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

Journal name:
Nature Reviews Genetics
Year published:
Published online


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


  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.;


  1. Wallace, D. C. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 14271430 (1988).
    Describes the first-identified human pathogenic mtDNA mutation, which was a homoplasmic point mutation in MTND4. It transpires that this mutation (m.11778A>G) is actually the most common pathogenic mtDNA mutation encountered in clinical practice.
  2. Holt, I., Harding, A. E. & Morgan-Hughes, J. A. Deletion of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717719 (1988).
  3. Gorman, G. S. et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann. Neurol. 77, 753759 (2015).
  4. Chinnery, P. F. et al. Epidemiology of pathogenic mitochondrial DNA mutations. Ann. Neurol. 48, 188193 (2000).
    The first epidemiological study of pathogenic mtDNA mutations, which shows that mtDNA diseases are not exceptionally rare, as previously thought.
  5. Di Mauro, S., Schon, E. A., Carelli, V. & Hirano, M. The clinical maze of mitochondrial neurology. Nat. Rev. Neurol. 9, 429444 (2013).
  6. Vafai, S. B. & Mootha, V. K. Mitochondrial disorders as windows into an ancient organelle. Nature 491, 374383 (2012).
  7. Wallace, D. C. Colloquium paper: bioenergetics, the origins of complexity, and the ascent of man. Proc. Natl Acad. Sci. USA 107 (Suppl. 2), 89478953 (2011).
  8. Pinto, M. & Moraes, C. T. Mechanisms linking mtDNA damage and aging. Free Radic. Biol. Med. 85, 250258 (2015).
  9. Pinto, M. & Moraes, C. T. Mitochondrial genome changes and neurodegenerative diseases. Biochim. Biophys. Acta 1842, 11981207 (2014).
  10. Ross, J. M. et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412415 (2013).
  11. Keogh, M. & Chinnery, P. F. Hereditary mtDNA heteroplasmy: a baseline for aging? Cell Metab. 18, 463464 (2013).
  12. Hudson, G., Gomez-Duran, A., Wilson, I. J. & Chinnery, P. F. Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases. PLoS Genet. 10, e1004369 (2014).
  13. Wallace, D. C. & Chalkia, D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb. Perspect. Med. 3, a021220 (2013).
  14. Gomez-Duran, A. et al. Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Hum. Mol. Genet. 19, 33433353 (2010).
  15. Mereschkowsky, K. Theorie der zwei Plasmaarten als Grundlage der Symbiogenesis, einer neuen Lehre von der Ent-stehung der Organismen. Biol. Centralbl. 30, 353367 (1910) (in German).
  16. Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112123 (2008).
  17. Vafai, S. B. & Mootha, V. K. Medicine. A common pathway for a rare disease? Science 342, 14531454 (2013).
  18. Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457465 (1981).
    Provides the first human mitochondrial DNA sequence, subsequently referred to as the Cambridge reference sequence (CRS). The published sequence was derived predominantly from a human placenta from a person belonging to haplogroup H, but difficult regions were derived from other sources, including the bovine sequence.
  19. Andrews, R. M. et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat. Genet. 23, 147 (1999).
    Sequence errors in the original CRS (reference 18) were corrected in this publication, resulting in a new sequence referred to as the revised CRS (rCRS).
  20. Calvo, S. E. & Mootha, V. K. The mitochondrial proteome and human disease. Annu. Rev. Genom. Hum. Genet. 11, 2544 (2010).
  21. Kukat, C. et al. Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA. Proc. Natl Acad. Sci. USA 108, 1353413539 (2011).
  22. Elson, J. L. et al. Analysis of European mtDNAs for recombination. Am. J. Hum. Genet. 68, 145153 (2001).
  23. Schon, E. A., DiMauro, S. & Hirano, M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 13, 878890 (2012).
  24. Chinnery, P. F. et al. Risk of developing a mitochondrial DNA deletion disorder. Lancet 364, 592596 (2004).
  25. McFarland, R. et al. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat. Genet. 30, 145146 (2002).
