anciendaze
Senior Member
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While there are many indications something weird is going on with mitochondria in ME/CFS there have been real problems pinning down what is going wrong. In many ways we seem to age suddenly in response to a minor infection. This paper on more general characteristic of mitochondrial genetics, and not just inherited genes, seems relevant to the problem. All mitochondria are not equal.
Universal heteroplasmy of human mitochondrial DNA
- Brendan A.I. Payne1,
- Ian J. Wilson1,
- Patrick Yu-Wai-Man1,
- Jonathan Coxhead1,
- David Deehan2,
- Rita Horvath1,
- Robert W. Taylor3,
- David C. Samuels4,
- Mauro Santibanez-Koref1 and
- Patrick F. Chinnery1,*
- 1Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne NE1 3BZ, UK
- 2Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK
- 3Institute for Ageing and Health, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK and
- 4Centre for Human Genetics Research, Vanderbilt University, Nashville, TN 37232, USA
- ↵*To whom correspondence should be addressed at: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ, UK. Tel: +44 1912418835; Email: patrick.chinnery{at}ncl.ac.uk, p.f.chinnery{at}ncl.ac.uk
- Received July 12, 2012.
- Accepted October 8, 2012.
Abstract
Mammalian cells contain thousands of copies of mitochondrial DNA (mtDNA). At birth, these are thought to be identical in most humans. Here, we use long read length ultra-deep resequencing-by-synthesis to interrogate regions of the mtDNA genome from related and unrelated individuals at unprecedented resolution. We show that very low-level heteroplasmic variance is present in all tested healthy individuals, and is likely to be due to both inherited and somatic single base substitutions. Using this approach, we demonstrate an increase in mtDNA mutations in the skeletal muscle of patients with a proofreading-deficient mtDNA polymerase γ due to POLG mutations. In contrast, we show that OPA1 mutations, which indirectly affect mtDNA maintenance, do not increase point mutation load. The demonstration of universal mtDNA heteroplasmy has fundamental implications for our understanding of mtDNA inheritance and evolution. Ostensibly de novo somatic mtDNA mutations, seen in mtDNA maintenance disorders and neurodegenerative disease and aging, will partly be due to the clonal expansion of low-level inherited variants.