RAS Institute of Cytology and Genetics

Novosibirsk, Russia

RAS Institute of Cytology and Genetics

Novosibirsk, Russia
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Agency: European Commission | Branch: FP7 | Program: CP-FP-SICA | Phase: HEALTH.2010.2.1.2-3 | Award Amount: 3.88M | Year: 2010

SYSPATHO focuses on the development of novel and generally applicable mathematical methods and algorithms for systems biology. These methods and algorithms will be applied to study the complex interactions of hepatitis C virus (HCV), a human-pathogenic virus of high medical relevance, with its host at the systems level. Using a multidisciplinary, integrative approach, PATHOSYS will (a) develop methods to analyze and integrate a wide variety of data from wet lab experiments, databases and biological literature, (b) develop and apply machine learning tools to reconstruct and study intracellular interaction networks from experimental data, (c) develop new and improve existing algorithms and mathematical methods for bottom-up modelling, to fit models to data, and to analyze the dynamic behaviour of models (d) generate new experimental data to gain novel insights into hepatitis C virus host interactions, and (e) use the newly developed methods and data to model and analyze HCV-host interactions at the systems level. Guided by biological data, PATHOSYS focuses on the design of novel algorithms and mathematical methods for systems biology, with the aim to provide generally applicable tools to elucidate biological processes. Based on developed models and using systems analysis, PATHOSYS will elucidate virus host interactions of Hepatitis C virus at an unprecedented level. As a direct spin-off, models and analysis methods developed in PATHOSYS will lead to the identification of new candidate host cell target genes applicable for the design of novel anti-viral drugs against hepatitis C. Targeting of host cell factors will reduce the likelihood for the development of therapy resistance and increase the chance for broad-spectrum antivirals. Inclusion of two SME partners will ensure exploitation of results generated in PATHOSYS and their transfer into industrial and pharmaceutical applications, thus strengthening economy and health care system in Europe.

Popova N.K.,RAS Institute of Cytology and Genetics | Naumenko V.S.,RAS Institute of Cytology and Genetics
Reviews in the Neurosciences | Year: 2013

Among an impressive variety of identified serotonin receptors, 5-HT 1A attracts particular attention due to its central role in the regulation of 5-HT-ergic neurotransmission and the data on its involvement in the mechanisms of stress response, aggressive behavior, anxiety, and depression. This review concentrates on the crossregulation between 5-HT receptors and the implication of the 5-HT1A receptor in the genetic control of 5-HT-related behavior. Specifically, it describes the (1) functional interactions between 5-HT1A , 5-HT2A , 5-HT3, and 5-HT7 receptors; (2) cross-talk between 5-HT1A receptor and genes encoding key members of the brain 5-HT system; (3) implication of the 5-HT1A receptor in natural hibernation and genetic predisposition to different kinds of defensive behavior; and (4) role of 5-HT1A autoreceptors and heteroreceptors in anxiety, depression, and suicide, and in the antidepressant effect of serotonin reuptake inhibitors. This review provides converging lines of evidence that the 5-HT1A receptor contributes to the action of other 5-HT receptors, modulating their effect on behavior, and describes new data on the unique role of the 5-HT 1A receptor in the indirect regulation of gene expression and in the autoregulation of the brain 5-HT system.

Agency: European Commission | Branch: FP7 | Program: CP-TP | Phase: KBBE.2011.3.1-02 | Award Amount: 3.93M | Year: 2011

Perennial grasses, which once established can be harvested and re-grow annually for many decades, have a number of other beneficial characteristics which suit them as biomass crops. These include high resource use efficiency, high productivity, good environmental qualities and a wide range of end uses. Environmental benefits include high rates of soil carbon sequestration, enhanced biodiversity and soil stabilisation. Furthermore, perennial grasses naturally colonise marginal areas of land which often impose severe restrictions on the growth of vegetation. Marginal land is defined as land of poor quality for agriculture and which yields poor returns for the farmer. The aim of this project is to identify, characterize and develop novel varieties of C3 grasses (Dactylis glomerata, Festuca arundinacea and Phalaris arundinacea) and the C4 genus Miscanthus that show high and stable productivity and require the minimum of additional inputs when grown on different forms of marginal land. In broad terms the work will contribute to overcoming specific bottlenecks along the whole perennial grass-based production chain. In particular it will use modelling to identify the optimal characteristics and geographical distribution of perennial grasses of potential use for biomass production, undertake pre-breeding of novel varieties, investigate stress tolerance and develop drying characteristics following harvest. The consortium assembled to achieve these outputs consists of 12 partners from eight countries representing Northern, Central and Western Europe and partners from Russia and China and involves three SME partners.

