Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase γ.

Autor: Samstag CL; Molecular and Cellular Biology Program, University of Washington, Seattle, WA, United States of America.; Department of Genome Sciences, University of Washington, Seattle, WA, United States of America., Hoekstra JG; Department of Pathology, University of Washington, Seattle, WA, United States of America., Huang CH; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States of America., Chaisson MJ; Computational Biology and Bioinformatics, University of Southern California, Los Angeles, CA, United States of America., Youle RJ; Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States of America., Kennedy SR; Department of Pathology, University of Washington, Seattle, WA, United States of America., Pallanck LJ; Department of Genome Sciences, University of Washington, Seattle, WA, United States of America.
Jazyk: angličtina
Zdroj: PLoS genetics [PLoS Genet] 2018 Nov 19; Vol. 14 (11), pp. e1007805. Date of Electronic Publication: 2018 Nov 19 (Print Publication: 2018).
DOI: 10.1371/journal.pgen.1007805
Abstrakt: Mitochondrial DNA (mtDNA) mutations cause severe maternally inherited syndromes and the accumulation of somatic mtDNA mutations is implicated in aging and common diseases. However, the mechanisms that influence the frequency and pathogenicity of mtDNA mutations are poorly understood. To address this matter, we created a Drosophila mtDNA mutator strain expressing a proofreading-deficient form of the mitochondrial DNA polymerase. Mutator flies have a dramatically increased somatic mtDNA mutation frequency that correlates with the dosage of the proofreading-deficient polymerase. Mutator flies also exhibit mitochondrial dysfunction, shortened lifespan, a progressive locomotor deficit, and loss of dopaminergic neurons. Surprisingly, the frequency of nonsynonymous, pathogenic, and conserved-site mutations in mutator flies exceeded predictions of a neutral mutational model, indicating the existence of a positive selection mechanism that favors deleterious mtDNA variants. We propose from these findings that deleterious mtDNA mutations are overrepresented because they selectively evade quality control surveillance or because they are amplified through compensatory mitochondrial biogenesis.
Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SRK is a paid consultant and equity holder of TwinStrand BioSciences Inc; SRK has a submitted two patent applications concerning methods to detect low frequency mutations; SRK is the recipient of patent royalty payments concerning Duplex Sequencing.
Databáze: MEDLINE
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