Genomic evolution of antibiotic resistance is contingent on genetic background following a long-term experiment with Escherichia coli
Genomic evolution of antibiotic resistance is contingent on genetic background following a long-term experiment with Escherichia coli
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DOI：
10.1073/pnas.2016886118
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发表时间：
2021-02-02
影响因子：
11.1
通讯作者：
Lenski, Richard E.
中科院分区：
文献类型：
--
作者：
Card, Kyle J.;Thomas, Misty D.;Lenski, Richard E.
抗生素耐药性是一个日益严重的健康问题。控制耐药性的努力将受益于预测耐药性何时以及如何演变的能力的提高。突变之间的上位性相互作用可以促进不同的进化轨迹，这使我们预测进化的能力变得复杂。我们最近发现，遗传背景之间的差异可能会导致特异性反应的表型耐药的可进化性，即使在密切相关的大肠杆菌菌株。在这项研究中，我们研究了菌株的遗传背景是否也影响抗性的基因型进化。由不同基因型建立的谱系是否采取平行或不同的突变路径来实现其进化的抗性状态？我们解决了这个问题，通过测序的完整基因组的抗疟疾克隆，从几个不同的遗传起点在我们早期的实验。我们首先通过量化基因组进化对抗生素治疗的特异性来验证我们的统计方法。正如预期的那样，特定基因的突变与每种药物密切相关。然后，我们确定，从相同的创始基因型进化而来的复制株系在基因水平上比从不同创始基因型进化而来的株系具有更多的平行突变，尽管这些效应比那些显示抗生素特异性的效应更微妙。结合我们以前的工作，我们得出结论，历史偶然性可以改变抗生素耐药性的基因型和表型途径。
Antibiotic resistance is a growing health concern. Efforts to control resistance would benefit from an improved ability to forecast when and how it will evolve. Epistatic interactions between mutations can promote divergent evolutionary trajectories, which complicates our ability to predict evolution. We recently showed that differences between genetic backgrounds can lead to idiosyncratic responses in the evolvability of phenotypic resistance, even among closely related Escherichia coli strains. In this study, we examined whether a strain's genetic background also influences the genotypic evolution of resistance. Do lineages founded by different genotypes take parallel or divergent mutational paths to achieve their evolved resistance states? We addressed this question by sequencing the complete genomes of antibiotic-resistant clones that evolved from several different genetic starting points during our earlier experiments. We first validated our statistical approach by quantifying the specificity of genomic evolution with respect to antibiotic treatment. As expected, mutations in particular genes were strongly associated with each drug. Then, we determined that replicate lines evolved from the same founding genotypes had more parallel mutations at the gene level than lines evolved from different founding genotypes, although these effects were more subtle than those showing antibiotic specificity. Taken together with our previous work, we conclude that historical contingency can alter both genotypic and phenotypic pathways to antibiotic resistance.