Synthetic Gene Recruitment Reveals Adaptive Reprogramming of Gene Regulation in Yeast

Abstract

The recruitment of a gene to a foreign regulatory system is a major evolutionary event that can lead to novel phenotypes. However, the evolvability potential of cells depends on their ability to cope with challenges presented by gene recruitment. To study this ability, we combined synthetic gene recruitment with continuous culture and online measurements of the metabolic and regulatory dynamics over long timescales. The gene HIS3 from the histidine synthesis pathway was recruited to the GAL system, responsible for galactose utilization in the yeast S. cerevisiae. Following a switch from galactose to glucose-from induced to repressed conditions of the GAL system-in histidine-lacking chemostats (where the recruited HIS3 is essential), the regulatory system reprogrammed to adaptively tune HIS3 expression, allowing the cells to grow competitively in pure glucose. The adapted state was maintained for hundreds of generations in various environments. The timescales involved and the reproducibility of separate experiments render spontaneous mutations an unlikely underlying mechanism. Essentially all cells could adapt, excluding selection over a genetically variable population. The results reveal heritable adaptation induced by the exposure to glucose. They demonstrate that genetic regulatory networks have the potential to support highly demanding events of gene recruitment.

Inherited adaptation of genome‐rewired cells in response to a challenging environment

“…Such events are well documented by comparative genomic studies and were reported to drive significantly the evolution of gene regulation [ (Carroll et al, 2001;Wilkins, 2002;Davidson, 2006) also, see the discussions in Alonso and Wilkins (2005); Stern and Orgogozo (2008); Erwin and Davidson (2009)]. In our experiments, a strain of the yeast Saccharomyces cerevisiae was engineered to recruit the gene HIS3, an essential enzyme from the histidine biosynthesis pathway, exclusively to the GAL system that is responsible for galactose utilization (Stolovicki et al, 2006). The arbitrary regulatory linkage between these two evolutionary conserved and highly specific modules was stressful, challenging and created incompatibilities in gene expression (Stolovicki et al, 2006).…”

“…In our experiments, a strain of the yeast Saccharomyces cerevisiae was engineered to recruit the gene HIS3, an essential enzyme from the histidine biosynthesis pathway, exclusively to the GAL system that is responsible for galactose utilization (Stolovicki et al, 2006). The arbitrary regulatory linkage between these two evolutionary conserved and highly specific modules was stressful, challenging and created incompatibilities in gene expression (Stolovicki et al, 2006). The cells had not exercised regulation of HIS3 by carbon sources availability along their history, so a substantial adaptive response was required for them to survive in a medium lacking histidine.…”

“…The cells had not exercised regulation of HIS3 by carbon sources availability along their history, so a substantial adaptive response was required for them to survive in a medium lacking histidine. Recently, we have shown that a cell population carrying this GAL-HIS3 rewired genome can rapidly adapt to grow competitively in histidine-lacking glucose medium despite the strong repression of the GAL system and HIS3 (Stolovicki et al, 2006;Stern et al, 2007). Once established, the adaptation have been propagated stably for hundreds of generations (Stolovicki et al, 2006).…”

“…Recently, we have shown that a cell population carrying this GAL-HIS3 rewired genome can rapidly adapt to grow competitively in histidine-lacking glucose medium despite the strong repression of the GAL system and HIS3 (Stolovicki et al, 2006;Stern et al, 2007). Once established, the adaptation have been propagated stably for hundreds of generations (Stolovicki et al, 2006). Our previous study (Stolovicki et al, 2006) was focused on the population average adaptation dynamics, which did not allow us to follow the population structure during this process.…”

“…Once established, the adaptation have been propagated stably for hundreds of generations (Stolovicki et al, 2006). Our previous study (Stolovicki et al, 2006) was focused on the population average adaptation dynamics, which did not allow us to follow the population structure during this process. Thus, it was impossible to conclude whether the observed adaptation phenomenon was due to the selection of a special subpopulation or other processes.…”