Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853;
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853;State Key Laboratory of Protein and Plant Gene Research, Center for Bioinformatics, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China;
Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10654-9. doi: 10.1073/pnas.1403521111. Epub 2014 Jul 7.
A majority of mitochondrial DNA (mtDNA) mutations reported to be implicated in diseases are heteroplasmic, a status with coexisting mtDNA variants in a single cell. Quantifying the prevalence of mitochondrial heteroplasmy and its pathogenic effect in healthy individuals could further our understanding of its possible roles in various diseases. A total of 1,085 human individuals from 14 global populations have been sequenced by the 1000 Genomes Project to a mean coverage of ∼2,000× on mtDNA. Using a combination of stringent thresholds and a maximum-likelihood method to define heteroplasmy, we demonstrated that ∼90% of the individuals carry at least one heteroplasmy. At least 20% of individuals harbor heteroplasmies reported to be implicated in disease. Mitochondrial heteroplasmy tend to show high pathogenicity, and is significantly overrepresented in disease-associated loci. Consistent with their deleterious effect, heteroplasmies with derived allele frequency larger than 60% within an individual show a significant reduction in pathogenicity, indicating the action of purifying selection. Purifying selection on heteroplasmies can also be inferred from nonsynonymous and synonymous heteroplasmy comparison and the unfolded site frequency spectra for different functional sites in mtDNA. Nevertheless, in comparison with population polymorphic mtDNA mutations, the purifying selection is much less efficient in removing heteroplasmic mutations. The prevalence of mitochondrial heteroplasmy with high pathogenic potential in healthy individuals, along with the possibility of these mutations drifting to high frequency inside a subpopulation of cells across lifespan, emphasizes the importance of managing mitochondrial heteroplasmy to prevent disease progression.
大多数被报道与疾病相关的线粒体 DNA（mtDNA）突变是异质性的，即在单个细胞中同时存在 mtDNA 变体。量化健康个体中线粒体异质性的流行率及其致病效应，可以进一步了解其在各种疾病中可能发挥的作用。来自 14 个全球人群的 1085 个人类个体已被 1000 基因组计划测序，mtDNA 的平均覆盖度约为 2000×。我们采用严格的阈值和最大似然法相结合的方法来定义异质性，结果表明约 90%的个体携带至少一种异质性。至少有 20%的个体携带有报道与疾病相关的异质性。线粒体异质性往往具有较高的致病性，并且在与疾病相关的基因座中显著过表达。与它们的有害效应一致，个体中具有大于 60%的衍生等位基因频率的异质性显示出明显降低的致病性，表明存在纯化选择。从非同义与同义异质性比较以及 mtDNA 不同功能位点的未折叠位点频率谱也可以推断出异质性的纯化选择。然而，与群体多态性 mtDNA 突变相比，异质性的纯化选择在去除异质性突变方面效率要低得多。健康个体中具有高致病性潜力的线粒体异质性的流行率，以及这些突变在细胞亚群的整个生命周期内漂移到高频率的可能性，强调了管理线粒体异质性以预防疾病进展的重要性。
