Pervasive Pairwise Intragenic Epistasis among Sequential Mutations in TEM-1 β-Lactamase
Pervasive Pairwise Intragenic Epistasis among Sequential Mutations in TEM-1 β-Lactamase
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DOI：
10.1016/j.jmb.2019.03.020
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发表时间：
2019-05-03
影响因子：
5.6
通讯作者：
Ostermeier, Marc
中科院分区：
文献类型：
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作者：
Gonzalez, Courtney E.;Ostermeier, Marc
突变之间的相互作用在塑造适应性景观中起着核心作用，但基因内上位性的清晰图景尚未出现。为了进一步揭示基因内上位性的发生率和模式，我们对TEM-1 β-内酰胺酶连续突变之间的上位性相互作用进行了调查。我们测量了类似于12，000对连续氨基酸取代的适应性效应，并使用我们先前对单个氨基酸取代的适应性效应的研究来计算超过8000个突变对的上位性。由于连续突变倾向于物理相互作用，我们假设我们的研究将是调查特异性上位性而不是非特异性上位性。我们发现了广泛的负上位性，特别是在β链中，并且在个体有益突变中负符号上位性的频率很高。负上位性（52%）的发生频率是正上位性（6.8%）的7.6倍。埋藏残体比暴露残体经历了更多的负上位性。然而，TEM-1表现出两个正上位性热点，最显著的是L221/R222，许多突变的组合在此正相互作用。这项研究是第一个系统地研究在其天然宿主中执行其天然功能的整个蛋白质的成对上位性。(C)2019爱思唯尔有限公司版权所有。
Interactions between mutations play a central role in shaping the fitness landscape, but a clear picture of intragenic epistasis has yet to emerge. To further reveal the prevalence and patterns of intragenic epistasis, we present a survey of epistatic interactions between sequential mutations in TEM-1 beta-lactamase. We measured the fitness effect of similar to 12,000 pairs of consecutive amino acid substitutions and used our previous study of the fitness effects of single amino acid substitutions to calculate epistasis for over 8000 mutation pairs. Since sequential mutations are prone to physically interact, we postulated that our study would be surveying specific epistasis instead of nonspecific epistasis. We found widespread negative epistasis, especially in beta-strands, and a high frequency of negative sign epistasis among individually beneficial mutations. Negative epistasis (52%) occurred 7.6 times as frequently as positive epistasis (6.8%). Buried residues experienced more negative epistasis that surface-exposed residues. However, TEM-1 exhibited a couple of hotspots for positive epistasis, most notably L221/R222 at which many combinations of mutations positively interacted. This study is the first to systematically examine pairwise epistasis throughout an entire protein performing its native function in its native host. (C) 2019 Elsevier Ltd. All rights reserved.