  26. Tiranti, V. et al. A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome. Hum. Mol. Genet. 9, 27332742 (2000).
  27. Limongelli, A. et al. Variable penetrance of a familial progressive necrotising encephalopathy due to a novel tRNAIle homoplasmic mutation in the mitochondrial genome. J. Med. Genet. 41, 342349 (2004).
  28. King, M. P. & Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500503 (1989).
  29. Boulet, L., Karpati, G. & Shoubridge, E. A. Distribution and threshold expression of the tRNALys mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am. J. Hum. Genet. 51, 11871200 (1992).
  30. Carelli, V., Giordano, C. & d'Amati, G. Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear–mitochondrial interaction. Trends Genet. 19, 257262 (2003).
  31. Elliott, H. R., Samuels, D. C., Eden, J. A., Relton, C. L. & Chinnery, P. F. Pathogenic mitochondrial DNA mutations are common in the general population. Am. J. Hum. Genet. 83, 254260 (2008).
  32. Cortopassi, G. A. & Arnheim, N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 18, 69276933 (1990).
  33. Brierley, E. J., Johnson, M. A., Lightowlers, R. N., James, O. F. & Turnbull, D. M. Role of mitochondrial DNA mutations in human aging: implications for the central nervous system and muscle. Ann. Neurol. 43, 217223 (1998).
  34. Corral-Debrinski, M., Shoffner, J. M., Lott, M. T. & Wallace, D. C. Association of mitochondrial DNA damage with aging and coronary atherosclerotic heart disease. Mutat. Res. 275, 169180 (1992).
    One of the early papers describing the presence of somatic mtDNA mutations in aged individuals and the association of these mutations with age-related diseases.
  35. Corral-Debrinski, M. et al. Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics 23, 471476 (1994).
  36. Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 38, 515517 (2006).
  37. Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 38, 518520 (2006).
  38. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417423 (2004).
  39. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481484 (2005).
    References 38 and 39 provides the first descriptions of a mouse with a defective mtDNA polymerase. They show that mtDNA mutations accumulated in somatic tissues over time and were accompanied by a premature ageing phenotype.
  40. Polyak, K. et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat. Genet. 20, 291293 (1998).
    A key paper describing clonally expanded mtDNA mutations in human tumours.
  41. He, Y. et al. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 464, 610614 (2010).
  42. Ju, Y. S. et al. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer. eLife 3, e02935 (2014).
  43. Payne, B. A. et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat. Genet. 43, 806810 (2011).
  44. Payne, B. A., Gardner, K., Coxhead, J. & Chinnery, P. F. Deep resequencing of mitochondrial DNA. Methods Mol. Biol. 1264, 5966 (2015).
  45. Hazkani-Covo, E., Zeller, R. M. & Martin, W. Molecular poltergeists: mitochondrial DNA copies (numts) in sequenced nuclear genomes. PLoS Genet. 6, e1000834 (2010).
  46. Dayama, G., Emery, S. B., Kidd, J. M. & Mills, R. E. The genomic landscape of polymorphic human nuclear mitochondrial insertions. Nucleic Acids Res. 42, 1264012649 (2014).
  47. Li, M. et al. Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am. J. Hum. Genet. 87, 237249 (2010).
  48. Ameur, A. et al. Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet. 7, e1002028 (2011).
  49. Payne, B. A. et al. Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384390 (2013).
  50. Rajasimha, H. K., Chinnery, P. F. & Samuels, D. C. Selection against pathogenic mtDNA mutations in a stem cell population leads to the loss of the 3243Aright arrowG mutation in blood. Am. J. Hum. Genet. 82, 333343 (2008).
  51. Lehtinen, S. K. et al. Genotypic stability, segregation and selection in heteroplasmic human cell lines containing np 3243 mutant mtDNA. Genetics 154, 363380 (2000).
  52. Raap, A. K. et al. Non-random mtDNA segregation patterns indicate a metastable heteroplasmic segregation unit in m.3243A>G cybrid cells. PLoS ONE 7, e52080 (2012).
