Hitchhiking and selective sweeps of Plasmodium falciparum sulfadoxine and pyrimethamine resistance alleles in a population from central Africa - PubMed (original) (raw)

Hitchhiking and selective sweeps of Plasmodium falciparum sulfadoxine and pyrimethamine resistance alleles in a population from central Africa

Andrea M McCollum et al. Antimicrob Agents Chemother. 2008 Nov.

Abstract

Sulfadoxine-pyrimethamine (SP) resistance in Plasmodium falciparum is encoded by a number of mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes. Here, we have characterized point mutations in dhfr and dhps and microsatellite loci around dhfr on chromosome 4 and dhps on chromosome 8 as well as neutral markers on chromosomes 2 and 3 in 332 samples from Yaoundé, Cameroon. The triple mutant dhfr haplotype that originated in Southeast Asia is the most predominant in this sample set, but we also find additional independent haplotypes at low frequency and an incipient process of genetic differentiation among alleles of Southeast Asian origin. As reported for other African populations, we find evidence of a selective sweep for resistant dhfr mutants in this Cameroonian population due to drug selection. Although we find evidence for a selective sweep in dhps mutants associated with SP resistance, the dynamics of dhps mutants appear different than those observed for dhfr mutants. Overall, our results yield support for the use of microsatellite markers to track resistant parasites; however, the detection of resistant dhfr alleles in low frequency, the evidence of divergence among dhfr alleles that share a common evolutionary origin, and the distinct dynamics of resistant dhps alleles emphasize the importance of comprehensive, population-based investigations to evaluate the effects of drug selection on parasite populations.

PubMed Disclaimer

Figures

FIG. 1.

Relationships among dhfr (A) and dhps (B) haplotypes in Cameroon, as determined by eBURST analysis. Each line connects haplotypes that are identical at 11 out of 12 loci. Haplotypes shown as single points differ from other haplotypes by alleles in at least two loci. The blue circles represent complex founders, and the yellow circles represent subgroup founders. The size of the circles is proportional to the number of isolates of the given haplotype. (A) One hundred ninety-one 12-locus dhfr microsatellite haplotypes. The central complex is composed mostly of haplotypes from 51I/59R/108N alleles. Triple mutant alleles marked with an asterisk are those that differ significantly from the Southeast Asian haplotype. A total of 7 samples with the sensitive dhfr allele, 2 with the 108N allele, 1 with the 51I/108N allele, 10 with the 59R/108N allele, and 171 with the 51I/59R/108N allele were used for this analysis. (B) One hundred forty-nine 10-locus dhps microsatellite haplotypes. The central complex is composed mostly of haplotypes from 437G mutant alleles. A total of 8 samples with the sensitive dhps allele, 35 with the 436A allele, 80 with the 437G allele, 1 with the 613S allele, 21 with the 436A/437G allele, 3 with the 437G/613S allele, and 1 with the 436A/613S allele were used for this analysis.

FIG. 2.

Expected heterozygosity around dhfr (A) and dhps (B) alleles. Only alleles that had a sample size greater than 12 are plotted. The horizontal dashed line across the top of the graph represents the mean He observed at neutral loci on chromosomes 2 and 3. (A) Sensitive alleles are represented by the black line, 59R/108N alleles are represented by the blue line, and 51I/59R/108N alleles are represented by the red line. (B) Sensitive alleles are represented by the black line, 436A alleles by the blue line, 437G alleles by the yellow line, and 436A/437G alleles by the red line.

FIG. 3.

Pairwise LD between microsatellite loci on different chromosomes (A) and between sites in dhfr and dhps (B). Each box represents one comparison between polymorphic pairs of loci; nonpolymorphic pairwise comparisons are not included. Bonferroni's correction for multiple comparisons was conducted for each comparison. Dark-gray cells represent significance at a P value of 0.01, light-gray cells represent significance at a P value of 0.05, and white cells represent values that were not significant. (A) The location of each microsatellite locus is at the top of the matrix (loci are named according to their positions relative to dhfr or dhps or along chromosome [ch] 2 or 3 according to the 3D7 genome sequence available from NCBI). The black boxes within chromosomes 4 and 8 represent the positions of dhfr and dhps, respectively. (B) Pairwise LD between sites in dhfr (codons 51, 59, and 108) and dhps (codons 436, 437, and 613).

References

1. Anderson, T. J., B. Haubold, J. T. Williams, J. G. Estrada-Franco, L. Richardson, R. Mollinedo, M. Bockarie, J. Mokili, S. Mharakurwa, N. French, J. Whitworth, I. D. Velez, A. H. Brockman, F. Nosten, M. U. Ferreira, and K. P. Day. 2000. Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Mol. Biol. Evol. 17**:**1467-1482. - PubMed
1. Anderson, T. J., and C. Roper. 2005. The origins and spread of antimalarial drug resistance: lessons for policy makers. Acta Trop. 94**:**269-280. - PubMed
1. Basco, L. K. 2003. Molecular epidemiology of malaria in Cameroon. XVI. Longitudinal surveillance of in vitro pyrimethamine resistance in Plasmodium falciparum. Am. J. Trop. Med. Hyg. 69**:**174-178. - PubMed
1. Basco, L. K., M. Ndounga, M. Tejiokem, V. F. Ngane, J. C. Youmba, P. Ringwald, and G. Soula. 2002. Molecular epidemiology of malaria in Cameroon. XI. Geographic distribution of Plasmodium falciparum isolates with dihydrofolate reductase gene mutations in southern and central Cameroon. Am. J. Trop. Med. Hyg. 67**:**378-382. - PubMed
1. Basco, L. K., and P. Ringwald. 2007. Molecular epidemiology of malaria in Cameroon. XXIV. Trends of in vitro antimalarial drug responses in Yaounde, Cameroon. Am. J. Trop. Med. Hyg. 76**:**20-26. - PubMed

Hitchhiking and selective sweeps of Plasmodium falciparum sulfadoxine and pyrimethamine resistance alleles in a population from central Africa - PubMed (original) (raw)