Prioritization of biological processes based on the reconstruction and analysis of associative gene networks describing the response of plants to adverse environmental factors

Methods for prioritizing or ranking candidate genes according to their importance based on specific criteria via the analysis of gene networks are widely used in biomedicine to search for genes associated with diseases and to predict biomarkers, pharmacological targets and other clinically relevant molecules. These methods have also been used in other fields, particularly in crop production. This is largely due to the development of technologies to solve problems in marker-oriented and genomic selection, which requires knowledge of the molecular genetic mechanisms underlying the formation of agriculturally valuable traits. A new direction for the study of molecular genetic mechanisms is the prioritization of biological processes based on the analysis of associative gene networks. Associative gene networks are heterogeneous networks whose vertices can depict both molecular genetic objects (genes, proteins, me tabolites, etc.) and the higher-level factors (biological processes, diseases, external environmental factors, etc.) related to regulatory, physicochemical or associative interactions. Using a previously developed method, biological processes involved in plant responses to increased cadmium content, saline stress and drought conditions were prioritized according to their degree of connection with the gene networks in the SOLANUM TUBEROSUM knowledge base. The prioritization results indicate that fundamental processes, such as gene expression, post-translational modifications, protein degradation, programmed cell death, photosynthesis, signal transmission and stress response play important roles in the common molecular genetic mechanisms for plant response to various adverse factors. On the other hand, a group of processes related to the development of seeds (“seeding development”) was revealed to be drought specific, while processes associated with ion transport (“ion transport”) were included in the list of responses specific to salt stress and processes associated with the metabolism of lipids were found to be involved specifically in the response to cadmium

Prioritization of potato genes involved in the formation of agronomically valuable traits using the SOLANUM TUBEROSUM knowledge base

The development of highly efficient technologies in genomics, transcriptomics, proteomics and metabolomics, as well as new technologies in agriculture has led to an “information explosion” in plant biology and crop production, including potato production. Only a small part of the information reaches formalized databases (for example, Uniprot, NCBI Gene, BioGRID, IntAct, etc.). One of the main sources of reliable biological data is the scientific literature. The well-known PubMed database contains more than 18 thousand abstracts of articles on potato. The effective use of knowledge presented in such a number of non-formalized documents in natural language requires the use of modern intellectual methods of analysis. However, in the literature, there is no evidence of a widespread use of intelligent methods for automatically extracting knowledge from scientific publications on cultures such as potatoes. Earlier we developed the SOLANUM TUBEROSUM knowledge base (http://www-bionet.sysbio.cytogen. ru/and/plant/). Integrated into the knowledge base information about the molecular genetic mechanisms underlying the selection of significant traits helps to accelerate the identification of candidate genes for the breeding characteristics of potatoes and the development of diagnostic markers for breeding. The article searches for new potential participants of the molecular genetic mechanisms of resistance to adverse factors in plants. Prioritizing candidate genes has shown that the PHYA, GF14, CNIH1, RCI1A, ABI5, CPK1, RGS1, NHL3, GRF8, and CYP21-4 genes are the most promising for further testing of their relationships with resistance to adverse factors. As a result of the analysis, it was shown that the molecular genetic relationships responsible for the formation of significant agricultural traits are complex and include many direct and indirect interactions. The construction of associative gene networks and their analysis using the SOLANUM TUBEROSUM knowledge base is the basis for searching for target genes for targeted mutagenesis and marker-oriented selection of potato varieties with valuable agricultural characteristics

