Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum
Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum
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DOI：
10.1038/nature00813
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发表时间：
2002-07-18
期刊：
影响因子：
64.8
通讯作者：
Su, XZ
中科院分区：
文献类型：
--
作者：
Wootton, JC;Feng, XR;Su, XZ
抗疟药物的广泛使用可以深刻影响人类疟原虫恶性疟原虫的进化。最近对耐药基因型的选择性清除可能限制了这种寄生虫的遗传多样性，类似于当前辩论中归因于历史种群瓶颈的影响(1-4)。大约 45 年前，东南亚和南美洲的两个疫源地首次报道了抗氯喹 (CQR) 寄生虫(5)，但 CQR 起始突变的数量以及氯喹对全世界寄生虫基因组的影响一直难以评估。使用遗传图谱 (6) 中的 342 个高度多态性微卫星标记，我们表明寄生虫基因组不同区域之间的遗传多样性水平差异很大，揭示了围绕关键 CQR 基因 pfcrt(7) 和至少四个 CQR 创始人事件的广泛连锁不平衡。这种不平衡及其在 pfcrt 侧翼区域的衰减率与仅在大约 20-80 个有性世代发生的强定向选择性扫描一致，特别是在亚洲和非洲大部分地区以非常高的频率传播的单一抗性 pfcrt 单倍型。连锁不平衡的存在为恶性疟原虫药物选择下的基因定位提供了基础。
Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates(1-4) to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America(5), but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map(6), here we show that the level of genetic diversity varies substantially among different regions of the parasite genome, revealing extensive linkage disequilibrium surrounding the key CQR gene pfcrt(7) and at least four CQR founder events. This disequilibrium and its decay rate in the pfcrt-flanking region are consistent with strong directional selective sweeps occurring over only similar to20-80 sexual generations, especially a single resistant pfcrt haplotype spreading to very high frequencies throughout most of Asia and Africa. The presence of linkage disequilibrium provides a basis for mapping genes under drug selection in P. falciparum.