Borrmann Steffen, Straimer Judith, Mwai Leah, Abdi Abdirahman, Rippert Anja, Okombo John, Muriithi Steven, Sasi Philip, Kortok Moses Mosobo, Lowe Brett, Campino Susana, Assefa Samuel, Auburn Sarah, Manske Magnus, Maslen Gareth, Peshu Norbert, Kwiatkowski Dominic P, Marsh Kevin, Nzila Alexis, Clark Taane G
1] KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya [2] Institute of Microbiology, Magdeburg University School of Medicine, Germany.
Sci Rep. 2013 Nov 25;3:3318. doi: 10.1038/srep03318.
Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed >75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.
早期鉴定抗疟药物耐药性背后的因果基因变异可为及时的公共卫生干预提供强有力的流行病学工具。我们采用一种用于绘制新候选基因的新型自然遗传学策略，分析了从27株恶性疟原虫的高分辨率全基因组测序数据中选取的超过75,000个高质量单核苷酸多态性。我们鉴定出了与双氢青蒿素敏感性相关的基因变异，这些变异涉及13号染色体上的一个区域、1号染色体上的一个候选基因（PFA0220w，一种UBP1直系同源物）以及其他在蛋白质稳态和应激反应中具有假定作用的基因（PFB0560w、PFB0630c、PFF0445w）。在PFA0220w上有强烈的正选择信号，但在其他候选基因座上没有。我们的结果证明了基于全基因组测序的关联研究在揭示决定寄生虫对青蒿素敏感性的候选基因方面的强大作用。我们的研究为解释耐药感染的结果提供了独特的参考。
