The rise and spread of the SARS-CoV-2 AY.122 lineage in Russia.

Delta has outcompeted most preexisting variants of SARS-CoV-2, becoming the globally predominant lineage by mid-2021. Its subsequent evolution has led to the emergence of multiple sublineages, most of which are well-mixed between countries. By contrast, here we show that nearly the entire Delta epidemic in Russia has probably descended from a single import event, or from multiple closely timed imports from a single poorly sampled geographic location. Indeed, over 90 per cent of Delta samples in Russia are characterized by the nsp2:K81N + ORF7a:P45L pair of mutations which is rare outside Russia, putting them in the AY.122 sublineage. The AY.122 lineage was frequent in Russia among Delta samples from the start, and has not increased in frequency in other countries where it has been observed, suggesting that its high prevalence in Russia has probably resulted from a random founder effect rather than a transmission advantage. The apartness of the genetic composition of the Delta epidemic in Russia makes Russia somewhat unusual, although not exceptional, among other countries.

The rise and spread of the SARS-CoV-2 AY.122 lineage in Russia.

BACKGROUND: Delta has outcompeted most preexisting variants of SARS-CoV-2, becoming the globally predominant lineage by mid-2021. Its subsequent evolution has led to emergence of multiple sublineages, many of which are well-mixed between countries. AIM: Here, we aim to study the emergence and spread of the Delta lineage in Russia. METHODS: We use a phylogeographic approach to infer imports of Delta sublineages into Russia, and phylodynamic models to assess the rate of their spread. RESULTS: We show that nearly the entire Delta epidemic in Russia has probably descended from a single import event despite genetic evidence of multiple Delta imports. Indeed, over 90% of Delta samples in Russia are characterized by the nsp2:K81N+ORF7a:P45L pair of mutations which is rare outside Russia, putting them in the AY.122 sublineage. The AY.122 lineage was frequent in Russia among Delta samples from the start, and has not increased in frequency in other countries where it has been observed, suggesting that its high prevalence in Russia has probably resulted from a random founder effect. CONCLUSION: The apartness of the genetic composition of the Delta epidemic in Russia makes Russia somewhat unusual, although not exceptional, among other countries.

Episodic evolution of coadapted sets of amino acid sites in mitochondrial proteins.

The rate of evolution differs between protein sites and changes with time. However, the link between these two phenomena remains poorly understood. Here, we design a phylogenetic approach for distinguishing pairs of amino acid sites that evolve concordantly, i.e., such that substitutions at one site trigger subsequent substitutions at the other; and also pairs of sites that evolve discordantly, so that substitutions at one site impede subsequent substitutions at the other. We distinguish groups of amino acid sites that undergo coordinated evolution and evolve discordantly from other such groups. In mitochondrion-encoded proteins of metazoans and fungi, we show that concordantly evolving sites are clustered in protein structures. By analysing the phylogenetic patterns of substitutions at concordantly and discordantly evolving site pairs, we find that concordant evolution has two distinct causes: epistatic interactions between amino acid substitutions and episodes of selection independently affecting substitutions at different sites. The rate of substitutions at concordantly evolving groups of protein sites changes in the course of evolution, indicating episodes of selection limited to some of the lineages. The phylogenetic positions of these changes are consistent between proteins, suggesting common selective forces underlying them.

Genetic diversity of Kemerovo virus and phylogenetic relationships within the Great Island virus genetic group.

Kemerovo virus (KEMV) is a member of the Great Island virus genetic group, belonging to the tick-borne arboviruses of the genus Orbivirus within the family Reoviridae. Nine strains of KEMV, which were isolated from various locations in Russia, were sequenced by high-throughput sequencing to study their intraspecific diversity and the interspecific relationships of viruses within the Great Island genetic group. For the first time, multiple reassortment within KEMV was reliably demonstrated. Different types of independently emerged alternative reading frames in segment 9 and heterogeneity of the viral population in one of the KEMV strains were found. The hypothesis of the role of an alternative open reading frame (ORF) in segment 9 in KEMV cellular tropism was not confirmed in this study.

Predictive models of protease specificity based on quantitative protease-activity profiling data.

