Refactoring the Genetic Code for Increased Evolvability

The genetic code is robust to mutations and base-pairing errors during transcription and translation. Point mutations are most likely to be synonymous or preserve the chemical properties of the original amino acid. Saturation mutagenesis experiments suggest that in some cases the best performing mutant requires a replacement of more than a single nucleotide within a codon. These replacements are essentially inaccessible to common laboratory engineering techniques that alter single nucleotide per mutation event, due to the extreme rarity of adjacent mutations. In our theoretical study, we suggest to radically reorder the genetic code for maximizing the mutagenic potential of single nucleotide replacements. We explore several possible genetic codes that allow a greater degree of accessibility to the complete mutational landscape and may result in a hyper-evolvable organism serving as an ideal platform for directed evolution experiments.