Universal heteroplasmy of human mitochondrial DNA

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...

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Bibliographic Details
Published in:	Human molecular genetics 2013-01, Vol.22 (2), p.384-390
Main Authors:	Payne, Brendan A I, Wilson, Ian J, Yu-Wai-Man, Patrick, Coxhead, Jonathan, Deehan, David, Horvath, Rita, Taylor, Robert W, Samuels, David C, Santibanez-Koref, Mauro, Chinnery, Patrick F
Format:	Article
Language:	eng
Subjects:	Aging Computational Biology DNA, Mitochondrial - genetics Evolution Genetic Variation Genomes Heredity heteroplasmy High-Throughput Nucleotide Sequencing Humans Inheritance Patterns Mammalian cells Mitochondrial DNA Muscle, Skeletal Neurodegenerative diseases Point mutation Skeletal muscle
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Summary:	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.
ISSN:	0964-6906 1460-2083