Journal of Molecular Evolution

, Volume 68, Issue 5, pp 516–527 | Cite as

Investigation of Heteroplasmy in the Human Mitochondrial DNA Control Region: A Synthesis of Observations from More Than 5000 Global Population Samples

  • Jodi A. Irwin
  • Jessica L. Saunier
  • Harald Niederstätter
  • Katharine M. Strouss
  • Kimberly A. Sturk
  • Toni M. Diegoli
  • Anita Brandstätter
  • Walther Parson
  • Thomas J. Parsons
Article

Abstract

Instances of point and length heteroplasmy in the mitochondrial DNA control region were compiled and analyzed from over 5,000 global human population samples. These data represent observations from a large and broad population sample, representing nearly 20 global populations. As expected, length heteroplasmy was frequently observed in the HVI, HVII and HVIII C-stretches. Length heteroplasmy was also observed in the AC dinucleotide repeat region, as well as other locations. Point heteroplasmy was detected in approximately 6% of all samples, and while the vast majority of heteroplasmic samples comprised two molecules differing at a single position, samples exhibiting two and three mixed positions were also observed in this data set. In general, the sites at which heteroplasmy was most commonly observed correlated with reported control region mutational hotspots. However, for some sites, observations of heteroplasmy did not mirror established mutation rate data, suggesting the action of other mechanisms, both selective and neutral. Interestingly, these data indicate that the frequency of heteroplasmy differs between particular populations, perhaps reflecting variable mutation rates among different mtDNA lineages and/or artifacts of particular population groups. The results presented here contribute to our general understanding of mitochondrial DNA control region heteroplasmy and provide additional empirical information on the mechanisms contributing to mtDNA control region mutation and evolution.

Keywords

Control region Heteroplasmy Mitochondrial DNA Mutation rate 

Supplementary material

239_2009_9227_MOESM1_ESM.doc (436 kb)
Supplementary Table S1 is available online. Haplotype data are available on request. Sequences from this data set may also be found at www.empop.org or under the following GenBank accession numbers: DQ906346-DQ906708; FJ026015-FJ026391; DQ418040-DQ418130; EU718790-EU719066; DQ418131-DQ418449; EU014897-EU015024; DQ359273-DQ359688; AY632902-AY633004; and DQ535903-DQ536089. 1 (DOC 436 kb)