Svishcheva G.R.,RAS Institute of Cytology and Genetics | Axenovich T.I.,RAS Institute of Cytology and Genetics | Belonogova N.M.,RAS Institute of Cytology and Genetics | Van Duijn C.M.,Erasmus Medical Center | Aulchenko Y.S.,RAS Institute of Cytology and Genetics
Nature Genetics | Year: 2012

The variance component tests used in genome-wide association studies (GWAS) including large sample sizes become computationally exhaustive when the number of genetic markers is over a few hundred thousand. We present an extremely fast variance components-based two-step method, GRAMMAR-Gamma, developed as an analytical approximation within a framework of the score test approach. Using simulated and real human GWAS data sets, we show that this method provides unbiased estimates of the SNP effect and has a power close to that of the likelihood ratio test-based method. The computational complexity of our method is close to its theoretical minimum, that is, to the complexity of the analysis that ignores genetic structure. The running time of our method linearly depends on sample size, whereas this dependency is quadratic for other existing methods. Simulations suggest that GRAMMAR-Gamma may be used for association testing in whole-genome resequencing studies of large human cohorts. © 2012 Nature America, Inc. All rights reserved.

Bryzgalov L.O.,RAS Institute of Cytology and Genetics
PloS one | Year: 2013

A vast amount of SNPs derived from genome-wide association studies are represented by non-coding ones, therefore exacerbating the need for effective identification of regulatory SNPs (rSNPs) among them. However, this task remains challenging since the regulatory part of the human genome is annotated much poorly as opposed to coding regions. Here we describe an approach aggregating the whole set of ENCODE ChIP-seq data in order to search for rSNPs, and provide the experimental evidence of its efficiency. Its algorithm is based on the assumption that the enrichment of a genomic region with transcription factor binding loci (ChIP-seq peaks) indicates its regulatory function, and thereby SNPs located in this region are more likely to influence transcription regulation. To ensure that the approach preferably selects functionally meaningful SNPs, we performed enrichment analysis of several human SNP datasets associated with phenotypic manifestations. It was shown that all samples are significantly enriched with SNPs falling into the regions of multiple ChIP-seq peaks as compared with the randomly selected SNPs. For experimental verification, 40 SNPs falling into overlapping regions of at least 7 TF binding loci were selected from OMIM. The effect of SNPs on the binding of the DNA fragments containing them to the nuclear proteins from four human cell lines (HepG2, HeLaS3, HCT-116, and K562) has been tested by EMSA. A radical change in the binding pattern has been observed for 29 SNPs, besides, 6 more SNPs also demonstrated less pronounced changes. Taken together, the results demonstrate the effective way to search for potential rSNPs with the aid of ChIP-seq data provided by ENCODE project.

Khlestkina E.,RAS Institute of Cytology and Genetics
Cereal Research Communications | Year: 2013

The flavonoid biosynthesis pathway yields a large family of phenolic compounds which are involved in many biological activities including plant defense response to a broad spectrum of abiotic and biotic stress factors. In recent years, a wide range of evidences of relationship between the flavonoid biosynthesis and stress has been accumulated based on genetic, physiological and biochemical studies. In this paper, possible mechanisms of counteraction of flavonoid substances to different stress factors are reviewed, and the evidences for relationship between biosynthesis of flavonoid compounds and response to biotic and abiotic stress are summarized with emphasis on cereals.

