BMC Biol.: co-auth.: A.Reymond

BMC Biol. 2023 May 8;21(1):103. doi: 10.1186/s12915-023-01606-1.

Secondary structure of the human mitochondrial genome affects formation of deletions

Victor Shamanskiy # 1Alina A Mikhailova # 1Evgenii O Tretiakov # 2Kristina Ushakova # 1Alina G Mikhailova # 1 3Sergei Oreshkov 1Dmitry A Knorre 4Natalia Ree 1Jonathan B Overdevest 5Samuel W Lukowski 6Irina Gostimskaya 7 8Valerian Yurov 1Chia-Wei Liou 9Tsu-Kung Lin 9Wolfram S Kunz 10 11Alexandre Reymond 12 13Ilya Mazunin 14Georgii A Bazykin 14 15Jacques Fellay 16Masashi Tanaka 17 18 19Konstantin Khrapko 20Konstantin Gunbin 1 21Konstantin Popadin 22 23 24


Background: Aging 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.

Results: By 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.

Conclusions: Overall, 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.

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