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News Article | May 16, 2017
Site: www.eurekalert.org

Researchers from the Vavilov Institute of General Genetics of the Russian Academy of Sciences (VIGG) and the Moscow Institute of Physics and Technology (MIPT) have established a catalog of mutations in 319 virulence genes of mycobacteria that cause tuberculosis. These genes encode proteins that suppress human immune response. Further analysis identified a set of three mutations which may enable mycobacteria to develop rapidly in an immunocompromised environment. The emerging strains of TB pathogens require new treatment approaches including the development of new genetically engineered vaccines that take into account both the immune status of a patient and the specific virulence features of a pathogen. The article was published in Genome Biology and Evolution (Oxford University Press, UK). According to the World Health Organization, TB remains one of the most dangerous human infectious diseases, causing over 1.8 million deaths annually. TB is caused by a bacterium known as Mycobacterium tuberculosis or Koch's bacillus. It is clear that HIV-positive individuals and patients with other immunodeficiency conditions are mainly at risk. More than 20 percent of TB cases are connected with smoking. TB is no longer a social disease: It affects members of all social strata. This change was caused by the stresses of modern life>M. tuberculosis has become increasingly resistant to both the environmental factors and antibiotics, which used to guarantee effective treatment. At the same time, the symptoms of TB have become less noticeable. The bacterium can remain in the host body for decades infecting other people. According to WHO statistics, one-third of the world's population is infected with TB. The most serious problem we are currently facing is drug resistant TB aggravated by the adaptation of new pathogenic strains to weakened immunity. Prof. Valery Danilenko of the Department of Biological and Medical Physics at MIPT, the head of the Department of Genetics and Biotechnology at VIGG, comments on the issue: "Humanity is trying to beat the disease with new drugs and innovative treatment methods, but we have -- tactically speaking -- already lost the battle. During the last 50 years of research, only one antibiotic with a novel type of action has been produced -- Bedaquiline. It has been in use for about two years now. However, mycobacteria have already developed mutations that make them resistant to that drug." New strains of drug-resistant bacteria with altered virulence have already sensed our weakness: They "know" if some of us have compromised immunity, and they are exploiting precisely this weakness by targeting immunodeficient patients. Bioinformatics and genetics help identify a dangerous strain of TB pathogens Researchers currently identify 7-8 major M. tuberculosis lineages (groups). They differ from one another in mutations in various genes. A genome can have from 300 to 1,000 of such lineage-specific mutations, or SNPs. The term SNP (pronounced "snip") means a mutation in a particular gene involving the substitution of only one nucleotide. If the mutation occurs in a functional part of a virulence gene, the protein encoded by that gene will trigger a different host immune response. This enables the pathogen to overcome host resistance mechanisms developed in childhood as a result of BCG (anti-TB) vaccination. Natalya Mikheecheva, a researcher at the Laboratory of Bacterial Genetics at VIGG with a bioinformatics degree from MIPT, explains: "We carried out research aimed at identifying the genes and mutations in them that allow mycobacteria to thrive in people with altered immune status including HIV-positive patients. We developed a catalog of SNPs in more than 300 virulence genes. Virulence was defined as the ability of a pathogen to cause disease, overcome host resistance via invasion and adhesion to host cells, and adapt to hostile environments, including immune response modulation." Each lineage was found to comprise dozens or even hundreds of sublineages, depending on the specific gene and the location of the mutation. Bioinformatics analysis conducted using software developed at MIPT's Department of Biological and Medical Physics (MIPT) revealed mutations specific to an epidemiologically dangerous sublineage within the Beijing-B0 lineage. The scientists used databases of sequenced and described genomes to track the spread of the epidemiologically dangerous B0/N-90 sublineage in Russia and the neighboring European countries Belarus, Moldova, and Sweden. To combat drug-resistant TB, an international consortium called TBResist was formed in 2008. Its members include leading experts in medicine, genetics, bioinformatics, etc. from the U.S., Sweden, Russia, the U.K., Bangladesh, Zimbabwe, South Africa, Taiwan, and other countries. Prof. Danilenko who led the research in Russia says: "Our work with the international consortium involved cooperating with our colleagues from South Africa and China to draft a project aimed at investigating the epidemiologically dangerous strain identified in our study. The project is currently being considered by expert communities of the three countries including the Ministry of Education and Science of the Russian Federation. Our goal is to warn the international community and the health ministries of the BRICS countries of the impending danger. In the '80s, it was the HIV. We may well expect something similar from new mutated TB strains--it's a Pandora's box." Treatments that are available now can cure the disease within a year or two. However, we could see the emergence of mutant pathogens developing rapidly in certain population groups. With the flu, there is an established practice of making a new vaccine every year to counteract the latest mutated strain of influenza. But unlike the influenza virus, which only has several genes, M. tuberculosis has more than 300 virulence genes, each of them potentially subject to mutations. For the last 30 years, scientists all over the world have been trying to design a genetically engineered TB vaccine. To do this, only certain genes of the bacterium are used, not its whole genome. These genes are cloned to obtain their protein products, which are then used to vaccinate patients and monitor their immune response. There are, however, hundreds of M. tuberculosis sublineages. The research findings indicate that vaccines need to take into account such factors as the host's immune status and the presence in the pathogen of any of at least a dozen epidemiologically dangerous lineages with mutations in particular virulence genes. Prof. Danilenko drives the point home: "We detected mutations that may enable the bacteria to thrive by exploiting compromised immunity. From that point, it is basically analogous to the flu: We suggest that vaccines against specific TB lineages need to be developed using the genes identified through the bioinformatics analysis of hundreds of sequenced genomes. This will help us to find a basic approach that could inhibit the spread of the dangerous lineages. We have also developed diagnostic tests to identify such lineages." On April 13-14, an international academic and research conference titled "Current Methods of Comprehensive Health Care for TB-infected and HIV-positive Patients: Implementation, Development, Resources" was held in Yekaterinburg. The plenary session of the conference featured a report on "Genetically Engineered TB Vaccination: Current Research, Problems, and Prospects." Prof. Igor Krasilnikov, a recognized expert in vaccine development, talked about the plans of several Russian research and government organizations (Federal Agency for Scientific Organizations, the Ministry of Health, Federal Medical and Biological Agency, MIPT) based on new ideas and paradigms that have emerged over the last years.

