Genome-Wide Mycobacterium tuberculosis Variation (GMTV) Database: A New Tool for Integrating Sequence Variations and Epidemiology

Background Tuberculosis (TB) poses a worldwide threat due to advancing multidrug-resistant strains and deadly co-infections with Human immunodeficiency virus. Today large amounts of Mycobacterium tuberculosis whole genome sequencing data are being assessed broadly and yet there exists no comprehensive online resource that connects M. tuberculosis genome variants with geographic origin, with drug resistance or with clinical outcome. Description Here we describe a broadly inclusive unifying Genome-wide Mycobacterium tuberculosis Variation (GMTV) database, (http://mtb.dobzhanskycenter.org) that catalogues genome variations of M. tuberculosis strains collected across Russia. GMTV contains a broad spectrum of data derived from different sources and related to M. tuberculosis molecular biology, epidemiology, TB clinical outcome, year and place of isolation, drug resistance profiles and displays the variants across the genome using a dedicated genome browser. GMTV database, which includes 1084 genomes and over 69,000 SNP or Indel variants, can be queried about M. tuberculosis genome variation and putative associations with drug resistance, geographical origin, and clinical stages and outcomes. Conclusions Implementation of GMTV tracks the pattern of changes of M. tuberculosis strains in different geographical areas, facilitates disease gene discoveries associated with drug resistance or different clinical sequelae, and automates comparative genomic analyses among M. tuberculosis strains

EPMA-World Congress 2015: Bonn, Germany. 3-5 September 2015

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Boyko A7 Towards personalized physiotherapeutic approach Joanna Bauer, Ewa Boerner, Halina Podbielska A8 Cells, animal, SHIME and in silico models for detection and verification of specific biomarkers of non-communicable chronic diseases Alojz Bomba, Viktor O. Petrov, Volodymyr G. Drobnych, Rostyslav V. Bubnov, Oksana M. Bykova, Nadiya V. Boyko A9 INTERACT-chronic care model: Self-treatment by patients with decision support e-Health solution Hans-Peter Brunner-La Rocca, Lutz Fleischhacker, Olga Golubnitschaja, Frank Heemskerk, Thomas Helms, Tiny Jaarsma, Judita Kinkorova, Jan Ramaekers, Peter Ruff, Ivana Schnur, Emilio Vanoli, Jose Verdu A10 PPPM in cardiovascular medicine in 2015 Hans-Peter Brunner-La Rocca A11 Magnetic resonance imaging of nanoparticles in mice, potential for theranostic and contrast media development – pilot results Rostyslav V. Bubnov, Sergiy A. Grabovetskyi, Olena M. Mykhalchenko, Natalia O. Tymoshok, Oleksandr B. Shcherbakov, Igor P. Semeniv, Mykola Y. Spivak A12 Ultrasound diagnosis for diabetic neuropathy - comparative study Rostyslav V. Bubnov, Tetyana V. Ostapenko A13 Ultrasound for stratification patients with diabetic foot ulcers for prevention and personalized treatment - pilot results Rostyslav V. Bubnov, Nazarii M. Kobyliak, Nadiya M. Zholobak, Mykola Ya. Spivak A14 Project ImaGenX – designing and executing a questionnaire on environment and lifestyle risk of breast cancer John Paul Cauchi A15 Genomics – a new structural brand of predictive, preventive and personalized medicine or the new driver as well? 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Ivanova, Michail V. Eremin, Maria V. Rostovtseva A23 Сentral aortic pressure and indexes of augmentation in young persons in view of risk factors Maria E. Evsevyeva, Michail V. Eremin, Vladimir I. Koshel, Oksana V. Sergeeva, Nadesgda M. Konovalova A24 Breast cancer prediction and prevention: Are reliable biomarkers in horizon? Shantanu Girotra, Olga Golubnitschaja A25 Flammer Syndrome and potential formation of pre-metastatic niches: A multi-centred study on phenotyping, patient stratification, prediction and potential prevention of aggressive breast cancer and metastatic disease Olga Golubnitschaja, Manuel Debald, Walther Kuhn, Kristina Yeghiazaryan, Rostyslav V. Bubnov, Vadym M. 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Unusual Large-Scale Chromosomal Rearrangements in <i>Mycobacterium tuberculosis</i> Beijing B0/W148 Cluster Isolates

