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

Nature Reviews Genetics

Volumn 16, Issue 9, 2015, Pages 530-542

  Stewart, James B ^a   Chinnery, Patrick F ^b  

^a MAX PLANCK INSTITUTE FOR BIOLOGY OF AGEING   (Germany)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

MITOCHONDRIAL DNA;

AFRICAN; AGING; ALZHEIMER DISEASE; BIOGENESIS; BOTTLENECK POPULATION; CELL DIVISION; DEGENERATIVE DISEASE; DNA RECOMBINATION; EUKARYOTE; GENE MUTATION; GENETIC DISORDER; GENETIC VARIABILITY; GERMLINE MUTATION; HEALTH; HETEROPLASMY; HUMAN; MITOCHONDRIAL DYNAMICS; MITOSIS; MONOGENIC DISORDER; PARKINSON DISEASE; POPULATION RISK; PRIORITY JOURNAL; REVIEW; SOMATIC MUTATION; ANIMAL; FEMALE; GENETICS; MALE; MUTATION;

EUKARYOTA; MAMMALIA;

AGING; ANIMALS; DNA, MITOCHONDRIAL; FEMALE; GENETIC DISEASES, INBORN; HUMANS; MALE; MUTATION;

EID: 84939538979     PISSN: 14710056     EISSN: 14710064     Source Type: Journal    
DOI: 10.1038/nrg3966     Document Type: Review

References (127)