Dragovich B.,Institute of Physics | Dragovich A.,Vavilov Institute of General Genetics
Computer Journal | Year: 2010

This paper presents the foundations of p-adic modelling in genomics. Considering nucleotides, codons, DNA and RNA sequences, amino acids and proteins as information systems, we have formulated the corresponding p-adic formalisms for their investigations. Each of these systems has its characteristic prime number used for construction of the related information space. Relevance of this approach is illustrated by some examples. In particular, it is shown that degeneration of the genetic code is a p-adic phenomenon. We have also put a forward a hypothesis on the evolution of the genetic code assuming that primitive code was based on single nucleotides and chronologically first four amino acids. This formalism of p-adic genomic information systems can be implemented in computer programs and applied to various concrete cases. © The Author 2007. Published by Oxford University Press on behalf of The British Computer Society. All rights reserved.

Mcdonald H.,London School of Hygiene and Tropical Medicine | Borinskya S.,Vavilov Institute of General Genetics | Kiryanov N.,Izhevsk State Medical Academy | Gil A.,London School of Hygiene and Tropical Medicine | And 3 more authors.
Addiction | Year: 2013

Aims: To assess the performance of a range of biomarkers of alcohol consumption in a heavy-drinking population of working-aged Russian men. Design: Cross-sectional study of men originally sampled at random from a population register. Setting: Izhevsk, a Russian city with a population of 650000 people. Participants: A total of 1023 men aged 27-59 years living in Izhevsk who took part in a health check examination in 2008-2009. Measurements: Self-reported alcohol consumption, hazardous drinking behaviours, socio-economic position, anthropometric measurements plus blood levels of alcohol biomarkers [carbohydrate-deficient transferrin (CDT, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and mean cell volume of erythrocytes (MCV)] and hepatitis B and C status. Findings: In the year before interview there was a high prevalence of high-risk alcohol consumption indicated by consumption of non-beverage alcohols (5%), problem drinking behaviours (4.4%) and alcohol consumption exceeding an average 40g per day (12.6%). All biomarkers were associated strongly with total beverage alcohol consumption even after adjustment for confounders. CDT performed best as an alcohol biomarker, with a sensitivity of 67% and specificity of 71% for detecting an average consumption of more than 40g per day versus less. For all biomarkers sensitivity was considerably lower than specificity. Hazardous drinking patterns per se were not well detected by any of the biomarkers, all with sensitivity below 60%. Conclusions: In a Russian population with high levels of alcohol consumption, carbohydrate-deficient transferrin (CDT) might be the most sensitive and specific biomarker for detecting ethanol consumption above 40g/day. A biomarker reflecting hazardous drinking patterns has yet to be established. © 2013 Society for the Study of Addiction.