  53. Chinnery, P. F. & Samuels, D. C. Relaxed replication of mtDNA: a model with implications for the expression of disease. Am. J. Hum. Genet. 64, 11581165 (1999).
  54. Elson, J. L., Samuels, D. C., Turnbull, D. M. & Chinnery, P. F. Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am. J. Hum. Genet. 68, 802806 (2001).
  55. Diaz, F. et al. Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control. Nucleic Acids Res. 30, 46264633 (2002).
  56. Clark, K. A. et al. Selfish little circles: transmission bias and evolution of large deletion-bearing mitochondrial DNA in Caenorhabditis briggsae nematodes. PLoS ONE 7, e41433 (2012).
  57. Samuels, D. C. et al. Recurrent tissue-specific mtDNA mutations are common in humans. PLoS Genet. 9, e1003929 (2013).
  58. Jenuth, J. P., Peterson, A. C. & Shoubridge, E. A. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat. Genet. 16, 9395 (1997).
  59. Takeda, K., Takahashi, S., Onishi, A., Hanada, H. & Imai, H. Replicative advantage and tissue-specific segregation of RR mitochondrial DNA between C57BL/6 and RR heteroplasmic mice. Genetics 155, 777783 (2000).
  60. Burgstaller, J. P. et al. mtDNA segregation in heteroplasmic tissues is common in vivo and modulated by haplotype differences and developmental stage. Cell Rep. 7, 20312041 (2014).
  61. Wanrooij, S. et al. In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication. EMBO Rep. 13, 11301137 (2012).
  62. Trifunovic, A. et al. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl Acad. Sci. USA 102, 1799317998 (2005).
  63. Durham, S. E., Brown, D. T., Turnbull, D. M. & Chinnery, P. F. Progressive depletion of mtDNA in mitochondrial myopathy. Neurology 67, 502504 (2006).
  64. Durham, S. E., Samuels, D. C., Cree, L. M. & Chinnery, P. F. Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243Aright arrowG. Am. J. Hum. Genet. 81, 189195 (2007).
  65. Chinnery, P. F., Samuels, D. C., Elson, J. & Turnbull, D. M. Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360, 13231325 (2002).
  66. Cree, L. M. et al. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat. Genet. 40, 249254 (2008).
  67. Battersby, B. J., Redpath, M. E. & Shoubridge, E. A. Mitochondrial DNA segregation in hematopoietic lineages does not depend on MHC presentation of mitochondrially encoded peptides. Hum. Mol. Genet. 14, 25872594 (2005).
  68. Jokinen, R. et al. Gimap3 regulates tissue-specific mitochondrial DNA segregation. PLoS Genet. 6, e1001161 (2010).
  69. Upholt, W. B. & Dawid, I. B. Mapping of mitochondrial DNA of individual sheep and goats: rapid evolution in the D loop region. Cell 11, 571583 (1977).
  70. Olivo, P. D., Van de Walle, M. J., Laipis, P. J. & Hauswirth, W. W. Nucleotide sequence evidence for rapid genotypic shifts in the bovine mitochondrial DNA D-loop. Nature 306, 400402 (1983).
    References 69 and 70 describe rapid shifts in mtDNA heteroplasmy in cows. These observations laid the foundations for the mtDNA bottleneck hypothesis, which explains differences in the level of heteroplasmy observed within human pedigrees transmitting pathogenic mtDNA mutations.
  71. Solignac, M., Génermont, J., Monnerot, M. & Mounolou, J.-C. Genetics of mitochondria in Drosophila: mtDNA inheritance in heteroplasmic strains of D.mauritania. Mol. Genet. Genomics 197, 183188 (1984).
  72. Rand, D. M. & Harrison, R. G. Mitochondrial DNA transmission genetics in crickets. Genetics 114, 955970 (1986).
  73. Birky, C. W. Relaxed and stringent genomes: why cytoplasmic genes don't obey Mendel's laws. J. Hered. 85, 355365 (1994).
  74. Wright, S. Evolution and the Genetics of Populations (University of Chicago Press, 1969).
  75. Howell, N. et al. Mitochondrial gene segregation in mammals: is the bottleneck always narrow? Hum. Genet. 90, 117120 (1992).
  76. Chinnery, P. F., Howell, N., Lightowlers, R. N. & Turnbull, D. M. MELAS and MERRF: the relationship between maternal mutation load and the frequency of clinically affected offspring. Brain 121, 18891894 (1998).
