Konstantin Vladimirovich Gunbin

Cutaneous melanoma and basal cell carcinoma (BCC) represent the two primary malignancies driven by solar ultraviolet (UV) radiation. To map the spatial topology and distance dependence of their mutational signatures, we deployed new analytical bioinformatics workflow utilizing two convergent strategies: a data-driven read-level phasing framework to discriminate between collateral mutational events versus independent ones and a hypothesis-driven spatial permutational simulation model to capture density-dependent local deviations. A whole-genome analysis employing this framework unexpectedly reveals two fundamentally distinct lesion-processing landscapes, present in both BCC and melanoma. While independent mutations consistently reproduce canonical UV signatures (SBS7a–c) in both tumor types, collateral mutations tell a distinct and more varied narrative between BCC and melanoma. These collateral mutations are unusually abundant for non-UV characteristics, such as age-related SBS1 and SBS5, and display a notable 3′ to 5′ asymmetry near UV-induced lesions in pyrimidine dimers. We also demonstrated that BCC displays a pronounced enrichment of dinucleotide base substitutions flanking UV-signature sites on the 3′ side, particularly CA>TG and CG>TA changes. Ultimately, these topological patterns in both tumors indicate that a primary photoproduct seeds secondary mutagenesis within its local chromatin environment, dramatically altering our understanding of UV-induced lesion processing.

Mutational biases can influence genome composition, but their contribution to protein evolution remains difficult to quantify. Here we utilize a nearly neutral framework that translates nucleotide mutational spectra into expected amino acid substitution patterns and equilibrium amino acid compositions. Using SARS-CoV-2 as a model system, we show that the viral mutational spectrum explains more than 50% of the variation in observed single-nucleotide amino acid substitutions and predicts the overall direction of proteome-wide amino acid composition change during the COVID-19 pandemic. The predictive power of the model varies with selection regime: effectively neutral and weakly deleterious substitutions conform most closely to the mutational expectation, whereas strongly constrained sites and mutational hotspots show larger deviations. This indicates that departures from the nearly neutral baseline provide a quantitative proxy for purifying and positive selection. Extending the analysis across 34 RNA virus species, we find that positive-sense, negative-sense and double-stranded RNA viruses differ systematically in their mutational spectra, and that these differences are associated with predictable shifts in proteome composition. The same relationship is detectable in RNA-dependent RNA polymerase sequences from more than 77,000 viral species. These results indicate that taxon-specific mutational bias contributes persistently to protein evolution across evolutionary scales.

The mutational spectrum is an increasingly important molecular phenotype that quantitatively describes mutagenesis in a given gene and species, enabling future comparative analyses to reveal differences in underlying mutagenic processes, whether internal, such as DNA repair processes, or external, such as ecological niches and conditions. Mutation accumulation experiments, although time-consuming and costly, remain the standard approach for reconstructing bacterial neutral mutation spectra. Here, we present BacNeMu, a phylogenetically informed pipeline that reconstructs neutral mutational spectra of bacterial genomes using open databases GTDB, AnnoTree and KEGG Orthology, building on previously developed NeMu pipeline. BacNeMu reconstructs mutation spectra that closely match mutation accumulation experiments results while requiring substantially less time, enabling comparative analyses across diverse bacterial taxa. Applied to obligate aerobes and anaerobes, BacNeMu recovered the expected excess of T:A>C:G transitions, consistent with oxidative-damage-associated mutational patterns previously described in mitochondrial genomes and yeast single-strand. We further asked if any other ecologic factors influence a mutational spectrum. As a pilot we compared three species living under different temperatures: one strong thermophile - Thermotoga maritima, one psychrophile - Clostridium algidicarnis, and one with intermediate temperature tolerance - Psychrobacter sanguinis. In the thermophile, the relative frequency of T:A>C:G substitutions was higher than in the psychrophile, consistent with the hypothesis that GC-biased mutagenesis contributes to thermal adaptation, although C:G>T:A transitions predominate across all three species. BacNeMu provides a rapid, phylogenetically informed framework for generating biologically meaningful mutation spectra from open databases.

These figures provide complementary information for the figures presented in the main text and illustrations of the methods section.

These tables present clinical data, sample data, whole-exome and transcriptome sequencing results, literature references, and external data sources that were used for the analyses presented in the main text.

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).

Introduction The number of hip and knee replacement surgeries is increasing annually in Russia and worldwide. The majority of patients receiving joint arthroplasties are elderly women.The objective was to assess the clinical, functional and neuropsychological status of patients undergoing total knee or hip replacement.Material and methods The study included 448 patients admitted for elective surgery of total knee or hip replacement at the Department of Traumatology and Orthopedics of the Federal Center for High Medical Technologies (CHMT, Kaliningrad Region). Anthropometric parameters of the patients were measured, the medical history and concomitant diseases recorded. Common blood count and biochemistry test were evaluated preoperatively. Neuropsychological examination included assessment of cognitive and executive functions, levels of distress, depression, anxiety and somatization.Results Almost all patients studied were found to have varying degrees of obesity. A typical combination of concomitant pathology in volunteers was stage 2 hypertension, risk degree 2–3, and chronic gastritis in remission. Half of the volunteers showed moderate and high levels of distress, depression, anxiety and somatization. A significant number of volunteers showed moderate to high levels of cognitive decline. Age- and sex-related blood counts were slightly different from the normal ranges for a CBC and biochemistry. Changes in leukocyte count were detected.Discussion Leukocyte counts indicated the osteoarthritis induced inflammatory process in most patients. Mitochondrial dysfunction and aging of the immune system contributed to the “proinflammatory status.” The high rate of cognitive impairment in volunteers was associated with age and comorbidity, cardiovascular conditions, in particular. Distress and anxiety were associated with emotional reactions to surgery.Conclusion The factors reported can affect the duration and course of rehabilitation. The “pro-inflammatory status” of patients can complicate the healing of a postoperative wound. Neuropsychological disorders noted during postoperative rehabilitation can have a significant impact on physical recovery, social and professional adaptation.

These figures provide complementary information for the figures presented in the main text and illustrations of the methods section.

These tables present clinical data, sample data, whole-exome and transcriptome sequencing results, literature references, and external data sources that were used for the analyses presented in the main text.

These tables present clinical data, sample data, whole-exome and transcriptome sequencing results, literature references, and external data sources that were used for the analyses presented in the main text.