2/3 Integrative Genomic Analysis of Human Brain Development and Autism

2/3 人脑发育和自闭症的综合基因组分析

• 批准号: 9330219
• 负责人: DANIEL H GESCHWIND
• 金额: $ 63.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-10 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330219
• 关键词: Address; Adolescence; Adult; Architecture; Area; Autistic Disorder; Autopsy; Bioinformatics; Brain; Brain Diseases; Brain region; Cell Nucleus; Cerebral cortex; ChIP-seq; Childhood; Chromatin; Chromatin Structure; Collaborations; Collection; Complement; Complex; Corpus striatum structure; Data; Data Analyses; Data Set; Development; Diagnostic tests; Disease; Epigenetic Process; Etiology; Family; Fetal Development; Fluorescence; Functional disorder; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomics; Genotype-Tissue Expression Project; Germ Lines; Goals; Health; Heterogeneity; Human; Impairment; Individual; Inherited; Investigation; Link; Mental disorders; Methodology; Molecular; Molecular Profiling; Mutation; Neurons; Nuclear; Pathogenicity; Pathway interactions; Patients; Pattern; Phase; Prefrontal Cortex; Principal Investigator; Process; Proteins; Publications; Records; Regulatory Element; Research; Research Personnel; Resolution; Resources; Sorting - Cell Movement; Syndrome; Systems Biology; Temporal Lobe; Time; Tissues; Transcript; Transcriptional Regulation; Untranslated RNA; Variant; Work; autism spectrum disorder; base; biobank; brain cell; cell type; chromatin remodeling; developmental neurobiology; epigenome; epigenomics; frontal lobe; functional genomics; genomic data; genomic profiles; human tissue; improved; infancy; insight; interest; mind control; neurodevelopment; neuropsychiatric disorder; novel; relating to nervous system; repetitive behavior; risk variant; scaffold; social communication; spatiotemporal; statistics; tissue/cell culture; transcriptome; transcriptome sequencing; transcriptomics; whole genome

ABSTRACT Genetic and genomic investigations have yielded important findings as to the genetic contributions to major psychiatric illnesses, illustrating significant etiological heterogeneity, as well as cross-disorder overlap. It has also become clear that understanding how this genetic variation leads to alterations in brain development and function that underlies psychiatric disease pathophysiology will be greatly advanced by a roadmap of the transcriptomic and epigenetic landscape of the human cerebral cortex across key developmental windows. Here, we propose, via a highly collaborative group of investigators, each with distinct areas of expertise and research focus, to create a scaffold of genomic data for understanding ASD pathophysiology, and psychiatric disorders more broadly. The work proposed here represents an ambitious multi-PI project (Yale, UCLA, and UCSF) that brings together three principal investigators and collaborators with strong publication records and expertise in all approaches necessary to perform this work using state-of-the-art and novel methodologies. We will perform time-, region-, and cell type-specific molecular profiling of control and ASD brains (Aim 1), including RNA-seq based transcriptomics, identifying cis-regulatory elements via ChIP-seq, and use Hi-C to determine the 3D chromatin architecture and physical relationships that underlie transcriptional regulation in three major regions implicated in neuropsychiatric disease (frontal and temporal cortex and striatum) across five major epochs representing disease-relevant stages in human brain development. This will include complementary genomic analyses in controls and matched post mortem ASD brain to identify genetic mechanisms underlying processes altered in ASD brain. We will address cellular heterogeneity via fluorescence-activated nuclear sorting (FANS) so as to profile neurons and non-neural cells separately, which will complement the whole tissue analyses. We will analyze and integrate these datasets to identify regional, developmental, and ASD-related processes to gain insight into underlying mechanisms, harmonizing these multi-omic data with other psychENCODE studies, as well as other large scale data sets, such as BrainSpan, ENCODE, GTEx and Roadmap Epigenomics Project (Aim 2). We will perform integrated analysis of germ-line ASD variations identified in more than 1000 families from the Simons Simplex Collection to characterize causal enrichments in developmental periods, brain regions, and cell types to better characterize the mechanisms by which genetic variation in humans alters brain development and function in health and disease (Aim 3). Completion of these aims will lead to a well-integrated resource across major periods in human cortical and striatal development that will permit generation of concrete testable hypotheses of ASD mechanisms, and inform our pathophysiological understanding of other related neuropsychiatric disorders.

抽象的 遗传和基因组研究对主要的遗传贡献提出了重要的发现 精神病，说明了严重的病因异质性以及跨疾病重叠。它有 还要清楚地知道，了解这种遗传变异如何导致大脑发育的改变和 基于精神病病理生理学的功能将通过路线图大大提高 跨关键发育窗口的人大脑皮层的转录组和表观遗传景观。 在这里，我们通过一个高度协作的调查人员组提出，每个小组都有不同的专业知识领域 研究重点，创建基因组数据的脚手架，以理解ASD病理生理学和精神病学 疾病更广泛。这里提出的工作代表了一个雄心勃勃的多PI项目（耶鲁大学，加州大学洛杉矶分校和 UCSF）汇集了三位主要调查员和合作者，并拥有强大的出版记录和 使用最先进和新颖的方法进行这项工作所需的所有方法的专业知识。我们 将执行对照和ASD大脑的时间，区域和细胞类型特异性分子分析（AIM 1）， 包括基于RNA-seq的转录组学，通过芯片seq识别顺式调节元素，然后使用HI-C进行 确定基于转录调节的3D染色质结构和物理关系 涉及神经精神疾病（额叶和颞皮质和纹状体）的三个主要区域 五个主要的时期，代表与疾病相关的人类脑发育中的阶段。这将包括 对照和匹配的尸体ASD大脑中的互补基因组分析以鉴定遗传 ASD大脑中的机制发生了变化。我们将通过 荧光激活的核分子（风扇）分别介绍神经元和非神经细胞， 将补充整个组织分析。我们将分析和集成这些数据集，以识别区域性， 发展和与ASD相关的过程，以深入了解基本机制，协调这些机制 带有其他精神码研究以及其他大规模数据集（例如brainspan）的多词数据， 编码，GTEX和路线图表观基因组学项目（AIM 2）。我们将对种系的综合分析 Simons单纯物收集的1000多个家庭中鉴定出的ASD变化，以表征因果关系 发育时期，大脑区域和细胞类型的富集，以更好地表征机制 人类的哪种遗传变异改变了脑发育和健康和疾病的功能（AIM 3）。 这些目标的完成将导致人类皮质和 纹状体开发将允许生成ASD机制的具体测试假设，并 告知我们对其他相关神经精神疾病的病理生理理解。