Rapid evolution of an overt metabolic defect restores balanced growth

In eukaryotes, conserved mechanisms ensure that cell growth is coordinated with nutrient availability. Overactive growth during nutrient limitation leads to rapid cell death. Here, we demonstrate that cells can adapt to this nutrient-growth imbalance by evolving major metabolic defects. Specifically, when yeast lysine auxotrophic mutant lys- suffered nutrient-growth imbalance in limited lysine, a sub-population repeatedly evolved to lose the ability to synthesize organosulfurs (lys-orgS-). Organosulfurs, mainly glutathione and glutathione conjugates, were released by lys- cells during lysine limitation when nutrient-growth is imbalanced, but not during glucose limitation when nutrient-growth is balanced. Limiting organosulfurs conferred a frequency-dependent fitness advantage to lys-orgS- by eliciting a proper slow growth program including autophagy. Thus, nutrient-growth imbalance can trigger rapid niche construction, which in turn enables the selection of an overt metabolic defect to better tune cell growth to the metabolic environment.