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Journal of Bacteriology, December 2008, p. 7838-7846, Vol. 190, No. 23
0021-9193/08/$08.00+0     doi:10.1128/JB.00827-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Frequent Homologous Recombination Events in Mycobacterium tuberculosis PE/PPE Multigene Families: Potential Role in Antigenic Variability ^{, ,}

Anis Karboul,¹ Alberto Mazza,² Nicolaas C. Gey van Pittius,³ John L. Ho,⁴ Roland Brousseau,² and Helmi Mardassi^1*

Unit of Typing and Genetics of Mycobacteria, Institut Pasteur de Tunis, Tunis, Tunisia,¹ Biotechnology Research Institute of Montreal, 6100 Royalmount, Montreal, Canada,² DST/NRF Centre of Excellence in Biomedical Tuberculosis Research, MRC Centre for Molecular and Cellular Biology, Department of Biomedical Sciences, Faculty of Health Sciences, Stellenbosch University, Tygerberg, South Africa,³ Division of International Medicine and Infectious Diseases, Weill Medical College of Cornell University, New York, New York⁴

Received 13 June 2008/ Accepted 20 September 2008

The PE and PPE (PE/PPE) multigene families of Mycobacterium tuberculosis are particularly GC-rich and share extensive homologous repetitive sequences. We hypothesized that they may undergo homologous recombination events, a mechanism rarely described in the natural evolution of mycobacteria. To test our hypothesis, we developed a specific oligonucleotide-based microarray targeting nearly all of the PE/PPE genes, aimed at detecting signals for homologous recombination. Such a microarray has never before been reported due to the multiplicity and highly repetitive and homologous nature of these sequences. Application of the microarray to a collection of M. tuberculosis clinical isolates (n = 33) representing prevalent spoligotype strain families in Tunisia allowed successful detection of six deleted genomic regions involving a total of two PE and seven PPE genes. Some of these deleted genes are known to be immunodominant or involved in virulence. The four precisely determined deletions were flanked by 400- to 500-bp stretches of nearly identical sequences lying mainly at the conserved N-terminal region of the PE/PPE genes. These highly homologous sequences thus serve as substrates to mediate both intergenic and intragenic homologous recombination events, indicating an important function in generating strain variation. Importantly, all recombination events yielded a new in-frame fusion chimeric gene. Hence, homologous recombination within and between PE/PPE genes likely increased their antigenic variability, which may have profound implications in pathogenicity and/or host adaptation. The finding of high prevalence (45% and 58%) for at least two of the genomic deletions suggests that they likely confer advantageous biological attributes.

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* Corresponding author. Mailing address: Institut Pasteur de Tunis, 13 Place Pasteur, B.P. 74, 1002 Tunis-Belvédère, Tunis, Tunisia. Phone: (216) 71 843 755. Fax: (216) 71 791 833. E-mail: helmi.merdassi{at}pasteur.rns.tn

Published ahead of print on 26 September 2008.

Supplemental material for this article may be found at http://jb.asm.org/.

This paper is dedicated to the memory of Roland Brousseau.

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Journal of Bacteriology, December 2008, p. 7838-7846, Vol. 190, No. 23
0021-9193/08/$08.00+0     doi:10.1128/JB.00827-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.