Bioinformatic Analysis Reveals the Role of Translation Elongation Efficiency Optimisation in the Evolution of Ralstonia Genus.

Translation efficiency modulates gene expression in prokaryotes. The comparative analysis of translation elongation efficiency characteristics of Ralstonia genus bacteria genomes revealed that these characteristics diverge in accordance with the phylogeny of Ralstonia. The first branch of this genus is a group of bacteria commonly found in moist environments such as soil and water that includes the species R. mannitolilytica, R. insidiosa, and R. pickettii, which are also described as nosocomial infection pathogens. In contrast, the second branch is plant pathogenic bacteria consisting of R. solanacearum, R. pseudosolanacearum, and R. syzygii. We found that the soil Ralstonia have a significantly lower number and energy of potential secondary structures in mRNA and an increased role of codon usage bias in the optimization of highly expressed genes' translation elongation efficiency, not only compared to phytopathogenic Ralstonia but also to Cupriavidus necator, which is closely related to the Ralstonia genus. The observed alterations in translation elongation efficiency of orthologous genes are also reflected in the difference of potentially highly expressed gene' sets' content among Ralstonia branches with different lifestyles. Analysis of translation elongation efficiency characteristics can be considered a promising approach for studying complex mechanisms that determine the evolution and adaptation of bacteria in various environments.

Trait-Based Method of Quantitative Assessment of Ecological Functional Groups in the Human Intestinal Microbiome.

We propose the trait-based method for quantifying the activity of functional groups in the human gut microbiome based on metatranscriptomic data. It allows one to assess structural changes in the microbial community comprised of the following functional groups: butyrate-producers, acetogens, sulfate-reducers, and mucin-decomposing bacteria. It is another way to perform a functional analysis of metatranscriptomic data by focusing on the ecological level of the community under study. To develop the method, we used published data obtained in a carefully controlled environment and from a synthetic microbial community, where the problem of ambiguity between functionality and taxonomy is absent. The developed method was validated using RNA-seq data and sequencing data of the 16S rRNA amplicon on a simplified community. Consequently, the successful verification provides prospects for the application of this method for analyzing natural communities of the human intestinal microbiota.

Bioinformatic Assessment of Factors Affecting the Correlation between Protein Abundance and Elongation Efficiency in Prokaryotes.

Protein abundance is crucial for the majority of genetically regulated cell functions to act properly in prokaryotic organisms. Therefore, developing bioinformatic methods for assessing the efficiency of different stages of gene expression is of great importance for predicting the actual protein abundance. One of these steps is the evaluation of translation elongation efficiency based on mRNA sequence features, such as codon usage bias and mRNA secondary structure properties. In this study, we have evaluated correlation coefficients between experimentally measured protein abundance and predicted elongation efficiency characteristics for 26 prokaryotes, including non-model organisms, belonging to diverse taxonomic groups The algorithm for assessing elongation efficiency takes into account not only codon bias, but also number and energy of secondary structures in mRNA if those demonstrate an impact on predicted elongation efficiency of the ribosomal protein genes. The results show that, for a number of organisms, secondary structures are a better predictor of protein abundance than codon usage bias. The bioinformatic analysis has revealed several factors associated with the value of the correlation coefficient. The first factor is the elongation efficiency optimization type-the organisms whose genomes are optimized for codon usage only have significantly higher correlation coefficients. The second factor is taxonomical identity-bacteria that belong to the class Bacilli tend to have higher correlation coefficients among the analyzed set. The third is growth rate, which is shown to be higher for the organisms with higher correlation coefficients between protein abundance and predicted translation elongation efficiency. The obtained results can be useful for further improvement of methods for protein abundance prediction.

ICBrainDB: An Integrated Database for Finding Associations between Genetic Factors and EEG Markers of Depressive Disorders.

