Secondary structure of the human mitochondrial genome affects formation of deletions.
Secondary structure of the human mitochondrial genome affects formation of deletions.
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DOI：
10.1186/s12915-023-01606-1
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发表时间：
2023-05-08
期刊：
影响因子：
5.4
通讯作者：
Popadin, Konstantin
中科院分区：
文献类型：
--
作者：
Shamanskiy, Victor;Mikhailova, Alina A.;Tretiakov, Evgenii O.;Ushakova, Kristina;Mikhailova, Alina G.;Oreshkov, Sergei;Knorre, Dmitry A.;Ree, Natalia;Overdevest, Jonathan B.;Lukowski, Samuel W.;Gostimskaya, Irina;Yurov, Valerian;Liou, Chia-Wei;Lin, Tsu-Kung;Kunz, Wolfram S.;Reymond, Alexandre;Mazunin, Ilya;Bazykin, Georgii A.;Fellay, Jacques;Tanaka, Masashi;Khrapko, Konstantin;Gunbin, Konstantin;Popadin, Konstantin
关键词：
有丝分裂后组织的衰老与体细胞线粒体缺失的克隆扩增有关，其起源尚不清楚。这种缺失通常两侧是直接的核苷酸重复序列，但这本身并不能完全解释它们的分布。在这里，我们假设，在单链线粒体DNA（mtDNA）上的直接重复序列的紧密接近可能在缺失的形成中发挥作用。通过分析人类mtDNA在复制过程中呈单链的大弧区的缺失，我们发现了一个非均匀分布的“热点”，即一个缺失断裂点发生在mtDNA的6-9 kb区域内，另一个缺失断裂点发生在mtDNA的13-16 kb区域内。这种分布不能用直接重复序列的存在来解释，这表明其他因素，如这两个区域的空间接近，可能是原因。计算机模拟分析表明，单链主弧可能被组织为一个大规模的发夹样环，其中心接近11 kb，接触区域在6-9 kb和13-16 kb之间，这将解释该接触区域中的高缺失活性。位于接触区内的同向重复序列，例如具有8470-8482 bp（碱基对）处的第一臂和13，447 - 13，459 bp处的第二臂的公知的共同重复序列，与位于接触区外的同向重复序列相比，引起缺失的可能性高三倍。年龄和疾病相关缺失的比较表明，接触区在解释年龄相关缺失方面发挥着至关重要的作用，强调了其在健康衰老速度中的重要性。总体而言，我们提供了拓扑见解的机制，年龄相关的缺失形成的人类mtDNA，这可用于预测体细胞缺失负担和最大寿命在不同的人类单倍型群和哺乳动物物种。在线版本包含补充材料，可通过10.1186/s12915-023-01606-1获得。
Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions. By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a “hot spot” where one deletion breakpoint occurred within the region of 6–9 kb and another within 13–16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6–9 kb and 13–16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470–8482 bp (base pair) and a second arm at 13,447–13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging. Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species. The online version contains supplementary material available at 10.1186/s12915-023-01606-1.
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影响因子：
82.9
作者：
Gammage PA;Viscomi C;Simard ML;Costa ASH;Gaude E;Powell CA;Van Haute L;McCann BJ;Rebelo-Guiomar P;Cerutti R;Zhang L;Rebar EJ;Zeviani M;Frezza C;Stewart JB;Minczuk M
通讯作者：
Minczuk M
影响因子：
14.9
作者：
Damas J;Carneiro J;Amorim A;Pereira F
通讯作者：
Pereira F
影响因子：
4
作者：
Chan, CCW;Liu, VWS;Ho, PC
通讯作者：
Ho, PC
影响因子：
5.3
作者：
Khaidakov, Magomed;Siegel, Eric R.;Shmookler Reis, Robert J.
通讯作者：
Shmookler Reis, Robert J.
DOI：
10.1186/1748-7188-6-26
发表时间：
2011-11-24
期刊：
Algorithms for molecular biology : AMB
影响因子：
--
作者：
Lorenz R;Bernhart SH;Höner Zu Siederdissen C;Tafer H;Flamm C;Stadler PF;Hofacker IL
通讯作者：
Hofacker IL