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Open Access Highly Accessed Research article

Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology

Karine Brudey1, Jeffrey R Driscoll2, Leen Rigouts3, Wolfgang M Prodinger4, Andrea Gori5, Sahal A Al-Hajoj6, Caroline Allix7, Liselotte Aristimuño8, Jyoti Arora9, Viesturs Baumanis10, Lothar Binder11, Patricia Cafrune12, Angel Cataldi13, Soonfatt Cheong14, Roland Diel15, Christopher Ellermeier16, Jason T Evans17, Maryse Fauville-Dufaux7, Séverine Ferdinand1, Dario Garcia de Viedma18, Carlo Garzelli19, Lidia Gazzola5, Harrison M Gomes20, M Cristina Guttierez21, Peter M Hawkey17, Paul D van Helden22, Gurujaj V Kadival23, Barry N Kreiswirth24, Kristin Kremer25, Milan Kubin26, Savita P Kulkarni23, Benjamin Liens1, Troels Lillebaek27, Ho Minh Ly28, Carlos Martin29, Christian Martin30, Igor Mokrousov31, Olga Narvskaïa31, Yun Fong Ngeow14, Ludmilla Naumann32, Stefan Niemann33, Ida Parwati34, Zeaur Rahim35, Voahangy Rasolofo-Razanamparany36, Tiana Rasolonavalona36, M Lucia Rossetti12, Sabine Rüsch-Gerdes33, Anna Sajduda37, Sofia Samper38, Igor G Shemyakin39, Urvashi B Singh9, Akos Somoskovi40, Robin A Skuce41, Dick van Soolingen25, Elisabeth M Streicher22, Philip N Suffys20, Enrico Tortoli42, Tatjana Tracevska10, Véronique Vincent21, Tommie C Victor22, Robin M Warren22, Sook Fan Yap14, Khadiza Zaman35, Françoise Portaels3, Nalin Rastogi1* and Christophe Sola1*

Author Affiliations

1 Unité de la Tuberculose et des Mycobactéries, Institut Pasteur de Guadeloupe, Guadeloupe

2 Wadsworth Center, New York State Dept. of Health, Albany, NY, USA

3 Mycobacteriology Unit, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium

4 Dept. Hygiene Microbiology and Social Medicine, Innsbruck Medical University, Innsbruck, Austria

5 Dept of Infectious Diseases, Institut of Infectious Diseases, Milano, Italy

6 Department of Comparative Medicine, King Faisal specialist Hospital and Research Center, Riyadh, Saudi Arabia

7 Laboratoire de la Tuberculose, Institut Pasteur de Bruxelles, Belgique

8 Universidad Centrooccidental Lisandro Alvarado, Barquisimeto, Venezuela and Universidad de Zaragoza, Spain

9 All India Institute of Medical Sciences, New Delhi, India

10 Biomedical Research and Study Center, Riga, Latvia

11 Institut for Hygiene, Microbiologie and Tropical Medicine, Austria

12 Universidade Federal do Rio Grande de Soul, Brazil

13 Instituto de Biotecnologia INTA, Castelar, Argentina

14 Dept of Medical Microbiology and Pathology, faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia, School of Public Health

15 University of Düsseldorf, Heinrich-Heine-University, Düsseldorf

16 Dept of Internal Medicine II, University of Regensbourg, Germany

17 Public Health Laboratory, Hearltlands Hospital, Birmingham, UK

18 Dept of Clinical Microbiology and Infectious Diseases, Hospital Gregorio Marañon, Madrid, Spain

19 Dept. of Experimental Pathology, Medical Biotechnology, Infection and Epidemiology, Pisa University, Pisa, Italy

20 Laboratory of Molecular Biology applied to Mycobacteria, Dept. Mycobacteriosis, Oswaldo Cruz Institute, Rio de Janeiro, Brazil

21 Centre National de Référence des Mycobactéries, Institut Pasteur, Paris, France

22 MRC Centre for Molecular and Cellular Biology, Dept of medical Biochemistry, University of Stellenbosch, Tygerberg, South Africa

23 Laboratory Nuclear Medicine Section, Isotope group, Bhabha Atomic Research Centre c/T.M.H. Annexe, Parel, Mumbai-400012, India

