Evaluating Length Heteroplasmy in the Human Mitochondrial DNA Control Region

Overview

Journal Int J Legal Med

Specialty Forensic Sciences

Date 2009 Nov 26

PMID 19937256

Citations 12

Authors

Lucy Forster

Peter Forster

Susan M R Gurney

Matthew Spencer

Christopher Huang

Arne Rohl

Bernd Brinkmann

Affiliations

Soon will be listed here.

Abstract

We present allelic data for three known and one new C-tract in the human mitochondrial DNA (mtDNA) control region, and we measure intergenerational mutation rates at such C-tracts. In detail, in a sample of 1,172 mtDNA sequences, we demonstrate the existence of an instability threshold of eight consecutive cytosines, at and above which the phenomenon of length heteroplasmy arises. To determine mutation rates, we draw on mtDNA sequences in up to four generations of 248 pedigrees for families living in high or low-radiation environmental conditions. The high-radiation sample gives the most conservative (fastest) mutation rate likely to be encountered in any forensic context. We find that the C-tract mutation rate is up to 6% per generation, and we observe an excess of cytosine gains over losses. Case studies and guidelines for evaluating mtDNA heteroplasmy are provided.

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References

Huhne J, Pfeiffer H, Brinkmann B . Heteroplasmic substitutions in the mitochondrial DNA control region in mother and child samples. Int J Legal Med. 1999; 112(1):27-30. DOI: 10.1007/s004140050193. View

Bendall K, Sykes B . Length heteroplasmy in the first hypervariable segment of the human mtDNA control region. Am J Hum Genet. 1995; 57(2):248-56. PMC: 1801530. View

Anderson S, Bankier A, Barrell B, de Bruijn M, Coulson A, Drouin J . Sequence and organization of the human mitochondrial genome. Nature. 1981; 290(5806):457-65. DOI: 10.1038/290457a0. View

Fish J, Raule N, Attardi G . Discovery of a major D-loop replication origin reveals two modes of human mtDNA synthesis. Science. 2004; 306(5704):2098-101. DOI: 10.1126/science.1102077. View

Bandelt H, Parson W . Consistent treatment of length variants in the human mtDNA control region: a reappraisal. Int J Legal Med. 2007; 122(1):11-21. DOI: 10.1007/s00414-006-0151-5. View

Forster L, Forster P, Lutz-Bonengel S, Willkomm H, Brinkmann B . Natural radioactivity and human mitochondrial DNA mutations. Proc Natl Acad Sci U S A. 2002; 99(21):13950-4. PMC: 129803. DOI: 10.1073/pnas.202400499. View

Torroni A, Lott M, Cabell M, Chen Y, Lavergne L, Wallace D . 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. 1994; 55(4):760-76. PMC: 1918284. View

Santos C, Sierra B, Alvarez L, Ramos A, Fernandez E, Nogues R . Frequency and pattern of heteroplasmy in the control region of human mitochondrial DNA. J Mol Evol. 2008; 67(2):191-200. DOI: 10.1007/s00239-008-9138-9. View

Lutz-Bonengel S, Sanger T, Pollak S, Szibor R . Different methods to determine length heteroplasmy within the mitochondrial control region. Int J Legal Med. 2004; 118(5):274-81. DOI: 10.1007/s00414-004-0457-0. View

10.

Chung U, Lee H, Yoo J, Park M, Shin K . Mitochondrial DNA CA dinucleotide repeats in Koreans: the presence of length heteroplasmy. Int J Legal Med. 2004; 119(1):50-3. DOI: 10.1007/s00414-004-0487-7. View

11.

Gill P, Ivanov P, Kimpton C, Piercy R, Benson N, Tully G . Identification of the remains of the Romanov family by DNA analysis. Nat Genet. 1994; 6(2):130-5. DOI: 10.1038/ng0294-130. View

12.

Marchington D, Macaulay V, Hartshorne G, Barlow D, Poulton J . Evidence from human oocytes for a genetic bottleneck in an mtDNA disease. Am J Hum Genet. 1998; 63(3):769-75. PMC: 1377397. DOI: 10.1086/302009. View

13.

Irwin J, Saunier J, Niederstatter H, Strouss K, Sturk K, Diegoli T . Investigation of heteroplasmy in the human mitochondrial DNA control region: a synthesis of observations from more than 5000 global population samples. J Mol Evol. 2009; 68(5):516-27. DOI: 10.1007/s00239-009-9227-4. View

14.

Ivanov P, Wadhams M, Roby R, Holland M, Weedn V, Parsons T . Mitochondrial DNA sequence heteroplasmy in the Grand Duke of Russia Georgij Romanov establishes the authenticity of the remains of Tsar Nicholas II. Nat Genet. 1996; 12(4):417-20. DOI: 10.1038/ng0496-417. View

15.

Pfeiffer H, Lutz-Bonengel S, Pollak S, Fimmers R, Baur M, Brinkmann B . Mitochondrial DNA control region diversity in hairs and body fluids of monozygotic triplets. Int J Legal Med. 2003; 118(2):71-4. DOI: 10.1007/s00414-003-0409-0. View

16.

Chang D, Clayton D . Priming of human mitochondrial DNA replication occurs at the light-strand promoter. Proc Natl Acad Sci U S A. 1985; 82(2):351-5. PMC: 397036. DOI: 10.1073/pnas.82.2.351. View

17.

Lacan M, Theves C, Amory S, Keyser C, Crubezy E, Salles J . Detection of the A189G mtDNA heteroplasmic mutation in relation to age in modern and ancient bones. Int J Legal Med. 2008; 123(2):161-7. DOI: 10.1007/s00414-008-0266-y. View

18.

Rohl A, Brinkmann B, Forster L, Forster P . An annotated mtDNA database. Int J Legal Med. 2001; 115(1):29-39. DOI: 10.1007/s004140100217. View