Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout aging.
Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout aging.
复制标题
线粒体单倍型和线粒体核匹配在整个衰老过程中驱动体细胞突变和选择。
DOI：
10.1101/2023.03.06.531392
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Sudmant,PeterH
中科院分区：
文献类型：
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作者：
Serrano,IsabelM;Hirose,Misa;Valentine,CharlesC;Roesner,Sharon;Schmidt,Elizabeth;Pratt,Gabriel;Williams,Lindsey;Salk,Jesse;Ibrahim,Saleh;Sudmant,PeterH
线粒体基因组在进化时间尺度上与核基因组共同进化，并通过雌性种系的选择而形成。在这里，我们研究了核祖先和线粒体祖先之间的不匹配如何影响整个衰老过程中不同组织中线粒体基因组的体细胞进化。我们使用超灵敏双链测序对年轻和老年小鼠的五种线粒体单倍型和三种组织的约 250 万个线粒体基因组进行了分析，对约 120 万个线粒体体细胞和超低频遗传突变进行了分类，其中 81,097 个是独特的。我们确定了单倍型特异性突变模式和几个突变热点，包括轻链复制起点，其始终表现出最高的突变频率。我们发现，与灵长类动物相比，啮齿动物表现出独特的线粒体体细胞突变谱，具有过多的活性氧相关的 G > T/C > A 突变，并且蛋白质编码基因的体细胞突变表现出负选择的特征。最后，我们发现了体细胞回复突变的广泛富集，这些突变在生物体的生命周期内“重新排列”线粒体-核祖先。总之，我们的研究结果表明，线粒体基因组是一个动态进化的亚细胞群体，由整个生物体生命周期的体细胞突变和选择形成。
Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the light strand origin of replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared with primates with a surfeit of reactive oxygen species-associated G > T/C > A mutations, and that somatic mutations in protein-coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that ‘re-align’ mito-nuclear ancestry within an organism’s lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.