Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals

Abstract

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.

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

“…4B). The higher hN/hS ratio is in keeping with previous observations, and probably reflects negative selection against some NS heteroplasmies that prevents them from reaching "fixation" within an individual, and thereby appearing as polymorphisms (2,4). Surprisingly, the hN/hS ratio for TSHs in the liver is 3.11 ( Fig.…”

“…In addition, we find a significantly elevated hN/hS ratio in liver tissue. These results indicate that positive selection, in addition to drift and negative selection (2,4,14,25), plays a major role in influencing human mtDNA heteroplasmies. Some of the HFH alleles that we identify are also associated with tumors of specific tissues (SI Appendix, Table S2); whether this association simply reflects the increased frequency of that allele in that tissue during aging, or whether the HFH plays a role in causing the tumor, remains an open question.…”

“…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).…”

“…For example, although certain nucleotide positions (nps) in the mtDNA genome are prone to heteroplasmy (2,4,11), it is not clear to what extent these positions simply have a high mutation rate, and thus are more prone to heteroplasmy across all tissues, vs. a role for tissue-specific processes in heteroplasmy (i.e., certain tissues may be more prone to heteroplasmy due to their metabolic requirements, rate of cellular turnover, etc.). Tissue-specific patterns of heteroplasmy are commonly observed with mtDNA mutations associated with disease and are thought to reflect the differing bioenergetic requirements of different tissues (10).…”

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

“…Within the spectrum of mitochondrial diseases, the onset of symptoms can vary according to Copyright © 2016 Apart from the occurrence of pathogenic mtDNA variants, naturally occurring variants have also been reported in humans (Li et al 2010;Goto et al 2011;Payne et al 2013), which also have the potential to affect the health of the individual and lead to disease (Kirches et al 2001;Coon et al 2006;He et al 2010;Ye et al 2014). A recent study has shown the effect of maternal age on heteroplasmic transmission between the mother and child (Rebolledo-Jaramillo et al 2014).…”