References

  1. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F et al (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465PubMedCrossRefGoogle Scholar
  2. Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23:147PubMedCrossRefGoogle Scholar
  3. Bandelt H-J, Parson W (2008) Consistent treatment of length variants in the human mtDNA control region: a reappraisal. Int J Legal Med 122:11–21PubMedCrossRefGoogle Scholar
  4. Bendall KE, Sykes BC (1995) Length heteroplasmy in the first hypervariable segment of the human mtDNA control region. Am J Hum Genet 57:248–256PubMedGoogle Scholar
  5. Boyer JC, Yamada NA, Roques CN, Hatch SB, Riess K, Farber RA (2002) Sequence dependent instability of mononucleotide microsatellites in cultured mismatch repair proficient and deficient mammalian cells. Hum Mol Genet 11:707–713PubMedCrossRefGoogle Scholar
  6. Brandstätter A, Peterson CT, Irwin JA, Mpoke S, Koech DK, Parson W, Parsons TJ (2004) Mitochondrial DNA control region sequences from Nairobi (Kenya): inferring phylogenetic parameters for the establishment of a forensic database. Int J Legal Med 118:294–306PubMedCrossRefGoogle Scholar
  7. Butler J (2005) Forensic DNA typing: biology, technology and genetics of STR markers, 2nd edn. Elsevier, Burlington, MAGoogle Scholar
  8. Calloway C, Reynolds R, Herrin G, Anderson W (2000) The frequency of heteroplasmy in the HVII region differs across tissue types and increases with age. Am J Hum Gen 66:1384–1397CrossRefGoogle Scholar
  9. Cann RL, Stoneking M, Wilson AC (1987) DNA and human evolution. Nature 325:31–36PubMedCrossRefGoogle Scholar
  10. Chung U, Lee HY, Yoo JE, Park MJ, Shin KJ (2005) Mitochondrial DNA CA dinucleotide repeats in Koreans: the presence of length heteroplasmy. Int J Legal Med 119:50–53PubMedCrossRefGoogle Scholar
  11. Ellegren H (2004) Microsatellites: simple sequences with complex evolution. Nat Rev Genet 5:435–445PubMedCrossRefGoogle Scholar
  12. Elliot HR, Samuels DC, Eden JA, Relton CL, Chinnery PF (2008) Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 83:254–260CrossRefGoogle Scholar
  13. Elson JL, Turnbull DM, Howell N (2004) Comparative genomics and the evolution of human mitochondrial DNA—assessing the effects of selection. Am J Hum Genet 74:229–238PubMedCrossRefGoogle Scholar
  14. Finnilä S, Lehtonen MS, Majamaa K (2001) Phylogenetic network for European mtDNA. Am J Hum Genet 68:1475–1484PubMedCrossRefGoogle Scholar
  15. Forster L, Forster P, Lutz-Bonengel S, Willkomm H, Brinkmann B (2002) Natural radioactivity and human mitochondrial DNA mutations. Proc Natl Acad Sci USA 99:13950–13954PubMedCrossRefGoogle Scholar
  16. Herrnstadt C, Elson JL, Fahy E, Preston G, Turnbull DM, Anderson C, Ghosh SS, Olefsky JM, Beal F et al (2002) Coding-region sequences for the major African, Asian and European haplogroups. Am J Hum Genet 70:1152–1171PubMedCrossRefGoogle Scholar
  17. Ho S, Phillips MJ, Cooper A, Drummon AJ (2005) Time dependency of molecular rate estimates and systematic overestimation of recent divergence times. Mol Biol Evol 22:1561–1568PubMedCrossRefGoogle Scholar
  18. Holland MM, Parsons TJ (1999) Mitochondrial DNA sequence analysis—validation and use for forensic casework. Forensic Sci Rev 11:21–50Google Scholar
  19. Howell N, Smejkal CB (2000) Persistent heteroplasmy of a mutation in the human mtDNA control region: hypermutation as an apparent consequence of simple-repeat expansion/contraction. Am J Hum Genet 66:1589–1598PubMedCrossRefGoogle Scholar
  20. Howell N, Kubacka I, Mackey DA (1996) How rapidly does the human mitochondrial genome evolve? Am J Hum Genet 59:501–509PubMedGoogle Scholar
  21. Howell N, Herrnstadt C, Mackey D (2001) Different patterns of expansion/contraction during the evolution of an mtDNA simple repeat. Mol Biol Evol 18:1593–1596PubMedGoogle Scholar
  22. Howell N, Smejkal CB, Mackey DA, Chinnery PF, Turnbull DM, Herrnstadt C (2003) The pedigree rate of sequence divergence in the human mitochondrial genome: there is a difference between phylogenetic and pedigree studies. Am J Hum Genet 72:659–670PubMedCrossRefGoogle Scholar
  23. Howell N, Elson JL, Turnbull DM, Herrnstadt C (2004) African haplogroup L mtDNA sequences show violations of clock-like evolution. Mol Biol Evol 21:1843–1854PubMedCrossRefGoogle Scholar
  24. Howell N, Elson J, Howell C, Turnbull D (2007) Relative rates of evolution in the coding and control regions of African mtDNAs. Mol Biol Evol 24:2213–2221PubMedCrossRefGoogle Scholar
