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

• 批准号: 9903893
• 负责人: JONATHAN PEVSNER
• 金额: $ 18.67万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903893
• 关键词: 9q21; Affect; 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; Structure; Sturge-Weber Syndrome; System; Testing; Therapeutic; Validation; Variant; autism spectrum disorder; base; case control; causal variant; 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; pyrosequencing; single molecule; single-cell RNA sequencing; skin disorder; synaptogenesis; whole genome

PROJECT SUMMARY/ABSTRACT 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.

项目总结/摘要 拟议研究的广泛，长期目标是确定发生在 自闭症谱系障碍（ASD）、精神分裂症（SZ）和双相情感障碍患者的大脑区域 （BD）.最终，体细胞突变的发现和表征可能有助于我们理解 这些疾病的病因学，并最终导致改善的治疗策略和诊断标志物。 ASD、SZ和BD都是常见的神经精神疾病，具有很大的遗传基础（ 每种条件的估计遗传率为~75%至80%）。然而，相对较少的DNA变体已经被 在病因学中具有因果作用。我们假设，体细胞嵌合现象-- 怀孕后身体特定区域的突变--发生在大脑中，并导致ASD的病因， SZ和BD。具体目标1是确定跨大脑的体细胞嵌合突变的性质和程度， 身体区域的尸检样本从明显正常的个人。我们将评估四类 体细胞变异：（1）单核苷酸变异（SNV），（2）结构变异（SV），包括拷贝数 变体，（3）L1反转录转座事件，和（4）线粒体异质性。这些类型的变化将是 使用全基因组测序（第1年和第2年）检测，使用DNA纳米通道进行单分子成像 (Year 2），和单核苷酸多态性（SNP）阵列。样本包括大脑区域（例如前额叶 皮质和小脑）和器官（例如心脏和肾脏）。在确定体细胞变异后，我们将执行 严格验证。具体目标2是鉴定基因组DNA中体细胞嵌合现象的性质和程度 来自ASD、SZ和BD患者。将应用与 目标1。具体目标3是在功能上对体细胞变体进行分类，特别是那些被预测为 破坏先前与这些疾病有关的基因的功能。一种方法是单细胞RNA测序 (to确定突变对转录的影响，并推断突变的起源细胞类型。 体细胞变体）。另一种方法是使用来自诱导多能干细胞（iPSC）的神经元（或神经胶质） 并稳定表达体细胞变体的野生型或突变体形式。这些研究将有助于建立 体细胞突变在神经精神障碍中的作用，包括这种突变的功能后果， 变化量

项目成果

Author Correction: The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing.

作者更正：超深度全基因组测序揭示了自闭症和神经正常个体大脑皮层体细胞突变的情况。

• DOI: 10.1038/s41593-023-01437-x
• 发表时间: 2023
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Rodin,RachelE;Dou,Yanmei;Kwon,Minseok;Sherman,MaxwellA;D'Gama,AlissaM;Doan,RyanN;Rento,LarizaM;Girskis,KellyM;Bohrson,CraigL;Kim,SoniaN;Nadig,Ajay;Luquette,LovelaceJ;Gulhan,DogaC;BrainSomaticMosaicismNetwork;Park,P
• 通讯作者: Park,P

A novel somatic mutation in GNB2 provides new insights to the pathogenesis of Sturge-Weber syndrome.

• DOI: 10.1093/hmg/ddab144
• 发表时间: 2021-10-13
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Fjær R;Marciniak K;Sundnes O;Hjorthaug H;Sheng Y;Hammarström C;Sitek JC;Vigeland MD;Backe PH;Øye AM;Fosse JH;Stav-Noraas TE;Uchiyama Y;Matsumoto N;Comi A;Pevsner J;Haraldsen G;Selmer KK
• 通讯作者: Selmer KK