Deciphering the Foundations of Mitochondrial Mutational Spectra: Replication-Driven and Damage-Induced Signatures Across Chordate Classes
Iliushchenko D. Efimenko B. Mikhailova A.G. Shamanskiy V. Saparbaev M.K. Matkarimov B.T. Mazunin I. Voronka A. Knorre D. Kunz W.S. Kapranov P. Denisov S. Fellay J. Khrapko K. Gunbin K. Popadin K.
1 February 2025Oxford University Press
Molecular Biology and Evolution
2025#42Issue 2
Mitochondrial DNA (mtDNA) mutagenesis remains poorly understood despite its crucial role in disease, aging, and evolutionary tracing. In this study, we reconstructed a comprehensive 192-component mtDNA mutational spectrum for chordates by analyzing 118,397 synonymous mutations in the CytB gene across 1,697 species and five classes. This analysis revealed three primary forces shaping mtDNA mutagenesis: (i) symmetrical, replication-driven errors by mitochondrial polymerase (POLG), resulting in C > T and A > G mutations that are highly conserved across classes; (ii) asymmetrical, damage-driven C > T mutations on the single-stranded heavy strand with clock-like dynamics; and (iii) asymmetrical A > G mutations on the heavy strand, with dynamics suggesting sensitivity to oxidative damage. The third component, sensitive to oxidative damage, positions mtDNA mutagenesis as a promising marker for metabolic and physiological processes across various classes, species, organisms, tissues, and cells. The deconvolution of the mutational spectra into mutational signatures uncovered deficiencies in both base excision repair (BER) and mismatch repair (MMR) pathways. Further analysis of mutation hotspots, abasic sites, and mutational asymmetries underscores the critical role of single-stranded DNA damage (components ii and iii), which, uncorrected due to BER and MMR deficiencies, contributes roughly as many mutations as POLG-induced errors (component i).
mitochondria , mutational spectrum , neutral evolution , phylogenetics
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Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation
Groupe “Mechanisms of DNA Repair and Carcinogenesis”, CNRS UMR9019, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
National Laboratory Astana, Nazarbayev University, Astana, Kazakhstan
Faculty of Information Technologies, L.N. Gumilyov Eurasian National University, Astana, Kazakhstan
Department of Biology and Genetics, Petrovsky Medical University, Moscow, Russian Federation
Research Centre for Medical Genetics, Moscow, Russian Federation
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russian Federation
Department of Epileptology, Institute of Experimental Epileptology and Cognition Research, University Bonn Medical Center, Bonn, Germany
School of Life Sciences, Xiamen University, Xiamen, China
Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Department of Biology, Northeastern University, Boston, MA, United States
Institute of Molecular and Cellular Biology SB RAS, Novosibirsk, Russian Federation
Center for Mitochondrial Functional Genomics
Groupe “Mechanisms of DNA Repair and Carcinogenesis”
National Laboratory Astana
Faculty of Information Technologies
Department of Biology and Genetics
Research Centre for Medical Genetics
Belozersky Institute of Physico-Chemical Biology
Department of Epileptology
School of Life Sciences
Faculty of Biology
School of Life Sciences
Department of Biology
Institute of Molecular and Cellular Biology SB RAS
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