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一定程度的智力障碍，而且大多数人需要终身援助，因此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。自闭症的高遗传率强调了遗传基因变异的重要作用，从而有可能(a)利用遗传作图来发现导致人类疾病的途径和过程，以及(b)在完全了解基因型和表型之间关系的基础上发展改进的临床预测和更有效地利用干预措施。以前对自闭症遗传学的研究都发现了在自闭症中起作用的特定基因、突变和生物机制。目前发现的许多自闭症基因都与可塑性过程有关，通过这种可塑性过程，神经元活动模式调节神经元之间突触连接的效力，而这种突触可塑性是学习和记忆的分子关联。然而，总的来说，已确定的基因仍然无法解释人类自闭症的绝大多数遗传性，并且可能（如果知道）重要的病因机制可能有效地指导治疗和预防的发展和部署。本提案的目标是将以下功能整合在一起：1)全外显子组和基因组测序；2)近亲家族的纯合子图谱；3)响应神经元活动的神经元转录的全基因组图谱；4)调节这种转录的因子结合位点的全基因组图谱，以生成和注释自闭症相关变异的目录。近亲家庭已经被纳入研究，并已被表型化。神经元转录和结合位点图谱将由哈佛医学院的格林伯格实验室开发。全外显子组和全基因组测序将在Broad研究所完成。儿童医院的沃尔什实验室将验证结果并分析变异数据。这项建议将产生并使公众可获得：85例近亲自闭症诊断个体的外显子序列数据和变异目录，35例近亲自闭症诊断个体的基因组序列数据和变异目录，下一代测序数据分析的计算管道，静息和去极化人类神经元中编码和非编码rna及替代转录物全基因组图谱，6种活性诱导转录因子（如MEF2， c-fos， SR， CREB, MEF2, c-fos）结合位点全基因组图谱。CBP等)在静息和去极化的人类神经元中，ASD相关罕见变异的验证分析结果。1

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.