  The genetic code underlying protein synthesis is a canonical example of a
degenerate biological system. Degeneracies in physical and biological systems
can be lifted by external perturbations thus allowing degenerate systems to
exhibit a wide range of behaviors. Here we show that the degeneracy of the
genetic code is lifted by environmental perturbations to regulate protein
levels in living cells. By measuring protein synthesis rates from a synthetic
reporter library in Escherichia coli, we find that environmental perturbations,
such as reduction of cognate amino acid supply, lift the degeneracy of the
genetic code by splitting codon families into a hierarchy of robust and
sensitive synonymous codons. Rates of protein synthesis associated with robust
codons are up to hundred-fold higher than those associated with sensitive
codons under these conditions. We find that the observed hierarchy between
synonymous codons is not determined by usual rules associated with tRNA
abundance and codon usage. Rather, competition among tRNA isoacceptors for
aminoacylation underlies the robustness of protein synthesis. Remarkably, the
hierarchy established using the synthetic library also explains the measured
robustness of synthesis for endogenous proteins in E. coli. We further found
that the same hierarchy is reflected in the fitness cost of synonymous
mutations in amino acid biosynthesis genes and in the transcriptional control
of sigma factor genes. Our study reveals that the degeneracy of the genetic
code can be lifted by environmental perturbations, and it suggests that
organisms can exploit degeneracy lifting as a general strategy to adapt protein
synthesis to their environment.