  25. Ingman M, Kaessmann H, Pääbo S, Gyllensten U (2000) Mitochondrial genome variation and the origin of modern humans. Nature 408:708–713PubMedCrossRefGoogle Scholar
  26. Irwin J, Saunier J, Strouss K, Sturk K, Diegoli T, Just R, Coble M, Parson W, Parsons T (2007) Development and expansion of high quality control region databases to improve forensic mtDNA evidence interpretation. Forensic Sci Int Genet 1:154–157PubMedCrossRefGoogle Scholar
  27. Kimura M (1980) A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol 16:111–120PubMedCrossRefGoogle Scholar
  28. Kivisild T, Shen P, Wall DP, Do B, Sung R, Davis K, Passarino G, Underhill PA, Scharfe C, Torroni A et al (2006) The role of selection in the evolution of human mitochondrial genomes. Genetics 172:373–387PubMedCrossRefGoogle Scholar
  29. Lutz-Bonengel S, Sänger T, Pollak S, Szibor R (2004) Different methods to determine length heteroplasmy within the mitochondrial control region. Int J Legal Med 118:274–281PubMedCrossRefGoogle Scholar
  30. Macaulay V, Richards M, Hickey E, Vega E, Cruciani F, Guida V, Scozzari R, Bonne-Tamir B, Sykes B, Torroni A (1999) The emerging tree of west Eurasian mtDNAs: a synthesis of control region sequences and RFLPs. Am J Hum Genet 64:232–249PubMedCrossRefGoogle Scholar
  31. Malyarchuk BA, Rogozin IB (2004) Mutagenesis by transient misalignment in the human mitochondrial DNA control region. Ann Hum Genet 68:324–339PubMedCrossRefGoogle Scholar
  32. Melton T (2004) Mitochondrial DNA heteroplasmy. Forensic Sci Rev 16:2–20Google Scholar
  33. Melton T, Dimick G, Higgins B, Lindstrom L, Nelson K (2005) Forensic mitochondrial DAN analysis of 691 casework hairs. J Forensic Sci 50:73–80PubMedCrossRefGoogle Scholar
  34. Mishmar D, Ruiz-Pesini E, Golik P, Macaulay V, Clark AG, Hosseini S, Brandon M, Easley K, Chen E, Brown MD et al (2003) Natural selection shaped regional mtDNA variation in humans. Proc Natl Acad Sci USA 100:171–176PubMedCrossRefGoogle Scholar
  35. Monson KL, Miller KWP, Wilson MR, DiZinno JA, Budowle B (2002) The mtDNA population database: An integrated software and database resource for forensic comparison. Forensic Sci Commun 4:(2). Available at: http://www.fbi.gov/hq/lab/fsc/backissu/april2002/miller1.htm. Accessed 13 April 2009
  36. Pai CY, Hsieh LL, Lee TC, Yang SB, Linville J, Chou SL, Yang CH (2006) Mitochondrial DNA sequence alterations observed between blood and buccal cells within the same individuals having a betel quid (BQ)-chewing habit. Forensic Sci Int 156:124–130PubMedCrossRefGoogle Scholar
  37. Parker LT, Keng Q, Zakeri H, Carlson C, Nickerson DA, Kwok PY (1995) Peak height variations in automated sequencing of PCR products using Taq dye-terminator chemistry. Biotechniques 19:116–121PubMedGoogle Scholar
  38. Parker LT, Zakeri H, Deng Q, Spurgeon S, Kwok PY, Nickerson DA (1996) AmpliTaq DNA polymerase, FS dye-terminator sequencing: analysis of peak height patterns. Biotechniques 21:694–699PubMedGoogle Scholar
  39. Parsons TJ, Muniec DS, Sullivan K, Woodyatt N, Alliston-Greiner R, Wilson MR, Berry DL, Holland KA, Weedn VW, Gill P et al (1997) A high observed substitution rate in the human mitochondrial DNA control region. Nat Genet 15:363–368PubMedCrossRefGoogle Scholar
  40. Pereira F, Soares P, Carneiro J, Pereira L, Richards MB, Samuels DC, Amorim A (2008) Evidence for variable selective pressures at a large secondary structure of the human mitochondrial DNA control region. Mol Biol Evol 25:2579–2880CrossRefGoogle Scholar
  41. Richards M, Corte-Real H, Forster P, Macaulay V, Wilkinson-Herbots H, Demain A, Papiha S, Hedges R, Bandelt HJ, Sykes B (1996) Paleolithic and Neolithic lineages in the European mitochondrial gene pool. Am J Hum Genet 59:185–203PubMedGoogle Scholar
  42. Santos C, Montiel R, Sierra B, Bettencourt C, Fernandez E, Alvarez L, Lima M, Abade A, Aluja MP (2005) Understanding differences between phylogenetic and pedigree-derived mtDNA mutation rate: a model using families from the Azores Islands (Portugal). Mol Biol Evol 22:1490–1505PubMedCrossRefGoogle Scholar
  43. Santos C, Sierra B, Alvarez L, Ramos A, Fernandez E, Nogues R, Aluha MP (2008) Frequency and pattern of heteroplasmy in the control region of human mitochondrial DNA. J Mol Evol 67:191–200PubMedCrossRefGoogle Scholar
  44. Shinde D, Lai Y, Sun F, Arnheim N (2003) Taq DNA polymerase slippage mutation rates measured by PCR and quasi-likelihood analysis: (CA/GT)n and (A/T)n microsatellites. Nucleic Acids Res 31:974–980PubMedCrossRefGoogle Scholar
