的目的旨在测试由 初步数据表明：（1）反向基因组片段代表了一种未被充分认识的深刻遗传风险 介导人类染色体畸变和异常引起的复杂染色体重排的因素 修复小的从头或遗传性局部倒位（目标 1），（2）来自高渗透性的表型不一致 未识别的遗传结构可减轻遗传损伤（目标 2），以及 (3) 平衡染色体 畸变是自闭症儿童无法解释的遗传病因学中的一个有意义的部分。 可检测的剂量不平衡（目标 3）。 培训：所有研究将在哈佛大学麻省总医院人类基因研究中心进行 医学院和布罗德研究所在 James F. Gusella 博士的指导下， 该领域的领导者，在人类遗传学方面拥有丰富的发现记录。培训将分三期进行 各个领域都有贡献专家的主要领域，包括 A) 研究 DNA 断裂的机制 修复和染色体重排，与外部顾问小组成员 James Lupski 博士合作，B) 深度 临床遗传学培训，以了解与神经发育相关的不同表型 哈佛大学顾问小组成员兼细胞遗传学主任 Cynthia Morton 博士的异常 医学院，以及 C) 分子遗传学、转录组学以及染色体畸变对 James Gusella 博士的基因表达人类基因研究中心主任、带头人 人类疾病分子遗传学博士和分析与转化负责人 Mark J. Daly CHGR 遗传学部门，计算基因组学专家，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完成课程， 参加定期研讨会和座谈会，继续领导自闭症基因组学小组，并参加年度会​​议 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，因为大多数基因研究设计仍然完全无法检测到它们。 随着自闭症人群患病率持续增加，细胞遗传学分辨率的估计表明 染色体异常对这些儿童的影响可能很大（估计约为六倍） 自闭症的发展成倍增加）。这些研究将满足人类研究的重要需求 发育异常，并可以为这些事件的机制提供重要的见解 发生并最终为目标 3 中研究的患者产生序列特异性和预测诊断。 总体而言，培训环境优越，提出的研究具有创新性，科学性及时， 假设解决了该领域尚未解决的重要问题，这些问题可能会在自闭症方面产生开创性的发现 遗传学、染色体组织的基因组学以及临床诊断的实施。这 在该奖项过程中培养的指导和研究技能无疑将提供强大的 为候选人成为一名成功的独立科学家和理解世界的领导者奠定了基础 人类发育异常的基因组学。确实，候选人的热情非常高涨 该应用程序提供了出色的培训和研究机会。