International Journal of Legal Medicine

, Volume 118, Issue 1, pp 47–54

Monitoring the inheritance of heteroplasmy by computer-assisted detection of mixed basecalls in the entire human mitochondrial DNA control region

  • Anita Brandstätter
  • Harald Niederstätter
  • Walther Parson
Original Article


The entire mitochondrial DNA control region (~1122 bp) of 270 blood samples (135 mother-child pairs) was determined by direct sequencing. Overall, 135 ‘generational events’ were screened and within these, 20 mother-offspring pairs demonstrated more than 1 mtDNA haplotype. In 13 families, differences in the haplotypes between mother and offspring were detected in the form of heteroplasmic substitutions. Intergenerational comparisons led to the identification of three heteroplasmic point mutations and eight heteroplasmic length mutations affecting the children only. In two cases, a point heteroplasmy of the maternal sequence was resolved to homoplasmy in the corresponding sequence of the child. These discordant maternal-offspring haplotypes suggest that the shift in the mtDNA haplotype was the result of segregation of a limited maternal subpopulation of mtDNA. As technical implement, quality values assigned to basecalls were tested for their application in automated point heteroplasmy detection.


Point heteroplasmy Length heteroplasmy Genetic bottleneck Sequence quality values Sequence analysis Forensic science 


  1. 1.
    Gocke CD, Benko FA, Rogan PK (1998) Transmission of mitochondrial DNA heteroplasmy in normal pedigrees. Hum Genet 102:182–186PubMedGoogle Scholar
  2. 2.
    Chinnery PF, Thorburn DR, Samuels DC et al. (2000) The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both? Trends Genet 16:500–505CrossRefPubMedGoogle Scholar
  3. 3.
    Parson W, Parsons TJ, Scheithauer R, Holland MM (1998) Population data for 101 Austrian Caucasian mitochondrial DNA d-loop sequences: application of mtDNA sequence analysis to a forensic case. Int J Legal Med 111:124–132PubMedGoogle Scholar
  4. 4.
    Calloway CD, Reynolds RL, Herrin GL Jr, Anderson WW (2000) The frequency of heteroplasmy in the HVII region of mtDNA differs across tissue types and increases with age. Am J Hum Genet 66:1384–1397PubMedGoogle Scholar
  5. 5.
    Hutchison CA III, Newbold JE, Potter SS, Edgell MH (1974) Maternal inheritance of mammalian mitochondrial DNA. Nature 251:536–538PubMedGoogle Scholar
  6. 6.
    Hagelberg E (2003) Recombination or mutation rate heterogeneity? Implications for mitochondrial Eve. Trends Genet 19:84–90CrossRefPubMedGoogle Scholar
  7. 7.
    Awadalla P, Eyre-Walker A, Smith JM (1999) Linkage disequilibrium and recombination in hominid mitochondrial DNA. Science 286:2524–2525CrossRefPubMedGoogle Scholar
  8. 8.
    Eyre-Walker A (2000) Do mitochondria recombine in humans? Philos Trans R Soc Lond B Biol Sci 355:1573–1580CrossRefPubMedGoogle Scholar
  9. 9.
    Strauss E (1999) Human genetics. mtDNA shows signs of paternal influence. Science 286:2436CrossRefPubMedGoogle Scholar
  10. 10.
    Hey J (2000) Human mitochondrial DNA recombination: can it be true? Trends Ecol Evol 15:181–182CrossRefPubMedGoogle Scholar
  11. 11.
    Parsons TJ, Irwin JA (2000) Questioning evidence for recombination in human mitochondrial DNA. Science 288:1931Google Scholar
  12. 12.
    Hedrick P, Kumar S (2001) Mutation and linkage disequilibrium in human mtDNA. Eur J Hum Genet 9:969–972CrossRefPubMedGoogle Scholar
  13. 13.
    Jorde LB, Bamshad M (2000) Questioning evidence for recombination in human mitochondrial DNA. Science 288:1931Google Scholar
  14. 14.
    Kivisild T, Villems R (2000) Questioning evidence for recombination in human mitochondrial DNA. Science 288:1931Google Scholar