Bioinformatics-based prediction of protease substrates can help to elucidate regulatory proteolytic pathways that control a broad range of biological processes such as apoptosis and blood coagulation. The majority of published predictive models are position weight matrices (PWM) reflecting specificity of proteases toward target sequence. These models are typically derived from experimental data on positions of hydrolyzed peptide bonds and show a reasonable predictive power. New emerging techniques that not only register the cleavage position but also measure catalytic efficiency of proteolysis are expected to improve the quality of predictions or at least substantially reduce the number of tested substrates required for confident predictions. The main goal of this study was to develop new prediction models based on such data and to estimate the performance of the constructed models. We used data on catalytic efficiency of proteolysis measured for eight major human matrix metalloproteinases to construct predictive models of protease specificity using a variety of regression analysis techniques. The obtained results suggest that efficiency-based (quantitative) models show a comparable performance with conventional PWM-based algorithms, while less training data are required. The derived list of candidate cleavage sites in human secreted proteins may serve as a starting point for experimental analysis.

VirGenA: a reference-based assembler for variable viral genomes.

Characterization of the within-host genetic diversity of viral pathogens is required for selection of effective treatment of some important viral infections, e.g. HIV, HBV and HCV. Despite the technical ability of detection, there are conflicting data regarding the clinical significance of low-frequency variants, partially because of the difficulty of their distinguishing from experimental artifacts. The issue of cross-contamination is relevant for all highly sensitive techniques, including deep sequencing: even trace contamination leads to a significant increase of false positives in identified SNVs. Determination of infections by multiple genotypes of some viruses, the incidence of which can be considerable, especially in risk groups, is also clinically significant in some cases. We developed a new viral reference-guided assembler, VirGenA, that can separate mixtures of strains of different intraspecies genetic groups (genotypes, subtypes, clades, etc.) and assemble a separate consensus sequence for each group in a mixture. It produced long assemblies for mixture components of extremely low frequencies (<1%) allowing detection of cross-contamination of samples by divergent genotypes. We tested VirGenA on both clinical and simulated data. On both types of data, VirGenA shows better or similar results than the existing de novo assemblers. Cross-platform implementation (including source code) is freely available at https://github.com/gFedonin/VirGenA/releases.

Evolution of Brain Active Gene Promoters in Human Lineage Towards the Increased Plasticity of Gene Regulation.

Adaptability to a variety of environmental conditions is a prominent feature of Homo sapiens. We hypothesize that this feature can be explained by evolutionary changes in gene promoters active in the brain prefrontal cortex leading to a more flexible gene regulation network. The genotype-dependent range of gene expression can be broader in humans than in other higher primates. Thus, we searched for specific signatures of evolutionary changes in promoter architectures of multiple hominid genes, including the genes active in human cortical neurons that may indicate an increase of variability of gene expression rather than just changes in the level of expression, such as downregulation or upregulation of the genes. We performed a whole-genome search for genetic-based alterations that may impact gene regulation "flexibility" in a process of hominids evolution, such as (i) CpG dinucleotide content, (ii) predicted nucleosome-DNA dissociation constant, and (iii) predicted affinities for TATA-binding protein (TBP) in gene promoters. We tested all putative promoter regions across the human genome and especially gene promoters in active chromatin state in neurons of prefrontal cortex, the brain region critical for abstract thinking and social and behavioral adaptation. Our data imply that the origin of modern man has been associated with an increase of flexibility of promoter-driven gene regulation in brain. In contrast, after splitting from the ancestral lineages of H. sapiens, the evolution of ape species is characterized by reduced flexibility of gene promoter functioning, underlying reduced variability of the gene expression.

Spatial proximity and similarity of the epigenetic state of genome domains.

Recent studies demonstrate that the organization of the chromatin within the nuclear space might play a crucial role in the regulation of gene expression. The ongoing progress in determination of the 3D structure of the nuclear chromatin allows one to study correlations between spatial proximity of genome domains and their epigenetic state. We combined the data on three-dimensional architecture of the whole human genome with results of high-throughput studies of the chromatin functional state and observed that fragments of different chromosomes that are spatially close tend to have similar patterns of histone modifications, methylation state, DNAse sensitivity, expression level, and chromatin states in general. Moreover, clustering of genome regions by spatial proximity produced compact clusters characterized by the high level of histone modifications and DNAse sensitivity and low methylation level, and loose clusters with the opposite characteristics. We also associated the spatial proximity data with previously detected chimeric transcripts and the results of RNA-seq experiments and observed that the frequency of formation of chimeric transcripts from fragments of two different chromosomes is higher among spatially proximal genome domains. A fair fraction of these chimeric transcripts seems to arise post-transcriptionally via trans-splicing.