Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck

Ian J. Wilson, Phillipa J. Carling, Charlotte L. Alston, Vasileios I. Floros, Angela Pyle, Gavin Hudson, Suzanne C E H Sallevelt, Costanza Lamperti, Valerio Carelli, L. A. Bindoff, David C. Samuels, Passorn Wonnapinij, Massimo Zeviani, R. W. Taylor, H. J M Smeets, Rita Horvath, Patrick F. Chinnery

Research output: Contribution to journalArticle

Abstract

With a combined carrier frequency of 1:200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in ~1:5000 of the population. Rapid shifts in the level of heteroplasmy seen within a single generation contribute to the wide range in the severity of clinical phenotypes seen in families transmitting mtDNA disease, consistent with a genetic bottleneck during transmission. Although preliminary evidence from human pedigrees points towards a random drift process underlying the shifting heteroplasmy, some reports describe differences in segregation pattern between different mtDNA mutations. However, based on limited observations and with no direct comparisons, it is not clear whether these observations simply reflect pedigree ascertainment and publication bias. To address this issue, we studied 577 mother-child pairs transmitting the m.11778G > A, m.3460G > A, m.8344A > G, m.8993T > G/C and m.3243A > G mtDNA mutations. Our analysis controlled for inter-assay differences, inter-laboratory variation and ascertainment bias. We found no evidence of selection during transmission but show that different mtDNA mutations segregate at different rates in human pedigrees. m.8993T > G/C segregated significantly faster than m.11778G > A, m.8344A > G and m.3243A > G, consistent with a tighter mtDNA genetic bottleneck in m.8993T > G/C pedigrees. Our observations support the existence of different genetic bottlenecks primarily determined by the underlying mtDNA mutation, explaining the different inheritance patterns observed in human pedigrees transmitting pathogenic mtDNA mutations.

Original languageEnglish
Pages (from-to)1031-1041
Number of pages11
JournalHuman Molecular Genetics
Volume25
Issue number5
DOIs
Publication statusPublished - Mar 1 2016

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Mitochondrial DNA
Pedigree
Mutation
Publication Bias
Mitochondrial Diseases
Inheritance Patterns
Mothers
Phenotype
Population

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Wilson, I. J., Carling, P. J., Alston, C. L., Floros, V. I., Pyle, A., Hudson, G., ... Chinnery, P. F. (2016). Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck. Human Molecular Genetics, 25(5), 1031-1041. https://doi.org/10.1093/hmg/ddv626

Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck. / Wilson, Ian J.; Carling, Phillipa J.; Alston, Charlotte L.; Floros, Vasileios I.; Pyle, Angela; Hudson, Gavin; Sallevelt, Suzanne C E H; Lamperti, Costanza; Carelli, Valerio; Bindoff, L. A.; Samuels, David C.; Wonnapinij, Passorn; Zeviani, Massimo; Taylor, R. W.; Smeets, H. J M; Horvath, Rita; Chinnery, Patrick F.

In: Human Molecular Genetics, Vol. 25, No. 5, 01.03.2016, p. 1031-1041.

Research output: Contribution to journalArticle

Wilson, IJ, Carling, PJ, Alston, CL, Floros, VI, Pyle, A, Hudson, G, Sallevelt, SCEH, Lamperti, C, Carelli, V, Bindoff, LA, Samuels, DC, Wonnapinij, P, Zeviani, M, Taylor, RW, Smeets, HJM, Horvath, R & Chinnery, PF 2016, 'Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck', Human Molecular Genetics, vol. 25, no. 5, pp. 1031-1041. https://doi.org/10.1093/hmg/ddv626
Wilson IJ, Carling PJ, Alston CL, Floros VI, Pyle A, Hudson G et al. Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck. Human Molecular Genetics. 2016 Mar 1;25(5):1031-1041. https://doi.org/10.1093/hmg/ddv626
Wilson, Ian J. ; Carling, Phillipa J. ; Alston, Charlotte L. ; Floros, Vasileios I. ; Pyle, Angela ; Hudson, Gavin ; Sallevelt, Suzanne C E H ; Lamperti, Costanza ; Carelli, Valerio ; Bindoff, L. A. ; Samuels, David C. ; Wonnapinij, Passorn ; Zeviani, Massimo ; Taylor, R. W. ; Smeets, H. J M ; Horvath, Rita ; Chinnery, Patrick F. / Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 5. pp. 1031-1041.
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