Robustness-epistasis link shapes the fitness landscape of a randomly drifting protein
Robustness-epistasis link shapes the fitness landscape of a randomly drifting protein
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DOI：
10.1038/nature05385
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发表时间：
2006-12-14
期刊：
影响因子：
64.8
通讯作者：
Tawfik, Dan S.
中科院分区：
文献类型：
--
作者：
Bershtein, Shimon;Segal, Michal;Tawfik, Dan S.
蛋白质突变的适应度效应的分布尚不清楚(1，2)。尤其令人感兴趣的是，累积的有害突变是否相互作用，以及由此产生的上位性效应如何塑造蛋白质的适应环境。在这里，我们应用了一个模型系统，在该系统中，细菌适合性与TEM-1β-内酰胺酶(抗生素降解)的酶活性相关。将TEM-1置于随机突变漂移和纯化选择(以清除有害突变)后，其适应状况发生了变化，表明了负上位性；也就是说，突变的综合有害影响平均大于预期的单个影响的乘积。正如在计算系统中观察到的那样(3-5)，负上位性与对突变的更高耐受性(健壮性)密切相关。因此，在低选择压力下，一大部分突变最初是被容忍的(高稳性)，但随着突变的积累，它们的适合度增加，导致观察到的负上位性。这些发现得到了突变效应的FoldX稳定性计算的支持(6)，促使建立了一个新的模型，在该模型中，在蛋白质和其他生物系统中观察到的突变稳健性(或中立性)主要是由于稳定裕度或阈值，该稳定裕度或阈值缓冲了突变对适应性的有害物理化学影响。阈值稳健性本质上是上位性的--一旦稳定性阈值耗尽，突变的有害影响就会变得完全明显，从而使蛋白质的健壮性远远低于通常假设的水平。
The distribution of fitness effects of protein mutations is still unknown(1,2). Of particular interest is whether accumulating deleterious mutations interact, and how the resulting epistatic effects shape the protein's fitness landscape. Here we apply a model system in which bacterial fitness correlates with the enzymatic activity of TEM-1 beta-lactamase ( antibiotic degradation). Subjecting TEM-1 to random mutational drift and purifying selection ( to purge deleterious mutations) produced changes in its fitness landscape indicative of negative epistasis; that is, the combined deleterious effects of mutations were, on average, larger than expected from the multiplication of their individual effects. As observed in computational systems(3-5), negative epistasis was tightly associated with higher tolerance to mutations ( robustness). Thus, under a low selection pressure, a large fraction of mutations was initially tolerated ( high robustness), but as mutations accumulated, their fitness toll increased, resulting in the observed negative epistasis. These findings, supported by FoldX stability computations of the mutational effects(6), prompt a new model in which the mutational robustness ( or neutrality) observed in proteins, and other biological systems, is due primarily to a stability margin, or threshold, that buffers the deleterious physico-chemical effects of mutations on fitness. Threshold robustness is inherently epistatic - once the stability threshold is exhausted, the deleterious effects of mutations become fully pronounced, thereby making proteins far less robust than generally assumed.