Inheritance of mitochondrial DNA in humans: implications for rare and common diseases

Abstract

The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease. Severe pathogenic mutations cause sporadic and inherited rare disorders that often involve the nervous system. However, some mutations cause mild organ-specific phenotypes that have a reduced clinical penetrance, and polymorphic variation of mtDNA is associated with an altered risk of developing several late-onset common human diseases including Parkinson's disease. mtDNA mutations also accumulate during human life and are enriched in affected organs in a number of age-related diseases. Thus, mtDNA contributes to a wide range of human pathologies. For many decades, it has generally been accepted that mtDNA is inherited exclusively down the maternal line in humans. Although recent evidence has challenged this dogma, whole-genome sequencing has identified nuclear-encoded mitochondrial sequences (NUMTs) that can give the false impression of paternally inherited mtDNA. This provides a more likely explanation for recent reports of 'bi-parental inheritance', where the paternal alleles are actually transmitted through the nuclear genome. The presence of both mutated and wild-type variant alleles within the same individual (heteroplasmy) and rapid shifts in allele frequency can lead to offspring with variable severity of disease. In addition, there is emerging evidence that selection can act for and against specific mtDNA variants within the developing germ line, and possibly within developing tissues. Thus, understanding how mtDNA is inherited has far-reaching implications across medicine. There is emerging evidence that this highly dynamic system is amenable to therapeutic manipulation, raising the possibility that we can harness new understanding to prevent and treat rare and common human diseases where mtDNA mutations play a key role.

Keywords: human mitochondrial DNA; mitochondrial DNA mutation; mitochondrial bottleneck; mitochondrial disorders; mitochondrial inheritance.

Fig. 1

mtDNA genetic bottleneck and changes of heteroplasmy level throughout the lifetime. Each oocyte can inherit a different proportion of mutated mtDNA molecules from maternal mitochondria. When cells divide (shown in pink), heteroplasmy levels in each daughter cell can either increase, decrease or stay approximately the same. Once inherited, mtDNA mutations can continuously ‘clonally expand’ throughout life, even in nondiving cells (shown in green, blue and yellow). If one genotype is copied more frequently than another, it will change the overall proportion of different genotypes within the cell over time. The direction of this change can be influenced by selection for or against a particular mtDNA variant (shown in blue and yellow). When a mutated mtDNA molecule has a replicative advantage, the level will increase during life and possibly exceed the biochemical threshold, and thus contribute to the age‐related pathologies or the ageing process (shown in the blue box).

Fig. 2

mtDNA variations in human diseases. Rare severe heteroplasmic mtDNA mutations usually have a strong effect size (middle left) (e.g. m. 3243A>G mutation in MELAS, see text). Conversely, some common mtDNA haplogroup‐associated variants have very weak effect size (right) (e.g. Parkinson’s disease). There are other variants have an intermediate effect size (middle right) (e.g. m. 11778A>G, m.3460A>G and m.14484T>C in LHON, see text).

Fig. 3

Illustration of nuclear‐encoded mitochondrial sequences (NUMTs) containing multiple concatenated copies of the mtDNA‐derived sequences inserted into the nuclear genome. A combination of NUMTs and mtDNA alleles can create the false impression of paternal inheritance of mtDNA.