Evolutionary dynamics determines adaptation to inactivation of an essential gene

TL;DR

This study investigates how E. coli adapts to the inactivation of an essential gene, DHFR, revealing multiple evolutionary pathways and metabolic rerouting strategies that enable survival under nutrient-limited conditions.

Contribution

It uncovers the specific genetic and metabolic mechanisms by which bacteria adapt to essential gene inactivation, highlighting multiple evolutionary trajectories and metabolic shifts.

Findings

Partial reversal of D27G mutation during adaptation

Adaptation involves loss of function mutations in thyA and deoB

Multiple pathways lead to suboptimal fitness peaks

Abstract

Genetic inactivation of essential genes creates an evolutionary scenario distinct from escape from drug inhibition, but the mechanisms of microbe adaptations in such cases remain unknown. Here we inactivate E. coli dihydrofolate reductase (DHFR) by introducing D27G,N,F chromosomal mutations in a key catalytic residue with subsequent adaptation by serial dilutions. The partial reversal G27->C occurred in three evolutionary trajectories. Conversely, in one trajectory for D27G and in all trajectories for D27F,N strains adapted to grow at very low supplement folAmix concentrations but did not escape entirely from supplement auxotrophy. Major global shifts in metabolome and proteome occurred upon DHFR inactivation, which were partially reversed in adapted strains. Loss of function mutations in two genes, thyA and deoB, ensured adaptation to low folAmix by rerouting the 2-Deoxy-D-ribose-phosphate metabolism from glycolysis towards synthesis of dTMP. Multiple evolutionary pathways of adaptation to low folAmix converge to highly accessible yet suboptimal fitness peak.