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Lookup NU author(s): Dr Brendan PayneORCiD, Dr Ian Wilson, Dr Patrick Yu Wai Man, Dr Jonathan Coxhead, Professor David Deehan, Professor Rita HorvathORCiD, Professor Robert Taylor, Dr Mauro Santibanez Koref, Professor Patrick Chinnery
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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 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.
Author(s): Payne BAI, Wilson IJ, Yu-Wai-Man P, Coxhead J, Deehan D, Horvath R, Taylor RW, Samuels DC, Santibanez-Koref M, Chinnery PF
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Year: 2012
Volume: 22
Issue: 2
Pages: 384-390
Print publication date: 16/10/2012
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/hmg/dds435
DOI: 10.1093/hmg/dds435
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