Human autism genetics and activity dependent gene activation

描述(由申请人提供)：自闭症谱系障碍(ASD)是一组神经精神疾病，其特征是沟通、建立关系和对环境做出适当反应的能力受损。由于许多自闭症患者都有不同程度的智力障碍，而且大多数人需要终身援助，社会的经济成本非常高，而家庭的情感和心理成本甚至无法估计。自闭症的高遗传性突出了遗传遗传变异的重要作用，使得(A)使用遗传图谱来发现人类人群中导致疾病的途径和过程，以及(B)在完全了解基因和表型之间的关系的基础上，改进了临床预测并更有效地使用了干预措施。以前的自闭症遗传学方法都导致了对自闭症起作用的特定基因、突变和生物机制的发现。迄今为止发现的许多自闭症基因都参与了神经元活动模式调节神经元间突触连接有效性的可塑性过程，而这种突触可塑性是学习和记忆的分子关联。然而，总而言之，已识别的基因仍然没有解释自闭症在人类中的绝大多数遗传性，而且可能是重要的病因机制，如果知道的话，可能会有效地指导治疗和预防的开发和部署。这一建议的目标是将以下方面的力量结合在一起：1)整个外显子组和基因组测序，2)近亲家庭的纯合性图谱，3)神经元活动响应的全基因组转录图谱，以及4)调节这种转录的因子结合位点的全基因组图谱，以生成和注释ASD相关变异的目录。这些血缘关系的家庭已经进行了研究，并进行了表型鉴定。神经元转录和结合部位图将由哈佛医学院格林伯格实验室开发。整个外显子组和全基因组测序将在布罗德研究所完成。儿童医院的沃尔什实验室将验证结果并分析不同的数据。这项提议将产生并公开提供：85名ASD血缘个体的外基因组序列数据和变异目录，35名ASD血缘个体的基因组序列数据和变异目录，用于分析下一代测序数据的计算管道，全基因组范围的编码和非编码RNA图以及静息和去极化的人类神经元的替代转录本，六种活性诱导转录因子(例如MEF2，c-fos，SR，CREB，CBP等)的全基因组结合位点图。在静息和去极化的人类神经元中，与ASD相关的罕见变异的验证分析结果。1 公共卫生相关性：自闭症和自闭症谱系障碍是一组神经疾病，其特征是沟通、建立关系和对环境做出适当反应的能力受损。发现导致自闭症的基因不仅对早期和更好的诊断至关重要，而且对预防和治疗策略的制定也至关重要。这项提议旨在利用最新技术显著增加我们对自闭症遗传原因的了解。

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) are a group of neuropsychiatric conditions characterized by impairment in the ability to communicate, form relationships, and respond appropriately to the environment. With many autistic individuals having some degree of mental retardation, and most requiring lifelong assistance, the financial costs to society are very high, while the emotional and psychological costs to families cannot even be estimated. The high heritability of autism underscores important roles for inherited genetic variation, making possible (a) the use of genetic mapping to discover the pathways and processes that are causal for disease in the human population, and (b) the development of improved clinical prediction and more efficient use of interventions based on a complete understanding of the relationship between genotype and phenotype. Previous approaches to autism genetics have each led to the discovery of specific genes, mutations and biological mechanisms that play a role in autism. Many autism genes discovered so far are involved in plastic processes by which patterns of neuronal activity regulate the efficacy of the synaptic connections between neurons, and this synaptic plasticity is the molecular correlate of learning and memory. Yet in sum, the genes identified still leave unexplained the vast majority of the heritability of autism in humans - and, presumably, important etiological mechanisms that might (if known) productively guide development and deployment of therapy and prevention. The goal of this proposal is to bring together the power of 1) whole exome and genome sequencing, 2) homozygosity mapping in consanguineous families, 3) genome-wide maps of neuronal transcription in response to neuronal activity, and 4) genome-wide maps of the binding sites of factors that regulate this transcription to generate and annotate a catalog of ASD-associated variants. The consanguineous families are already enrolled in research, and have been phenotyped. The neuronal transcription and binding site maps will be developed by the Greenberg Lab at Harvard Medical School. The whole exome and whole genome sequencing will be done at the Broad Institute. And the Walsh lab at Children's Hospital will validate the results and analyze the variant data. This proposal will generate and make publicly available: Exomic sequence data and a catalog of variants in 85 consanguineous individuals diagnosed with ASD, Genomic sequence data and a catalog of variants in 35 consanguineous individuals diagnosed with ASD, Computational pipelines for analysis of next generation sequencing data Genome-wide map of coding and noncoding RNAs and alternative transcripts in resting and depolarized human neurons, Genome-wide map of binding sites for six activity-induced transcription factors (e.g. MEF2, c-fos, SR, CREB, CBP, etc.) in resting and depolarized human neurons, Results of validation analysis of rare variants associated with ASD. 1 PUBLIC HEALTH RELEVANCE: Autism and autism spectrum disorders are a group of neurological conditions characterized by impairment in the ability to communicate, form relationships, and respond appropriately to the environment. The discovery of genes that contribute to autism is critical not only for earlier and better diagnosis but also for informing strategies for prevention and therapy. This proposal aims to use the latest technologies to significantly increase our knowledge of the genetic causes of autism.