The mtDNA mutation spectrum in the PolG mutator mouse reveals germline and somatic selection.
The mtDNA mutation spectrum in the PolG mutator mouse reveals germline and somatic selection.
复制标题
DOI：
10.1186/s12863-021-01005-x
复制
发表时间：
2021-11-26
期刊：
影响因子：
1.9
通讯作者：
Havird JC
中科院分区：
文献类型：
--
作者：
Maclaine KD;Stebbings KA;Llano DA;Havird JC
线粒体DNA(MtDNA)编码电子传递和线粒体基因翻译所需的产物。线粒体DNA突变可能导致人类疾病，并影响机体的健康。Polg Mutator小鼠缺乏mtDNA校对功能，可以快速积累mtDNA突变，使其成为研究线粒体突变原因和后果的模型。Polg小鼠的过早衰老及其生理学已被深入研究，但其mtDNA突变的位置、频率和多样性仍未得到充分研究。识别Polg小鼠mtDNA突变的位置和谱可以揭示选择如何在生物体内和跨生物体塑造mtDNA。在这里，我们对Polg小鼠大脑和肝脏组织中的体细胞和生殖系mtDNA突变进行了表征，以量化突变数量(独特突变的数量)和频率(突变发生率)。总体而言，线粒体DNA突变的数量和频率在复制起点所在的D-环中最低，但在线粒体基因组中其他方面是一致的。体细胞mtDNA突变比胚系突变具有更高的突变数量。然而，生殖系突变保持较高的频率，也更有可能保持沉默。复制错误的特征是胞嘧啶到胸腺嘧啶的突变是多种碱基的改变，而错义C到T突变主要导致蛋白质疏水性的增加。与野生型小鼠不同，Polg小鼠在mtDNA突变中似乎没有表现出链不对称。Indel突变的数量和频率低于点突变，并且倾向于较短的移码缺失。我们的结果提供了强有力的证据，证明纯化选择在Polg小鼠的mtDNA中起着重要作用。错义突变不太可能在生殖系中遗传，它们也不太可能传播到高频。D-环似乎对突变具有抵抗力，无论是通过选择还是作为复制过程的副产品。降低疏水性的错义突变也倾向于被选中，这反映了mtDNA编码蛋白质的膜结合性质。与活性氧物种(ROS)损伤相比，聚合酶错误导致的大量突变支持了之前的研究，即ROS在加剧Polg表型方面起到的作用很小，但我们对链不对称的发现为聚合酶错误在野生型生物中的作用提供了讨论。我们的结果为进一步了解选择如何形成线粒体DNA突变以及Polg小鼠的衰老机制提供了进一步的见解。网上版载有补充材料，可在10.1186/s12863-021-01005-x查阅。
Mitochondrial DNA (mtDNA) codes for products necessary for electron transport and mitochondrial gene translation. mtDNA mutations can lead to human disease and influence organismal fitness. The PolG mutator mouse lacks mtDNA proofreading function and rapidly accumulates mtDNA mutations, making it a model for examining the causes and consequences of mitochondrial mutations. Premature aging in PolG mice and their physiology have been examined in depth, but the location, frequency, and diversity of their mtDNA mutations remain understudied. Identifying the locations and spectra of mtDNA mutations in PolG mice can shed light on how selection shapes mtDNA, both within and across organisms. Here, we characterized somatic and germline mtDNA mutations in brain and liver tissue of PolG mice to quantify mutation count (number of unique mutations) and frequency (mutation prevalence). Overall, mtDNA mutation count and frequency were the lowest in the D-loop, where an mtDNA origin of replication is located, but otherwise uniform across the mitochondrial genome. Somatic mtDNA mutations have a higher mutation count than germline mutations. However, germline mutations maintain a higher frequency and were also more likely to be silent. Cytosine to thymine mutations characteristic of replication errors were the plurality of basepair changes, and missense C to T mutations primarily resulted in increased protein hydrophobicity. Unlike wild type mice, PolG mice do not appear to show strand asymmetry in mtDNA mutations. Indel mutations had a lower count and frequency than point mutations and tended to be short, frameshift deletions. Our results provide strong evidence that purifying selection plays a major role in the mtDNA of PolG mice. Missense mutations were less likely to be passed down in the germline, and they were less likely to spread to high frequencies. The D-loop appears to have resistance to mutations, either through selection or as a by-product of replication processes. Missense mutations that decrease hydrophobicity also tend to be selected against, reflecting the membrane-bound nature of mtDNA-encoded proteins. The abundance of mutations from polymerase errors compared with reactive oxygen species (ROS) damage supports previous studies suggesting ROS plays a minimal role in exacerbating the PolG phenotype, but our findings on strand asymmetry provide discussion for the role of polymerase errors in wild type organisms. Our results provide further insight on how selection shapes mtDNA mutations and on the aging mechanisms in PolG mice. The online version contains supplementary material available at 10.1186/s12863-021-01005-x.
登录
查看更多内容
影响因子：
4.5
作者：
Ameur A;Stewart JB;Freyer C;Hagström E;Ingman M;Larsson NG;Gyllensten U
通讯作者：
Gyllensten U
影响因子：
7.7
作者：
Ju YS;Alexandrov LB;Gerstung M;Martincorena I;Nik-Zainal S;Ramakrishna M;Davies HR;Papaemmanuil E;Gundem G;Shlien A;Bolli N;Behjati S;Tarpey PS;Nangalia J;Massie CE;Butler AP;Teague JW;Vassiliou GS;Green AR;Du MQ;Unnikrishnan A;Pimanda JE;Teh BT;Munshi N;Greaves M;Vyas P;El-Naggar AK;Santarius T;Collins VP;Grundy R;Taylor JA;Hayes DN;Malkin D;ICGC Breast Cancer Group;ICGC Chronic Myeloid Disorders Group;ICGC Prostate Cancer Group;Foster CS;Warren AY;Whitaker HC;Brewer D;Eeles R;Cooper C;Neal D;Visakorpi T;Isaacs WB;Bova GS;Flanagan AM;Futreal PA;Lynch AG;Chinnery PF;McDermott U;Stratton MR;Campbell PJ
通讯作者：
Campbell PJ
DOI：
10.1111/j.1532-5415.1972.tb00787.x
发表时间：
1972-01-01
影响因子：
6.3
作者：
HARMAN, D
通讯作者：
HARMAN, D
DOI：
10.1146/annurev.cb.07.110191.002321
发表时间：
1991-01-01
期刊：
ANNUAL REVIEW OF CELL BIOLOGY
影响因子：
--
作者：
CLAYTON, DA
通讯作者：
CLAYTON, DA
影响因子：
30.8
作者：
Cree, Lynsey M.;Samuels, David C.;Chinnery, Patrick F.
通讯作者：
Chinnery, Patrick F.