Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.
Identification and functional validation of the novel antimalarial resistance locus PF10_0355 in Plasmodium falciparum.
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DOI：
10.1371/journal.pgen.1001383
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发表时间：
2011-04
期刊：
影响因子：
4.5
通讯作者：
Sabeti PC
中科院分区：
文献类型：
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作者：
Van Tyne D;Park DJ;Schaffner SF;Neafsey DE;Angelino E;Cortese JF;Barnes KG;Rosen DM;Lukens AK;Daniels RF;Milner DA Jr;Johnson CA;Shlyakhter I;Grossman SR;Becker JS;Yamins D;Karlsson EK;Ndiaye D;Sarr O;Mboup S;Happi C;Furlotte NA;Eskin E;Kang HM;Hartl DL;Birren BW;Wiegand RC;Lander ES;Wirth DF;Volkman SK;Sabeti PC
恶性疟原虫适应环境压力（例如人体免疫系统和抗疟药物）的能力使疟疾成为公共卫生的持久负担。了解这些适应的遗传基础对于成功干预疟疾至关重要。为此，我们创建了一个高密度基因分型阵列，可检测超过 17,000 个单核苷酸多态性 (∼1 SNP/kb)，并将其应用于来自三大洲的 57 种培养适应寄生虫。我们描述了种群内部和种群之间的全基因组遗传多样性，并鉴定了许多具有自然选择信号的基因座，表明它们在最近的适应中的作用。此外，我们还进行了全基因组关联研究（GWAS），寻找与 13 种抗疟药耐药性相关的基因座；我们检测到了已知的和新的耐药位点，包括新的卤泛群耐药位点 PF10_0355。通过功能测试，我们证明 PF10_0355 过度表达会降低对卤泛群、甲氟喹和本芴群的敏感性，但不会降低对结构不相关的抗疟药的敏感性，并且基因拷贝数增加会介导耐药性。我们的 GWAS 和后续功能验证证明了全基因组研究在阐明疟原虫基因组中功能重要位点的潜力。人类病原体恶性疟原虫感染疟疾每年导致近百万人死亡，其中大部分是非洲儿童。消除疟疾的努力正在进行中，但这种寄生虫善于逃避人类免疫反应和抗疟疾治疗。因此，了解寄生虫如何对药物产生耐药性并制定克服耐药机制的策略非常重要。为此，我们使用群体遗传策略来识别有助于寄生虫适应的遗传位点，并识别参与耐药性的候选基因。我们检查了 50 多个菌株的寄生虫基因组中的 17,000 多个遗传变异，我们还测量了对许多已知抗疟化合物的反应。我们发现许多基因位点显示出最近自然选择的迹象，并且许多基因位点可能参与调节寄生虫对药物的反应。我们进一步证明，新的候选基因之一（PF10_0355）可调节对抗疟化合物卤泛群、甲氟喹和本芴群的耐药性。总的来说，这项研究证实我们可以使用全基因组方法来识别临床相关基因，并通过功能测试证明这些候选基因中至少有一个确实与抗疟药物耐药性有关。
The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome. Malaria infection with the human pathogen Plasmodium falciparum results in almost a million deaths each year, mostly in African children. Efforts to eliminate malaria are underway, but the parasite is adept at eluding both the human immune response and antimalarial treatments. Thus, it is important to understand how the parasite becomes resistant to drugs and to develop strategies to overcome resistance mechanisms. Toward this end, we used population genetic strategies to identify genetic loci that contribute to parasite adaptation and to identify candidate genes involved in drug resistance. We examined over 17,000 genetic variants across the parasite genome in over 50 strains in which we also measured responses to many known antimalarial compounds. We found a number of genetic loci showing signs of recent natural selection and a number of loci potentially involved in modulating the parasite's response to drugs. We further demonstrated that one of the novel candidate genes (PF10_0355) modulates resistance to the antimalarial compounds halofantrine, mefloquine, and lumefantrine. Overall, this study confirms that we can use genome-wide approaches to identify clinically relevant genes and demonstrates through functional testing that at least one of these candidate genes is indeed involved in antimalarial drug resistance.