Somatic mutations in epilepsy: whole genome sequence analysis of single neurons
癫痫的体细胞突变:单个神经元的全基因组序列分析
基本信息
- 批准号:8585129
- 负责人:
- 金额:$ 34.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-01 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAccountingAneuploidyApplications GrantsAreaAutistic DisorderAutopsyBlood CellsBrainBrain DiseasesCandidate Disease GeneCatalogingCatalogsCell NucleusCellsCerebrumComplexCopy Number PolymorphismCortical DysplasiaCritiquesCytolysisDNADNA amplificationDNA biosynthesisDataDiagnosisDiseaseDistantEmbryoEpilepsyEtiologyEvaluationExcisionFamilyFertilizationFosteringFundingFunding OpportunitiesGene MutationGenesGeneticGenomeHealthHigh-Throughput Nucleotide SequencingHumanIndividualInheritedInstitutesInstructionInvestigationKnowledgeMethodologyMissionMitosisMutationNeurogliaNeuronsOperative Surgical ProceduresPatientsPilot ProjectsPlayPopulationPrevalenceProbabilityRecording of previous eventsReportingResearchRiskRoleScienceSeizuresSequence AnalysisSomatic CellSomatic MutationSorting - Cell MovementSpecificityStudy SectionSyndromeTSC1 geneTSC1/2 geneTechnologyTestingUnited States National Institutes of HealthUpdateWorkWritingbasebrain cellbrain tissuedesigndevelopmental geneticsexomeexome sequencinggenome sequencinghippocampal pyramidal neuronimprovedinnovationlifetime riskmalformationmeetingsneuronal cell bodynext generation sequencingnovelpreventtraittumor
项目摘要
DESCRIPTION (provided by applicant): Although epilepsy has a large genetic contribution, causative genes are not known for most epilepsy patients. And while epilepsy can be inherited in families, it is more commonly 'sporadic' or spontaneous, without a clear family history, and causes of sporadic epilepsy cases are mostly unknown. Since the cause of epilepsy often directs the choice of treatments, categorizing patients is of great importance therapeutically. Many epilepsy syndromes appear to involve 'somatic' mutations, in which a subpopulation of brain cells shows a mutation not shared by all cells of the body, because the mutation occurred during mitosis of somatic cells of the embryo after fertilization. Our lab and other have reported on somatic mutations is several genes known to cause epilepsy, however until now, technological limitations have prevented a systematic search for somatic mutations in epilepsy. Whole genome or whole exome sequencing will not identify somatic mutations unless the study is designed to detect them: responsible mutations may not be present in most blood cells, but would instead be limited to cells in the brain. Even relevant mutations limited to neurons may be missed by bulk brain sequencing because 1] neurons are surrounded by glial cells with distinct embryological origins, and with whom they would not be expected to share mutations, and 2] neurons themselves are derived from two embryological origins, with pyramidal neurons derived from cortical proliferative regions, and inhibitory nonpyramidal neurons migrating into cortex from distant subcortical regions, so that bulk sequencing of postmortem brain tissue may also not detect mutations limited to specific neuronal populations. We have recently developed technology that allows sorting of single or small numbers of cerebral cortical neuronal nuclei, and amplification of their genomes in quantities sufficient for any next-generation sequencing. We are proposing to use this technology to examine cortical neurons from postmortem brains or cortical resections from epilepsy patients in order to 1) perform a systematic assessment of copy number variation (CNV) in cerebral neurons; and 2) perform whole exome sequencing to identify mutations in known epilepsy genes. Comparison of single neuron sequence to that from other cells of the body could then determine how frequently spontaneous mutations occur in cortical neurons, and identify and catalogue these mutations. Our proposed study thus enables a systematic analysis of all mechanisms of somatic mutation in the epileptic human brain.
