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Infection and Immunity, May 2009, p. 2230-2238, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01099-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Comprehensive Survey of Single Nucleotide Polymorphisms (SNPs) across Mycobacterium bovis Strains and M. bovis BCG Vaccine Strains Refines the Genealogy and Defines a Minimal Set of SNPs That Separate Virulent M. bovis Strains and M. bovis BCG Strains{triangledown} ,{dagger}

M. Carmen Garcia Pelayo,1,{ddagger} Swapna Uplekar,2,{ddagger} Andrew Keniry,3,§ Pablo Mendoza Lopez,1,4 Thierry Garnier,5 Javier Nunez Garcia,1 Laura Boschiroli,6 Xiangmei Zhou,7 Julian Parkhill,3 Noel Smith,1,8 R. Glyn Hewinson,1 Stewart T. Cole,2 and Stephen V. Gordon1,9,10,11,12*

TB Research Group, VLA Weybridge, New Haw, Surrey KT15 3NB, United Kingdom,1 Global Health Institute, EPFL, CH-1015 Lausanne, Switzerland,2 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom,3 Department of Biochemistry and Molecular Biology, Universidad de Granada, Granada, Spain,4 Unité de Génétique et Génomique des Insectes Vecteurs, Institut Pasteur, 28 Rue du Dr Roux, Paris 75015, France,5 Agence Française de Sécurité Sanitaire des Aliments, 23 avenue du Général-de-Gaulle, 94706 Maisons-Alfort Cedex, France,6 College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Haidian District, Beijing, People's Republic of China, 100193,7 Centre for the Study of Evolution (CSE), University of Sussex, Brighton BN1 9QL, United Kingdom,8 UCD Schools of Agriculture, Food Science and Veterinary Medicine,9 Medicine and Medical Science,10 Biomolecular and Biomedical Science, College of Life Sciences,11 UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland,12

Received 3 September 2008/ Returned for modification 26 October 2008/ Accepted 4 March 2009

To further unravel the mechanisms responsible for attenuation of the tuberculosis vaccine Mycobacterium bovis BCG, comparative genomics was used to identify single nucleotide polymorphisms (SNPs) that differed between sequenced strains of Mycobacterium bovis and M. bovis BCG. SNPs were assayed in M. bovis isolates from France and the United Kingdom and from different BCG vaccines in order to identify those that arose during the attenuation process which gave rise to BCG. Informative data sets were obtained for 658 SNPs from 21 virulent M. bovis strains and 13 BCG strains; these SNPs showed phylogenetic clustering that was consistent with the geographical origin of the strains and previous schemes for BCG genealogies. The data revealed a closer relationship between BCG Tice and BCG Pasteur than was previously appreciated, while we were able to position BCG Beijing within a grouping of BCG Denmark-derived strains. Only 186 SNPs were identified between virulent M. bovis strains and all BCG strains, with 115 nonsynonymous SNPs affecting important functions such as global regulators, transcriptional factors, and central metabolism, which might impact on virulence. We therefore refine previous genealogies of BCG vaccines and define a minimal set of SNPs between virulent M. bovis strains and the attenuated BCG strain that will underpin future functional analyses.

* Corresponding author. Mailing address: School of Agriculture, Food Science and Veterinary Medicine, College of Life Sciences, University College Dublin, Dublin 4, Ireland. Phone: 353 1 7166181. Fax: 353 1 7166185. E-mail: stephen.gordon{at}ucd.ie

{triangledown} Published ahead of print on 16 March 2009.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: J. L. Flynn

{ddagger} These authors made equal contributions to this work.

§ Present address: Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB22 3AT, United Kingdom.

Infection and Immunity, May 2009, p. 2230-2238, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01099-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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