Dynamics of the most common pathogenic mtDNA variant m.3243A>G demonstrate frequency-dependency in blood and positive selection in the germline

Abstract

The A-to-G point mutation at position 3243 in the human mitochondrial genome (m.3243A>G) is the most common pathogenic mtDNA variant responsible for disease in humans. It is widely accepted that m.3243A>G levels decrease in blood with age, and correction representing ~2% annual decline is often applied to account for this change in mutation level. Here we report that recent data indicate the dynamics of m.3243A>G are far more complex and depend on the blood mutation level in a bi-phasic way. As a consequence, the traditional 2% correction, which is adequate on 'average', creates opposite predictive biases at high and low mutation levels. Thus, overall accuracy of traditional correction depends on the proportion of individuals with high and low mutant levels in the dataset. Unbiased age correction is needed to circumvent these drawbacks of the standard model. We propose to abolish both biases by using an approach where correction depends on mutation level in biphasic way, to account for the biphasic dynamics of m.3243A>G in blood. The significance of removing bias was further tested using germline selection as a model, in which we detected mutation patterns consistent with the possibility of positive selection for m.3243A>G. We conclude that use of bi-phasic approach will greatly improve the predictive accuracy of modeling data for changes in mtDNA mutations in the germline and in somatic cells during aging.

Aneuploidy in human embryos is associated with a maternal age-independent increase in mitochondrial DNA content and an enrichment of ultra-rare mitochondrial DNA variants

“…The binary logic, above or below the phenotypically important heteroplasmic threshold, is commonly used for somatic mtDNA variants, and here we would like to use it for germline variants. There are several mechanisms, explaining how de novo or very rare deleterious mtDNA variants can affect the mitochondrial phenotype in the same generation: (i) a narrow stochastic mtDNA bottle-neck (about 20 inherited mtDNA copies) leads to a minimal heteroplasmy level of a deleterious variant of at least 5% or more; (ii) deterministic positive selection of deleterious variants in the germline (Franco et al 2022); (iii) some mutations with a dominant effect may affect a phenotype even at very low heteroplasmy level (Fan et al 2008); (iv) damage of oocytes in early life due to chemical or hormonal stresses can affect mtDNA nucleotide modifications, such as N-Deoxyadenosine methylation, having a pleiotropic effect on the whole mitochondria (Hao et al 2020). Altogether, we propose that the effect of the germ-line or early somatic deleterious variants, mediated by the increased mtDNA content, can be a common age-independent mechanism of some aneuploidies.…”

“…4). There are several ways that mitochondrial phenotype and function could be perturbed fast in the absence of predisposing genetic variants from the previous generation: (a) de-novo germline mutations in nuclear-encoded mitochondrial regulatory genes; (b) de-novo or inherited low-heteroplasmic germline mtDNA variant, which after narrow stochastic mtDNA bottleneck of about 20 inherited mtDNA copies can increase its heteroplasmy level drastically by chance; (c) deterministic positive selection of deleterious mtDNA variants in the germline 20 ; (d) mtDNA mutations with dominant negative effects on mitochondrial phenotype and function even at very low heteroplasmy levels 21 ; and, (e) damage of oocytes in early life by chemical or hormonal stresses that lead to mtDNA nucleotide modifications, such as N-deoxyadenosine methylation, which have pleiotropic effects on the mitochondrion 22 . As described above, the ultra-rare mtDNA variants enriched in NRFT embryos (Fig.…”