Discordant Patterns of Genetic Variation at Two Chloroquine Resistance Loci in Worldwide Populations of the Malaria Parasite Plasmodium falciparum

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Abstract
Mutations in the chloroquine resistance (CQR) transporter gene of Plasmodium falciparum (Pf crt ; chromosome 7) play a key role in CQR, while mutations in the multidrug resistance gene (Pf mdr1 ; 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 Pf crt and Pf mdr1 loci, we investigated 460 blood samples from P. falciparum -infected patients from four Asian, three African, and three South American countries, analyzing microsatellite (MS) loci flanking Pf crt (five loci [∼40 kb]) and Pf mdr1 (either two loci [∼5 kb] or four loci [∼10 kb]). CQR Pf mdr1 allele-associated MS haplotypes showed considerably higher genetic diversity and higher levels of subdivision than CQR Pf crt allele-associated MS haplotypes in both Asian and African parasite populations. However, both Pf crt and Pf mdr1 MS haplotypes showed similar levels of low diversity in South American parasite populations. Median-joining network analyses showed that the Pf crt MS haplotypes correlated well with geography and CQR Pf crt alleles, whereas there was no distinct Pf mdr1 MS haplotype that correlated with geography and/or CQR Pf mdr1 alleles. Furthermore, multiple independent origins of CQR Pf mdr1 alleles in Asia and Africa were inferred. These results suggest that variation at Pf crt and Pf mdr1 loci in both Asian and African parasite populations is generated and/or maintained via substantially different mechanisms. Since Pf mdr1 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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