Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance.
Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance.
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DOI：
10.1186/s13059-017-1204-4
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发表时间：
2017-04-28
期刊：
影响因子：
12.3
通讯作者：
Neafsey DE
中科院分区：
文献类型：
--
作者：
Cerqueira GC;Cheeseman IH;Schaffner SF;Nair S;McDew-White M;Phyo AP;Ashley EA;Melnikov A;Rogov P;Birren BW;Nosten F;Anderson TJC;Neafsey DE
基于青蒿素的联合疗法是全球治疗恶性疟原虫感染的第一线疗法，但过去十年来，青蒿素耐药性在东南亚迅速上升。kelch 13基因的突变与这种耐药性有关。我们使用纵向基因组监测来检测kelch 13和其他基因座中导致青蒿素或合作伙伴耐药性的信号。我们回顾性地对来自泰国西北部五个地点的194株恶性疟原虫分离株的基因组进行了测序，这些分离株在青蒿素耐药性出现迅速增加的时期（2001-2014年）。我们评估了单个SNP频率随时间变化的统计指标，假设在此期间与耐药相关的SNP频率增加。在Kelch 13-C580 Y之后，在磷脂酰肌醇4-激酶中的SNP处观察到最强的时间变化，所述磷脂酰肌醇4-激酶参与最近与青蒿素抗性有关的途径。此外，其他基因座表现出强烈的时间签名，值得进一步调查参与青蒿素耐药性演变。通过全基因组关联分析，我们确定了10号染色体上含有kelch结构域的基因的一个变异体，该变异体可能上位调节青蒿素抗性。这项分析表明，纵向基因组监测方法的潜力，以检测耐药相关基因位点，以提高我们的机制了解如何耐药发展。与青蒿素耐药寄生虫相关的kelch 13基因座以外的其他基因组区域的证据可能会产生新的耐药性监测分子标记，这可能有助于减少非洲寄生虫种群中青蒿素耐药性的出现或传播。本文的在线版本（doi：10.1186/s13059-017-1204-4）包含补充材料，可供授权用户使用。
Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001–2014). We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance. This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations. The online version of this article (doi:10.1186/s13059-017-1204-4) contains supplementary material, which is available to authorized users.