Complex Genetic Architecture of Chromosomal Aberrations in Autism

项目总结/摘要 意义和研究：平衡染色体重排代表了临床诊断和治疗的两个方面。 人类遗传学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， 单基因座半合子对人类疾病的影响。然而，它们对复杂疾病的贡献 仍然在很大程度上未被量化，因为它们不能通过传统的关联方法检测到。未能 我认为BCR绕过了对复杂疾病中传统联合方法的有力补充 因为它们可以直接暗示因果基因座或序列基序，并可能有助于解释部分缺失的基因。 自闭症谱系障碍（ASD）等疾病的遗传性。在这份提案中，候选人将深入研究 通过利用他目前的创新测序技术， NRSA评估可能影响人类发育的全谱染色体畸变 如ASD异常，他们的遗传，以及他们出现的机制。拟议的研究 经过精心设计，在三个主要培训领域发展专业知识; DNA断裂机制 染色体畸变的修复和形成，临床遗传学和异质表型 染色体异常对基因表达的分子遗传学后果 （转录组学）。这些技能需要建立成为基因组学领导者所需的专业知识 人类神经发育异常和染色体畸变。 假设：本提案的目的是检验 初步数据表明：（1）倒置的基因组片段代表了一种被低估的和深刻的遗传风险 介导异常染色体畸变和复杂染色体重排的因子 修复小的从头或遗传性局部倒位（目的1），（2）高度外显的表型不一致性 未识别的遗传结构减轻了遗传损伤（目标2），以及（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一个有意义的部分， 可检测的剂量失衡（目标3）。 培训：所有研究将在哈佛MGH人类遗传研究中心进行 医学院和布罗德研究所的指导下，詹姆斯F。Gusella博士，一个既定 在人类遗传学领域有着丰富发现记录的领导者。培训将在三个 主要领域，每个领域的贡献专家，包括A）研究DNA断裂的机制 修复和染色体重排与詹姆斯Lupski博士，外部顾问小组成员，B）深度 临床遗传学培训，以了解与神经发育相关的各种表型 Cynthia Morton博士的异常顾问团成员，哈佛细胞遗传学主任 分子遗传学，转录组学，以及染色体畸变对 基因表达与James Gusella博士人类基因研究中心主任， 在人类疾病的分子遗传学和马克J戴利，首席分析和翻译 CHGR的遗传学单位，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：平衡染色体畸变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，因为它们仍然完全无法被大多数遗传研究设计检测到。 随着孤独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 - 10岁）。 自闭症的发展增加一倍）。这些研究将满足人类研究的迫切需要。 发育异常，并可以提供重要的洞察机制，这些事件 发生，并最终产生序列特异性和目标3中研究的患者的预测性诊断。 总的来说，培训环境是特殊的，拟议的研究是创新的，科学是及时的， 这些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。的 在这个奖项的过程中发展的指导和研究技能无疑将提供一个强大的 为候选人成为一个成功的独立科学家和领导者在理解的基础 人类发育异常背后的基因组学事实上，候选人的热情非常高， 在这一应用中提供的显着的培训和研究机会。

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.