Vavilov Institute of General Genetics

Moscow, Russia

Vavilov Institute of General Genetics

Moscow, Russia
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News Article | May 16, 2017

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.

Danilenko V.N.,Vavilov Institute of General Genetics | Osolodkin D.I.,Moscow State University | Lakatosh S.A.,RAS Gause Institute of New Antibiotics | Preobrazhenskaya M.N.,RAS Gause Institute of New Antibiotics | Shtil A.A.,Research Center for Biotechnology of Antibiotics
Current Topics in Medicinal Chemistry | Year: 2011

Signaling through protein kinases is an evolutionary conserved, widespread language of biological regulation. The eukaryotic type serine-threonine protein kinases (STPKs) found in normal human microbiote and in pathogenic bacteria play a key role in regulation of microbial survival, virulence and pathogenicity. Therefore, down-regulation of bacterial STPKs emerges as an attractive approach to cure infections. In this review we focused on actinobacterial STPKs to demonstrate that these enzymes can be used for crystal structure studies, modeling of 3D structure, construction of test systems and design of novel chemical libraries of low molecular weight inhibitors. In particular, the prototypic pharmacological antagonists of Mycobacterium tuberculosis STPKs are perspective for development of a novel generation of drugs to combat the socially important disease. These inhibitors may modulate both actinobacterial and host STPKs and trigger programmed death of pathogenic bacteria. © 2011 Bentham Science Publishers Ltd.

Kaev A.M.,Sakhalin State University | Zhivotovsky L.A.,Vavilov Institute of General Genetics
Journal of Ichthyology | Year: 2017

The scale structure of pink salmon Oncorhynchus gorbuscha inhabiting southern Sakhalin and Iturup Island were studied in 2014. These locations are characterized by the unusual dynamics of catches and biological parameters of the fish that come to spawn in different areas in the Sakhalin-Kuril region. The pink salmon that has originated from Iturup Island appeared en masse in the waters of southern Sakhalin, according to the analysis of the scleritogram fragments that reflect the fish growth during the first months of life. This is the first confirmation of the hypothesis of the fluctuating stocks of pink salmon approved by the ichthyological methods. It is suggested that wide-scale straying of pink salmon takes place in the years of dominance shift between the generations of even and odd spawning years. © 2017, Pleiades Publishing, Ltd.

Balanovsky O.,Vavilov Institute of General Genetics
Human Genetics | Year: 2017

The mutation rate on the Y-chromosome matters for estimating the time-to-the-most-recent-common-ancestor (TMRCA, i.e. haplogroup age) in population genetics, as well as for forensic, medical, and genealogical studies. Large-scale sequencing efforts have produced several independent estimates of Y-SNP mutation rates. Genealogical, or pedigree, rates tend to be slightly faster than evolutionary rates obtained from ancient DNA or calibrations using dated (pre)historical events. It is, therefore, suggested to report TMRCAs using an envelope defined by the average aDNA-based rate and the average pedigree-based rate. The current estimate of the “envelope rate” is 0.75–0.89 substitutions per billion base pairs per year. The available Y-SNP mutation rates can be applied to high-coverage data from the entire X-degenerate region, but other datasets may demand recalibrated rates. While a consensus on Y-SNP rates is approaching, the debate on Y-STR rates has continued for two decades, because multiple genealogical rates were consistent with each other but three times faster than the single evolutionary estimate. Applying Y-SNP and Y-STR rates to the same haplogroups recently helped to clarify the issue. Genealogical and evolutionary STR rates typically provide lower and upper bounds of the “true” (SNP-based) age. The genealogical rate often—but not always—works well for haplogroups less than 7000 years old. The evolutionary rate, although calibrated using recent events, inflates ages of young haplogroups and deflates the age of the entire Y-chromosomal tree, but often provides reasonable estimates for intermediate ages (old haplogroups). Future rate estimates and accumulating case studies should further clarify the Y-SNP rates. © 2017, Springer-Verlag Berlin Heidelberg.

Mikheecheva N.E.,Vavilov Institute of General Genetics | Mikheecheva N.E.,Moscow Institute of Physics and Technology | Zaychikova M.V.,Vavilov Institute of General Genetics | Melerzanov A.V.,Moscow Institute of Physics and Technology | Danilenko V.N.,Vavilov Institute of General Genetics
Genome biology and evolution | Year: 2017

Mycobacterium tuberculosis is divided into several distinct lineages, and various genetic markers such as IS-elements, VNTR, and SNPs are used for lineage identification. We propose an M. tuberculosis classification approach based on functional polymorphisms in virulence genes. An M. tuberculosis virulence genes catalog has been established, including 319 genes from various protein groups, such as proteases, cell wall proteins, fatty acid and lipid metabolism proteins, sigma factors, toxin-antitoxin systems. Another catalog of 1,573 M. tuberculosis isolates of different lineages has been developed. The developed SNP-calling program has identified 3,563 nonsynonymous SNPs. The constructed SNP-based phylogeny reflected the evolutionary relationship between lineages and detected new sublineages. SNP analysis of sublineage F15/LAM4/KZN revealed four lineage-specific mutations in cyp125, mce3B, vapC25, and vapB34. The Ural lineage has been divided into two geographical clusters based on different SNPs in virulence genes. A new sublineage, B0/N-90, was detected inside the Beijing-B0/W-148 by SNPs in irtB, mce3F and vapC46. We have found 27 members of B0/N-90 among the 227 available genomes of the Beijing-B0/W-148 sublineage. Whole-genome sequencing of strain B9741, isolated from an HIV-positive patient, was demonstrated to belong to the new B0/N-90 group. A primer set for PCR detection of B0/N-90 lineage-specific mutations has been developed. The prospective use of mce3 mutant genes as genetically engineered vaccine is discussed. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

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.

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.

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.

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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