Compensatory Mutations Restore Fitness during the Evolution of Dihydrofolate Reductase
Compensatory Mutations Restore Fitness during the Evolution of Dihydrofolate Reductase
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DOI：
10.1093/molbev/msq160
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发表时间：
2010-12-01
影响因子：
10.7
通讯作者：
Hartl, Daniel L.
中科院分区：
文献类型：
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作者：
Brown, Kyle M.;Costanzo, Marna S.;Hartl, Daniel L.
鲁棒性和进化性之间是否存在权衡是蛋白质进化的一个重要问题。尽管传统观点认为，现有的功能必须受到新活动进化的损害，但最近的研究表明，现有的表型可能对新蛋白质功能的进化具有强大的作用。作为竞争性抑制剂的抗生素靶标酶必须进化降低药物亲和力，同时保持其功能和维持生长。利用表达疟原虫恶性疟原虫二氢叶酸还原酶（DHFR）的转基因酿酒酵母模型，研究了其生长速度对耐药突变的稳健性。我们分析了与疟原虫田间分离株耐药性增加相关的6种DHFR点突变的所有48种组合的生长速率和耐药性。我们观察到DHFR等位基因的生长速率和抗性表型之间没有一致的关系。主导DHFR进化的三种进化途径表明，抗性增强的突变可以补偿先前获得的突变导致的生长速度的初始下降。换句话说，在进化轨迹中较晚发生的抗性突变可以补偿较早突变的适应性后果。我们的研究结果表明，在不损害整体健康的情况下，可以选择高水平的抵抗力。
Whether a trade-off exists between robustness and evolvability is an important issue for protein evolution. Although traditional viewpoints have assumed that existing functions must be compromised by the evolution of novel activities, recent research has suggested that existing phenotypes can be robust to the evolution of novel protein functions. Enzymes that are targets of antibiotics that are competitive inhibitors must evolve decreased drug affinity while maintaining their function and sustaining growth. Utilizing a transgenic Saccharomyces cerevisiae model expressing the dihydrofolate reductase (DHFR) enzyme from the malarial parasite Plasmodium falciparum, we examine the robustness of growth rate to drug-resistance mutations. We assay the growth rate and resistance of all 48 combinations of 6 DHFR point mutations associated with increased drug resistance in field isolates of the parasite. We observe no consistent relationship between growth rate and resistance phenotypes among the DHFR alleles. The three evolutionary pathways that dominate DHFR evolution show that mutations with increased resistance can compensate for initial declines in growth rate from previously acquired mutations. In other words, resistance mutations that occur later in evolutionary trajectories can compensate for the fitness consequences of earlier mutations. Our results suggest that high levels of resistance may be selected for without necessarily jeopardizing overall fitness.