Prediction of Cross-resistance and Collateral Sensitivity by Gene Expression profiles and Genomic Mutations.. Escherichia coli str. K-12 substr. MDS42

In adaptive evolution, an increase in fitness to an environment is frequently accompanied by changes in fitness to other environmental conditions, called cross-resistance and sensitivity. Although the networks between fitness changes affect the course of evolution substantially, the mechanisms underlying such fitness changes are yet to be fully elucidated. Herein, we performed high-throughput laboratory evolution of Escherichia coli under various stress conditions using an automated culture system, and quantified how the acquisition of resistance to one stressor alters the resistance to other stressors. We demonstrated that resistance changes could be quantitatively predicted based on changes in the transcriptome of the resistant strains. We also identified several genes and gene functions, for which mutations were commonly fixed in the strains resistant to the same stress, which could partially explain the observed cross-resistance and collateral sensitivity. The integration of transcriptome and genome data enabled us to clarify the bacterial stress resistance mechanisms. Overall design: To examine the contribution of the gene expression changes to the stress resistances, transcriptome of the parent strain (triplicated) and 55 resistant strains (5 parallel-evolved resistant strains for 11 stresses) were analyzed.

在适应性进化过程中，生物对某一环境的适应度提升，往往伴随对其他环境条件的适应度改变，这类现象被称为交叉抗性（cross-resistance）与附带敏感性（collateral sensitivity）。尽管适应度变化间的关联网络会显著影响进化进程，但这类适应度变化背后的分子机制仍未完全阐明。
本研究中，我们借助自动化培养系统，对大肠杆菌（Escherichia coli）在多种胁迫条件下开展了高通量实验室进化实验，并定量分析了菌株获得对某一胁迫因子的抗性后，其对其他胁迫因子的抗性会发生何种变化。我们证实，可基于抗性菌株的转录组（transcriptome）变化，对抗性的改变进行定量预测。我们还鉴定出多个基因及基因功能类别：在针对同一胁迫产生抗性的菌株中，这类基因的突变往往会被固定保留，这可部分解释观测到的交叉抗性与附带敏感性现象。通过整合转录组与基因组数据，我们得以阐明细菌的胁迫抗性机制。
实验整体设计：为探究基因表达变化对胁迫抗性的贡献，我们对亲本菌株（设置3次生物学重复）与55株抗性菌株（针对11种胁迫各获得5株平行进化的抗性菌株）的转录组进行了分析。