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（由申请人提供）：虽然人类正常性状和疾病易感性方面的大部分变异是由遗传性遗传变异控制的，包括以孟德尔方式遗传的变异和亲本配子发生中发生的从头突变，但体细胞突变越来越多地被然而，我们缺乏对体细胞突变的全面了解，因为到目前为止，技术限制阻碍了对低嵌合体基因组变异的检查，我们的实验室已经开发出使我们能够检查体细胞突变的新技术。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对镶嵌现象进行了研究。在本次应用中，我建议扩展此分析。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随着年龄的增长而增加，这表明它可能是衰老的一种机制？ ,以及组织和器官水平，与年龄相关的认知能力下降是老年人的主要健康问题。神经元寿命较长且处于有丝分裂后，因此随着个体年龄的增长，神经元有较长的时间暴露于基因毒性损伤。 ，例如氧化或放射损伤，因此，随着年龄的增加，有丝分裂后神经元的体细胞突变数量也可能增加。因此，我将确定年龄和体细胞嵌合体之间是否存在相关性。突变的过程引起特征签名改变，通过识别哪些类型的突变随着年龄的增长而积累，我将定义一个过程的候选列表 这可能是大脑衰老的原因。