24 Public Health Research Institute, Newark, NJ, USA

25 Mycobacteria reference unit, Diagnostic Laboratory for Infectious Diseases and Perinatal Screening, National Institute of Public Health and the Environment, Bilthoven, The Netherlands

26 Municipal Institute of Hygiene, Prague, Czech Republic

27 Statens Serum Institute, Int. Ref. lab. for Mycobacteriology, Copenhagen Denmark

28 Institute of Hygiene and Epidemiology, Hanoi, Vietnam

29 Universidad de Zaragoza, Zaragoza, Spain

30 Laboratoire de Bactério-virologie-hygiène, CHU Dupuytren, Limoges, France

31 Institut Pasteur de Saint-Petersbourg, Saint Petersbourg, Russia

32 Bavarian Health and Food Safety Authority, Oberschleissheim, Germany

33 Forschungszentrum, National Reference Center for Mycobacteria, Borstel, Germany

34 Dept of Clinical Pathology, Padjadjaran University, Dr. Hasan Sadikin Hospital, Bandung, Indonesia

35 Tuberculosis Laboratory, International Centre for Diarrhoeal Research, Dhaka, Bangladesh

36 Institut Pasteur de Madagascar, Tananarive, Madagascar

37 Dept of Genetics of Microorganisms, University of Lódz, Lodz, Poland

38 Servicio Microbiología, Hospital Universitario Miguel Servet, Zaragoza, Spain

39 State Research Center for Applied Microbiology, Obolensk, Russian Federation

40 Dept. of Respiratory Medicine School of Medicine Semmelweis University, Budapest, Hungary

41 Veterinary Sciences Division, Department of agriculture for Northern Ireland, Belfast, UK

42 Centro regionale di Riferimento per i Micobatteri, Laboratorio de Microbiologia e Virologia, Ospedale Careggi, Firenze, Italy

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BMC Microbiology 2006, 6:23  doi:10.1186/1471-2180-6-23

Published: 6 March 2006

Abstract

Background

The Direct Repeat locus of the Mycobacterium tuberculosis complex (MTC) is a member of the CRISPR (Clustered regularly interspaced short palindromic repeats) sequences family. Spoligotyping is the widely used PCR-based reverse-hybridization blotting technique that assays the genetic diversity of this locus and is useful both for clinical laboratory, molecular epidemiology, evolutionary and population genetics. It is easy, robust, cheap, and produces highly diverse portable numerical results, as the result of the combination of (1) Unique Events Polymorphism (UEP) (2) Insertion-Sequence-mediated genetic recombination. Genetic convergence, although rare, was also previously demonstrated. Three previous international spoligotype databases had partly revealed the global and local geographical structures of MTC bacilli populations, however, there was a need for the release of a new, more representative and extended, international spoligotyping database.

Results

The fourth international spoligotyping database, SpolDB4, describes 1939 shared-types (STs) representative of a total of 39,295 strains from 122 countries, which are tentatively classified into 62 clades/lineages using a mixed expert-based and bioinformatical approach. The SpolDB4 update adds 26 new potentially phylogeographically-specific MTC genotype families. It provides a clearer picture of the current MTC genomes diversity as well as on the relationships between the genetic attributes investigated (spoligotypes) and the infra-species classification and evolutionary history of the species. Indeed, an independent Naïve-Bayes mixture-model analysis has validated main of the previous supervised SpolDB3 classification results, confirming the usefulness of both supervised and unsupervised models as an approach to understand MTC population structure. Updated results on the epidemiological status of spoligotypes, as well as genetic prevalence maps on six main lineages are also shown. Our results suggests the existence of fine geographical genetic clines within MTC populations, that could mirror the passed and present Homo sapiens sapiens demographical and mycobacterial co-evolutionary history whose structure could be further reconstructed and modelled, thereby providing a large-scale conceptual framework of the global TB Epidemiologic Network.

Conclusion

Our results broaden the knowledge of the global phylogeography of the MTC complex. SpolDB4 should be a very useful tool to better define the identity of a given MTC clinical isolate, and to better analyze the links between its current spreading and previous evolutionary history. The building and mining of extended MTC polymorphic genetic databases is in progress.