Human autism genetics and activity dependent gene activation

人类自闭症遗传学和活动依赖性基因激活

• 批准号: 7941723
• 负责人: Christopher A. Walsh
• 金额: $ 263.95万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941723
• 关键词: Area; Autistic Disorder; Binding Sites; Biological; Brain; CREB1 gene; Candidate Disease Gene; Cataloging; Catalogs; Chromosome Mapping; Clinical; Code; Collection; Complex; Computer Analysis; DNA; DNA Sequence; Data; Data Analyses; Development; Diagnosis; Disease; Emotional; Enrollment; Environment; FOS gene; Family; Financial cost; Funding; Gene Activation; Gene Mutation; Genes; Genetic; Genetic Determinism; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Goals; Heritability; Human; Human Genetics; Human Genome; Human Genome Project; Impairment; Individual; Inherited; Institutes; International; Intervention; Knowledge; Leadership; Learning; Left; Maps; Medical; Memory; Mental Retardation; Methods; Molecular; Mutation; National Center for Research Resources; Neurologic; Neurons; Pathway interactions; Patients; Pediatric Hospitals; Phase; Phenotype; Plastics; Play; Population; Population Genetics; Prevention therapy; Process; Production; Research; Rest; Role; Sampling; Societies; Sum; Synapses; Synaptic plasticity; Technology; TimeLine; Transcript; Untranslated RNA; Validation; Variant; analytical method; analytical tool; autism spectrum disorder; base; cohort; cost; exome; experience; gene discovery; genetic analysis; genetic linkage; genetic linkage analysis; genetic pedigree; genome sequencing; genome wide association study; genome-wide; genome-wide linkage; improved; medical schools; multidisciplinary; neuronal patterning; neuropsychiatry; new technology; next generation; programs; psychologic; public health relevance; response; success; technology development; transcription factor

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.

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。由于很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，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。 自闭症的高遗传性强调了遗传变异的重要作用，使得（a）使用遗传图谱来发现人类疾病的致病途径和过程成为可能，（B）在完全理解基因型和表型之间关系的基础上，开发改进的临床预测和更有效地使用干预措施成为可能。 以前的自闭症遗传学方法都导致发现了在自闭症中发挥作用的特定基因，突变和生物机制。迄今为止发现的许多自闭症基因都参与了可塑性过程，通过这些过程，神经元的活动模式调节了神经元之间突触连接的功效，而这种突触可塑性是学习和记忆的分子相关物。然而，总而言之，这些基因仍然无法解释人类自闭症的绝大多数遗传可能性--而且，据推测，重要的病因机制可能（如果知道的话）有效地指导治疗和预防的开发和部署。 该提案的目标是汇集以下各项的力量：1）全外显子组和基因组测序，2）血缘家族中的纯合性作图，3）响应神经元活性的神经元转录的全基因组图谱，以及4）调节该转录的因子的结合位点的全基因组图谱，以生成和注释ASD相关变体的目录。这些近亲家庭已经参加了研究，并进行了表型分析。神经元转录和结合位点图将由哈佛医学院的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变异数据。 该提案将产生并公开提供：诊断为ASD的85个近亲个体中的外显子组序列数据和变体目录，诊断为ASD的35个近亲个体中的基因组序列数据和变体目录，用于分析下一代测序数据的计算管道，静息和去极化人类神经元中编码和非编码RNA以及替代转录物的全基因组图谱，六种活性诱导转录因子（如MEF 2、c-fos、SR、CREB、CBP等）的全基因组结合位点图谱在静息和去极化的人类神经元中，与ASD相关的罕见变体的验证分析结果。1 公共卫生关系：自闭症和自闭症谱系障碍是一组神经系统疾病，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也至关重要。该提案旨在利用最新技术来显著增加我们对自闭症遗传原因的了解。