Institute of Integrative Biology, ETH Zurich, Switzerland.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
PLoS Biol. 2019 May 13;17(5):e3000265. doi: 10.1371/journal.pbio.3000265. eCollection 2019 May.
Transition bias, an overabundance of transitions relative to transversions, has been widely reported among studies of the rates and spectra of spontaneous mutations. However, demonstrating the role of transition bias in adaptive evolution remains challenging. In particular, it is unclear whether such biases direct the evolution of bacterial pathogens adapting to treatment. We addressed this challenge by analyzing adaptive antibiotic-resistance mutations in the major human pathogen Mycobacterium tuberculosis (MTB). We found strong evidence for transition bias in two independently curated data sets comprising 152 and 208 antibiotic-resistance mutations. This was true at the level of mutational paths (distinct adaptive DNA sequence changes) and events (individual instances of the adaptive DNA sequence changes) and across different genes and gene promoters conferring resistance to a diversity of antibiotics. It was also true for mutations that do not code for amino acid changes (in gene promoters and the 16S ribosomal RNA gene rrs) and for mutations that are synonymous to each other and are therefore likely to have similar fitness effects, suggesting that transition bias can be caused by a bias in mutation supply. These results point to a central role for transition bias in determining which mutations drive adaptive antibiotic resistance evolution in a key pathogen.
转换偏向，即转换相对于颠换的过度出现，在自发突变率和突变谱的研究中得到了广泛报道。然而，证明转换偏向在适应性进化中的作用仍然具有挑战性。特别是，尚不清楚这种偏向是否指导了适应治疗的细菌病原体的进化。我们通过分析主要人类病原体结核分枝杆菌（MTB）中的适应性抗生素耐药突变来应对这一挑战。我们在两个独立编辑的数据集（包含 152 个和 208 个抗生素耐药突变）中发现了强烈的转换偏向证据。这在突变路径（不同的适应性 DNA 序列变化）和事件（适应性 DNA 序列变化的单个实例）以及不同基因和基因启动子的水平上是真实的，这些基因和基因启动子赋予了对各种抗生素的耐药性。对于不编码氨基酸变化的突变（基因启动子和 16S 核糖体 RNA 基因 rrs）以及彼此同义的突变也是如此，因此可能具有相似的适应度效应，这表明转换偏向可能是由突变供应的偏向引起的。这些结果表明，转换偏向在决定哪些突变驱动关键病原体中的适应性抗生素耐药性进化方面起着核心作用。
