Secondary structure of the human mitochondrial genome affects formation of deletions.

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.

A mitochondria-specific mutational signature of aging: increased rate of A > G substitutions on the heavy strand.

The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria are responsible for aerobic respiration, it is expected that mtDNA mutational spectrum is affected by oxidative damage. Assuming that oxidative damage increases with age, we analyse mtDNA mutagenesis of different species in regards to their generation length. Analysing, (i) dozens of thousands of somatic mtDNA mutations in samples of different ages (ii) 70053 polymorphic synonymous mtDNA substitutions reconstructed in 424 mammalian species with different generation lengths and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH > GH substitutions (H: heavy strand notation) is twice bigger in species with high versus low generation length making their mtDNA more AH poor and GH rich. Considering that AH > GH substitutions are also sensitive to the time spent single-stranded (TSSS) during asynchronous mtDNA replication we demonstrated that AH > GH substitution rate is a function of both species-specific generation length and position-specific TSSS. We propose that AH > GH is a mitochondria-specific signature of oxidative damage associated with both aging and TSSS.

Survey of Barbell Trajectory and Kinematics of the Snatch Lift from the 2015 World and 2017 Pan-American Weightlifting Championships.

Analysis of elite performances is important to elucidate the characteristics of effective weightlifting technique contributing to the highest level of achievement. The general technique of the weightlifting movements is well established. However, it is also apparent that weightlifting technique can differ based on athlete characteristics. Thus, existing technical models may not accurately reflect current technique of top performers or be applied generically to athletes of different skill, size, sex, or ability. Therefore, the purpose of this descriptive study was to update the scientific knowledge of snatch technique of top international weightlifters. This study used video analysis to determine barbell trajectory and kinematics of 319 successful snatch attempts from two major international competitions. Relative frequencies of barbell trajectory types differed based on competition, sex, category, and ranking. No statistical differences were observed among the top-three performers for either sex for most kinematic variables, and there were no overall discernible patterns of effect size differences for individual or clusters of kinematic variables. The results of this study indicate that weightlifting success can be achieved with a variety of technique profiles.

mtProtEvol: the resource presenting molecular evolution analysis of proteins involved in the function of Vertebrate mitochondria.

BACKGROUND: Heterotachy is the variation in the evolutionary rate of aligned sites in different parts of the phylogenetic tree. It occurs mainly due to epistatic interactions among the substitutions, which are highly complex and make it difficult to study protein evolution. The vast majority of computational evolutionary approaches for studying these epistatic interactions or their evolutionary consequences in proteins require high computational time. However, recently, it has been shown that the evolution of residue solvent accessibility (RSA) is tightly linked with changes in protein fitness and intra-protein epistatic interactions. This provides a computationally fast alternative, based on comparison of evolutionary rates of amino acid replacements with the rates of RSA evolutionary changes in order to recognize any shifts in epistatic interaction. RESULTS: Based on RSA information, data randomization and phylogenetic approaches, we constructed a software pipeline, which can be used to analyze the evolutionary consequences of intra-protein epistatic interactions with relatively low computational time. We analyzed the evolution of 512 protein families tightly linked to mitochondrial function in Vertebrates and created "mtProtEvol", the web resource with data on protein evolution. In strict agreement with lifespan and metabolic rate data, we demonstrated that different functional categories of mitochondria-related proteins subjected to selection on accelerated and decelerated RSA rates in rodents and primates. For example, accelerated RSA evolution in rodents has been shown for Krebs cycle enzymes, respiratory chain and reactive oxygen species metabolism, while in primates these functions are stress-response, translation and mtDNA integrity. Decelerated RSA evolution in rodents has been demonstrated for translational machinery and oxidative stress response components. CONCLUSIONS: mtProtEvol is an interactive resource focused on evolutionary analysis of epistatic interactions in protein families involved in Vertebrata mitochondria function and available at http://bioinfodbs.kantiana.ru/mtProtEvol /. This resource and the devised software pipeline may be useful tool for researchers in area of protein evolution.