In this study, we collected and systemized diverse information related to depressive and anxiety disorders as the first step on the way to investigate the associations between molecular genetics, electrophysiological, behavioral, and psychological characteristics of people. Keeping that in mind, we developed an internet resource including a database and tools for primary presentation of the collected data of genetic factors, the results of electroencephalography (EEG) tests, and psychological questionnaires. The sample of our study was 1010 people from different regions of Russia. We created the integrated ICBrainDB database that enables users to easily access, download, and further process information about individual behavioral characteristics and psychophysiological responses along with inherited trait data. The data obtained can be useful in training neural networks and in machine learning construction processes in Big Data analysis. We believe that the existence of such a resource will play an important role in the further search for associations of genetic factors and EEG markers of depression.

Leave or Stay: Simulating Motility and Fitness of Microorganisms in Dynamic Aquatic Ecosystems.

Motility is a key adaptation factor in scarce marine environments inhabited by bacteria. The question of how a capacity for adaptive migrations influences the success of a microbial population in various conditions is a challenge addressed in this study. We employed the agent-based model of competition of motile and sedentary microbial populations in a confined aquatic environment supplied with a periodic batch nutrient source to assess the fitness of both. Such factors as nutrient concentration in a batch, batch period, mortality type and energetic costs of migration were considered to determine the conditions favouring different strategies: Nomad of a motile population and Settler of a sedentary one. The modelling results demonstrate that dynamic and nutrient-scarce environments favour motile populations, whereas nutrient-rich and stagnant environments promote sedentary microorganisms. Energetic costs of migration determine whether or not the Nomad strategy of the motile population is successful, though it also depends on such conditions as nutrient availability. Even without penalties for migration, under certain conditions, the sedentary Settler population dominates in the ecosystem. It is achieved by decreasing the local nutrient availability near the nutrient source, as motile populations relying on a local optimizing strategy tend to follow benign conditions and fail, enduring stress associated with crossing the valleys of suboptimal nutrient availability.

Reconstruction and Analysis of Gene Networks of Human Neurotransmitter Systems Reveal Genes with Contentious Manifestation for Anxiety, Depression, and Intellectual Disabilities.

BACKGROUND: The study of the biological basis of anxiety, depression, and intellectual disabilities in humans is one of the most actual problems of modern neurophysiology. Of particular interest is the study of complex interactions between molecular genetic factors, electrophysiological properties of the nervous system, and the behavioral characteristics of people. The neurobiological understanding of neuropsychiatric disorders requires not only the identification of genes that play a role in the molecular mechanisms of the occurrence and course of diseases, but also the understanding of complex interactions that occur between these genes. A systematic study of such interactions obviously contributes to the development of new methods of diagnosis, prevention, and treatment of disorders, as the orientation to allele variants of individual loci is not reliable enough, because the literature describes a number of genes, the same alleles of which can be associated with different, sometimes extremely different variants of phenotypic traits, depending on the genetic background, of their carriers, habitat, and other factors. RESULTS: In our study, we have reconstructed a series of gene networks (in the form of protein-protein interactions networks, as well as networks of transcription regulation) to build a model of the influence of complex interactions of environmental factors and genetic risk factors for intellectual disability, depression, and other disorders in human behavior. CONCLUSION: A list of candidate genes whose expression is presumably associated with environmental factors and has potentially contentious manifestation for behavioral and neurological traits is identified for further experimental verification.

Pluripotency gene network dynamics: System views from parametric analysis.

Multiple experimental data demonstrated that the core gene network orchestrating self-renewal and differentiation of mouse embryonic stem cells involves activity of Oct4, Sox2 and Nanog genes by means of a number of positive feedback loops among them. However, recent studies indicated that the architecture of the core gene network should also incorporate negative Nanog autoregulation and might not include positive feedbacks from Nanog to Oct4 and Sox2. Thorough parametric analysis of the mathematical model based on this revisited core regulatory circuit identified that there are substantial changes in model dynamics occurred depending on the strength of Oct4 and Sox2 activation and molecular complexity of Nanog autorepression. The analysis showed the existence of four dynamical domains with different numbers of stable and unstable steady states. We hypothesize that these domains can constitute the checkpoints in a developmental progression from naïve to primed pluripotency and vice versa. During this transition, parametric conditions exist, which generate an oscillatory behavior of the system explaining heterogeneity in expression of pluripotent and differentiation factors in serum ESC cultures. Eventually, simulations showed that addition of positive feedbacks from Nanog to Oct4 and Sox2 leads mainly to increase of the parametric space for the naïve ESC state, in which pluripotency factors are strongly expressed while differentiation ones are repressed.

