Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations
Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations
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DOI：
10.1073/pnas.1419651112
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发表时间：
2015-02-24
影响因子：
11.1
通讯作者：
Stoneking, Mark
中科院分区：
文献类型：
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作者：
Li, Mingkun;Schroeder, Roland;Stoneking, Mark
人类mtDNA的异质性可能在癌症、其他疾病和衰老中发挥作用，但不同组织间异质性变异的模式尚未得到彻底研究。在这里，我们分析了152个人尸检时获得的12个组织中每个组织的完整mtDNA基因组序列，平均覆盖率接近3500倍。我们在整个mtDNA基因组的393个位置发现了4,577个异质（等位基因频率至少为0.5%）。令人惊讶的是，不同的核苷酸位置（nps）在不同的组织中表现出高频率的异质性，而且，异质性强烈依赖于np上特定的一致等位基因。所有这些组织相关和等位基因相关的异质性都显示出显著的年龄相关积累，表明特定组织中特定位置的特定等位基因存在正向选择。我们还发现了肝脏特异性异质的高度显著过剩，涉及非同义变化，其中大多数预测对蛋白质功能有影响。这种对肝脏线粒体功能降低的明显积极选择可能反映了减少肝脏线粒体代谢的有害副产物的选择（即“最慢的生存”）。总的来说，我们的结果提供了积极选择作用于一些体细胞mtDNA突变的令人信服的证据。
Heteroplasmy in human mtDNA may play a role in cancer, other diseases, and aging, but patterns of heteroplasmy variation across different tissues have not been thoroughly investigated. Here, we analyzed complete mtDNA genome sequences at similar to 3,500x average coverage from each of 12 tissues obtained at autopsy from each of 152 individuals. We identified 4,577 heteroplasmies (with an alternative allele frequency of at least 0.5%) at 393 positions across the mtDNA genome. Surprisingly, different nucleotide positions (nps) exhibit high frequencies of heteroplasmy in different tissues, and, moreover, heteroplasmy is strongly dependent on the specific consensus allele at an np. All of these tissue-related and allele-related heteroplasmies show a significant age-related accumulation, suggesting positive selection for specific alleles at specific positions in specific tissues. We also find a highly significant excess of liver-specific heteroplasmies involving nonsynonymous changes, most of which are predicted to have an impact on protein function. This apparent positive selection for reduced mitochondrial function in the liver may reflect selection to decrease damaging byproducts of liver mitochondrial metabolism (i.e., "survival of the slowest"). Overall, our results provide compelling evidence for positive selection acting on some somatic mtDNA mutations.