期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 50, 页码 25162-25171出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1912257116
关键词
evolution; gene circuit; reversal; loss of function; bistability
资金
- NIH/National Institute of General Medical Sciences Maximizing Investigator's Research Award (MIRA) [R35 GM122561]
- Laufer Center for Physical and Quantitative Biology
- Swiss National Science Foundation [PZ00P3_180147]
- Swiss National Science Foundation (SNF) [PZ00P3_180147] Funding Source: Swiss National Science Foundation (SNF)
Evolutionary reversibility-the ability to regain a lost function-is an important problem both in evolutionary and synthetic biology, where repairing natural or synthetic systems broken by evolutionary processes may be valuable. Here, we use a synthetic positive-feedback (PF) gene circuit integrated into haploid Saccharomyces cerevisiae cells to test if the population can restore lost PF function. In previous evolution experiments, mutations in a gene eliminated the fitness costs of PF activation. Since PF activation also provides drug resistance, exposing such compromised or broken mutants to both drug and inducer should create selection pressure to regain drug resistance and possibly PF function. Indeed, evolving 7 PF mutant strains in the presence of drug revealed 3 adaptation scenarios through genomic, PF-external mutations that elevate PF basal expression, possibly by affecting transcription, translation, degradation, and other fundamental cellular processes. Nonfunctional mutants gained drug resistance without ever developing high expression, while quasifunctional and dysfunctional PF mutants developed high expression nongenetically, which then diminished, although more slowly for dysfunctional mutants where revertant clones arose. These results highlight how intracellular context, such as the growth rate, can affect regulatory network dynamics and evolutionary dynamics, which has important consequences for understanding the evolution of drug resistance and developing future synthetic biology applications.
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