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Lookup NU author(s): Dr Charlotte Alston, Professor Grainne Gorman, Emeritus Professor Doug Turnbull, Professor Bobby McFarlandORCiD, Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2020 The Author(s).Background: Acquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease. Results: To 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. Conclusions: These patterns implicate replication by DNA polymerase γas 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.
Author(s): Lujan SA, Longley MJ, Humble MH, Lavender CA, Burkholder A, Blakely EL, Alston CL, Gorman GS, Turnbull DM, McFarland R, Taylor RW, Kunkel TA, Copeland WC
Publication type: Article
Publication status: Published
Journal: Genome Biology
Year: 2020
Volume: 21
Issue: 1
Online publication date: 17/09/2020
Acceptance date: 07/08/2020
Date deposited: 20/11/2020
ISSN (print): 1474-7596
ISSN (electronic): 1474-760X
Publisher: BioMed Central Ltd
URL: https://doi.org/10.1186/s13059-020-02138-5
DOI: 10.1186/s13059-020-02138-5
Data Access Statement: https://doi.org/10.5281/zenodo.3966359
PubMed id: 32943091
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