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）是一组神经精神病学疾病，其特征是沟通，形成关系和对环境适当反应的能力受损。由于许多自闭症患者具有一定程度的智力障碍，并且大多数需要终身援助，因此对社会的财务成本很高，而对家庭的情感和心理成本也无法估计。 自闭症的高遗传力强调了遗传遗传变异的重要作用，这使得（a）使用遗传图来发现人口中疾病是因果关系的途径和过程，以及（b）基于对基因模型和概况之间关系的完整理解，改善了临床预测和更有效地使用干预措施。 以前的自闭症遗传学方法各自发现了在自闭症中起作用的特定基因，突变和生物学机制。到目前为止发现的许多自闭症基因都参与了塑性过程，神经元活动的模式调节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性。总而言之，所鉴定的基因仍然无法解释人类自闭症的绝大多数遗传力，而且大概是重要的病因机制，这些机制可能（如果已知）可以有效地指导治疗和预防的发展和部署。 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.亲密的家庭已经参与研究，并且已经表现出来。神经元转录和绑定位点图将由哈佛医学院的格林伯格实验室开发。整个外显子组和整个基因组测序将在Broad Institute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。 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,六个活性引起的转录因子（例如MEF2，C-FOS，SR，CREB，CBP等）的结合位点的全基因组图在静止和去极化的人类神经元中，对与ASD相关的稀有变体进行了验证分析结果。 1 公共卫生相关性：自闭症和自闭症谱系障碍是一组神经系统疾病，其特征是交流，建立关系和适当反应环境的能力受损。促进自闭症的基因的发现不仅对于早期诊断和更好的诊断至关重要，而且对于预防和治疗策略提供了信息。该建议旨在使用最新技术来大大提高我们对自闭症遗传原因的了解。