Tuzhikov A.,University of Miami | Tuzhikov A.,Institute for Information Transmission Problems | Panchin A.,Institute for Information Transmission Problems | Shestopalov V.I.,University of Miami | Shestopalov V.I.,Vavilov Institute of General Genetics
BioTechniques | Year: 2014

Pyrosequencing of 16S ribosomal RNA (rRNA) genes has become the gold standard in human microbiome studies. Te routine task of taxonomic classification using 16S rRNA reads is commonly performed by the Ribosomal Database Project (RDP) II Classifier, a robust tool that relies on a set of well-characterized reference sequences. However, the RDP II Classifier may be unable to classify a significant part of the data set due to the absence of proper reference sequences. Te taxonomic classification for some unclassified sequences might still be performed using BLAST searches against large and frequently updated nucleotide databases. Here we introduce TUIT (Taxonomic Unit Identification Tool)-an efficient open source and platform-independent application that can perform taxonomic classification on its own or can be used in combination with the RDP II Classifier to maximize the taxonomic identification rate. Using a set of simulated DNA sequences, we demonstrate that the algorithm performs taxonomic classification with high specificity for sequences as short as 125 base pairs. TUIT is applicable for 16S rRNA gene sequence classifications; however, it is not restricted to 16S rRNA sequences. In addition, TUIT may be used as a complementary tool for effective taxonomic classification of nucleotide sequences generated by many current platforms, such as Roche 454 and Illumina.

PubMed | Bryansk Regional and Dermatology Center, Atlas Oncology Diagnostics, George Mason University and Vavilov Institute of General Genetics
Type: Journal Article | Journal: Experimental & molecular medicine | Year: 2016

Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the regulatory molecular mechanisms of the disease, we performed RNA sequencing analysis of 14 pairs of skin samples collected from patients with psoriasis. Subsequent pathway analysis and extraction of the transcriptional regulators governing psoriasis-associated pathways was executed using a combination of the MetaCore Interactome enrichment tool and the cisExpress algorithm, followed by comparison to a set of previously described psoriasis response elements. A comparative approach allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFB, IRF9, JUN, FOS, SRF), the activity of T cells in psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1), the hyperproliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C) and lipid metabolism (TFAP2, RARA, VDR). In addition to the core regulators, we identified 38 transcription factors previously not associated with the disease that can clarify the pathogenesis of psoriasis. To illustrate these findings, we analyzed the regulatory role of one of the identified transcription factors (TFs), FOXA1. Using ChIP-seq and RNA-seq data, we concluded that the atypical expression of the FOXA1 TF is an important player in the disease as it inhibits the maturation of naive T cells into the (CD4+FOXA1+CD47+CD69+PD-L1(hi)FOXP3-) regulatory T cell subpopulation, therefore contributing to the development of psoriatic skin lesions.

Konovalov F.,Vavilov Institute of General Genetics | Shaturova A.,Moscow State University | Mitrofanova O.,Vavilov All Russian Institute of Plant Industry | Kudryavtsev A.,Vavilov Institute of General Genetics
Euphytica | Year: 2012

The non-transgenic manipulation of starch properties in common wheat (Triticum aestivum L.) generally implies combining mutant alleles of the particular gene copies in all three subgenomes (A, B and D). The redundancy of the hexaploid wheat chromosome set substantially complicates the identification of recessive mutations and breeding. Nevertheless, naturally occurring or induced genetic polymorphism has already been successfully exploited for the production of waxy (GBSSI-deficient) and elevated amylose (SSIIa-deficient) wheats. However, in order to achieve the amylose content above 50% of wheat endosperm starch, it may be necessary to inactivate the starch branching enzyme (SBEIIa) isoforms, as the RNAi repression results and gene expression data strongly suggest. The identification of null SBEIIa alleles and their combination in a single genotype is therefore a promising approach to the production of non-transgenic high-amylose wheat; however, wheat SBEIIa polymorphism has not been characterized as of yet. In order to develop an approach to SBEIIa mutation screening, we sequenced the SBEIIa central region (exons 9-12) from the three subgenomes of common wheat cv. Chinese Spring and the A genome of diploid einkorn T. monococcum. The genome-specific primers were developed that amplify the exons downstream from intron 11 selectively from each homeologous gene. Using a single-stranded DNA conformation polymorphism (SSCP) approach, we screened 60 wheat cultivars, landraces, and rare species for naturally occurring SNPs in exons 12, 13 and 14 of the three SBEIIa homeologs. In total, 13 SNPs were discovered in the A and B wheat genomes. Two of these SNPs affect the amino acid sequences of SBEIIa isoforms and may change the enzyme functional properties. The presence of restriction site polymorphism at SNP positions enables their easy genotyping with CAPS assays. Our results indicate that the mining for naturally occurring sequence polymorphism in starch biosynthesis genes of wheat can be successfully performed at the DNA level, providing the starting point for a search for SBEIIa mutants at a larger scale. © 2011 Springer Science+Business Media B.V.

