Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues.
Advanced age increases frequencies of de novo mitochondrial mutations in macaque oocytes and somatic tissues.
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DOI：
10.1073/pnas.2118740119
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发表时间：
2022-04-12
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
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多种人类遗传疾病是由母体传递的线粒体 DNA 突变引起的，线粒体是细胞的动力源。研究这些突变如何随着年龄的增长而产生和积累非常重要，特别是因为许多社会中的人类现在选择在较大年龄生孩子。然而，这在人类中很难实现，特别是对于女性生殖细胞、卵母细胞。为了克服这一限制，我们研究了灵长类模型物种恒河猴的线粒体突变起源和随年龄增长的积累。我们发现新突变在代谢活跃的肝脏中积累最快，在卵母细胞中积累最慢。因此，灵长类卵母细胞可能已经发展出一种机制来保护其线粒体DNA免受过度突变，从而允许在以后的生命中繁殖。线粒体 DNA (mtDNA) 突变会导致多种疾病。然而，由于当前测序技术的高错误率，新的 mtDNA 突变如何随着年龄的增长而产生和积累仍然没有得到充分研究。双链测序通过独立标记和分析两条模板 DNA 链，将错误率降低了几个数量级。在这里，我们使用双工测序获得了 30 只 1 岁至 23 岁不相关恒河猴的体组织（肝脏和骨骼肌）和单个卵母细胞的高质量 mtDNA 序列。对单个卵母细胞进行测序可最大限度地减少自然选择对种系突变的影响。我们总共鉴定了 17,637 个组织特异性从头突变。在评估的 20 年间，它们的频率在肝脏中增加了 3.5 倍，在肌肉中增加了 2.8 倍。直到 9 岁之前，卵母细胞的突变频率增加了约 2.5 倍，但此后不再增加，这表明老年动物的卵母细胞保持了线粒体 DNA 的质量。我们发现轻链复制起点（OriL）是肝脏衰老过程中突变积累的热点。事实上，33 个核苷酸长的 OriL 包含 12 个变异热点，其中 10 个可能破坏其发夹结构并影响复制效率。此外，在体细胞组织中，蛋白质编码变体受到正选择（可能减轻线粒体活性的毒性作用），其强度随着携带变体的猕猴数量的增加而增加。我们的工作阐明了灵长类动物衰老过程中体细胞和种系 mtDNA 突变的起源和积累，并对现代人类社会的延迟繁殖产生了影响。
Multiple human genetic diseases are caused by mutations in the maternally transmitted DNA of mitochondria, the powerhouses of the cell. It is important to study how these mutations arise and accumulate with age, especially because humans in many societies now choose to have children at an older age. However, this is difficult to accomplish in humans, particularly for female germline cells, oocytes. To overcome this limitation, we studied mitochondrial mutation origins and accumulation with age in a primate model species, rhesus macaque. We found that new mutations accumulate the fastest in metabolically active liver and the slowest in oocytes. Thus, primate oocytes might have developed a mechanism to protect their mitochondrial DNA from excessive mutations, allowing reproduction later in life. Mutations in mitochondrial DNA (mtDNA) contribute to multiple diseases. However, how new mtDNA mutations arise and accumulate with age remains understudied because of the high error rates of current sequencing technologies. Duplex sequencing reduces error rates by several orders of magnitude via independently tagging and analyzing each of the two template DNA strands. Here, using duplex sequencing, we obtained high-quality mtDNA sequences for somatic tissues (liver and skeletal muscle) and single oocytes of 30 unrelated rhesus macaques, from 1 to 23 y of age. Sequencing single oocytes minimized effects of natural selection on germline mutations. In total, we identified 17,637 tissue-specific de novo mutations. Their frequency increased ∼3.5-fold in liver and ∼2.8-fold in muscle over the ∼20 y assessed. Mutation frequency in oocytes increased ∼2.5-fold until the age of 9 y, but did not increase after that, suggesting that oocytes of older animals maintain the quality of their mtDNA. We found the light-strand origin of replication (OriL) to be a hotspot for mutation accumulation with aging in liver. Indeed, the 33-nucleotide-long OriL harbored 12 variant hotspots, 10 of which likely disrupt its hairpin structure and affect replication efficiency. Moreover, in somatic tissues, protein-coding variants were subject to positive selection (potentially mitigating toxic effects of mitochondrial activity), the strength of which increased with the number of macaques harboring variants. Our work illuminates the origins and accumulation of somatic and germline mtDNA mutations with aging in primates and has implications for delayed reproduction in modern human societies.
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影响因子：
9.8
作者：
Brown, DT;Samuels, DC;Chinnery, PF
通讯作者：
Chinnery, PF
DOI：
10.1073/pnas.1419651112
发表时间：
2015-02-24
影响因子：
11.1
作者：
Li, Mingkun;Schroeder, Roland;Stoneking, Mark
通讯作者：
Stoneking, Mark
影响因子：
13.3
作者：
May-Panloup, Pascale;Boucret, Lisa;Reynier, Pascal
通讯作者：
Reynier, Pascal
影响因子：
9.8
作者：
Gigarel, Nadine;Hesters, Laetitia;Steffann, Julie
通讯作者：
Steffann, Julie
影响因子：
7.2
作者：
Iismaa SE;Kaidonis X;Nicks AM;Bogush N;Kikuchi K;Naqvi N;Harvey RP;Husain A;Graham RM
通讯作者：
Graham RM