  15. 15.
    Kumar S, Hedrick P, Dowling T, Stoneking M (2000) Questioning evidence for recombination in human mitochondrial DNA. Science 288:1931Google Scholar
  16. 16.
    Shoubridge EA (2000) Mitochondrial DNA segregation in the developing embryo. Hum Reprod 15 [Suppl 2]:229–234Google Scholar
  17. 17.
    Jansen RP (2000) Germline passage of mitochondria: quantitative considerations and possible embryological sequelae. Hum Reprod 15 [Suppl 2]:112–128Google Scholar
  18. 18.
    Bianchi NO, Bianchi MS, Richard SM (2001) Mitochondrial genome instability in human cancers. Mutat Res 488:9–23PubMedGoogle Scholar
  19. 19.
    Howell N, Chinnery PF, Ghosh SS, Fahy E, Turnbull DM (2000) Transmission of the human mitochondrial genome. Hum Reprod 15 [Suppl 2]:235–245Google Scholar
  20. 20.
    Parsons TJ, Muniec DS, Sullivan K et al. (1997) A high observed substitution rate in the human mitochondrial DNA control region. Nat Genet 15:363–368PubMedGoogle Scholar
  21. 21.
    Huhne J, Pfeiffer H, Brinkmann B (1999) Heteroplasmic substitutions in the mitochondrial DNA control region in mother and child samples. Int J Legal Med 112:27–30CrossRefPubMedGoogle Scholar
  22. 22.
    Lutz S, Weisser HJ, Heizmann J, Pollak S (2000) Mitochondrial heteroplasmy among maternally related individuals. Int J Legal Med 113:155–161PubMedGoogle Scholar
  23. 23.
    Walsh PS, Metzger DA, Higuchi R (1991) Chelex 100 as a medium for simple extraction of DNA for PCR-based typing from forensic material. Biotechniques 10:506–513PubMedGoogle Scholar
  24. 24.
    Szibor R, Michael M (1999) Correct mitochondrial L-strand sequencing after C-stretches. Int J Legal Med 112:348–349CrossRefPubMedGoogle Scholar
  25. 25.
    Lutz S, Weisser HJ, Heizmann J, Pollak S (1998) Location and frequency of polymorphic positions in the mtDNA control region of individuals from Germany. Int J Legal Med 111:67–77PubMedGoogle Scholar
  26. 26.
    Anderson S, Bankier AT, Barrell BG et al. (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465PubMedGoogle Scholar
  27. 27.
    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 23:147PubMedGoogle Scholar
  28. 28.
    Bär W, Brinkmann B, Budowle B et al. (2000) DNA Commission of the International Society for Forensic Genetics: guidelines for mitochondrial DNA typing. Int J Legal Med 113:193–196CrossRefPubMedGoogle Scholar
  29. 29.
    Carracedo A, Bär W, Lincoln P et al. (2000) DNA Commission of the International Society for Forensic Genetics: guidelines for mitochondrial DNA typing. Forensic Sci Int 110:79–85PubMedGoogle Scholar
  30. 30.
    Wilson MR, Allard MW, Monson K, Miller KW, Budowle B (2002) Recommendations for consistent treatment of length variants in the human mitochondrial DNA control region. Forensic Sci Int 129:35–42CrossRefPubMedGoogle Scholar
  31. 31.
    Bidooki SK, Johnson MA, Chrzanowska-Lightowlers Z, Bindoff LA, Lightowlers RN (1997) Intracellular mitochondrial triplasmy in a patient with two heteroplasmic base changes. Am J Hum Genet 60:1430–1438PubMedGoogle Scholar
  32. 32.
    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 1 of the human mtDNA control region. Am J Hum Genet 67:432–443CrossRefPubMedGoogle Scholar
  33. 33.
    Brandstätter A, Parson W (2003) Mitochondrial DNA heteroplasmy or artefacts—a matter of the amplification strategy? Int J Legal Med 117:180–184PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Anita Brandstätter
    • 1
  • Harald Niederstätter
    • 1
  • Walther Parson
    • 1
  1. 1.Institute of Legal MedicineUniversity of Innsbruck InnsbruckAustria

Personalised recommendations