AAC Accepts, published online ahead of print on 14 April 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00089-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Discordant patterns of genetic variation at two chloroquine-resistant loci in worldwide populations of malaria parasite Plasmodium falciparum

Rajeev K. Mehlotra^*, Gabriel Mattera, Moses J. Bockarie, Jason D. Maguire, J. Kevin Baird, Yagya D. Sharma, Michael Alifrangis, Grant Dorsey, Philip J. Rosenthal, David J. Fryauff, James W. Kazura, Mark Stoneking, and Peter A. Zimmerman

Center for Global Health and Diseases, Case Western Reserve University, School of Medicine, Cleveland, Ohio; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; U.S. Naval Medical Research Unit No. 2, Jakarta, Indonesia; Department of Biotechnology, All India Institute of Medical Sciences, New Delhi, India; Centre for Medical Parasitology, Institute for International Health, Immunology and Microbiology, Copenhagen, Denmark; Department of Medicine, University of California San Francisco, San Francisco, California; U.S. Naval Medical Research Unit No. 3, Cairo, Egypt; and Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany

^* To whom correspondence should be addressed. Email: rkm{at}case.edu.

Mutations in the chloroquine resistance transporter gene of Plasmodium falciparum (pfcrt, chromosome 7) play a key role in chloroquine resistance (CQR), while mutations in the multidrug resistance gene (pfmdr1, chromosome 5) play a significant role in the parasite's resistance to a variety of antimalarials, and also modulate CQR. To compare patterns of genetic variation at pfcrt and pfmdr1 loci, we investigated 460 P. falciparum-infected blood samples from four Asian, three African, and three South American countries, analyzing microsatellite (MS) loci flanking pfcrt (five loci, 40 kb) and pfmdr1 (either two loci [5 kb] or four loci [10 kb]). CQR pfmdr1 allele-associated MS haplotypes showed considerably higher genetic diversity and higher subdivision than CQR pfcrt allele-associated MS haplotypes in both Asian and African parasite populations. However, both pfcrt and pfmdr1 MS haplotypes showed similar levels of low diversity in South American parasite populations. Median-joining network analyses showed that pfcrt MS haplotypes correlated well with geography and CQR pfcrt alleles, whereas there was no distinct pfmdr1 MS haplotype that correlated with geography and/or CQR pfmdr1 alleles. Furthermore, multiple independent origins of CQR pfmdr1 alleles in Asia and Africa were inferred. These results suggest that variation at pfcrt and pfmdr1 loci in both Asian and African parasite populations is generated and/or maintained via substantially different mechanisms. Since pfmdr1 mutations may be associated with resistance to artemisinin combination therapies that are replacing CQ, particularly in Africa, it is important to determine if, and how, the genetic characteristics of this locus change over time.

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