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实验机会，因为它们为研究人类疾病中单基因座半合子的影响提供了独特的窗口。然而，它们对复杂疾病的贡献在很大程度上仍然无法量化，因为它们不能通过传统的关联方法检测到。未能考虑BCR绕过了复杂疾病中传统关联方法的有力补充，因为它们可以直接涉及因果基因座或序列基序，并可能有助于解释自闭症谱系障碍（ASD）等疾病中缺失的遗传性的一部分。在这项提案中，候选人将通过利用在他目前的NRSA期间创新的新型测序技术来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的全谱染色体畸变，如ASD，其遗传以及它们产生的机制。拟议的研究经过精心设计，以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，临床遗传学和异质性表型表现，以及染色体异常对基因表达的分子遗传学后果（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域领导者所需的专业知识。假设：本提案的目的是检验初步数据所支持的具体假设，即：（1）倒置基因组区段代表了一种未被充分认识的和深刻的遗传风险因素，其通过小的从头或遗传性局部倒位的异常修复介导人类染色体畸变和复杂的染色体重排（Aim 1），（2）未识别的遗传结构减轻了来自高度外显遗传损伤的表型不一致性（Aim 2），和（3）平衡的染色体畸变是自闭症儿童无法解释的遗传病因学的一个有意义的部分的基础，并且没有可检测的剂量失衡（目标3）。培训内容：所有的研究都将在麻省总医院的人类遗传研究中心、哈佛医学院和布罗德研究所内进行，由詹姆斯·F。Gusella博士，在人类遗传学领域拥有丰富发现记录的公认领导者。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James Lupski博士一起研究DNA断裂修复和染色体重排的机制，外部顾问小组成员，B）在临床遗传学方面的深入培训，以了解与辛西娅·莫顿博士的神经发育异常相关的多种表型，顾问小组成员和哈佛医学院细胞遗传学主任，和C）分子遗传学，转录组学，染色体畸变对基因表达的影响与詹姆斯Gusella博士。人类遗传研究中心主任，人类疾病分子遗传学的领导者，CHGR分析和翻译遗传学部门负责人Mark J. Daly，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，候选人将通过哈佛大学和麻省理工学院进行课程，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。重要性：平衡染色体畸变在自闭症和其他人类发育异常中的影响在很大程度上是未知的，因为它们仍然完全无法被大多数遗传研究设计检测到。随着自闭症的人群患病率继续增加，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（估计自闭症的发展增加约6倍）。这些研究将满足人类发育异常研究的重要需求，并可提供对这些事件发生机制的重要见解，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，培训环境是特殊的，拟议的研究是创新的，科学是及时的，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，染色体组织的基因组学和临床诊断的实施方面产生开创性的发现。在这个奖项的过程中发展的指导和研究技能无疑将为候选人成为一个成功的独立科学家和领导者在理解人类发育异常的基因组学提供坚实的基础。事实上，候选人的热情是非常高的显着的培训和研究机会，在此应用程序提供。