Role of somatic mosaicism in autism, schizophrenia, and bipolar disorder brain

体细胞镶嵌在自闭症、精神分裂症和双相情感障碍大脑中的作用

基本信息

批准号：
9308008
负责人：
JONATHAN PEVSNER
金额：
$ 41.03万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-22 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308008
关键词：
9q21 Affect Autistic Disorder Autopsy Bipolar Disorder Bipolar I Body Regions Body part Brain Brain Diseases Brain region Calcium Signaling Categories Cells Cerebellum Child Chromosomes Conceptions Copy Number Polymorphism DNA DNA Sequence Alteration Detection Diagnosis Dideoxy Chain Termination DNA Sequencing Disease Enzymes Etiology Event GNAQ gene GTP-Binding Protein alpha Subunits GTP-Binding Protein alpha Subunits, Gs Genes Genetic Genetic Transcription Genomic DNA Germ-Line Mutation Goals Heart Heritability Incidence Individual Inherited Kidney Lead Malignant Neoplasms Measures Mental disorders Mitochondria Mosaicism Mutation Nature Neoplastic Processes Neurites Neuroglia Neurons Nucleotides Organ Parents Pattern Phenotype Port-Wine Stain Prefrontal Cortex Prevalence Public Health Recurrence Research Retrotransposition Role Sampling Schizophrenia Single Nucleotide Polymorphism Skin Somatic Cell Somatic Mutation Sturge-Weber Syndrome System Testing Therapeutic Validation Variant autism spectrum disorder base case control cell type diagnostic biomarker exome sequencing gain of function gene function gene product genetic pedigree genetic variant genome sequencing genome wide association study improved induced pluripotent stem cell locked nucleic acid loss of function loss of function mutation molecular imaging mutant nanochannel nerve stem cell neuropsychiatric disorder neurotransmitter release next generation sequencing public health relevance pyrosequencing single molecule skin disorder synaptogenesis transcriptome sequencing whole genome

项目摘要

DESCRIPTION (provided by applicant): The broad, long-term objective of the proposed research is to identify somatic genetic mutations that occur in brain regions of individuals with autism spectrum disorder (ASD), schizophrenia (SZ), and bipolar disorder (BD). Ultimately the discovery and characterization of somatic mutations may help us to understand the etiology of these disorders and eventually lead to improved therapeutic strategies and diagnostic markers. ASD, SZ, and BD are all commonly occurring neuropsychiatric disorders that have a large genetic basis (with estimated heritability of ~75% to 80% for each condition). However, relatively few DNA variants have been identified that have causal roles in the etiology. We hypothesize that somatic mosaicism--the occurrence of mutations in selected body regions after conception--occurs in brain and contributes to the etiology of ASD, SZ, and BD. Specific Aim 1 is to identify the nature and extent of somatic mosaic mutations across brain and body regions in postmortem samples from apparently normal individuals. We will assess four categories of somatic variation: (1) single nucleotide variants (SNVs), (2) structural variants (SVs) including copy number variants, (3) L1 retrotransposition events, and (4) mitochondrial heteroplasmy. These types of variation will be detected using whole genome sequencing (Years 1 and 2), single molecule imaging with DNA nanochannels (Year 2), and single nucleotide polymorphism (SNP) arrays. Samples include brain regions (e.g. prefrontal cortex and cerebellum) and organs (e.g. heart and kidney). After identifying somatic variants we will perform rigorous validation. Specific Aim 2 is to identify the nature and extent of somatic mosaicism in genomic DNA from individuals with ASD, SZ, and BD. The same approaches for discovery and validation will be applied as in Aim 1. Specific Aim 3 is to functionally categorize somatic variants, particularly those that are predicted to disrupt the functions of genes previously implicated in those disorders. One approach is single-cell RNA-seq (to determine the consequence of the mutation on transcription, and to infer the cell type of origin of the somatic variant). Another approach uses neurons (or glia) derived from induced pluripotent stem cells (iPSCs) and stably expressing the wildtype or mutant forms of the somatic variants. These studies will help to establish the role of somatic mutation in neuropsychiatric disorders, including the functional consequences of such variation.

描述（由适用提供）：拟议的研究的广泛长期目标是确定在自闭症谱系障碍（ASD），精神分裂症（SZ）和双相情感障碍（BD）大脑区域中发生的体细胞基因突变。最终，躯体突变的发现和表征可能有助于我们了解这些疾病的病因，并最终导致改善的治疗策略和诊断标记。 ASD，SZ和BD都是通常发生的神经精神疾病，具有较大的遗传基础（每种疾病的遗传力估计约为75％至80％）。但是，已经鉴定出相对较少的DNA变异在病因中具有因果关系。我们假设体细胞镶嵌物（概念之后选定的身体区域突变的发生）在大脑中占有，并有助于ASD，SZ和BD的病因。具体目的1是确定来自明显正常个体的事后样本中大脑和身体区域的体细胞镶嵌突变的性质和程度。我们将评估四类的体细胞变异：（1）单核苷酸变体（SNV），（2）结构变体（SVS），包括拷贝数变体，（3）L1转载置换事件，以及（4）线粒体异质质。将使用整个基因组测序（1年和2年），具有DNA纳米通道（2年级）的单分子成像以及单个核肽多态性（SNP）阵列来检测这些类型的变异。样品包括大脑区域（例如前额叶皮层和小脑）和器官（例如心脏和肾脏）。在识别躯体变体后，我们将执行严格的验证。具体目的2是确定来自ASD，SZ和BD个体的基因组DNA中体细胞镶嵌性的性质和程度。发现和验证的方法将与AIM 1一样应用。特定的目标3是在功能上对体细胞变体进行分类，尤其是那些预计会破坏以前在这些疾病中实施的基因功能的变体。一种方法是单细胞RNA-seq（确定突变对转录的结果，并推断体细胞变体的原点类型）。另一种方法使用源自诱导的多能干细胞（IPSC）的神经元（或神经胶质），并稳定地表达体细胞变体的野生型或突变形式。这些研究将有助于确定体细胞突变在神经精神疾病中的作用，包括这种变异的功能后果。