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Universal heteroplasmy of human mitochondrial DNA

Lookup NU author(s): Dr Brendan Payne, Dr Ian Wilson, Dr Patrick Yu Wai Man, Dr Jonathan Coxhead, Professor David Deehan, Professor Rita Horvath, Professor Robert Taylor, Dr Mauro Santibanez Koref, Professor Patrick Chinnery

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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 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.


Publication metadata

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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