Secondary structure of the human mitochondrial genome affects formation of deletions

BMC Biology

Research Article

Dmitry A. Knorre¹  Alexandre Reymond²  Sergei Oreshkov³  Victor Shamanskiy³  Alina A. Mikhailova³  Natalia Ree³  Kristina Ushakova³  Valerian Yurov³  Konstantin Gunbin⁴  Konstantin Popadin⁵  Alina G. Mikhailova⁶  Ilya Mazunin⁷  Georgii A. Bazykin⁸  Masashi Tanaka⁹  Evgenii O. Tretiakov^1,10  Tsu-Kung Lin^1,11  Chia-Wei Liou^1,11  Jonathan B. Overdevest^1,12  Wolfram S. Kunz^1,13  Jacques Fellay^1,14  Samuel W. Lukowski^1,15  Irina Gostimskaya^1,16  Konstantin Khrapko^1,17 

[1] Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russian Federation;Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland;Swiss Institute of Bioinformatics, Lausanne, Switzerland;Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russia;Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russia;Institute of Molecular and Cellular Biology SB RAS, Novosibirsk, Russia;Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russia;Swiss Institute of Bioinformatics, Lausanne, Switzerland;Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland;Center for Mitochondrial Functional Genomics, Immanuel Kant Baltic Federal University, Kaliningrad, Russia;Vavilov Institute of General Genetics RAS, Moscow, Russia;Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, Russia;Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, Russia;Laboratory of Molecular Evolution, Institute for Information Transmission Problems (Kharkevich Institute) of the Russian Academy of Sciences, Moscow, Russia;Department for Health and Longevity Research, National Institutes of Biomedical Innovation, Health and Nutrition, 1-23-1 Toyama, Shinjuku-Ku, 162-8636, Tokyo, Japan;Department of Neurology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, 113-8421, Tokyo, Japan;Department of Clinical Laboratory, IMS Miyoshi General Hospital, Fujikubo, Miyoshi-Machi, 974-3354-0041, Iruma, Saitama Prefecture, Japan;Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria;Department of Neurology, Kaohsiung Chang-Gung Memorial Hospital and Chang-Gung University, Kaohsiung, Taiwan;Department of Otolaryngology, Columbia University Irving Medical Center, New York, USA;Division of Neurochemistry, Department of Experimental Epileptology and Cognition Research, University Bonn, Bonn, Germany;Department of Epileptology, University Hospital of Bonn, Bonn, Germany;Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland;Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Australia;Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK;Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK;Northeastern University, Boston, MA, USA;

关键词: Mitochondrial DNA;    Deletions;    Aging;    Single-stranded DNA;    Global secondary structure;    Contact zone;    Direct repeats;    Inverted repeats;    mtDNA replication;   

DOI  :  10.1186/s12915-023-01606-1

 received in 2022-06-17, accepted in 2023-04-19,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions.ResultsBy analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a “hot spot” where one deletion breakpoint occurred within the region of 6–9 kb and another within 13–16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6–9 kb and 13–16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470–8482 bp (base pair) and a second arm at 13,447–13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging.ConclusionsOverall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.

【 授权许可】

CC BY   
© The Author(s) 2023

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