Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite Plasmodium falciparum
Discordant patterns of genetic variation at two chloroquine resistance loci in worldwide populations of the malaria parasite Plasmodium falciparum
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DOI：
10.1128/aac.00089-08
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发表时间：
2008-06-01
影响因子：
4.9
通讯作者：
Zimmerman, Peter A.
中科院分区：
文献类型：
--
作者：
Mehlotra, Rajeev K.;Mattera, Gabriel;Zimmerman, Peter A.
恶性疟原虫氯喹抗性(CQR)转运蛋白基因(Pfcrt；7号染色体)突变在CQR中起关键作用，而多药耐药基因(Pfmdr1；5号染色体)突变在疟原虫对多种抗疟疾药物的耐药性中起重要作用，并调节CQR。为了比较Pfcrt和Pfmdr1基因座的遗传变异模式，我们调查了来自4个亚洲、3个非洲和3个南美国家的460名恶性疟原虫感染者的血液样本，分析了Pfcrt(5个座位[类似于40kb])和Pfmdr1(两个座位[类似于5kb]或4个座位[类似于10kb])两侧的微卫星(MS)座位。在亚洲和非洲寄生虫种群中，CQR Pfmdr1等位基因相关的MS单倍型表现出比CQR Pfcrt等位基因相关的MS单倍型更高的遗传多样性和更高的细分水平。然而，Pfcrt和Pfmdr1 MS单倍型在南美寄生虫种群中显示出相似的低多样性水平。中位联接网络分析表明，Pfcrt MS单倍型与地理和CQR Pfcrt等位基因有很好的相关性，而没有明显的Pfmdr1 MS单倍型与地理和/或CQR Pfmdr1等位基因相关。此外，还推测了CQR Pfmdr1等位基因在亚洲和非洲的多个独立来源。这些结果表明，亚洲和非洲寄生虫种群中Pfcrt和Pfmdr1基因座的变异是通过本质上不同的机制产生和/或维持的。由于Pfmdr1突变可能与青蒿素联合疗法的耐药性有关，青蒿素联合疗法正在取代CQ，特别是在非洲，因此确定该基因座的遗传特征是否以及如何随着时间的推移发生变化是很重要的。
Mutations in the chloroquine resistance (CQR) transporter gene of Plasmodium falciparum (Pfcrt; chromosome 7) play a key role in 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 blood samples from P. falciparum-infected patients from four Asian, three African, and three South American countries, analyzing microsatellite (MS) loci flanking Pfcrt (five loci [similar to 40 kb]) and Pfmdr1 (either two loci [similar to 5 kb] or four loci [similar to 10 kb]). CQR Pfmdr1 allele-associated MS haplotypes showed considerably higher genetic diversity and higher levels of 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 the 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.