Complex Genetic Architecture of Chromosomal Aberrations in Autism

描述（由申请人提供）：平衡染色体重排代表了人类遗传学的临床诊断困境和特殊的实验机会，因为它们为人类疾病中单位点半合子的影响提供了一个独特的窗口。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是对复杂疾病中传统关联方法的有力补充，因为它们可以直接涉及因果位点或序列基序，并且可能有助于解释自闭症谱系障碍（asd）等疾病中部分缺失的遗传性。在本提案中，候选人将通过利用在他目前的NRSA期间创新的新测序技术来深入研究这个未开发的基因组空间，以评估可能影响人类发育异常（如ASD）的全谱染色体畸变，其遗传及其产生的机制。拟议的研究经过精心设计，以发展三个主要培训领域的专门知识；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）。这些技能是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所必需的。假设：本建议的目的是测试由初步数据支持的具体假设：(1)倒置的基因组片段代表了一个未被充分认识和深刻的遗传风险因素，介导人类染色体畸变和复杂的染色体重排，通过小的新生或遗传性局部倒置的异常修复（Aim 1）；(2)高渗透遗传病变的表型不一致通过未被识别的遗传结构得到缓解（Aim 2）；(3)平衡的染色体畸变是自闭症儿童的遗传病因中有意义的一部分，没有检测到剂量失衡（目的3）。培训：所有研究将在MGH人类基因研究中心、哈佛医学院和Broad研究所进行，在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，在人类遗传学方面有着丰富的发现记录。培训将在三个主要领域进行，每个领域都有贡献专家，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)与Cynthia Morton博士一起进行临床遗传学深度培训，以了解与神经发育异常相关的多种表型，顾问小组成员兼哈佛医学院细胞遗传学主任，C)分子遗传学。转录组学，以及染色体畸变对基因表达的影响，与人类遗传研究中心主任，人类疾病分子遗传学的领导者James Gusella博士和CHGR分析和转化遗传学部门主任，计算基因组学专家，自闭症遗传学研究的新兴领导者Mark J. Daly一起。除了研究培训之外，候选人还将在哈佛大学和麻省理工学院学习课程，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的持续增加，细胞遗传学分辨率的估计表明，这些儿童的染色体异常的影响可能很高（据估计，自闭症的发展大约增加了六倍）。这些研究将满足人类发育异常研究的重要需求，可以为这些事件发生的机制提供重要的见解，并最终为Aim 3研究的患者提供序列特异性和预测性诊断。总的来说，培训环境是特殊的，提出的研究是创新的，科学是及时的，假设解决了该领域尚未解决的重要问题，这些问题可能在自闭症遗传学，染色体组织基因组学和临床诊断实施方面产生开创性的发现。在这个奖项的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的基因组学的领导者提供坚实的基础。事实上，候选人对这个申请所提供的卓越的培训和研究机会的热情非常高。

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.