Department of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland.
Swiss Institute of Bioinformatics, Quartier Sorge-Batiment Genopode, Lausanne, Switzerland.
J Evol Biol. 2021 Aug;34(8):1302-1315. doi: 10.1111/jeb.13892. Epub 2021 Jul 7.
Darwinian evolution preferentially follows mutational pathways whose individual steps increase fitness. Alternative pathways with mutational steps that do not increase fitness are less accessible. Here, we show that mistranslation, the erroneous incorporation of amino acids into nascent proteins, can increase the accessibility of such alternative pathways and, ultimately, of high fitness genotypes. We subject populations of the beta-lactamase TEM-1 to directed evolution in Escherichia coli under both low- and high-mistranslation rates, selecting for high activity on the antibiotic cefotaxime. Under low mistranslation rates, different evolving TEM-1 populations ascend the same high cefotaxime-resistance peak, which requires three canonical DNA mutations. In contrast, under high mistranslation rates they ascend three different high cefotaxime-resistance genotypes, which leads to higher genotypic diversity among populations. We experimentally reconstruct the adaptive DNA mutations and the potential evolutionary paths to these high cefotaxime-resistance genotypes. This reconstruction shows that some of the DNA mutations do not change fitness under low mistranslation, but cause a significant increase in fitness under high-mistranslation, which helps increase the accessibility of different high cefotaxime-resistance genotypes. In addition, these mutations form a network of pairwise epistatic interactions that leads to mutually exclusive evolutionary trajectories towards different high cefotaxime-resistance genotypes. Our observations demonstrate that protein mistranslation and the phenotypic mutations it causes can alter the evolutionary exploration of fitness landscapes and reduce the predictability of evolution.
达尔文进化更倾向于沿着能够提高适应性的突变途径进行。而那些突变步骤不能提高适应性的替代途径则不太容易被选择。在这里，我们表明，翻译错误，即错误地将氨基酸掺入新生蛋白质中，可以增加这些替代途径的可及性，最终也可以提高高适应性基因型的出现概率。我们在大肠杆菌中对β-内酰胺酶 TEM-1 进行了定向进化实验，在低和高错译率下选择对抗生素头孢噻肟具有高活性的菌株。在低错译率下，不同的进化 TEM-1 群体上升到相同的头孢噻肟高抗性峰，这需要三个典型的 DNA 突变。相比之下，在高错译率下，它们上升到三个不同的头孢噻肟高抗性基因型，导致群体之间的基因型多样性更高。我们实验重建了适应的 DNA 突变和这些高头孢噻肟抗性基因型的潜在进化路径。这种重建表明，一些 DNA 突变在低错译率下不会改变适应性，但在高错译率下会导致适应性显著增加，这有助于增加不同高头孢噻肟抗性基因型的可及性。此外，这些突变形成了一个具有相互作用的网络，导致不同的高头孢噻肟抗性基因型朝着相互排斥的进化轨迹发展。我们的观察表明，蛋白质错译及其导致的表型突变可以改变适应性景观的进化探索，并降低进化的可预测性。