ANALYSIS OF THE INTERACTIONS OF NEURONAL APOPTOSIS GENES IN THE ASSOCIATIVE GENE NETWORK OF PARKINSON’S DISEASE

Parkinson’s disease (PD) affects an estimated 7–10 million people worldwide and 210000 people in Russia. PD is accompanied by degeneration of dopaminergic neurons and because of that neuronal apoptosis is an important factor in this disease. Analysis of gene networks is one of the key approaches in systems biology. We previously developed the ANDSystem tool, designed to automatically extract knowledge from scientific publications and reconstruct on this basis associative gene networks describing the molecular genetic mechanisms of biological processes. The aim of this work was prioritization of neuronal apoptosis genes by their involvement in PD pathogenesis, taking into account the structure of the PD associative gene network using ANDSystem. Analysis of the centrality of neuronal apoptosis genes, associated with PD, revealed that mean values of degree, closeness and betweenness centralities statistically significantly exceed such values of all nodes of the PD network. The APOE, CASP3 and GAPDH genes involved in neuronal apoptosis were among the most central genes. Prioritization of neuronal apoptosis genes for which there was no data in ANDSystem on their associations with PD was performed using standard methods (Endeavor and ToppGene) and the criteria of centrality and specificity of genes interactions with the PD gene network. Analysis revealed that genes involved in such processes as positive and negative regulation of neu ronal apoptosis, MAPK and ephrin receptor signaling pathways, are mainly represented among candidate genes with the highest priority (top 50, 70, 100 genes were considered). In particular, TP53, JUN, BCL2, PIK3CA and APP were among candidate genes with the highest priority

THE SOLANUM TUBEROSUM KNOWLEDGE BASE: THE SECTION ON MOLECULAR-GENETIC REGULATION OF METABOLIC PATHWAYS

Rapid development of high-performance genomic, transcriptomic, proteomic and metabolic technologies led to an information explosion in the field of plant biology and agrobiology. To date, the number of scientific publications on only one of the most important agricultural crops of Solanum tuberosum L. (potato) has exceeded 1.5 million. Effective access to knowledge distributed over such a multitude of non-formalized natural language textual sources requires the use of special computer-assisted intelligent methods of data mining (text-mining). However, in the literature, there is no data on the application of intellectual methods of automatic knowledge extraction from publications on agricultural crops, such as potato. Previously we have developed a pilot version of the SOLANUM TUBEROSUM knowledge base. SOLANUM TUBEROSUM is a computer platform for complex intellectual processing of large data bodies, including (1) automatic analysis of scientific publications and databases for extraction of information on genetics, markers, breeding, diagnostics, protection and storage technologies for potato, (2) formalized representation of extracted information in the knowledge base, (3) user access to these data, (4) analysis and visualization of query results. The ontology of the SOLANUM TUBEROSUM knowledge base contains dictionaries of molecular genetic objects (proteins, genes, metabolites, microRNAs, biomarkers); phenotypic characteristics of potato varieties; potato diseases and pests; biotic/abiotic environmental factors; potato agrobiotechnologies. This article describes the current version of the SOLANUM TUBEROSUM knowledge base developed from an extensive analysis of scientific publications on the moleculargenetic regulation of metabolic pathways in potatoes, as well as model plant organisms (maize, rice, Arabidopsis  thaliana). In total, about 9,000 full-text articles and more than 130,000 abstracts of PubMed were analyzed. With the help of automatic analysis of scientific publications, more than 59,000 facts on molecular genetic interactions and genetic regulation were identified, and the analysis of factual databases revealed more than 380,000 such interactions in the examined organisms. It turned out that about 3 % of extracted facts about molecular genetic interactions and genetic regulation were related to Solanum tuberosum L. Thus, the inclusion of information on well-studied model species during the extraction of information on the molecular-genetic regulation of metabolic processes is important. It allows prediction of orthologous genes in potato and their further identification and analysis based on homology. An associative network of genetic regulation of starch biosynthesis in potatoes, including 33 metabolites, 36 proteins, 6 metabolic pathways and 132 interactions between them, 86 of which describe catalytic reactions, and the rest – regulatory events, was reconstructed. The reconstructed network is the basis for the search for target genes for directed mutagenesis and marker-oriented selection of potato varieties with specified starch properties. The trial version of the SOLANUM TUBEROSUM knowledge base is available at http://www-bionet.sysbio.cytogen.ru/and/ plant/

Computer analysis of regulation of hepatocarcinoma marker genes hypermethylated by HCV proteins

