Genome-wide investigation of somatic mutation in the developing and aging brain

发育和衰老大脑体细胞突变的全基因组研究

基本信息

  • 批准号:
    8762213
  • 负责人:
  • 金额:
    $ 75.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-01 至 2019-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Mutations that arise after fertilization in somatic cell lineages are linked to cancer and aging an have been shown to contribute to an increasing number of human disorders. Similarly, de novo germline mutations in neuronal genes are responsible for cases of autism, schizophrenia and intellectual disability, suggesting that similar types of somatic mutations could contribute to these and other neurological disorders by providing large-effect mutations in specific cell types, that may act alone or in concert with inherited variants. Despite the growing awareness of the importance of genomic mosaicism for human health, our present understanding of somatic mutation in different cellular lineages of the body and brain is minimal. This question has been difficult to address because conventional genome-wide methods cannot detect variants that are rare within a cell population, and most tissues are composed of diverse cell types and intermixed lineages. Single cell sequencing offers one solution, however, current methods suffer from high error-rates and low resolution, and do not allow for independent validation of mutations detected in merely one cell. A second means to amplify genomes from single cells is through clonal expansion. This is feasible for cancer and some self-renewing cell types, but not for many interesting or aged cell types such as post-mitotic neurons. Here, we propose to use two innovative strategies to profile genomes from individual neurons and control fibroblasts from young and aged mice. First, we take advantage of the only known method to amplify neuronal cells without use of oncogenic factors: cloning by somatic cell nuclear transfer. This will enable deep whole genome sequencing and comprehensive mutational profiling of neuron-derived cell lines. Second, we will use nuclear transfer to produce pairs of sister cells derived from single neurons after one division. Single cell sequencing of replicate sister cells will enable sensitive and accurate detection of de novo copy number variation in a context where bona-fide mutations can be clearly distinguished from DNA amplification artifacts. Our application of these complementary technologies will reveal the full spectrum of genome variation that arises in different cell lineages during development and aging, and will help resolve longstanding hypotheses regarding the extent, impact and origins of neuronal genome diversity.
描述(由申请人提供): 在体细胞谱系中受精后出现的突变与癌症有关,并且已显示衰老有助于越来越多的人类疾病。同样,神经元基因中的从头种系突变导致自闭症,精神分裂症和智力障碍病例,这表明类似类型的体细胞突变可能通过在特定细胞类型中提供大型效应突变会导致这些和其他神经系统疾病,这些突变可能单独或与继承的变体一起起作用。尽管人们对基因组镶嵌物对人类健康的重要性的认识越来越大,但我们目前对身体和大脑不同细胞谱系中的体细胞突变的理解却很小。这个问题很难解决,因为传统的全基因组方法无法检测到细胞种群中很少见的变异,并且大多数组织由各种细胞类型和混合谱系组成。单细胞测序提供一种解决方案,但是,当前方法患有高误差和低分辨率,并且不允许仅在一个单元中对突变进行独立验证。从单细胞扩增基因组的第二种手段是通过克隆扩张。这对于癌症和某些自我更新细胞类型是可行的,但对于许多有趣或老化的细胞类型,例如有丝分裂后神经元。在这里,我们建议使用两种创新策略来介绍来自单个神经元的基因组,并控制年轻小鼠和老年小鼠的成纤维细胞。首先,我们利用唯一已知的方法来扩增神经元细胞而无需使用致癌因素:通过体细胞核转移克隆。这将使整个基因组测序和神经元衍生细胞系的全面突变分析。其次,我们将使用核转移来产生一个分裂后衍生自单神经元的姐妹细胞对。复制姊妹细胞的单细胞测序将在可以明确区分与DNA扩增伪像的善意突变的情况下对从头拷贝数变化进行敏感和准确检测。我们对这些互补技术的应用将揭示在发育和衰老过程中不同细胞谱系中产生的全基因组变异,并将有助于解决关于神经元基因组多样性的程度,影响和起源的长期假设。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Kristin Kay Baldwin其他文献

Kristin Kay Baldwin的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Kristin Kay Baldwin', 18)}}的其他基金

