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Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging

  • Lujan, Scott A.1
  • Longley, Matthew J.1
  • Humble, Margaret H.1
  • Lavender, Christopher A.1
  • Burkholder, Adam1
  • Blakely, Emma L.2, 3
  • Alston, Charlotte L.2, 3
  • Gorman, Grainne S.2
  • Turnbull, Doug M.2
  • McFarland, Robert2
  • Taylor, Robert W.2, 3
  • Kunkel, Thomas A.1
  • Copeland, William C.1
  • 1 National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA , Research Triangle Park (United States)
  • 2 Newcastle University, Newcastle upon Tyne, NE2 4HH, UK , Newcastle upon Tyne (United Kingdom)
  • 3 Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK , Newcastle upon Tyne (United Kingdom)
Published Article
Publication Date
Sep 17, 2020
DOI: 10.1186/s13059-020-02138-5
Springer Nature


BackgroundAcquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease.ResultsTo decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns.ConclusionsThese patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.

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