Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes.
Deep sequencing of the mitochondrial genome reveals common heteroplasmic sites in NADH dehydrogenase genes.
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DOI：
10.1007/s00439-018-1873-4
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发表时间：
2018-03
期刊：
影响因子：
5.3
通讯作者：
Levy D
中科院分区：
文献类型：
--
作者：
Liu C;Fetterman JL;Liu P;Luo Y;Larson MG;Vasan RS;Zhu J;Levy D
越来越多的证据表明线粒体功能障碍与衰老和年龄相关的疾病有关。但是对于这种联系的分子基础知之甚少。一个可能的原因可能是线粒体DNA（mtDNA）的突变，这通常是异质性的-在同一个体的单个基因座上联合存在不同的等位基因。然而，线粒体DNA异质性在衰老和与年龄相关的条件的参与还没有得到彻底的调查。我们对356名心脏病研究参与者（52%为女性，平均年龄43岁，平均覆盖率4570倍）的完整mtDNA基因组进行了深度测序，确定了2880个独特的突变，并通过MITOMAP和PolyPhen-2对其进行了全面注释。我们发现了11个异质性“热点”[NADH脱氢酶（ND）亚基1、4、5和6基因，n=7;细胞色素c氧化酶I（COI），n=2; 16 S rRNA，n=1; D环，n=1]，其中替代等位基因与参考等位基因的比率随着年龄的增长而显著增加（Bonferroni校正p<0.001）。预测ND和COI基因中的这些异质性突变中的四个是有害的非同义突变，其可能对ATP产生有直接影响。我们证实了以前的研究结果，即健康个体携带许多具有潜在有害影响的低频异质性突变。我们假设，一个单一的有害异质性的影响可能是最小的，由于低的突变与野生型等位基因的比例，而许多有害突变的聚集效应可能会导致线粒体功能的变化，并有助于与年龄相关的疾病。年龄相关mtDNA突变的鉴定是了解年龄相关疾病遗传结构的重要一步，并可能发现此类疾病的新治疗靶点。
Increasing evidence implicates mitochondrial dysfunction in aging and age-related conditions. But little is known about the molecular basis for this connection. A possible cause may be mutations in the mitochondrial DNA (mtDNA), which are often heteroplasmic – the joint presence of different alleles at a single locus in the same individual. However, the involvement of mtDNA heteroplasmy in aging and age-related conditions has not been investigated thoroughly. We deep-sequenced the complete mtDNA genomes of 356 Framingham Heart Study participants (52% women, mean age 43, mean coverage 4570-fold), identified 2880 unique mutations and comprehensively annotated them by MITOMAP and PolyPhen-2. We discovered 11 heteroplasmic “hot” spots [NADH dehydrogenase (ND) subunit 1, 4, 5 and 6 genes, n=7; cytochrome c oxidase I (COI), n=2; 16S rRNA, n=1; D-loop, n=1] for which the alternative-to-reference allele ratios significantly increased with advancing age (Bonferroni correction p<0.001). Four of these heteroplasmic mutations in ND and COI genes were predicted to be deleterious nonsynonymous mutations which may have direct impact on ATP production. We confirmed previous findings that healthy individuals carry many low-frequency heteroplasmy mutations with potentially deleterious effects. We hypothesize that the effect of a single deleterious heteroplasmy may be minimal due to a low mutant-to-wildtype allele ratio, whereas the aggregate effects of many deleterious mutations may cause changes in mitochondrial function and contribute to age-related diseases. The identification of age-related mtDNA mutations is an important step to understand the genetic architecture of age-related diseases and may uncover novel therapeutic targets for such diseases.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
8
作者：
Scaglia, F;Towbin, JA;Vogel, H
通讯作者：
Vogel, H
影响因子：
30.8
作者：
Kern, AD;Kondrashov, FA
通讯作者：
Kondrashov, FA
MitoRCA-seq 揭示了 Polg 突变小鼠中胞嘧啶向胸腺嘧啶转变的不平衡。
影响因子：
4.6
作者：
Ni T;Wei G;Shen T;Han M;Lian Y;Fu H;Luo Y;Yang Y;Liu J;Wakabayashi Y;Li Z;Finkel T;Xu H;Zhu J
通讯作者：
Zhu J
影响因子：
8.2
作者：
Byrne, E. M.;McRae, A. F.;Montgomery, G. W.
通讯作者：
Montgomery, G. W.