  77. White, S. L. et al. Genetic counseling and prenatal diagnosis for the mitochondrial DNA mutations at nucleotide 8993. Am. J. Hum. Genet. 65, 474482 (1999).
  78. Wai, T., Teoli, D. & Shoubridge, E. A. The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes. Nat. Genet. 40, 14841488 (2008).
  79. Cao, L. et al. The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nat. Genet. 39, 386390 (2007).
    References 66, 78 and 79 describe a reduction in the amount of mtDNA present within the germ line of mice, thus providing the first direct evidence of the existence of a mammalian mtDNA genetic bottleneck.
  80. Freyer, C. et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nat. Genet. 44, 12821285 (2012).
  81. Cree, L. M., Samuels, D. C. & Chinnery, P. F. The inheritance of pathogenic mitochondrial DNA mutations. Biochim. Biophys. Acta 1792, 10971102 (2009).
  82. Chinnery, P. F. et al. The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both? Trends Genet. 16, 500505 (2000).
  83. Jenuth, J., Peterson, A. C., Fu, K. & Shoubridge, E. A. Random genetic drift in the female germ line explains the rapid segregation of mammalian mitochondrial DNA. Nat. Genet. 14, 146151 (1996).
  84. Brown, D. T., Samuels, D. C., Michael, E. M., Turnbull, D. M. & Chinnery, P. F. Random genetic drift determines the level of mutant mtDNA in human primary oocytes. Am. J. Hum. Genet. 68, 533536 (2001).
  85. Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 (2008).
  86. Fan, W. et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319, 958962 (2008).
    References 85 and 86 provide evidence of selection against mtDNA variants during maternal transmission in different mouse models.
  87. Greaves, L. C. et al. Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations. PLoS Genet. 8, e1003082 (2012).
  88. Ma, H., Xu, H. & O'Farrell, P. H. Transmission of mitochondrial mutations and action of purifying selection in Drosophila melanogaster. Nat. Genet. 46, 393397 (2014).
  89. Hill, J. H., Chen, Z. & Xu, H. Selective propagation of functional mitochondrial DNA during oogenesis restricts the transmission of a deleterious mitochondrial variant. Nat. Genet. 46, 389392 (2014).
  90. Chacinska, A., Koehler, C. M., Milenkovic, D., Lithgow, T. & Pfanner, N. Importing mitochondrial proteins: machineries and mechanisms. Cell 138, 628644 (2009).
  91. Piko, L. & Taylor, K. D. Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Dev. Biol. 123, 364374 (1987).
  92. Stewart, J. B. & Larsson, N. G. Keeping mtDNA in shape between generations. PLoS Genet. 10, e1004670 (2014).
  93. Krakauer, D. C. & Mira, A. Mitochondria and germ-cell death. Nature 400, 125126 (1999).
  94. Kaare, M. et al. Do mitochondrial mutations cause recurrent miscarriage? Mol. Hum. Reprod. 15, 295300 (2009).
  95. Behar, D. M. et al. The Genographic Project public participation mitochondrial DNA database. PLoS Genet. 3, e104 (2007).
  96. Soares, P. et al. Correcting for purifying selection: an improved human mitochondrial molecular clock. Am. J. Hum. Genet. 84, 740759 (2009).
  97. Salas, A., Carracedo, A., Macaulay, V., Richards, M. & Bandelt, H. J. A practical guide to mitochondrial DNA error prevention in clinical, forensic, and population genetics. Biochem. Biophys. Res. Commun. 335, 891899 (2005).
  98. Bandelt, H. J., Yao, Y. G., Salas, A., Kivisild, T. & Bravi, C. M. High penetrance of sequencing errors and interpretative shortcomings in mtDNA sequence analysis of LHON patients. Biochem. Biophys. Res. Commun. 352, 283291 (2007).
  99. Blier, P. U., Dufresne, F. & Burton, R. S. Natural selection and the evolution of mtDNA-encoded peptides: evidence for intergenomic co-adaptation. Trends Genet. 17, 400406 (2001).
  100. Ruiz-Pesini, E., Mishmar, D., Brandon, M., Procaccio, V. & Wallace, D. C. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science 303, 223226 (2004).
  101. Mishmar, D. et al. Natural selection shaped regional mtDNA variation in humans. Proc. Natl Acad. Sci. USA 100, 171176 (2003).
  102. Samuels, D. C., Carothers, A. D., Horton, R. & Chinnery, P. F. The power to detect disease associations with mitochondrial DNA haplogroups. Am. J. Hum. Genet. 78, 713720 (2006).