Hepatitis C virus (HCV) is a risk factor that leads to hepatocellular carcinoma (HCC) development. Epigenetic changes are known to play an important role in the molecular genetic mechanisms of virus-induced oncogenesis. Aber rant DNA methylation is a mediator of epigenetic changes that are closely associated with the HCC pathogenesis and considered a biomarker for its early diagnosis. The ANDSystem software package was used to reconstruct and evaluate the statistical significance of the pathways HCV could potentially use to regulate 32 hypermethylated genes in HCC, including both oncosuppressor and protumorigenic ones identified by genome-wide analysis of DNA methylation. The reconstructed pathways included those affecting protein-protein interactions (PPI), gene expression, protein activity, stability, and transport regulations, the expression regulation pathways being statistically significant. It has been shown that 8 out of 10 HCV proteins were involved in these pathways, the HCV NS3 protein being implicated in the largest number of regulatory pathways. NS3 was associated with the regulation of 5 tumor-suppressor genes, which may be the evidence of its central role in HCC pathogenesis. Analysis of the reconstructed pathways has demonstrated that following the transcription factor inhibition caused by binding to viral proteins, the expression of a number of oncosuppressors (WT1, MGMT, SOCS1, P53) was suppressed, while the expression of others (RASF1, RUNX3, WIF1, DAPK1) was activated. Thus, the performed gene-network reconstruction has shown that HCV proteins can influence not only the methylation status of oncosuppressor genes, but also their transcriptional regulation. The results obtained can be used in the search for pharmacological targets to develop new drugs against HCV-induced HCC

Role of apoptosis genes in aggression revealed using combined analysis of ANDSystem gene networks, expression and genomic data in grey rats with aggressive behavior

Aggressive behavior in animals plays an important role in protecting the territory, offspring, establishing social hierarchical relations, etc. Increased aggression is observed in a number of diseases ( schizophrenia, bipolar disorder, brain degenerative disorders). Neuronal apoptosis is crucial in the maintenance of developmental processes during neurogenesis. Alterations in neuronal apoptosis are observed in aging and neuropathologies accompanied by changes in psycho­emo­ tional state (epilepsy, Alzheimer’s disease, neurotrauma). The expression of key neuronal apoptosis genes (Casp3, Bax and Bcl-xl) in the brain of highly aggressive rats is significantly altered. The aim of this work was to analyze associative networks that describe genetic interactions between genes/proteins involved in neuronal apoptosis, differentially expressed genes and genes with polymorphisms in grey rats with aggressive behavior. Analysis revealed 819 differentially expressed genes in the hypothalamus, ventral tegmental region and periaqueductus Sylvii grey matter in grey rats with aggressive and tame behavior. The Stx1a, Mbp and Th genes have the highest index of betweenness centrality in the associative network of differentially expressed genes. Genome analysis revealed 137 polymorphic genes. Three of them (Lig4, Parp1 and Pigt) were involved in neuronal apoptosis. It was shown that polymorphic and differentially expressed genes were statistically significantly overrepresented among ge nes interacting with neuronal apoptosis genes (p value < 0.01). Three molecular­genetic chains describing connections between polymorphic and neuronal apoptosis genes mediated by differentially expressed genes were reconstructed. Chains included the polymorphic genes Tsc1, Adamts4 and Lgals3, differentially expressed genes Ezr, Acan, Th and 19 neuronal apoptosis genes. It was shown that neuronal apoptosis is closely related to aggressive behavior in animals

Molecular-genetic mechanisms of the interaction between processes of cell response to mechanical stress and neuronal apoptosis in primary open-angle glaucoma

Glaucoma is a chronic and progressive disease, which affects more than 60 million people worldwide. Primary open-angle glaucoma (POAG) is one of the most common forms of glaucoma. For example, about 2.71 million people in the USA had primary open-angle glaucoma in 2011. Currently POAG is a major cause of irreversible vision loss. In patients with treated open-angle glaucoma the risk of blindness reached to be about 27 %. It is known that the death of optic nerve cells can be triggered by mechanical stress caused by increased intraocular pressure, which induces neuronal apoptosis and is observed in patients with POAG. Currently, there is a large number of scientific publications describing proteins and genes involved in the pathogenesis of POAG, including neuronal apoptosis and the cell response to mechanical stress. However, the molecular- genetic mechanisms underlying the pathophysiology of POAG are still poorly understood. Reconstruction of associative networks describing the functional interactions between these genes/proteins, including biochemical reactions, regulatory interactions, transport, etc., requires the use of methods of automated knowledge extraction from texts of scientific publications. The aim of the work was the analysis of associative networks, describing the molecular-genetic interactions between proteins and genes involved in cell response to mechanical stress (CRMS), neuronal apoptosis and pathogenesis of POAG using ANDSystem, our previous development for automated text analysis. It was shown that genes associated with POAG are statistically significantly more often represented among the genes involved in the interactions between CRMS and neuronal apoptosis than it was expected by random reasons, which can be an explanation for the effect of POAG leading to the retinal ganglion cell death