  45. Sigurdardottir S, Helgason A, Gulcher JR, Stefansson K, Donnelly P (2000) The mutation rate in the human mtDNA control region. Am J Hum Genet 66:1599–1609CrossRefGoogle Scholar
  46. Stewart JE, Fisher CL, Aagaard PJ, Wilson MR, Isenberg AR, Polanskey D, Pokorak E, DiZinno JA, Budowle B (2001) Length variation in HV2 of the human mitochondrial DNA control region. J Forensic Sci 46:862–870PubMedGoogle Scholar
  47. Strouss K (2006) Relative evolutionary rate estimation for sites in the mtDNA control region. Master’s thesis. George Washington University, Washington, DCGoogle Scholar
  48. Swofford D (2003) PAUP*. Phylogenetic analysis using parsimony (*and other methods) version 4. Sinauer Assosiates, Sunderland, MAGoogle Scholar
  49. Szibor R, Plate I, Heinrich M, Michael M, Schoning R, Wittig H, Lutz-Bonengel S (2006) Mitochondrial D-loop (CA)(n) repeat length heteroplasmy: frequency in a German population sample and inheritance studies in two pedigrees. Int J Legal Med 121:207–213PubMedCrossRefGoogle Scholar
  50. Tamura K, Nei M (1993) Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. Mol Biol Evol 10:512–526PubMedGoogle Scholar
  51. Torroni A, Schurr TG, Cabell MF, Brown MD, Neel JV et al (1993) Asian affinities and continental radiation of the four founding Native American mtDNAs. Am J Hum Genet 53:563–590PubMedGoogle Scholar
  52. Torroni A, Lott MT, Cabell MF, Chen YS, Lavergne L, Wallace DC (1994) mtDNA and the origin of Caucasians: identification of ancient Caucasian-specific haplogroups, one of which is prone to a recurrent somatic duplication in the D-loop region. Am J Hum Genet 55:760–776PubMedGoogle Scholar
  53. Torroni A, Rengo C, Guida V, Cruciani F, Sellitto D, Coppa A, Calderon FL, Simionati B, Valle G, Richards M et al (2001) Do the four clades of the mtDNA haplogroup L2 evolve at different rates? Am J Hum Genet 69:1348–1356PubMedCrossRefGoogle Scholar
  54. Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ (2006) Harvesting the fruit of the human mtDNA tree. Trends Genet 22:339–345PubMedCrossRefGoogle Scholar
  55. Tully LA, Parsons TJ, Steighner RJ, Holland MM, Marino MA, Prenger VL (2000) A sensitive denaturing gradient gel electrophoresis assay reveals a high frequency of heteroplasmy in hypervariable region I of the human mtDNA control region. Am J Hum Genet 67:432–443PubMedCrossRefGoogle Scholar
  56. Underhill P, Kivisild T (2007) Use of Y chromosome and mitochondrial DNA population structure in tracing human migrations. Annu Rev Genet 41:539–564PubMedCrossRefGoogle Scholar
  57. Vigilant L, Stoneking M, Harpending H, Hawkes K, Wilson AC (1991) African populations and the evolution of human mitochondrial DNA. Science 253:1503–1507PubMedCrossRefGoogle Scholar
  58. Wakeley J (1993) Substitution rate variation among sites in hypervariable region 1 of human mitochondrial DNA. J Mol Evol 37:613–623PubMedCrossRefGoogle Scholar
  59. Watson E, Forster P, Richards M, Bandelt H-J (1997) Mitochondrial footprints of human expansions in Africa. Am J Hum Genet 61:691–704PubMedCrossRefGoogle Scholar
  60. Wilson M, Allard M, Monson K, Miller K, Budowle B (2002a) Recommendations for consistent treatment of length variants in the human mitochondrial DNA control region. Forensic Sci Int 129:35–42PubMedCrossRefGoogle Scholar
  61. Wilson M, Allard M, Monson K, Miller K, Budowle B (2002b) Further discussion of the consistent treatment of length variants in the human mitochondrial DNA control region. Forensic Sci Commun 4:4Google Scholar
  62. Yang Z (1994) Estimating the pattern of nucleotide substitution. J Mol Evol 39:105–111PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jodi A. Irwin
    • 1
  • Jessica L. Saunier
    • 1
  • Harald Niederstätter
    • 2
  • Katharine M. Strouss
    • 3
  • Kimberly A. Sturk
    • 1
  • Toni M. Diegoli
    • 1
  • Anita Brandstätter
    • 4
  • Walther Parson
    • 2
  • Thomas J. Parsons
    • 5
  1. 1.Research DepartmentArmed Forces DNA Identification LaboratoryRockvilleUSA
  2. 2.Institute of Legal MedicineInnsbruck Medical UniversityInnsbruckAustria
  3. 3.Seattle Biomedical Research InstituteSeattleUSA
  4. 4.Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical PharmacologyInnsbruck Medical UniversityInnsbruckAustria
  5. 5.International Commission on Missing PersonsSarajevoBosnia and Herzegovina

Personalised recommendations