  103. Moreno-Loshuertos, R. et al. Differences in reactive oxygen species production explain the phenotypes associated with common mouse mitochondrial DNA variants. Nat. Genet. 38, 12611268 (2006).
  104. Baudouin, S. V. et al. Mitochondrial DNA and survival after sepsis: a prospective study. Lancet 366, 21182121 (2005).
  105. Jimenez-Sousa, M. A. et al. Mitochondrial DNA haplogroups are associated with severe sepsis and mortality in patients who underwent major surgery. J. Infect. 70, 2029 (2015).
  106. Hudson, G. et al. Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. Neurology 80, 20422048 (2013).
  107. Ghezzi, D. et al. Mitochondrial DNA haplogroup K is associated with a lower risk of Parkinson's disease in Italians. Eur. J. Hum. Genet. 13, 748752 (2005).
  108. Reinhardt, K., Dowling, D. K. & Morrow, E. H. Medicine. Mitochondrial replacement, evolution, and the clinic. Science 341, 13451346 (2013).
  109. Chinnery, P. F. et al. The challenges of mitochondrial replacement. PLoS Genet. 10, e1004315 (2014).
  110. Kmietowicz, Z. UK becomes first country to allow mitochondrial donation. BMJ 350, h1103 (2015).
  111. Shadel, G. S. & Clayton, D. A. Mitochondrial DNA maintenance in vertebrates. Annu. Rev. Biochem. 66, 409435 (1997).
  112. Holt, I. J., Lorimer, H. E. & Jacobs, H. T. Coupled leading- and lagging-strand synthesis of mammalian mitochondrial DNA. Cell 100, 515524 (2000).
  113. Yang, M. Y. et al. Biased incorporation of ribonucleotides on the mitochondrial L-strand accounts for apparent strand-asymmetric DNA replication. Cell 111, 495505 (2002).
  114. Yasukawa, T., Yang, M. Y., Jacobs, H. T. & Holt, I. J. A bidirectional origin of replication maps to the major noncoding region of human mitochondrial DNA. Mol. Cell 18, 651662 (2005).
  115. Terzioglu, M. et al. MTERF1 binds mtDNA to prevent transcriptional interference at the light-strand promoter but is dispensable for rRNA gene transcription regulation. Cell Metab. 17, 618626 (2013).
  116. Kuhl, I. et al. POLRMT does not transcribe nuclear genes. Nature 514, E7E11 (2014).
  117. Kirkman, M. A. et al. Gene–environment interactions in Leber hereditary optic neuropathy. Brain 132, 23172326 (2009).
  118. Hudson, G. et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am. J. Hum. Genet. 81, 228233 (2007).
  119. Chinnery, P. F., Andrews, R. M., Turnbull, D. M. & Howell, N. Leber's hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am. J. Med. Genet. 98, 235243 (2001).
  120. Kennedy, S. R., Salk, J. J., Schmitt, M. W. & Loeb, L. A. Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet. 9, e1003794 (2013).
  121. Boore, J. L., Macey, J. R. & Medina, M. Sequencing and comparing whole mitochondrial genomes of animals. Methods Enzymol. 395, 311348 (2005).
  122. Lou, D. I. et al. High-throughput DNA sequencing errors are reduced by orders of magnitude using circle sequencing. Proc. Natl Acad. Sci. USA 110, 1987219877 (2013).
  123. Cao, L. et al. New evidence confirms that the mitochondrial bottleneck is generated without reduction of mitochondrial DNA content in early primordial germ cells of mice. PLoS Genet. 5, e1000756 (2009).
  124. Carling, P. J., Cree, L. M. & Chinnery, P. F. The implications of mitochondrial DNA copy number regulation during embryogenesis. Mitochondrion 11, 686692 (2011).
  125. Wallace, D. C., Brown, M. D. & Lott, M. T. Mitochondrial DNA variation in human evolution and disease. Gene 238, 211230 (1999).
  126. Torroni, A. et al. Classification of European mtDNAs from an analysis of three European populations. Genetics 144, 18351850 (1996).
  127. van Oven, M. & Kayser, M. Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum. Mutat. 30, E386E394 (2009).

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  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

Competing interests statement

The authors declare no competing interests.

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Author details

  • 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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