Contributions of cell type and exosome signaling to prodromal synaptic and circuit changes in Alzheimer's Disease models
细胞类型和外泌体信号传导对阿尔茨海默病模型中前驱期突触和回路变化的贡献
  • 批准号:
    10540117
  • 财政年份:
    2022
  • 资助金额:
    $ 75.29万
  • 项目类别:
Defining a transcriptional periodic table of the human brain using reprogramming
使用重编程定义人脑的转录周期表
  • 批准号:
    10263622
  • 财政年份:
    2020
  • 资助金额:
    $ 75.29万
  • 项目类别:
Defining a transcriptional periodic table of the human brain using reprogramming
使用重编程定义人脑的转录周期表
  • 批准号:
    9163516
  • 财政年份:
    2016
  • 资助金额:
    $ 75.29万
  • 项目类别:
Genome-wide investigation of somatic mutation in the developing and aging brain
发育和衰老大脑体细胞突变的全基因组研究
  • 批准号:
    9105769
  • 财政年份:
    2014
  • 资助金额:
    $ 75.29万
  • 项目类别:
The architecture and development of a sensory processing circuit for smell
气味感觉处理电路的架构和开发
  • 批准号:
    9088401
  • 财政年份:
    2012
  • 资助金额:
    $ 75.29万
  • 项目类别:
The architecture and development of a sensory processing circuit for smell
气味感觉处理电路的架构和开发
  • 批准号:
    8350354
  • 财政年份:
    2012
  • 资助金额:
    $ 75.29万
  • 项目类别:
The architecture and development of a sensory processing circuit for smell
气味感觉处理电路的架构和开发
  • 批准号:
    8678898
  • 财政年份:
    2012
  • 资助金额:
    $ 75.29万
  • 项目类别:
The architecture and development of a sensory processing circuit for smell
气味感觉处理电路的架构和开发
  • 批准号:
    8485576
  • 财政年份:
    2012
  • 资助金额:
    $ 75.29万
  • 项目类别:
The architecture and development of a sensory processing circuit for smell
气味感觉处理电路的架构和开发
  • 批准号:
    8871710
  • 财政年份:
    2012
  • 资助金额:
    $ 75.29万
  • 项目类别:
Elucidating cardiovascular phenotaypes employing genome editing of iPS cells
利用 iPS 细胞基因组编辑阐明心血管表型
  • 批准号:
    8689147
  • 财政年份:
    2011
  • 资助金额:
    $ 75.29万
  • 项目类别:

相似国自然基金

成人型弥漫性胶质瘤患者语言功能可塑性研究
  • 批准号:
    82303926
  • 批准年份:
    2023
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
MRI融合多组学特征量化高级别成人型弥漫性脑胶质瘤免疫微环境并预测术后复发风险的研究
  • 批准号:
    82302160
  • 批准年份:
    2023
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
SMC4/FoxO3a介导的CD38+HLA-DR+CD8+T细胞增殖在成人斯蒂尔病MAS发病中的作用研究
  • 批准号:
    82302025
  • 批准年份:
    2023
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目
融合多源异构数据应用深度学习预测成人肺部感染病原体研究
  • 批准号:
    82302311
  • 批准年份:
    2023
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

The neural underpinnings of speech and nonspeech auditory processing in autism: Implications for language
自闭症患者言语和非言语听觉处理的神经基础:对语言的影响
  • 批准号:
    10827051
  • 财政年份:
    2024
  • 资助金额:
    $ 75.29万
  • 项目类别:
Computational and neural signatures of interoceptive learning in anorexia nervosa
神经性厌食症内感受学习的计算和神经特征
  • 批准号:
    10824044
  • 财政年份:
    2024
  • 资助金额:
    $ 75.29万
  • 项目类别:
The Proactive and Reactive Neuromechanics of Instability in Aging and Dementia with Lewy Bodies
衰老和路易体痴呆中不稳定的主动和反应神经力学
  • 批准号:
    10749539
  • 财政年份:
    2024
  • 资助金额:
    $ 75.29万
  • 项目类别:
Developing Real-world Understanding of Medical Music therapy using the Electronic Health Record (DRUMMER)
使用电子健康记录 (DRUMMER) 培养对医学音乐治疗的真实理解
  • 批准号:
    10748859
  • 财政年份:
    2024
  • 资助金额:
    $ 75.29万
  • 项目类别:
Core B: B-HEARD Core
核心 B:B-HEARD 核心
  • 批准号:
    10555691
  • 财政年份:
    2023
  • 资助金额:
    $ 75.29万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了