González Caleb, Ray Joe Christian J, Manhart Michael, Adams Rhys M, Nevozhay Dmitry, Morozov Alexandre V, Balázsi Gábor
Department of Systems Biology - Unit 950, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Systems Biology - Unit 950, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Center for Computational Biology & Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA.
Mol Syst Biol. 2015 Aug 31;11(8):827. doi: 10.15252/msb.20156185.
Stress response genes and their regulators form networks that underlie drug resistance. These networks often have an inherent tradeoff: their expression is costly in the absence of stress, but beneficial in stress. They can quickly emerge in the genomes of infectious microbes and cancer cells, protecting them from treatment. Yet, the evolution of stress resistance networks is not well understood. Here, we use a two-component synthetic gene circuit integrated into the budding yeast genome to model experimentally the adaptation of a stress response module and its host genome in three different scenarios. In agreement with computational predictions, we find that: (i) intra-module mutations target and eliminate the module if it confers only cost without any benefit to the cell; (ii) intra- and extra-module mutations jointly activate the module if it is potentially beneficial and confers no cost; and (iii) a few specific mutations repeatedly fine-tune the module's noisy response if it has excessive costs and/or insufficient benefits. Overall, these findings reveal how the timing and mechanisms of stress response network evolution depend on the environment.
应激反应基因及其调控因子构成了耐药性的基础网络。这些网络通常存在内在的权衡：在没有应激的情况下，它们的表达成本高昂，但在应激时却有益。它们能在感染性微生物和癌细胞的基因组中迅速出现，保护它们免受治疗。然而，应激抗性网络的进化尚未得到很好的理解。在这里，我们使用整合到芽殖酵母基因组中的双组分合成基因电路，在三种不同情况下通过实验模拟应激反应模块及其宿主基因组的适应性。与计算预测一致，我们发现：（i）如果模块对细胞仅产生成本而无任何益处，模块内突变会靶向并消除该模块；（ii）如果模块具有潜在益处且不产生成本，模块内和模块外突变会共同激活该模块；（iii）如果模块成本过高和/或益处不足，一些特定突变会反复微调模块的噪声反应。总体而言，这些发现揭示了应激反应网络进化的时间和机制如何依赖于环境。
