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ANALYSIS OF THE GENETIC DIVERSITY OF THE PLASMODIUM FALCIPARUM MULTIDRUG RESISTANCE GENE 5' UPSTREAM REGION

Recent findings indicating a low level of polymorphism in the Plasmodium falciparum genome have led to the hypothesis that existent polymorphisms are likely to have functional significance. We tested this hypothesis by developing a map of the polymorphism in the P. falciparum multidrug resistance 1 (pfmdr1) gene 5' upstream region and assaying its correlation with drug resistance in a sample of field isolates from Dakar, Senegal. A comparison of six geographically diverse laboratory strains showed that the 1.94-kb 5'-untranslated region is highly monomorphic, with a total of four unique single nucleotide polymorphisms (SNPs) being identified. All of the mutations were localized to a 462-basepair region proximal to the transcription start point. Analysis of this region in field isolates shows the prevalence of one SNP throughout the entire population of parasites, irrespective of drug resistance status. The SNP frequency of the pfmdr1 upstream region is lower than that found in the noncoding region of other genes.

Received July 28, 2003. Accepted for publication July 7, 2004.

Acknowledgments: We thank Cathy Ndiaye and Abdoulaye Diallo for technical support. We also acknowledge the entire research team in Dakar, as well as the study participants, for their support. Dr. Peter Bachetti (Division of Biostatistics, University of California at San Francisco) made the random chance calculation.

Financial support: This work was supported by the Fogarty International Center, the National Institutes of Health (RO1 GM061351), and the Harvard Malaria Initiative.

Author’s addresses: Alissa Myrick, Department of Medicine, Building 10, Room 3402, University of California at San Francisco, 1001 Potrero Avenue, San Francisco, CA 94110. Ousmane Sarr and Souleymane Mboup, Laboratory of Bacteriology and Virology, Le Dantec Hospital, Dakar, Senegal, Telephone: 221-821-6420, Fax: 221-822-5919. Therese Dieng and Omar Ndir, Laboratory of Parasitology, Faculty of Medicine and Pharmacy, Cheikh Anta Diop University, Dakar, Senegal, Telephone: 221-824-5588, Fax: 221-825-3668. Dyann F. Wirth, Department of Immunology and Infectious Diseases, Building 1, Room 704, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA, 02115, USA, Telephone: 617-432-1621, Fax: 617-432-4766, E-mail: dfwirth{at}hsph.harvard.edu.

Reprint requests: Department of Immunology and Infectious Diseases, Building 1, Room 704, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA, 02115.

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