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

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.

Publication metadata

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


DOI: 10.1186/s13059-020-02138-5

PubMed id: 32943091


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Funder referenceFunder name
Medical Research Council
Wellcome Centre for Mitochondrial Research (203105/Z/16/Z),