The role of somatic mutation in neurodegenerative disease

体细胞突变在神经退行性疾病中的作用

• 批准号: 9924421
• 负责人: Eunjung Alice Lee
• 金额: $ 13.1万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924421
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Ataxia; Ataxia Telangiectasia; Autopsy; Brain; Cancer Etiology; Cells; Cerebellum; Cerebral cortex; Computing Methodologies; Copy Number Polymorphism; DNA; DNA Double Strand Break; DNA biosynthesis; Data; Defect; Detection; Development; Double Strand Break Repair; Elderly; Epilepsy; Frequencies; Generations; Genes; Genetic Diseases; Genetic Transcription; Genome; Genomics; Goals; Human; Human body; Huntington Disease; Individual; Inherited; Lead; Length; Life; Malignant Neoplasms; Memory Loss; Microsatellite Repeats; Mitotic; Modeling; Mosaicism; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neurons; Noise; Oxidative Stress; Patients; Pattern; Play; Process; Protocols documentation; Quality Control; Radiology Specialty; Replication Error; Research; Resistance; Retrotransposon; Role; Science; Single Nucleotide Polymorphism; Somatic Mutation; Stress; Tandem Repeat Sequences; Testing; Tissues; Variant; Work; analytical method; brain malformation; cognitive function; computerized tools; effective therapy; genome sequencing; hemimegalencephaly; neuron loss; novel; presenilin-1; single cell analysis; single cell sequencing; synaptic function; telomere; whole genome

The goal of this project is to understand the role of somatic mutations in neurodegeneration, specifically in neurodegenerative disorders Alzheimer’s Disease and Ataxia Telangiectasia, using single-cell analysis. Alzheimer’s Disease is a progressive neurodegenerative disorder leading to the loss of memory and other cognitive functions; Ataxia Telangiectasia is another neurodegenerative disorder with inherited defects in DNA double strand break (DSB) repair. Somatic mutations have been studied most extensively in cancer, but they also cause neurodevelopmental disorders such as epilepsy and hemimegalencephaly. Previous studies have found somatic mosaic mutations in causally implicated genes in some neurodegenerative diseases, such as presenilin-1 in Alzheimer’s Disease. Other studies, including our work, have suggested that the lack of proper DSB repair in Ataxia Telangiectasia may allow increased accumulation of somatic mutations, including those in repetitive DNA, and lead to neuronal cell death. Our recent single-neuron genomic studies showed that even neurologically normal human brains are a patchwork of somatic mutations that occur throughout one’s life, and that active transcription may play a role in generation of rare somatic mutations. We therefore hypothesize that late-development or even post-mitotic mutations in a small number of neurons may have a functional role in the loss of synaptic function and cell loss in Alzheimer’s Disease. To overcome the limited detection sensibility for low frequency variants in current bulk-cell analysis, we will employ single-cell genomics to test our hypothesis, using novel computational tools to circumvent the noise in the data introduced by the genome amplification process necessary in current single-cell sequencing protocols. In Aim 1, we propose to develop robust analytical methods to mitigate the impact of genome amplification bias in detecting multiple forms of somatic mutations, including repeat aberrations (tandem repeats such as telomere and retrotransposons). In Aim 2, we will analyze somatic mutations in post-mortem brains of patients with Alzheimer’s Disease and Ataxia Telangiectasia using single-neuron whole genome sequencing.

该项目的目标是了解体细胞突变在神经退行性疾病中的作用，特别是在神经退行性疾病阿尔茨海默病和共济失调毛细血管扩张症中，使用单细胞分析。阿尔茨海默病是一种进行性神经退行性疾病，导致记忆和其他认知功能丧失;共济失调毛细血管扩张症是另一种神经退行性疾病，具有DNA双链断裂（DSB）修复的遗传缺陷。体细胞突变在癌症中的研究最为广泛，但它们也会导致神经发育障碍，如癫痫和半侧巨脑畸形。先前的研究已经在一些神经退行性疾病的因果相关基因中发现了体细胞嵌合突变，例如阿尔茨海默病中的早老素-1。包括我们的工作在内的其他研究表明，共济失调毛细血管扩张症缺乏适当的DSB修复可能会增加体细胞突变的积累，包括重复DNA中的突变，并导致神经元细胞死亡。我们最近的单神经元基因组研究表明，即使是神经学上正常的人类大脑也是一个人一生中发生的体细胞突变的拼凑，并且活跃的转录可能在罕见的体细胞突变的产生中发挥作用。因此，我们假设，在少数神经元中的晚期发育甚至有丝分裂后突变可能在阿尔茨海默病中的突触功能丧失和细胞丧失中具有功能性作用。为了克服当前批量细胞分析中对低频变异的有限检测灵敏度，我们将采用单细胞基因组学来测试我们的假设，使用新的计算工具来规避当前单细胞测序方案中所需的基因组扩增过程引入的数据中的噪声。在目标1中，我们建议开发稳健的分析方法，以减轻基因组扩增偏倚对检测多种形式的体细胞突变的影响，包括重复序列畸变（串联重复序列，如端粒和逆转录转座子）。在目标2中，我们将使用单神经元全基因组测序分析阿尔茨海默病和共济失调毛细血管扩张症患者死后大脑中的体细胞突变。

项目成果

Genomic approaches to trace the history of human brain evolution with an emerging opportunity for transposon profiling of ancient humans.

• DOI: 10.1186/s13100-021-00250-2
• 发表时间: 2021-10-18
• 期刊: Mobile DNA
• 影响因子: 4.9
• 作者: Wang Y;Zhao B;Choi J;Lee EA
• 通讯作者: Lee EA

Identification and Genotyping of Transposable Element Insertions From Genome Sequencing Data.

• DOI: 10.1002/cphg.102
• 发表时间: 2020-09
• 期刊: Current protocols in human genetics
• 作者: Chu C;Zhao B;Park PJ;Lee EA
• 通讯作者: Lee EA

Novel Alzheimer's disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers.

• DOI: 10.1038/s41398-021-01412-9
• 发表时间: 2021-05-19
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Park JH;Park I;Youm EM;Lee S;Park JH;Lee J;Lee DY;Byun MS;Lee JH;Yi D;Chung SJ;Park KW;Choi N;Kim SY;Yoon W;An H;Kim KW;Choi SH;Jeong JH;Kim EJ;Kang H;Lee J;Kim Y;Lee EA;Seo SW;Na DL;Kim JW
• 通讯作者: Kim JW

DeviCNV: detection and visualization of exon-level copy number variants in targeted next-generation sequencing data.

• DOI: 10.1186/s12859-018-2409-6
• 发表时间: 2018-10-16
• 期刊: BMC bioinformatics
• 影响因子: 3
• 作者: Kang Y;Nam SH;Park KS;Kim Y;Kim JW;Lee E;Ko JM;Lee KA;Park I
• 通讯作者: Park I