1. Wallace, D. C. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427-1430 (1988).
2. Holt, I., Harding, A. E. & Morgan-Hughes, J. A. Deletion of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717-719 (1988).
3. Gorman, G. S. et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann. Neurol. 77, 753-759 (2015).
4. Chinnery, P. F. et al. Epidemiology of pathogenic mitochondrial DNA mutations. Ann. Neurol. 48, 188-193 (2000).
5. Di Mauro, S., Schon, E. A., Carelli, V. & Hirano, M. The clinical maze of mitochondrial neurology. Nat. Rev. Neurol. 9, 429-444 (2013).
6. Vafai, S. B. & Mootha, V. K. Mitochondrial disorders as windows into an ancient organelle. Nature 491, 374-383 (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), 8947-8953 (2011).
8. Pinto, M. & Moraes, C. T. Mechanisms linking mtDNA damage and aging. Free Radic. Biol. Med. 85, 250-258 (2015).
9. Pinto, M. & Moraes, C. T. Mitochondrial genome changes and neurodegenerative diseases. Biochim. Biophys. Acta 1842, 1198-1207 (2014).
10. Ross, J. M. et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501, 412-415 (2013).
11. Keogh, M. & Chinnery, P. F. Hereditary mtDNA heteroplasmy: a baseline for aging? Cell Metab. 18, 463-464 (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, 3343-3353 (2010).
15. Mereschkowsky, K. Theorie der zwei Plasmaarten als Grundlage der Symbiogenesis, einer neuen Lehre von der Ent-stehung der Organismen. Biol. Centralbl. 30, 353-367 (1910) (in German).
16. Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112-123 (2008).
17. Vafai, S. B. & Mootha, V. K. Medicine. A common pathway for a rare disease? Science 342, 1453-1454 (2013).
18. Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457-465 (1981).
19. Andrews, R. M. et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat. Genet. 23, 147 (1999).
20. Calvo, S. E. & Mootha, V. K. The mitochondrial proteome and human disease. Annu. Rev. Genom. Hum. Genet. 11, 25-44 (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, 13534-13539 (2011).
22. Elson, J. L. et al. Analysis of European mtDNAs for recombination. Am. J. Hum. Genet. 68, 145-153 (2001).
23. Schon, E. A., DiMauro, S. & Hirano, M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat. Rev. Genet. 13, 878-890 (2012).
24. Chinnery, P. F. et al. Risk of developing a mitochondrial DNA deletion disorder. Lancet 364, 592-596 (2004).
25. McFarland, R. et al. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat. Genet. 30, 145-146 (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, 2733-2742 (2000).
27. Ile homoplasmic mutation in the mitochondrial genome. J. Med. Genet. 41, 342-349 (2004).
28. King, M. P. & Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500-503 (1989).
29. Lys mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am. J. Hum. Genet. 51, 1187-1200 (1992).
30. Carelli, V., Giordano, C. & d'Amati, G. Pathogenic expression of homoplasmic mtDNA mutations needs a complex nuclear-mitochondrial interaction. Trends Genet. 19, 257-262 (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, 254-260 (2008).
32. Cortopassi, G. A. & Arnheim, N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 18, 6927-6933 (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, 217-223 (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, 169-180 (1992).
35. Corral-Debrinski, M. et al. Marked changes in mitochondrial DNA deletion levels in Alzheimer brains. Genomics 23, 471-476 (1994).
36. Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat. Genet. 38, 515-517 (2006).
37. Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nat. Genet. 38, 518-520 (2006).
38. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417-423 (2004).
39. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481-484 (2005).
40. Polyak, K. et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat. Genet. 20, 291-293 (1998).
41. He, Y. et al. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature 464, 610-614 (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, 806-810 (2011).
44. Payne, B. A., Gardner, K., Coxhead, J. & Chinnery, P. F. Deep resequencing of mitochondrial DNA. Methods Mol. Biol. 1264, 59-66 (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, 12640-12649 (2014).
47. Li, M. et al. Detecting heteroplasmy from high-throughput sequencing of complete human mitochondrial DNA genomes. Am. J. Hum. Genet. 87, 237-249 (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, 384-390 (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 3243A→G mutation in blood. Am. J. Hum. Genet. 82, 333-343 (2008).
51. Lehtinen, S. K. et al. Genotypic stability, segregation and selection in heteroplasmic human cell lines containing np 3243 mutant mtDNA. Genetics 154, 363-380 (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, 1158-1165 (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, 802-806 (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, 4626-4633 (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, 93-95 (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, 777-783 (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, 2031-2041 (2014).
61. Wanrooij, S. et al. In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication. EMBO Rep. 13, 1130-1137 (2012).
62. Trifunovic, A. et al. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc. Natl Acad. Sci. USA 102, 17993-17998 (2005).
63. Durham, S. E., Brown, D. T., Turnbull, D. M. & Chinnery, P. F. Progressive depletion of mtDNA in mitochondrial myopathy. Neurology 67, 502-504 (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.3243A→G. Am. J. Hum. Genet. 81, 189-195 (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, 1323-1325 (2002).
66. Cree, L. M. et al. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat. Genet. 40, 249-254 (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, 2587-2594 (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, 571-583 (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, 400-402 (1983).
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, 183-188 (1984).
72. Rand, D. M. & Harrison, R. G. Mitochondrial DNA transmission genetics in crickets. Genetics 114, 955-970 (1986).
73. Birky, C. W. Relaxed and stringent genomes: why cytoplasmic genes don't obey Mendel's laws. J. Hered. 85, 355-365 (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, 117-120 (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, 1889-1894 (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, 474-482 (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, 1484-1488 (2008).
79. Cao, L. et al. The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nat. Genet. 39, 386-390 (2007).
80. Freyer, C. et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nat. Genet. 44, 1282-1285 (2012).
81. Cree, L. M., Samuels, D. C. & Chinnery, P. F. The inheritance of pathogenic mitochondrial DNA mutations. Biochim. Biophys. Acta 1792, 1097-1102 (2009).
82. Chinnery, P. F. et al. The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both? Trends Genet. 16, 500-505 (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, 146-151 (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, 533-536 (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, 958-962 (2008).
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, 393-397 (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, 389-392 (2014).
90. Chacinska, A., Koehler, C. M., Milenkovic, D., Lithgow, T. & Pfanner, N. Importing mitochondrial proteins: machineries and mechanisms. Cell 138, 628-644 (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, 364-374 (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, 125-126 (1999).
94. Kaare, M. et al. Do mitochondrial mutations cause recurrent miscarriage? Mol. Hum. Reprod. 15, 295-300 (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, 740-759 (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, 891-899 (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, 283-291 (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, 400-406 (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, 223-226 (2004).
101. Mishmar, D. et al. Natural selection shaped regional mtDNA variation in humans. Proc. Natl Acad. Sci. USA 100, 171-176 (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, 713-720 (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, 1261-1268 (2006).
104. Baudouin, S. V. et al. Mitochondrial DNA and survival after sepsis: a prospective study. Lancet 366, 2118-2121 (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, 20-29 (2015).
106. Hudson, G. et al. Two-stage association study and meta-analysis of mitochondrial DNA variants in Parkinson disease. Neurology 80, 2042-2048 (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, 748-752 (2005).
108. Reinhardt, K., Dowling, D. K. & Morrow, E. H. Medicine. Mitochondrial replacement, evolution, and the clinic. Science 341, 1345-1346 (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, 409-435 (1997).
112. Holt, I. J., Lorimer, H. E. & Jacobs, H. T. Coupled leading-and lagging-strand synthesis of mammalian mitochondrial DNA. Cell 100, 515-524 (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, 495-505 (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, 651-662 (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, 618-626 (2013).
116. Kuhl, I. et al. POLRMT does not transcribe nuclear genes. Nature 514, E7-E11 (2014).
117. Kirkman, M. A. et al. Gene-environment interactions in Leber hereditary optic neuropathy. Brain 132, 2317-2326 (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, 228-233 (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, 235-243 (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, 311-348 (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, 19872-19877 (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, 686-692 (2011).
125. Wallace, D. C., Brown, M. D. & Lott, M. T. Mitochondrial DNA variation in human evolution and disease. Gene 238, 211-230 (1999).
126. Torroni, A. et al. Classification of European mtDNAs from an analysis of three European populations. Genetics 144, 1835-1850 (1996).
127. van Oven, M. & Kayser, M. Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum. Mutat. 30, E386-E394 (2009).