Universal heteroplasmy of human mitochondrial DNA

Payne, Brendan; Wilson, I. J.; Yu‐Wai‐Man, Patrick; Coxhead, Jonathan; Deehan, David J.; Horvath, Rita; Taylor, Robert W.; Samuels, David C.; Santibanez‐Koref, Mauro; Chinnery, Patrick F.

doi:10.1093/hmg/dds435

Cited by 339 publications

(332 citation statements)

References 37 publications

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“…Considering that heteroplasmy [11,40,44,45,107] and gene duplication of mitochondrial genes [46][47][48] are pervasive across taxa, the intraindividual level provides a new frontier for exploration of the evolutionary and medical significance of the mitonuclear interaction. A very striking example of the potential for intraindividual mitonuclear interaction was found in mice with artificially induced heteroplasmy between two wild-type mtDNAs, that of the Balb/cByJ mouse and that of the NZB/ BINJ mouse [108].…”

Section: Intraindividual Interactions and Biomedical Implicationsmentioning

confidence: 99%

“…Heteroplasmy [44,45], gene duplication of nuclear-encoded mitochondrial genes [48,116], as well as the genetic footprint of adaptive selection in mitochondrial gene trees [117][118][119] are pervasive in humans, and all of these factors have the potential to fuel mitonuclear interactions for key phenotypes, as outlined above. Thus, the coevolutionary processes underpinning the mitonuclear interaction may provide tangible insights into our understanding of the origins of mitochondrial disease, and ultimately help us to predict incidences and severity of disease expression.…”

Section: Intraindividual Interactions and Biomedical Implicationsmentioning

confidence: 99%

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Mitonuclear interactions: evolutionary consequences over multiple biological scales

Wolff

Ladoukakis

Enrı́quez

et al. 2014

Phil. Trans. R. Soc. B

196

214

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Fundamental biological processes hinge on coordinated interactions between genes spanning two obligate genomes—mitochondrial and nuclear. These interactions are key to complex life, and allelic variation that accumulates and persists at the loci embroiled in such intergenomic interactions should therefore be subjected to intense selection to maintain integrity of the mitochondrial electron transport system. Here, we compile evidence that suggests that mitochondrial–nuclear (mitonuclear) allelic interactions are evolutionarily significant modulators of the expression of key health-related and life-history phenotypes, across several biological scales—within species (intra- and interpopulational) and between species. We then introduce a new frontier for the study of mitonuclear interactions—those that occur within individuals, and are fuelled by the mtDNA heteroplasmy and the existence of nuclear-encoded mitochondrial gene duplicates and isoforms. Empirical evidence supports the idea of high-resolution tissue- and environment-specific modulation of intraindividual mitonuclear interactions. Predicting the penetrance, severity and expression patterns of mtDNA-induced mitochondrial diseases remains a conundrum. We contend that a deeper understanding of the dynamics and ramifications of mitonuclear interactions, across all biological levels, will provide key insights that tangibly advance our understanding, not only of core evolutionary processes, but also of the complex genetics underlying human mitochondrial disease.

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Section: Intraindividual Interactions and Biomedical Implicationsmentioning

confidence: 99%

Section: Intraindividual Interactions and Biomedical Implicationsmentioning

confidence: 99%

Mitonuclear interactions: evolutionary consequences over multiple biological scales

Wolff

Ladoukakis

Enrı́quez

et al. 2014

Phil. Trans. R. Soc. B

196

214

View full text Add to dashboard Cite

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“…mtDNA | heteroplasmy | selection | human | tissue variation A lthough mtDNA heteroplasmy (intraindividual variability in mtDNA sequences) was initially thought to be rare in humans, studies using next-generation sequencing platforms have documented extensive heteroplasmy at low levels (<2%) (1)(2)(3)(4). Heteroplasmy is thought to represent an intermediate stage in the fixation of mtDNA mutations within an individual, and heteroplasmic mtDNA mutations have been implicated in various diseases, cancer, and aging (5)(6)(7)(8).…”

mentioning

confidence: 99%

Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations

Schröder

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

184

253

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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 ∼3,500× 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.mtDNA | heteroplasmy | selection | human | tissue variation

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“…Without considering these low-frequency heteroplasmy, the population prevalence of mitochondrial heteroplasmy is underestimated (12)(13)(14). Moreover, a preliminary study with ultra-deep sequencing (4,158∼20,803×) of two ∼300-bp mtDNA regions was able to find heteroplasmies with very low frequency (>0.2%) in all tested healthy samples (17). Further investigation with a large sample size and deep sequencing coverage across the whole mitochondrial genome is needed to reveal the universal prevalence of mtDNA heteroplasmy in healthy human populations.…”

mentioning

confidence: 99%

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

Lü

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

212

219

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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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Universal heteroplasmy of human mitochondrial DNA

Cited by 339 publications

References 37 publications

Mitonuclear interactions: evolutionary consequences over multiple biological scales

Mitonuclear interactions: evolutionary consequences over multiple biological scales

Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations

Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

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