Vogwill T, Kojadinovic M, MacLean R C
Department of Zoology, University of Oxford, Oxford, UK
Department of Zoology, University of Oxford, Oxford, UK Université Aix-Marseille-CNRS, Marseille, France.
Proc Biol Sci. 2016 May 11;283(1830). doi: 10.1098/rspb.2016.0151.
Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase (rpoB) across eight strains that span the diversity of the genus Pseudomonas We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional basis of epistasis, and because rpoB plays a central role in transcription, we measured the effects of common rpoB mutations on transcriptional efficiency across three strains of Pseudomonas Transcriptional efficiency correlates strongly to fitness across strains, and epistasis arises because individual rpoB mutations have differential effects on transcriptional efficiency in different genetic backgrounds.
抗生素耐药性通常通过必需基因保守位点的突变而演变，导致不同细菌菌株和物种之间出现平行的分子进化。然而，这些耐药性突变是否对不同细菌类群的适应性产生平行影响尚不清楚。这是一个需要解决的重要问题，因为耐药性突变的适应性影响在病原体群体中耐药性的传播和维持中起着关键作用。我们通过测量RNA聚合酶（rpoB）β亚基中一系列利福平耐药性突变在跨越假单胞菌属多样性的八个菌株中的适应性影响来探讨这一问题。我们发现，近50%的rpoB突变具有背景依赖性的适应性代价，这表明rpoB与基因组其他部分之间的上位性相互作用很常见。此外，上位性通常很强，并且它是耐药性突变代价的主要遗传决定因素。为了研究上位性的功能基础，并且由于rpoB在转录中起核心作用，我们测量了常见rpoB突变对三种假单胞菌菌株转录效率的影响。转录效率与不同菌株的适应性密切相关，上位性的出现是因为单个rpoB突变在不同遗传背景下对转录效率有不同影响。