Shulha H.P.,University of Massachusetts Medical School | Crisci J.L.,University of Massachusetts Medical School | Reshetov D.,Vavilov Institute of General Genetics | Tushir J.S.,University of Massachusetts Medical School | And 17 more authors.
PLoS Biology | Year: 2012

Cognitive abilities and disorders unique to humans are thought to result from adaptively driven changes in brain transcriptomes, but little is known about the role of cis-regulatory changes affecting transcription start sites (TSS). Here, we mapped in human, chimpanzee, and macaque prefrontal cortex the genome-wide distribution of histone H3 trimethylated at lysine 4 (H3K4me3), an epigenetic mark sharply regulated at TSS, and identified 471 sequences with human-specific enrichment or depletion. Among these were 33 loci selectively methylated in neuronal but not non-neuronal chromatin from children and adults, including TSS at DPP10 (2q14.1), CNTN4 and CHL1 (3p26.3), and other neuropsychiatric susceptibility genes. Regulatory sequences at DPP10 and additional loci carried a strong footprint of hominid adaptation, including elevated nucleotide substitution rates and regulatory motifs absent in other primates (including archaic hominins), with evidence for selective pressures during more recent evolution and adaptive fixations in modern populations. Chromosome conformation capture at two neurodevelopmental disease loci, 2q14.1 and 16p11.2, revealed higher order chromatin structures resulting in physical contact of multiple human-specific H3K4me3 peaks spaced 0.5-1 Mb apart, in conjunction with a novel cis-bound antisense RNA linked to Polycomb repressor proteins and downregulated DPP10 expression. Therefore, coordinated epigenetic regulation via newly derived TSS chromatin could play an important role in the emergence of human-specific gene expression networks in brain that contribute to cognitive functions and neurological disease susceptibility in modern day humans. © 2012 Shulha et al.

Bick J.,Yale University | Naumova O.,Yale University | Naumova O.,Vavilov Institute of General Genetics | Hunter S.,Yale University | And 8 more authors.
Development and Psychopathology | Year: 2012

In recent years, translational research involving humans and animals has uncovered biological and physiological pathways that explain associations between early adverse circumstances and long-term mental and physical health outcomes. In this article, we summarize the human and animal literature demonstrating that epigenetic alterations in key biological systems, the hypothalamus-pituitary-adrenal axis and immune system, may underlie such disparities. We review evidence suggesting that changes in DNA methylation profiles of the genome may be responsible for the alterations in hypothalamus-pituitary-adrenal axis and immune system trajectories. Using some preliminary data, we demonstrate how explorations of genome-wide and candidate-gene DNA methylation profiles may inform hypotheses and guide future research efforts in these areas. We conclude our article by discussing the many important future directions, merging perspectives from developmental psychology, molecular genetics, neuroendocrinology, and immunology, that are essential for furthering our understanding of how early adverse circumstances may shape developmental trajectories, particularly in the areas of stress reactivity and physical or mental health. © Cambridge University Press 2012.

Melnikova N.V.,Vavilov Institute of General Genetics | Konovalov F.A.,Vavilov Institute of General Genetics | Kudryavtsev A.M.,Vavilov Institute of General Genetics
Plant Genetic Resources: Characterisation and Utilisation | Year: 2011

The recombinant inbred line mapping population Opata85 × Synthetic W7984 was used to map Jeli long terminal repeat retrotransposon insertion sites in the hexaploid wheat genome. Sequence-specific amplified polymorphism technique was applied to reveal Jeli insertions. Jeli was found to provide multiple genetic markers for common wheat. Our marker system revealed A-genome Jeli insertions, and therefore can be used for targeted analysis of the A genome. © 2011 NIAB.

Variability at the locus of major histocompatibility complex MHC-I A1 in 20 populations of pink salmon Oncorhynchus gorbuscha from the five major geographical regions of the Russian Far East was studied. Indices of genetic differentiation at all levels of the hierarchy were unexpectedly high and comparable with the corresponding estimates in related species of Pacific salmon. The data obtained allow us to revise the existing hypotheses concerning intraspecific structure of pink salmon, in particular, to reject the "fluctuating stock" hypothesis. Good resolution of the detected marker will find application in the problems of identification of populations in mixed catches. © 2012 Pleiades Publishing, Ltd.

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