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.

Correction to: ImtRDB: a database and software for mitochondrial imperfect interspersed repeats annotation.

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ImtRDB: a database and software for mitochondrial imperfect interspersed repeats annotation.

BACKGROUND: Mitochondria is a powerhouse of all eukaryotic cells that have its own circular DNA (mtDNA) encoding various RNAs and proteins. Somatic perturbations of mtDNA are accumulating with age thus it is of great importance to uncover the main sources of mtDNA instability. Recent analyses demonstrated that somatic mtDNA deletions depend on imperfect repeats of various nature between distant mtDNA segments. However, till now there are no comprehensive databases annotating all types of imperfect repeats in numerous species with sequenced complete mitochondrial genome as well as there are no algorithms capable to call all types of imperfect repeats in circular mtDNA. RESULTS: We implemented naïve algorithm of pattern recognition by analogy to standard dot-plot construction procedures allowing us to find both perfect and imperfect repeats of four main types: direct, inverted, mirror and complementary. Our algorithm is adapted to specific characteristics of mtDNA such as circularity and an excess of short repeats - it calls imperfect repeats starting from the length of 10 b.p. We constructed interactive web available database ImtRDB depositing perfect and imperfect repeats positions in mtDNAs of more than 3500 Vertebrate species. Additional tools, such as visualization of repeats within a genome, comparison of repeat densities among different genomes and a possibility to download all results make this database useful for many biologists. Our first analyses of the database demonstrated that mtDNA imperfect repeats (i) are usually short; (ii) associated with unfolded DNA structures; (iii) four types of repeats positively correlate with each other forming two equivalent pairs: direct and mirror versus inverted and complementary, with identical nucleotide content and similar distribution between species; (iv) abundance of repeats is negatively associated with GC content; (v) dinucleotides GC versus CG are overrepresented on light chain of mtDNA covered by repeats. CONCLUSIONS: ImtRDB is available at http://bioinfodbs.kantiana.ru/ImtRDB/ . It is accompanied by the software calling all types of interspersed repeats with different level of degeneracy in circular DNA. This database and software can become a very useful tool in various areas of mitochondrial and chloroplast DNA research.

Purifying selection in mammalian mitochondrial protein-coding genes is highly effective and congruent with evolution of nuclear genes.

The mammalian mitochondrial genomes differ from the nuclear genomes by maternal inheritance, absence of recombination, and higher mutation rate. All these differences decrease the effective population size of mitochondrial genome and make it more susceptible to accumulation of slightly deleterious mutations. It was hypothesized that mitochondrial genes, especially in species with low effective population size, irreversibly degrade leading to decrease of organismal fitness and even to extinction of species through the mutational meltdown. To interrogate this hypothesis, we compared the purifying selections acting on the representative set of mitochondrial (potentially degrading) and nuclear (potentially not degrading) protein-coding genes in species with different effective population size. For 21 mammalian species, we calculated the ratios of accumulation of slightly deleterious mutations approximated by Kn/Ks separately for mitochondrial and nuclear genomes. The 75% of variation in Kn/Ks is explained by two independent variables: type of a genome (mitochondrial or nuclear) and effective population size of species approximated by generation time. First, we observed that purifying selection is more effective in mitochondria than in the nucleus that implies strong evolutionary constraints of mitochondrial genome. Mitochondrial de novo nonsynonymous mutations have at least 5-fold more harmful effect when compared with nuclear. Second, Kn/Ks of mitochondrial and nuclear genomes is positively correlated with generation time of species, indicating relaxation of purifying selection with decrease of species-specific effective population size. Most importantly, the linear regression lines of mitochondrial and nuclear Kn/Ks's from generation times of species are parallel, indicating congruent relaxation of purifying selection in both genomes. Thus, our results reveal that the distribution of selection coefficients of de novo nonsynonymous mitochondrial mutations has a similar shape with the distribution of de novo nonsynonymous nuclear mutations, but its mean is five times smaller. The harmful effect of mitochondrial de novo nonsynonymous mutations triggers highly effective purifying selection, which maintains the fitness of the mammalian mitochondrial genome.

Repeats, longevity and the sources of mtDNA deletions: evidence from 'deletional spectra'.

Perfect direct repeats and, in particular, the prominent 13 bp repeat, are thought to cause mitochondrial DNA (mtDNA) deletions, which have been associated with the aging process. Accordingly, individuals lacking the 13 bp repeat are highly prevalent among centenarians and overall number of perfect repeats in mammalian mitochondrial genomes negatively correlates with species' longevity. However, detailed examination of the distribution of mtDNA deletions challenges a special role of the 13 bp repeat in generating mtDNA deletions. Instead, deletions appear to depend on long and stable, albeit imperfect, duplexes between distant mtDNA segments. Furthermore, significant dissimilarities in breakpoint distributions suggest that multiple mechanisms are involved in creating mtDNA deletions.

A manually curated database of tetrapod mitochondrially encoded tRNA sequences and secondary structures.

BACKGROUND: Mitochondrial tRNAs have been the subject of study for structural biologists interested in their secondary structure characteristics, evolutionary biologists have researched patterns of compensatory and structural evolution and medical studies have been directed towards understanding the basis of human disease. However, an up to date, manually curated database of mitochondrially encoded tRNAs from higher animals is currently not available. DESCRIPTION: We obtained the complete mitochondrial sequence for 277 tetrapod species from GenBank and re-annotated all of the tRNAs based on a multiple alignment of each tRNA gene and secondary structure prediction made independently for each tRNA. The mitochondrial (mt) tRNA sequences and the secondary structure based multiple alignments are freely available as Supplemental Information online. CONCLUSION: We compiled a manually curated database of mitochondrially encoded tRNAs from tetrapods with completely sequenced genomes. In the course of our work, we reannotated more than 10% of all tetrapod mt-tRNAs and subsequently predicted the secondary structures of 6060 mitochondrial tRNAs. This carefully constructed database can be utilized to enhance our knowledge in several different fields including the evolution of mt-tRNA secondary structure and prediction of pathogenic mt-tRNA mutations. In addition, researchers reporting novel mitochondrial genome sequences should check their tRNA gene annotations against our database to ensure a higher level of fidelity of their annotation.