The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease

Journal name:
Nature Reviews Genetics
Volume:
16,
Pages:
530–542
Year published:
DOI:
doi:10.1038/nrg3966
Published online

Abstract

Common genetic variants of mitochondrial DNA (mtDNA) increase the risk of developing several of the major health issues facing the western world, including neurodegenerative diseases. In this Review, we consider how these mtDNA variants arose and how they spread from their origin on one single molecule in a single cell to be present at high levels throughout a specific organ and, ultimately, to contribute to the population risk of common age-related disorders. mtDNA persists in all aerobic eukaryotes, despite a high substitution rate, clonal propagation and little evidence of recombination. Recent studies have found that de novo mtDNA mutations are suppressed in the female germ line; despite this, mtDNA heteroplasmy is remarkably common. The demonstration of a mammalian mtDNA genetic bottleneck explains how new germline variants can increase to high levels within a generation, and the ultimate fixation of less-severe mutations that escape germline selection explains how they can contribute to the risk of late-onset disorders.

At a glance

Figures

  1. mtDNA heteroplasmy and the threshold effect.
    Figure 1: mtDNA heteroplasmy and the threshold effect.

    Mitochondrial DNA (mtDNA) mutations that have occurred within approximately three human generations are usually heteroplasmic, and the same cell can contain varying proportions of mutated and wild-type mtDNA. If a mutation is pathogenic, the cell can usually tolerate a high percentage level of this variant before the biochemical threshold is exceeded and a defect in the respiratory chain is detected. Typically, this threshold level is >80%, suggesting that most mtDNA mutations are haploinsufficient or recessive64.

  2. New technologies to analyse mtDNA.
    Figure 2: New technologies to analyse mtDNA.

    a | The frequency distribution (y axis) of mitochondrial DNA (mtDNA) variants detected at different levels of heteroplasmy (x axis) in a typical deep-sequencing experiment. The mtDNA variants present in vivo and artefacts generated by the sequencing can be indistinguishable when a single subject is sequenced. The rarer variants are more likely to be sequencing errors or nuclear mitochondrial DNA sequences (NUMTs), but they could also be rare variants present in the original DNA sample. b | Appropriate computational filtering of the data is critical to identifying true mtDNA variants from the various artefacts in the data47. Applying stringent standards, heteroplasmies as infrequent as 0.2% have been identified49. c,d | Other approaches include the use of a barcode-adapted library120; and rolling circle amplification of circularized and barcoded DNA fragments with enzymes such as φ29 (Ref. 121). DNA that has been oxidized or otherwise damaged during extraction can also be eliminated by the addition of appropriate DNA glycosylases to cleave DNA containing damaged bases prior to amplification122.

  3. mtDNA heteroplasmy can change throughout the lifetime of an individual.
    Figure 3: mtDNA heteroplasmy can change throughout the lifetime of an individual.

    When cells divide, the proportion of mutated (red) and wild-type (blue) mitochondrial DNA (mtDNA) can differ in the daughter cells, leading to a shift in heteroplasmy levels (either up or down) over time through vegetative segregation. Furthermore, mtDNA is continuously turned over at all points in the cell cycle, even in non-dividing cells (crosses represent destruction, whereas curved arrows represent replication). Molecules are selected for replication at random, independently of the cell cycle, in a process known as relaxed replication. If one particular variant is copied more frequently than another, changes in the proportion of mutated and wild-type molecules occur over time, either up or down. Computational models predict that these two mechanisms will lead to changes in heteroplasmy in human cells throughout an individual's lifetime. The two mechanisms can occur simultaneously in some tissues and organs. Selection for or against a particular variant of mtDNA will influence the speed and direction of the heteroplasmic shift, and thus alter mutation levels over time.

  4. Models for the mtDNA genetic bottleneck.
    Figure 4: Models for the mtDNA genetic bottleneck.

    a | The rate of vegetative segregation is faster if the mitochondrial DNA (mtDNA) content of the cells is smaller. Unequal partitioning (segregation) of mutated (red) and wild-type (blue) genotypes will lead to shifts in heteroplasmy in oocytes as a consequence of the reduction in mtDNA copy number immediately prior to expansion of the primordial germ cell (PGC) population, as observed in mice66, 78. b | If mtDNA molecules are packaged into homoplasmic nucleoids, or simply kept separate within discrete homoplasmic mitochondria, this reduces the number of segregating units and accelerates the rate of drift, as proposed in Refs 79,123. c | The replication of a subpopulation of mitochondrial genomes would also lead to a bottleneck effect. There is some evidence that this might occur during postnatal oocyte maturation78. Adapted with permission from Ref. 124, Elsevier.

  5. Human population migrations and major mtDNA haplogroups.
    Figure 5: Human population migrations and major mtDNA haplogroups.

    As mitochondrial DNA (mtDNA) is uniparentally inherited, it undergoes negligible recombination at the population level, and mutations acquired over time have subdivided the human population into several discrete haplogroups. The major haplogroups arose 40,000–150,000 years before present (YBP) and have defined different human populations as they migrated out of Africa and populated the globe. The African root was the source of four lineages specific for sub-Saharan Africa: L0, L1, L2 and L3 (130,000–200,000 YBP). Two more haplogroups, M and N, arose from the African haplogroup L3 65,000–70,000 YBP to populate the rest of the world125. As humans migrated, haplogroup N was directed to Eurasia and haplogroup M lineages moved to Asia, giving rise to the haplogroups A, B, C, D, G and F. In Europe, haplogroup N led to haplogroup R, which is the root of the European haplogroups H, J, T, U and V, which emerged 39,000–51,000 YBP126. Haplogroups S, P, and Q are found in Australasia and were formed ~48,000 YBP, and haplogroups A, B, C and D arose <20,000 YBP and populated East Asia and the Americas. These low-resolution single-nucleotide variant studies have been superseded by massive whole-mtDNA-genome-sequencing studies, which have identified many different sub-haplogroups that define the contemporary mtDNA phylogenetic tree. For example, haplogroup H, the most common in Europe, is comprised of almost 90 different sub-haplogroups127. Adapted with permission from MITOMAP (original authors Lott, M. T. et al.; http://creativecommons.org/licenses/by/3.0/).

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Affiliations

  1. Max Planck Institute for Biology of Ageing, Cologne 50931, Germany.

    • James B. Stewart
  2. Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 1BZ, UK.

    • Patrick F. Chinnery

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The authors declare no competing interests.

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  • James B. Stewart

    James B. Stewart received his Ph.D. from Simon Fraser University, Burnaby, British Columbia, Canada, studying mitochondrial genomics and evolution. He is currently a research group leader at the Max Planck Institute for Biology of Ageing in Cologne, Germany, where he studies mitochondrial mutations and mitonuclear interactions, and their roles in ageing and disease.

  • Patrick F. Chinnery

    Patrick F. Chinnery obtained his Ph.D. from Newcastle University, Newcastle upon Tyne, UK, where he is a practicing clinical neurologist and professor of neurogenetics. He directs the Institute of Genetic Medicine and the UK National Institute for Health Research Biomedical Research Centre in Newcastle, where he studies the role of mitochondria in human disease and is developing new treatments for mitochondrial diseases.

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