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Lookup NU author(s): Dr Ian Wilson, Pip Carling, Dr Charlotte Alston, Vasileios Floros, Dr Angela Pyle, Professor Gavin Hudson, Professor Laurence Bindoff, Professor David Samuels, Professor Robert Taylor, Professor Rita HorvathORCiD, Professor Patrick Chinnery
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
With a combined carrier frequency of 1:200, heteroplasmic mitochondrial DNA (mtDNA) mutations cause human disease in similar to 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.
Author(s): 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
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 2016
Volume: 25
Issue: 5
Pages: 1031-1041
Print publication date: 01/01/2016
Online publication date: 05/01/2016
Acceptance date: 22/12/2015
Date deposited: 12/05/2016
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/hmg/ddv626
DOI: 10.1093/hmg/ddv626
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