<div><p>The <i>Mycobacterium tuberculosis</i> (MTB) Beijing family isolates are geographically widespread, and there are examples of Beijing isolates that are hypervirulent and associated with drug resistance. One-fourth of Beijing genotype isolates found in Russia belong to the B0/W148 group. The aim of the present study was to investigate features of these endemic strains on a genomic level. Four Russian clinical isolates of this group were sequenced, and the data obtained was compared with published sequences of various MTB strain genomes, including genome of strain W-148 of the same B0/W148 group. The comparison of the W-148 and H37Rv genomes revealed two independent inversions of large segments of the chromosome. The same inversions were found in one of the studied strains after deep sequencing using both the fragment and mate-paired libraries. Additionally, inversions were confirmed by RFLP hybridization analysis. The discovered rearrangements were verified by PCR in all four newly sequenced strains in the study and in four additional strains of the same Beijing B0/W148 group. The other 32 MTB strains from different phylogenetic lineages were tested and revealed no inversions. We suggest that the initial largest inversion changed the orientation of the three megabase (Mb) segment of the chromosome, and the second one occurred in the previously inverted region and partly restored the orientation of the 2.1 Mb inner segment of the region. This is another remarkable example of genomic rearrangements in the MTB in addition to the recently published of large-scale duplications. The described cases suggest that large-scale genomic rearrangements in the currently circulating MTB isolates may occur more frequently than previously considered, and we hope that further studies will help to determine the exact mechanism of such events.</p></div

Schematic presentation of duplicated bases flanking the IS<i>6110</i> insertion sites between LCBs II&III and III&IV.

<p>Schematic presentation of duplicated bases flanking the IS<i>6110</i> insertion sites between LCBs II&III and III&IV.</p

Genotyping and drug resistance data of the B0/W148 strains sequenced in this study.

<p>¹ RIF - rifampicin, INH - isoniazid, EMB - ethambutol, STR - streptomycin, PZA - pyrazinamide, ETH - ethionamide, AMI- amikacin, CAPR - capreomycin, OFL – ofloxacin.</p><p>² B0 designation according to Narvskaya <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084971#pone.0084971-Narvskaya1" target="_blank">[6]</a>, W148 according to Bifani <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084971#pone.0084971-Bifani1" target="_blank">[14]</a>.</p><p>³ SITVITWEB was used for identification of data <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084971#pone.0084971-Demay1" target="_blank">[15]</a>.</p><p>⁴ 24 – VNTR: s154, s580, s960, s1644, s2059, s2531, s2687, s2996, s3007, s3192, s4348, s802, s2165, s2461, s577, s2163, s4052, s4156, s424, s1955, s2347, s2401, s3171, s3690 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084971#pone.0084971-Supply1" target="_blank">[16]</a>.</p

Schematic representation of genome rearrangements' and primer design strategy.

<p>Each local collinear block (LCB) corresponds to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084971#pone-0084971-t002" target="_blank">Table 2</a> and is represented by a different color.</p

Genome rearrangements' representation for W-148 Progenitor I like H37Rv, W-148 Progenitor II and W-148 genomes.

<p>Each local collinear block (LCB) I–V is represented by a different color. Upside-down blocks (LCBs II and IV) represent the location of the reverse strand, which means an inversion has occurred. Asterisk indicates a terminus of a replication site. Terminus of a replication site was calculated based on GraphDNA (GC-skew mode) software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084971#pone.0084971-Thomas1" target="_blank">[19]</a>.</p

Results of PCR verification of inversions.

<p>Electrophoregram of PCR products obtained for MTB strains during the amplification with primer sets 1–8 (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084971#pone-0084971-t003" target="_blank">Table 3</a>).(A) SP 21 B0/W148 Beijing strain and (B) SP 5 non-B0/W148 Beijing strain. Lanes 1–8 correspond to primer sets 1–8; M is a marker GeneRuler 100 bp Plus DNA Ladder (Fermentas, SM0324); K- is a negative control.</p