描述(由申请人提供):虽然癫痫有很大的遗传贡献,但大多数癫痫患者的致病基因尚不清楚。虽然癫痫可以在家族中遗传,但更常见的是“散发性”或自发性,没有明确的家族史,散发性癫痫病例的病因大多是未知的。由于癫痫的病因常常指导治疗的选择,对患者进行分类在治疗上是非常重要的。许多癫痫综合征似乎与“体细胞”突变有关,在这种突变中,脑细胞的一个亚群显示出一种不为身体所有细胞共有的突变,因为这种突变发生在受精后胚胎体细胞有丝分裂期间。我们的实验室和其他实验室已经报道了几种已知引起癫痫的基因的体细胞突变,但是直到现在,技术限制已经阻止了对癫痫的体细胞突变的系统搜索。全基因组或全外显子组测序将无法识别体细胞突变,除非该研究是为了检测它们而设计的:负责任的突变可能不存在于大多数血细胞中,而是仅限于大脑细胞。即使是局限于神经元的相关突变也可能在大量脑测序中被遗漏,因为1]神经元被具有不同胚胎起源的胶质细胞包围,它们不会与这些细胞共享突变,2]神经元本身来源于两个胚胎起源,锥体神经元来源于皮层增殖区域,抑制性非锥体神经元从遥远的皮层下区域迁移到皮层。因此,对死后脑组织的大量测序也可能无法检测到局限于特定神经元群的突变。我们最近开发了一种技术,可以对单个或少量的大脑皮层神经元核进行分类,并对其基因组进行扩增,其数量足以进行任何下一代测序。我们建议使用这项技术来检查死后大脑或癫痫患者皮质切除的皮层神经元,以便1)对大脑神经元的拷贝数变异(CNV)进行系统评估;2)进行全外显子组测序,以确定已知癫痫基因的突变。将单个神经元序列与来自身体其他细胞的序列进行比较,可以确定皮层神经元中自发突变发生的频率,并识别和分类这些突变。因此,我们提出的研究能够系统地分析癫痫人类大脑中体细胞突变的所有机制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher A. Walsh其他文献
Unveiling causal regulatory mechanisms through cell-state parallax
通过细胞状态视差揭示因果调节机制
- DOI:
10.1101/2023.03.02.530529 - 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Alexander P. Wu;Rohit Singh;Christopher A. Walsh;Bonnie Berger - 通讯作者:
Bonnie Berger
Spatial transcriptomics reveals human cortical layer and area specification
空间转录组学揭示人类皮质层和区域的特化
- DOI:
10.1038/s41586-025-09010-1 - 发表时间:
2025-05-14 - 期刊:
- 影响因子:48.500
- 作者:
Xuyu Qian;Kyle Coleman;Shunzhou Jiang;Andrea J. Kriz;Jack H. Marciano;Chunyu Luo;Chunhui Cai;Monica Devi Manam;Emre Caglayan;Abbe Lai;David Exposito-Alonso;Aoi Otani;Urmi Ghosh;Diane D. Shao;Rebecca E. Andersen;Jennifer E. Neil;Robert Johnson;Alexandra LeFevre;Jonathan L. Hecht;Nicola Micali;Nenad Sestan;Pasko Rakic;Michael B. Miller;Liang Sun;Carsen Stringer;Mingyao Li;Christopher A. Walsh - 通讯作者:
Christopher A. Walsh
Mechanisms of cerebral cortical patterning in mice and humans
小鼠和人类大脑皮质模式形成的机制
- DOI:
10.1038/nn752 - 发表时间:
2001-10-29 - 期刊:
- 影响因子:20.000
- 作者:
Edwin S. Monuki;Christopher A. Walsh - 通讯作者:
Christopher A. Walsh
Bi-allelic variants in emINTS11/em are associated with a complex neurological disorder
emINTS11 中的双等位基因变异与复杂的神经系统疾病有关。
- DOI:
10.1016/j.ajhg.2023.03.012 - 发表时间:
2023-05-04 - 期刊:
- 影响因子:8.100
- 作者:
Burak Tepe;Erica L. Macke;Marcello Niceta;Monika Weisz Hubshman;Oguz Kanca;Laura Schultz-Rogers;Yuri A. Zarate;G. Bradley Schaefer;Jorge Luis Granadillo De Luque;Daniel J. Wegner;Benjamin Cogne;Brigitte Gilbert-Dussardier;Xavier Le Guillou;Eric J. Wagner;Lynn S. Pais;Jennifer E. Neil;Ganeshwaran H. Mochida;Christopher A. Walsh;Nurit Magal;Valerie Drasinover;Hugo J. Bellen - 通讯作者:
Hugo J. Bellen
APP gene copy number changes reflect exogenous contamination
APP 基因拷贝数变化反映了外源性污染
- DOI:
10.1038/s41586-020-2522-3 - 发表时间:
2020-08-19 - 期刊:
- 影响因子:48.500
- 作者:
Junho Kim;Boxun Zhao;August Yue Huang;Michael B. Miller;Michael A. Lodato;Christopher A. Walsh;Eunjung Alice Lee - 通讯作者:
Eunjung Alice Lee
Christopher A. Walsh的其他文献
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{{ truncateString('Christopher A. Walsh', 18)}}的其他基金
Somatic mutations in epilepsy: whole genome sequence analysis of single neurons
癫痫的体细胞突变:单个神经元的全基因组序列分析
- 批准号:
8333652 - 财政年份:2012
- 资助金额:
$ 34.45万 - 项目类别:
Somatic mutations in epilepsy: whole genome sequence analysis of single neurons
癫痫的体细胞突变:单个神经元的全基因组序列分析
- 批准号:
8451280 - 财政年份:2012
- 资助金额:
$ 34.45万 - 项目类别:
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:
7854091 - 财政年份:2009
- 资助金额:
$ 34.45万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 34.45万 - 项目类别:
Genetic Analysis of Microcephaly in Tunisian Population
突尼斯人群小头畸形的遗传分析
- 批准号:
7429860 - 财政年份:2008
- 资助金额:
$ 34.45万 - 项目类别:
Autism genetics: homozygosity mapping and functional validation
自闭症遗传学:纯合性作图和功能验证
- 批准号:
8531350 - 财政年份:2007
- 资助金额:
$ 34.45万 - 项目类别:
Finding Autism Genes by Genomic Copy Number Analysis
通过基因组拷贝数分析寻找自闭症基因
- 批准号:
7872965 - 财政年份:2007
- 资助金额:
$ 34.45万 - 项目类别:
INVESTIGATION OF THE CLINICAL FEATURES OF PERIVENTRICULAR NODULAR HETEROTOPIA
脑室周围结节性异位的临床特征探讨
- 批准号:
7606921 - 财政年份:2007
- 资助金额:
$ 34.45万 - 项目类别:
Finding Autism Genes by Genomic Copy Number Analysis
通过基因组拷贝数分析寻找自闭症基因
- 批准号:
7631226 - 财政年份:2007
- 资助金额:
$ 34.45万 - 项目类别:
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