Stress‐response balance drives the evolution of a network module and its host genome

Molecular Systems Biology

Caleb González¹  Joe Christian J Ray¹  Michael Manhart²  Rhys M Adams¹  Dmitry Nevozhay¹  Alexandre V Morozov² 

[1] Department of Systems Biology - Unit 950, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Department of Physics & Astronomy, Rutgers University, Piscataway, NJ, USA

关键词: drug resistance;    experimental evolution;    positive feedback;    synthetic gene circuit;    tradeoff;   

DOI  :  10.15252/msb.20156185

来源: Wiley

【 摘 要 】

Abstract

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.

Synopsis

The evolution of a synthetic gene circuit that trades off costly gene expression for drug resistance is analyzed computationally. The predictions are validated experimentally by adjusting gene expression in the absence or presence of environmental stress.

• A synthetic gene circuit is integrated into the yeast genome to model the evolution of drug resistance networks with inherent tradeoff.
• Computational models are constructed to predict the speed and mechanisms of adaptation for various levels of gene expression and stress.
• The cell population adapts by mutations eliminating the module quickly when the network gratuitously responds in the absence of stress or by mutations that fine-tune the module's suboptimal response and establish slowly in the presence of stress.
• If the module initially fails to respond to stress, the population adapts by mutations that activate gene expression within the module.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.