Complex Genetic Architecture of Chromosomal Aberrations in Autism

项目摘要/摘要 意义和研究：平衡的染色体重排代表着临床诊断 人类遗传学中的困境和特殊的实验机会，因为它们提供了一个独特的窗口 单基因座半杂合性在人类疾病中的影响。然而，他们对复杂疾病的贡献 仍然在很大程度上没有被量化，因为它们不能被传统的关联方法检测到。未能做到 认为BCR在复杂疾病中绕过了传统关联方法的强大补充 因为它们可以直接牵涉到因果位置或序列基序，并可能有助于解释部分缺失 自闭症谱系障碍(ASDS)等疾病的遗传性。在这项提案中，候选人将深入研究 通过利用在他目前的研究中创新的新的测序技术 NRSA评估可能影响人类发育的全谱染色体异常 异常，如自闭症，它们的遗传，以及它们产生的机制。建议进行的研究 精心设计以开发三个主要培训领域的专业知识；DNA断裂的机制 染色体异常的修复和形成、临床遗传学和异质性表型 以及染色体异常对基因表达的分子遗传学后果 (转录学)。这些技能是建立成为基因组学领导者所需的专业知识所必需的 人类神经发育异常和染色体异常。 假设：这项提议的目的是测试由 初步数据表明：(1)基因组片段倒置代表了一种被低估的、深刻的遗传风险 通过异常介导人类染色体异常和复杂染色体重排的因子 修复小的新生或遗传性局部反转(目标1)，(2)高度渗透的表型不一致 遗传损伤通过未被识别的遗传结构减轻(目标2)，以及(3)染色体平衡 异常是自闭症和非自闭症儿童不明遗传病因的重要组成部分。 可检测到的剂量失衡(目标3)。 培训：所有研究将在哈佛大学麻省理工学院人类基因研究中心内进行 在詹姆斯·F·古塞拉(James F.Gusella)博士的指导下， 该领域的领导者，在人类遗传学方面有丰富的发现记录。培训将在三年内进行 主要领域，每个领域有贡献的专家，包括A)研究DNA断裂的机制 与詹姆斯·卢普斯基博士的修复和染色体重排，外部顾问小组成员，B)深度 接受临床遗传学培训，以了解与神经发育相关的不同表型 哈佛大学咨询小组成员兼细胞遗传学主任辛西娅·莫顿博士的异常 以及C)分子遗传学、转录学和染色体异常对 与詹姆斯·古塞拉的基因表达，博士，人类遗传研究中心主任，一位领导者 在人类疾病的分子遗传学和马克·J·戴利，分析和翻译研究所所长 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， 定期参加研讨会和座谈会，继续领导自闭症基因组学小组，并参加年度 科学会议。 意义：平衡染色体异常对自闭症和其他人类发育的影响 异常在很大程度上是未知的，因为它们仍然是大多数基因研究设计完全无法检测到的。 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 染色体异常对这些儿童的影响可能很高(估计约为6-6岁)。 自闭症的发展增加了一倍)。这些研究将满足人类研究的一个重要需求。 发育异常，并可能为这些事件的机制提供重要的洞察 发生并最终产生序列特异性和对目标3中研究的患者的预测性诊断。 总体而言，培训环境特殊，拟议的研究具有创新性，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方面产生开创性的发现。 遗传学，染色体组织的基因组学，以及临床诊断的实施。这个 在这个奖项的过程中发展起来的指导和研究技能无疑将提供强大的 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基础。事实上，候选人对竞选的热情非常高 在这一应用中提供了非凡的培训和研究机会。

Project Summary / Abstract Significance & Research: 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.