Orthoscape: a cytoscape application for grouping and visualization KEGG based gene networks by taxonomy and homology principles.

BACKGROUND: There are many available software tools for visualization and analysis of biological networks. Among them, Cytoscape ( http://cytoscape.org/ ) is one of the most comprehensive packages, with many plugins and applications which extends its functionality by providing analysis of protein-protein interaction, gene regulatory and gene co-expression networks, metabolic, signaling, neural as well as ecological-type networks including food webs, communities networks etc. Nevertheless, only three plugins tagged 'network evolution' found in Cytoscape official app store and in literature. We have developed a new Cytoscape 3.0 application Orthoscape aimed to facilitate evolutionary analysis of gene networks and visualize the results. RESULTS: Orthoscape aids in analysis of evolutionary information available for gene sets and networks by highlighting: (1) the orthology relationships between genes; (2) the evolutionary origin of gene network components; (3) the evolutionary pressure mode (diversifying or stabilizing, negative or positive selection) of orthologous groups in general and/or branch-oriented mode. The distinctive feature of Orthoscape is the ability to control all data analysis steps via user-friendly interface. CONCLUSION: Orthoscape allows its users to analyze gene networks or separated gene sets in the context of evolution. At each step of data analysis, Orthoscape also provides for convenient visualization and data manipulation.

AltORFev facilitates the prediction of alternative open reading frames in eukaryotic mRNAs.

Motivation: Protein synthesis is not a straight forward process and one gene locus can produce many isoforms, for example, by starting mRNA translation from alternative start sites. altORF evaluator (altORFev) predicts alternative open reading frames within eukaryotic mRNA translated by a linear scanning mechanism and its modifications (leaky scanning and reinitiation). The program reveals the efficiently translated altORFs recognized by the majority of 40S ribosomal subunits landing on the 5'-end of an mRNA. This information aids to reveal the functions of eukaryotic genes connected to synthesis of either unknown isoforms of annotated proteins or new unrelated polypeptides. Availability and Implementation: altORFev is available at http://www.bionet.nsc.ru/AUGWeb/ and has been developed in Java 1.8 using the BioJava library; and the Vaadin framework to produce the web service. Contact: ak@bionet.nsc.ru.

Bacteriophages affect evolution of bacterial communities in spatially distributed habitats: a simulation study.

BACKGROUND: Bacteriophages are known to be one of the driving forces of bacterial evolution. Besides promoting horizontal transfer of genes between cells, they may induce directional selection of cells (for instance, according to more or less resistance to phage infection). Switching between lysogenic and lytic pathways results in various types of (co)evolution in host-phage systems. Spatial (more generally, ecological) organization of the living environment is another factor affecting evolution. In this study, we have simulated and analyzed a series of computer models of microbial communities evolving in spatially distributed environments under the pressure of phage infection. RESULTS: We modeled evolving microbial communities living in spatially distributed flowing environments. Non-specific nutrient supplied in the only spatial direction, resulting in its non-uniform distribution in environment. We varied the time and the location of initial phage infestation of cells as well as switched chemotaxis on and off. Simulations were performed with the Haploid evolutionary constructor software ( http://evol-constructor.bionet.nsc.ru/ ). CONCLUSION: Simulations have shown that the spatial location of initial phage invasion may lead to different evolutionary scenarios. Phage infection decreases the speciation rate by more than one order as far as intensified selection blocks the origin of novel viable populations/species, which could carve out potential ecological niches. The dependence of speciation rate on the invasion node location varied on the time of invasion. Speciation rate was found to be lower when the phage invaded fully formed community of sedentary cells (at middle and late times) at the species-rich regions. This is especially noticeable in the case of late-time invasion. Our simulation study has shown that phage infection affects evolution of microbial community slowing down speciation and stabilizing the system as a whole. This influencing varied in its efficiency depending on spatially-ecological factors as well as community state at the moment of phage invasion.

