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 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.
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastleupon-Tyne NE1 3BZ, UK.
Brendan A I
BA
Payne
Ian J
IJ
Wilson
Patrick
P
Yu-Wai-Man
Jonathan
J
Coxhead
David
D
Deehan
Rita
R
Horvath
Robert W
RW
Taylor
David C
DC
Samuels
Mauro
M
Santibanez-Koref
Patrick F
PF
Chinnery
D019295:Computational Biology; D004272:DNA, Mitochondrial / Q000235:genetics*; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D040582:Inheritance Patterns; D018482:Muscle, Skeletal
D004272:DNA, Mitochondrial