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）：均衡的染色体重排既代表了人类遗传学的临床诊断难题，又代表了异常的实验机会，因为它们为单个基因座半加对人类疾病的影响提供了独特的窗口。但是，由于传统关联方法未检测到它们对复杂疾病的贡献在很大程度上仍然没有量化。不考虑BCR绕过复杂疾病中常规关联方法的强大补充，因为它们可以直接暗示因果基因座或序列基序，并可能有助于解释一部分缺失的遗传性，例如自闭症谱系障碍（ASDS）。在该提案中，候选人将利用当前NRSA期间创新的新型测序技术来深入研究这一未开发的基因组空间，以评估可能影响人类发育异常的全光谱染色体畸变，例如ASD，其遗传，其遗传和机制。拟议的研究经过精心设计，以在三个主要训练领域发展专业知识。 DNA断裂修复的机制和形成染色体畸变，临床遗传学和异质表型表现的机制，以及染色体异常对基因表达（转录组学）的分子遗传后果。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的领导者所需的专业知识。 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无法识别的遗传结构（AIM 2）缓解遗传病变，（3）平衡的染色体畸变是自闭症儿童无法解释的遗传病因的有意义的部分，没有可检测的剂量失衡（AIM 3）。培训：所有研究都将在MGH，哈佛医学院的人类遗传研究中心和广大研究所的指导下进行，该研究所是该领域的既定领导者，该领域是人类遗传学中发现的多产记录。培训将在每个领域的三个主要领域中进行，包括a）研究DNA断裂修复的机制和与詹姆斯·卢普斯基（James Lupski）博士，外部咨询小组成员的染色体重排，b）临床遗传学的深入培训，以了解与神经发育成员有关的多元化表型，并了解与神经发展症状的成员有关哈佛医学院的细胞遗传学以及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）博士的基因表达的影响。人类遗传研究中心主任，是人类疾病分子遗传学的领导者，CHGR分析和转化遗传学单位的负责人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工作，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异常的影响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它们。随着自闭症的人口流行率的不断增加，细胞遗传学分辨率的估计表明，这些儿童染色体异常的影响可能很高（估计自闭症的发展大约增加了六倍）。这些研究将在研究人类发育异常的研究中满足至关重要的需求，并可以对这些事件发生的机制进行重大见解，并最终对目标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。拟议的研究是及时的，在统一的统治中，拟议中的研究是及时的，该问题是及时解决的。染色体组织和临床诊断的实施。在本奖项过程中发展的指导和研究技能无疑将为候选人成为成功的独立科学家和领导者，以理解人类发育异常的基因组学。的确，对于本申请中提供的非凡培训和研究机会，候选人的热情非常高。