Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains.
Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains.
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DOI：
10.1186/s40478-016-0404-6
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发表时间：
2017-02-02
影响因子：
7.1
通讯作者：
Chinnery PF
中科院分区：
文献类型：
--
作者：
Wei W;Keogh MJ;Wilson I;Coxhead J;Ryan S;Rollinson S;Griffin H;Kurzawa-Akanbi M;Santibanez-Koref M;Talbot K;Turner MR;McKenzie CA;Troakes C;Attems J;Smith C;Al Sarraj S;Morris CM;Ansorge O;Pickering-Brown S;Ironside JW;Chinnery PF
线粒体在常见的神经退行性疾病中发挥着关键作用，并包含自己的基因组：mtDNA。线粒体 DNA 的常见遗传多态性变异与多种神经退行性疾病有关，并且在受影响的大脑区域发现了线粒体 DNA 的体细胞缺失。然而，关于罕见遗传变异和体细胞点突变在神经退行性疾病中的作用的报道相互矛盾，而且最近的证据也涉及 mtDNA 水平。为了解决这些问题，我们研究了 1363 例死后人类大脑，这些大脑的组织病理学诊断为帕金森病 (PD)、阿尔茨海默病 (AD)、额颞叶痴呆 - 肌萎缩侧索硬化症 (FTD-ALS)、克雅氏病 (CJD) 和健康对照。我们利用全外显子组测序的脱靶读数获得了高深度的全线粒体基因组序列，以确定 mtDNA 变异与疾病发生和进展的关联，并更好地了解衰老大脑中 mtDNA 突变和拷贝数的发展。通过这种方法，我们发现 32.3% 的受试者中异质 mtDNA 变异的出现频率惊人地高。然而，我们没有发现 mtDNA 的罕见遗传变异或 mtDNA 异质性与疾病之间存在关联的证据。相比之下，我们观察到 AD 和 CJD 中线粒体 DNA 拷贝量均减少。基于这些发现，mtDNA 的单核苷酸变异不太可能在这些神经退行性疾病的发病机制中发挥主要作用，但 mtDNA 水平值得进一步研究。本文的在线版本 (doi:10.1186/s40478-016-0404-6) 包含补充材料，可供授权用户使用。
Mitochondria play a key role in common neurodegenerative diseases and contain their own genome: mtDNA. Common inherited polymorphic variants of mtDNA have been associated with several neurodegenerative diseases, and somatic deletions of mtDNA have been found in affected brain regions. However, there are conflicting reports describing the role of rare inherited variants and somatic point mutations in neurodegenerative disorders, and recent evidence also implicates mtDNA levels. To address these issues we studied 1363 post mortem human brains with a histopathological diagnosis of Parkinson’s disease (PD), Alzheimer’s disease (AD), Frontotemporal dementia – Amyotrophic Lateral Sclerosis (FTD-ALS), Creutzfeldt Jacob disease (CJD), and healthy controls. We obtained high-depth whole mitochondrial genome sequences using off target reads from whole exome sequencing to determine the association of mtDNA variation with the development and progression of disease, and to better understand the development of mtDNA mutations and copy number in the aging brain. With this approach, we found a surprisingly high frequency of heteroplasmic mtDNA variants in 32.3% of subjects. However, we found no evidence of an association between rare inherited variants of mtDNA or mtDNA heteroplasmy and disease. In contrast, we observed a reduction in the amount of mtDNA copy in both AD and CJD. Based on these findings, single nucleotide variants of mtDNA are unlikely to play a major role in the pathogenesis of these neurodegenerative diseases, but mtDNA levels merit further investigation. The online version of this article (doi:10.1186/s40478-016-0404-6) contains supplementary material, which is available to authorized users.