Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck.

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Wilson, Ian J 
Carling, Phillipa J 
Alston, Charlotte L 
Floros, Vasileios I 
Pyle, Angela 

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.

Bayes Theorem, Child, DNA, Mitochondrial, Female, Humans, Inheritance Patterns, Mitochondrial Diseases, Models, Genetic, Pedigree, Phenotype, Point Mutation, Polymorphism, Restriction Fragment Length, Publication Bias
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Hum Mol Genet
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Oxford University Press (OUP)
Wellcome Trust (101876/Z/13/Z)
Medical Research Council (MC_UP_1002/1)
European Research Council (322424)
P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science (101876/Z/13/Z), and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UP_1501/2), the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Muscle Disease research (G0601943), EU FP7 TIRCON, and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. R.H. is supported by the European Research Council (309548). P.F.C. and R.H. are supported by the Mitochondrial European Educational Training, ITN Marie Curie People (317433). R.W.T. also receives support from The Lily Foundation and the UK NHS Specialist Commissioners, which funds the ‘Rare Mitochondrial Disorders of Adults and Children’ Diagnostic Service in Newcastle upon Tyne. C.L.A. is the recipient of an NIHR doctoral fellowship (NIHR-HCS-D12-03-04). We acknowledge the ‘Cell lines and DNA Bank of Paediatric Movement Disorders and Neurodegenerative Diseases’ of the Telethon Network of Genetic Biobanks (grant GTB12001J) and the EurobiobanK Network. This work was supported by the Medical Research Council, the Pierfranco and Luisa Mariani Foundation, Telethon Grant GGP11011 and ERC Advanced Grant FP7-322424. The publication is the work of the authors, and Patrick Chinnery will serve as guarantor for the contents of this paper.