The Standard Genetic Code Facilitates Exploration of the Space of Functional Nucleotide Sequences

Mutations occur in the genomic DNA while most cellular functions are carried out by proteins, which largely determine the organism’s phenotype. Governing the translation of genomic transcripts into proteins, the genetic code plays a crucial role in steering molecular evolution. We investigated the number of functional variants of the E. coli PhoQ protein explored at different numbers of mutational steps under translation using different genetic codes and found that the standard code was optimized for exploring a greater number of functional PhoQ variants at intermediate time scales as compared to random such codes. Greater genetic diversity in the population is beneficial in response to environmental changes which are more likely to occur at these intermediate time scales. Our results indicated that, independent of the property of the standard code to minimize the phenotypic effects of mutations, the property to explore more functional sequence variants arises from a balance between robustness and flexibility in the face of mutations. We propose that selection for this property while minimizing phenotypic effects of mutations contributed towards the emergence of the standard code as the universal genetic code.