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Nucleic Acids Research Advance Access published online on January 7, 2009
Nucleic Acids Research, doi:10.1093/nar/gkn1069
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum

Philippe Leprohon1, Danielle Légaré1, Frédéric Raymond1, Éric Madore1, Gary Hardiman2, Jacques Corbeil1 and Marc Ouellette1,*

1Centre de Recherche en Infectiologie et Division de Microbiologie, Université Laval, Québec, Canada, G1V 4G2 and 2BIOGEM, University of California, San Diego, CA 92093, USA

*To whom correspondence should be addressed. Tel: +1 418 654 2705; Fax: +1 418 654 2715; Email: marc.ouellette{at}crchul.ulaval.ca

Received October 21, 2008. Revised December 19, 2008. Accepted December 20, 2008.

Antimonials remain the first line drug against the protozoan parasite Leishmania but their efficacy is threatened by resistance. We carried out a RNA expression profiling analysis comparing an antimony-sensitive and -resistant (Sb2000.1) strain of Leishmania infantum using whole-genome 70-mer oligonucleotide microarrays. Several genes were differentially expressed between the two strains, several of which were found to be physically linked in the genome. MRPA, an ATP-binding cassette (ABC) gene known to be involved in antimony resistance, was overexpressed in the antimony-resistant mutant along with three other tandemly linked genes on chromosome 23. This four gene locus was flanked by 1.4 kb repeated sequences from which an extrachromosomal circular amplicon was generated in the resistant cells. Interestingly, gene expression modulation of entire chromosomes occurred in the antimony-resistant mutant. Southern blots analyses and comparative genomic hybridizations revealed that this was either due to the presence of supernumerary chromosomes or to the loss of one chromosome. Leishmania parasites with haploid chromosomes were viable. Changes in copy number for some of these chromosomes were confirmed in another antimony-resistant strain. Selection of a partial revertant line correlated antimomy resistance levels and the copy number of aneuploid chromosomes, suggesting a putative link between aneuploidy and drug resistance in Leishmania.


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