Dissecting the genetic complexity of artemisinin resistance

摘要 最近发现的kelch13基因是疟疾和疟疾青蒿素抗性(ART-R)的重要标志 与缓解率(CR)临床表型以及治疗失败有关。尽管如此 一个影响性状的主基因的令人兴奋的发现，有几个迹象表明额外的(或替代的) 基因和基因间的相互作用对抗性水平都有贡献，用缓慢的清除时间来衡量。 临床期和环期在实验室存活。了解各种kelch13的详细功能作用 突变体，它们更广泛的生物学作用和功能伙伴，以及它们对健康的影响呈现出战略意义 理解和减缓ART的演变和传播的障碍-R。 认识到主要抗性基因的表型效应存在于共同进化的全基因组中 背景，我们将使用数量性状基因座(QTL)定位与密集和精确的表型相结合 通过使用我们的新型FRG huHep/huRBC小鼠构建的一组八个相互关联的实验杂交 我们将利用这一点来确定 对青蒿素和伙伴药物，如哌喹和鲁米芬的耐药性和/或敏感性 确定多种化合物的药物靶点和易感决定因素。此外，我们还将 检查ART-R水平和红细胞竞争性增长之间的关系，作为替代衡量 确定将影响疟疾耐药性在非洲人口中传播的因素的适宜性。 来剖析这种生物复杂性。寻找基因和途径的途径 为了确定影响抗药性起源和传播的基因和途径，我们将(I) 绘制地图 ART-R的遗传决定因素来验证我们的假设，即复杂的遗传结构和多个基因 参与ART-R，(Ii)绘制对24种抗疟疾药物易感性的遗传决定因素图，包括 ART的合作药物，哌喹，以及针对广泛生物过程的抗疟疾药物 和一组药物靶点未知的候选药物，以及(Iii)映射ART-R对 竞争增长使用小批量的正面竞争增长结果来计算相对 QTL定位的适合度指数量化得分。

ABSTRACT The recently identified kelch13 gene is an important marker of artemisinin resistance (ART-R) in malaria and has been linked to the slow-clearance rate (CR) clinical phenotype as well as treatment failures. In spite of this exciting discovery of a major gene affecting the trait, there are several indications that additional (or alternative) genes and gene interactions contribute to both the level of resistance, as measured by slow clearance times in the clinic and ring stage survival in the laboratory. Understanding the detailed functional role of various kelch13 mutants, their broader biological roles and functional partners, and their impact on fitness presents strategic hurdles to understanding and slowing the evolution and spread of ART-R. Recognizing that the phenotypic effect of a major resistance gene resides in a co-evolved whole-genome context, we will use quantitative trait locus (QTL) mapping combined with intensive and precise phenotyping across a set of eight inter-related experimental crosses constructed using our novel FRG huHep/huRBC mice We will use this that determine resistance and/or susceptibility to artemisinin and to partner drugs such as piperaquine and lumefantrine and to identify drug targets and susceptibility determinants for a wide range of compounds. In addition, we will examine the relationship between levels of ART-R and competitive growth in RBCs as a surrogate measure of fitness to identify the factors that will influence the spread of malarial resistance in African populations. to dissect this biological complexity. approach to find genes and pathways To identify the genes and pathways that influence the origins and spread of resistance we will (i) map the genetic determinants of ART-R to test our hypothesis that a complex genetic architecture and multiple genes are involved in ART-R, (ii) map genetic determinants of susceptibility to 24 antimalarial drugs, including the partner drugs of ART, piperiquine, along with antimalarial drugs targeting a wide range of biological processes and a set of candidate drugs for which the drug target is not known and, (iii) map the impact of ART-R on competitive growth using small volume head-to-head competitive-growth outcomes to compute a `relative fitness index' quantitative score for QTL mapping.