McCollum Andrea M, Basco Leonardo K, Tahar Rachida, Udhayakumar Venkatachalam, Escalante Ananias A
Program in Population Biology, Ecology, and Evolution, Emory University, Atlanta, Georgia, USA.
Antimicrob Agents Chemother. 2008 Nov;52(11):4089-97. doi: 10.1128/AAC.00623-08. Epub 2008 Sep 2.
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.
恶性疟原虫对磺胺多辛-乙胺嘧啶（SP）的耐药性由二氢叶酸还原酶（dhfr）和二氢蝶酸合酶（dhps）基因中的多个突变编码。在此，我们对喀麦隆雅温得332份样本中dhfr和dhps的点突变、4号染色体上dhfr周围及8号染色体上dhps周围的微卫星位点以及2号和3号染色体上的中性标记进行了特征分析。起源于东南亚的三重突变dhfr单倍型在该样本集中最为常见，但我们也发现了低频的其他独立单倍型以及东南亚起源等位基因间初步的遗传分化过程。正如其他非洲人群所报道的那样，我们发现由于药物选择，在这个喀麦隆人群中存在对耐药dhfr突变体的选择性清除证据。虽然我们发现了与SP耐药性相关的dhps突变体存在选择性清除的证据，但dhps突变体的动态变化似乎与dhfr突变体不同。总体而言，我们的结果支持使用微卫星标记来追踪耐药寄生虫；然而，低频耐药dhfr等位基因的检测、具有共同进化起源的dhfr等位基因间的分化证据以及耐药dhps等位基因的独特动态变化强调了基于人群的全面调查对于评估药物选择对寄生虫群体影响的重要性。
