Analysis of somatic mutations in the aging human brain using single-cell whole genome sequencing

使用单细胞全基因组测序分析衰老人脑的体细胞突变

• 批准号: 9044918
• 负责人: Michael Anthony Lodato
• 金额: $ 5.6万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2016-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044918
• 关键词: 17 year old; Age; Age-associated memory impairment; Aging; Autopsy; Base Pairing; Biological; Biological Process; Brain; Cell Nucleus; Cells; Cerebral cortex; Characteristics; DNA; DNA Sequence; Deterioration; Disease susceptibility; Elderly; Elements; Endogenous Factors; Environmental Risk Factor; Gametogenesis; Genetic Variation; Genome; Genomics; Health; Human; Human Genome; Human Genome Project; Human body; Individual; Inherited; Legal patent; Life; Metabolic; Mitotic; Molecular; Mosaicism; Mutate; Mutation; Neurons; Noise; Organ; Persons; Phenotype; Process; Resolution; Retrotransposon; Roentgen Rays; Sampling; Shapes; Site; Somatic Mutation; Techniques; Technology; Testing; Time; Tissues; Ultraviolet Rays; Variant; age related; base; free radical oxygen; genetic variant; genome sequencing; novel; pressure; prevent; public health relevance; research study; trait

 DESCRIPTION (provided by applicant): While a large part of human variation in both normal traits and disease susceptibility is controlled by inherited genetic variation, including variants inherited in a Mendelian fashion and de novo mutations which occur in parental gametogenesis, somatic mutation is increasingly being appreciated as a powerful force which determines human phenotypes. However, we lack a global understanding of somatic mutation because until now technological limitations have prevented examination of low mosaicism genomic variants. Our lab has developed novel techniques which allow us to examine somatic mosaicism at unprecedented resolution by performing whole genome sequencing on single human postmortem neuronal nuclei. I have used this technology to perform extensive characterization of somatic mutations in postmortem human neurons from a normal 17 year old individual. In this application, I propose to extend this analysis to test the hypothesis that somatic mutations accumulate with age in the human brain. Question- Does the burden of somatic mutations increase with age, indicating that it may be a mechanism of aging? Aging is a biological process characterized by the gradual deterioration at the cell, and tissue and organ level, and age-related cognitive decline is a major health concern for the elderly. Neurons are long-lived and post-mitotic, and thus as an individual ages neurons have an extended period of time to be exposed to genotoxic insults, such as oxidative or radiological damage, and as a result acquire mutations. Thus, as age increases so might the number of somatic mutations in post-mitotic neurons. Therefore, I will determine whether a correlation exists between age and somatic mosaicism. Since specific mutational process induce characteristic signature alterations, by identifying which types of mutations accumulate with age, I will define a candidate list of process which may causal in aging in the brain.

 描述(申请人提供)：虽然人类正常性状和疾病易感性的很大一部分变异是由遗传遗传变异控制的，包括孟德尔式遗传变异和发生在父母配子发生中的从头突变，但体细胞突变越来越被认为是决定人类表型的强大力量。然而，我们缺乏对体细胞突变的全球了解，因为到目前为止，技术限制阻碍了对低嵌合性基因组变异的检查。我们的实验室已经开发出新的技术，使我们能够通过对单个人类死后神经元核进行全基因组测序，以前所未有的分辨率检查体细胞嵌合体。我使用这项技术对一个17岁的正常个体的死后人类神经元的体细胞突变进行了广泛的表征。在这一应用中，我建议扩展这一分析，以检验体细胞突变在人脑中随着年龄的增长而积累的假设。问题--体细胞突变的负担是否会随着年龄的增长而增加，这表明这可能是衰老的一种机制？衰老是一个生物学过程，其特征是细胞、组织和器官水平的逐渐恶化，与年龄相关的认知能力下降是老年人的主要健康问题。神经元是长寿命和有丝分裂后的，因此随着个体年龄的增长，神经元有更长的时间暴露在遗传毒性的侮辱下，如氧化或辐射损伤，并因此获得突变。因此，随着年龄的增长，有丝分裂后神经元中的体细胞突变数量也会增加。因此，我将确定年龄和体细胞嵌合体之间是否存在相关性。由于特定突变过程会导致特征性签名改变，因此通过确定哪些类型的突变会随着年龄的增长而累积，我将定义一个候选过程列表 这可能是大脑老化的原因。