Bazykin G.A.,Russian Academy of Sciences | Kochetov A.V.,RAS Institute of Cytology and Genetics
Nucleic Acids Research | Year: 2011

Alternative start AUG codons within a single transcript can contribute to diversity of the proteome; however, their functional significance remains controversial. Here, we provide comparative genomics evidence that alternative start codons are under negative selection in vertebrates, insects and yeast. In genes where the annotated start codon (sAUG) resides within the suboptimal nucleotide context, the downstream in-frame AUG codons (dAUG) among the first ∼30 codon sites are significantly more conserved between species than in genes where the sAUG resides within the optimal context. Proteomics data show that this difference is not an annotation artifact and that dAUGs are in fact under selection as alternative start sites. The key optimal, and sometimes suboptimal, context-determining nucleotides of both the sAUG and dAUGs are conserved. Selection for secondary start sites is stronger in genes with the weak primary start site. Genes with multiple conserved start sites are enriched for transcription factors, and tend to have longer 5′UTRs and higher degree of alternative splicing. Together, these results imply that the use of alternative start sites by means of leaky mRNA scanning is a functional mechanism under selection for increased efficiency of translation and/or for translation of different N-terminal protein variants. © 2010 The Author(s).

Bazhan N.,RAS Institute of Cytology and Genetics | Zelena D.,Hungarian Academy of Sciences
Brain Research Bulletin | Year: 2013

Emotional stress induces anorexia in laboratory animals, and obesity in humans.Stress per se does not result in overeating and obesity, only at high caloric diet.Glucocorticoids stimulate and stress inhibits food intake in laboratory animals.In animals the orexigenic effects of glucocorticoids are overcome by other factors (like CRH) at acute and chronic stresses. The prevalence of obesity is increasing worldwide with serious consequences such as diabetes mellitus type 2 and cardiovascular diseases. Emotional stress is considered to be one of the main reasons of obesity development in humans. However, there are some contradictory results, which should be addressed. First of all stress induces anorexia, but not overeating in laboratory animals. Glucocorticoids, the effector molecules of the hypothalamo-pituitary-adrenocortical (HPA) axis stimulate and stress inhibits food intake. It is also not clear if stress is diabetogenic or an antidiabetogenic factor. The review will discusses these issues and the involvement of the whole HPA axis and its separate molecules (glucocorticoids, adrenocorticotropin, corticotropin-releasing hormone) in food intake regulation under stress. © 2013 Elsevier Inc.

Mironova V.V.,RAS Institute of Cytology and Genetics
Annals of botany | Year: 2012

The root apical meristem (RAM) is the plant stem cell niche which provides for the formation and continuous development of the root. Auxin is the main regulator of RAM functioning, and auxin maxima coincide with the sites of RAM initiation and maintenance. Auxin gradients are formed due to local auxin biosynthesis and polar auxin transport. The PIN family of auxin transporters plays a critical role in polar auxin transport, and two mechanisms of auxin maximum formation in the RAM based on PIN-mediated auxin transport have been proposed to date: the reverse fountain and the reflected flow mechanisms. The two mechanisms are combined here in in silico studies of auxin distribution in intact roots and roots cut into two pieces in the proximal meristem region. In parallel, corresponding experiments were performed in vivo using DR5::GFP Arabidopsis plants. The reverse fountain and the reflected flow mechanism naturally cooperate for RAM patterning and maintenance in intact root. Regeneration of the RAM in decapitated roots is provided by the reflected flow mechanism. In the excised root tips local auxin biosynthesis either alone or in cooperation with the reverse fountain enables RAM maintenance. The efficiency of a dual-mechanism model in guiding biological experiments on RAM regeneration and maintenance is demonstrated. The model also allows estimation of the concentrations of auxin and PINs in root cells during development and under various treatments. The dual-mechanism model proposed here can be a powerful tool for the study of several different aspects of auxin function in root.

Shchelkunov S.N.,RAS Institute of Cytology and Genetics
Vaccine | Year: 2011

The review summarizes the archive data on smallpox, history of ancient civilizations, and the most recent data on the genome organization of orthopoxviruses, their evolutionary relationships, and the time points of smallpox emergence. The performed analysis provides the grounds for the hypothesis that smallpox could have emerged several times as a result of evolutionary changes in the zoonotic ancestor virus and disappeared due to insufficient population size of ancient civilizations. Smallpox reemerged in the Indian subcontinent approximately 2500-3000 years before present, which resulted in endemization of this anthroponotic infection, which had been preserved until the smallpox eradication in the 20th century AD. The conclusion suggests a potential possibility of future variola virus reemergence, presenting a great menace for mankind, as well as the need for development of new safe smallpox vaccines, design of anti-smallpox drugs, and activation of the control of zoonotic human orthopoxvirus infections. © 2011 Elsevier Ltd.

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