Complex Genetic Architecture of Chromosomal Aberrations in Autism

描述(由申请人提供)：平衡的染色体重排既代表了临床诊断难题，也代表了人类遗传学的特殊实验机会，因为它们提供了一个独特的窗口，可以了解单基因座半杂合性对人类疾病的影响。然而，它们对复杂疾病的贡献在很大程度上仍然没有被量化，因为它们不能被传统的关联方法检测到。未能考虑BCR绕过了传统关联方法在复杂疾病中的强大补充，因为它们可以直接牵涉到因果位置或序列基序，并可能有助于解释自闭症谱系障碍(ASD)等疾病中缺失的部分遗传性。在这项提案中，候选人将通过利用在他目前的NRSA期间创新的新测序技术来深入研究这一未知的基因组空间，以评估可能影响人类发育异常的全谱染色体异常，如ASD，它们的遗传，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断裂修复和染色体异常形成的机制，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后果(转录学)。这些技能是建立成为人类神经发育异常和染色体异常基因组学领导者所需的专业知识所必需的。假设：本建议旨在检验得到初步数据支持的具体假设：(1)基因组片段倒置代表着一种未被充分认识的、深刻的遗传风险因素，可通过小的从头修复或遗传的局部倒位的异常修复来介导人类染色体异常和复杂的染色体重排(目标1)，(2)高穿透性遗传损伤的表型不一致性可通过未知的遗传结构得到缓解(目标2)，以及(3)在自闭症儿童的不明原因的遗传病因中，有很大一部分染色体异常是由染色体异常引起的，而且没有检测到剂量失衡(目标3)。培训：所有研究将在麻省理工学院人类基因研究中心、哈佛医学院和博德研究所内进行，由詹姆斯·F·古塞拉博士指导，古塞拉博士是该领域的知名领导者，在人类遗传学方面有丰富的发现记录。培训将在三个主要领域进行，每个领域都有专家参与，包括A)与外部顾问小组成员James Lupski博士研究DNA断裂修复和染色体重排的机制，B)与哈佛医学院顾问小组成员兼细胞遗传学主任Cynthia Morton博士一起深入培训临床遗传学，以了解与神经发育异常有关的各种表型，以及C)分子遗传学、转录学以及染色体异常对基因表达的影响，与James Gusella博士和Mark J.Daly博士一起，他是人类遗传研究中心主任和人类疾病分子遗传学的领导者CHGR分析和翻译遗传学中心主任，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，候选人还将通过哈佛大学和麻省理工学院进行课程学习，参加定期的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：平衡染色体异常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。随着自闭症人口患病率的持续增加，细胞遗传学分辨率的估计表明，这些儿童中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)。这些研究将满足人类发育异常研究的重要需求，并可能为这些事件发生的机制提供重要的洞察，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，培训环境特殊，拟议的研究是创新的，科学是及时的，假说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以及临床诊断的实施方面产生重大发现。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了解人类发育异常背后的基因组学方面的领导者提供坚实的基础。事实上，应聘者对这份申请中提供的非凡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.