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Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10654-9. doi: 10.1073/pnas.1403521111. Epub 2014 Jul 7.

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals.

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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;
Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China; and.
Department of Biostatistics and Computational Biology, Cornell University, Ithaca, NY 14853.


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.

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