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: 8492163
• 负责人: MICHAEL E TALKOWSKI
• 金额: $ 9.29万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492163
• 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; Data; Data Analyses; Development; Diagnostic; Diagnostic and Statistical Manual; 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; Genome; Genomic Segment; Genomics; Genotype; Goals; Hand; Heritability; Heterogeneity; Human; Human Genetics; Individual; Inherited; Institutes; Investigation; Knowledge; Lead; Lesion; Life; Malignant Neoplasms; Mediating; 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; autism spectrum disorder; base; cancer cell; career; cohort; design; dosage; exome sequencing; genetic risk factor; genome wide association study; human disease; innovation; insight; medical schools; meetings; member; microdeletion; novel; patient population; predictive modeling; repaired; skills; symposium; transcriptomics

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：平衡染色体重排代表了人类遗传学中的临床诊断困境和特殊的实验机会，因为它们提供了了解单基因座半合性对人类疾病的影响的独特窗口。然而，它们对复杂疾病的贡献在很大程度上仍未量化，因为传统的关联方法无法检测到它们。不考虑 BCR 就绕过了对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自闭症谱系障碍 (ASD) 等疾病中缺失的部分遗传性。在此提案中，候选人将利用当前 NRSA 期间创新的新颖测序技术，深入研究这个未经探索的基因组空间，以评估可能影响人类发育异常（例如自闭症谱系障碍）的全谱染色体畸变、其遗传及其产生机制。拟议的研究经过精心设计，旨在发展三个主要培训领域的专业知识； DNA断裂修复和染色体畸变形成的机制、临床遗传学和异质表型表现，以及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人类神经发育异常和染色体畸变基因组学领导者所需的专业知识。假设：本提案的目的旨在测试初步数据支持的具体假设：（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因素，通过小从头的异常修复介导人类染色体畸变和复杂的染色体重排。或遗传性局部倒位（目标 1），(2) 通过以下方式减轻了高度渗透性遗传病变引起的表型不一致未识别的遗传结构（目标 2）和（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有意义的一部分，并且没有可检测到的剂量不平衡（目标 3）。培训：所有研究都将在 MGH 人类基因研究中心、哈佛医学院和博德研究所的 James F. Gusella 博士的指导下进行，James F. Gusella 博士是该领域的知名领导者，拥有丰富的研究记录人类遗传学的发现。培训将在三个主要领域进行，每个领域的专家都有贡献，包括 A) 与外部顾问小组成员 James Lupski 博士一起研究 DNA 断裂修复和染色体重排的机制，B) 临床遗传学方面的深度培训与哈佛医学院顾问小组成员兼细胞遗传学主任 Cynthia Morton 博士一起了解与神经发育异常相关的多种表型，以及 C) 分子遗传学、转录组学以及James Gusella 博士研究染色体畸变对基因表达的影响人类遗传学研究中心主任、人类疾病分子遗传学领域的领军人物，以及 CHGR 分析和转化遗传学部门负责人、计算基因组学专家、自闭症遗传学研究新兴领军人物 Mark J. Daly。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，参加定期研讨会和专题讨论会，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异常的影响在很大程度上尚不清楚，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（估计自闭症的发展增加约六倍）。这些研究将满足人类发育异常研究的重要需求，并可以为这些事件发生的机制提供重要的见解，并最终为目标 3 中研究的患者提供序列特异性和预测性诊断。总体而言，培训环境非常好所提出的研究具有创新性，科学性是及时的，这些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遗传学、染色体组织基因组学和临床诊断的实施方面产生开创性的发现。在该奖项过程中培养的指导和研究技能无疑将为候选人成为一名成功的独立科学家和理解人类发育异常基因组学的领导者提供坚实的基础。事实上，候选人对该应用程序提供的出色培训和研究机会的热情非常高。