Web application for automatic prediction of gene translation elongation efficiency.

Expression efficiency is one of the major characteristics describing genes in various modern investigations. Expression efficiency of genes is regulated at various stages: transcription, translation, posttranslational protein modification and others. In this study, a special EloE (Elongation Efficiency) web application is described. The EloE sorts the organism's genes in a descend order on their theoretical rate of the elongation stage of translation based on the analysis of their nucleotide sequences. Obtained theoretical data have a significant correlation with available experimental data of gene expression in various organisms. In addition, the program identifies preferential codons in organism's genes and defines distribution of potential secondary structures energy in 5´ and 3´ regions of mRNA. The EloE can be useful in preliminary estimation of translation elongation efficiency for genes for which experimental data are not available yet. Some results can be used, for instance, in other programs modeling artificial genetic structures in genetically engineered experiments.

Modeling evolution of spatially distributed bacterial communities: a simulation with the haploid evolutionary constructor.

BACKGROUND: Multiscale approaches for integrating submodels of various levels of biological organization into a single model became the major tool of systems biology. In this paper, we have constructed and simulated a set of multiscale models of spatially distributed microbial communities and study an influence of unevenly distributed environmental factors on the genetic diversity and evolution of the community members. RESULTS: Haploid Evolutionary Constructor software http://evol-constructor.bionet.nsc.ru/ was expanded by adding the tool for the spatial modeling of a microbial community (1D, 2D and 3D versions). A set of the models of spatially distributed communities was built to demonstrate that the spatial distribution of cells affects both intensity of selection and evolution rate. CONCLUSION: In spatially heterogeneous communities, the change in the direction of the environmental flow might be reflected in local irregular population dynamics, while the genetic structure of populations (frequencies of the alleles) remains stable. Furthermore, in spatially heterogeneous communities, the chemotaxis might dramatically affect the evolution of community members.

Haploid evolutionary constructor: new features and further challenges.

In this paper we consider the recent advances in methodology for modeling of prokaryotic communities evolution and new features of the software package "Haploid evolutionary constructor" (http://evol-constructor.bionet.nsc.ru). We show the principles of building complex computer models in our software tool. These models describe several levels of biological organization: genetic, metabolic, population, ecological. New features of the haploid evolutionary constructor include the modeling of gene networks and phage infections.

Simulation of coevolution in community by using the "Evolutionary Constructor" program.

An original modeling tool called Evolutionary Constructor has been proposed and described. Evolutionary Constructor combines the advantages of both generalized and portrait modeling and, additionally, provides an option to modify a current model's structure. The evolution of communities comprising atrophic ring-like network with the horizontal transfer of metabolism genes occurring among the communities has been modeled and presented. It has been demonstrated that a prolonged increase in the fitness of any single population that forms part of that trophic ring-like network of antagonistic communities will eventually lead that system to becoming absolutely dependent on environmental fluctuations. This result challenges the intuitive attitudes that the higher population fitness, the more stability is given to that population. Modeling of a system comprised by symbiotic communities has revealed that horizontal transfer confers a selective advantage not only on the acceptor population (which is up to expectations) but also on the donor population. It has therefore been demonstrated that horizontal transfer can be preserved by selection along evolution even without "selfish genes". Evolutionary Constructor can handle any phenotypic trait that is controlled genetically, epigenetically, etc., which extends the applicability of this tool to various processes of information transduction among populations, provided that these processes resemble horizontal gene transfer.

GeneNet database: description and modeling of gene networks.

Almost all cellular processes in an organism are controlled by gene networks. Here we report on the analysis of gene networks functioning using two associated methods - data accumulation in GeneNet system and generalized chemical kinetic method for mathematical simulation of gene network functional dynamics. The technology of the usage of these methods is shown on the example of the gene network of macrophage activation.