Many alternative and theoretical genetic codes are more robust to amino acid replacements than the standard genetic code.

We evaluated the differences between the standard genetic code (SGC) and its known alternative variants in terms of the consequences of amino acids replacements. Furthermore, the properties of all the possible theoretical genetic codes, which differ from the SGC by one, two or three changes in codon assignments were also tested. Although the SGC is closer to the best theoretical codes than to the worst ones due to the minimization of amino acid replacements, from 10% to 27% of the all possible theoretical codes minimize the effect of these replacements better than the SGC. Interestingly, many types of codon reassignments observed in the alternative codes are also responsible for the substantial robustness to amino acid replacements. As many as 18 out of 21 alternatives perform better than the SGC under the assumed optimization criteria. These findings suggest that not all reassignments in the alternative codes are neutral and some of them could be selected to reduce harmful effects of mutations or translation of protein-coding sequences. The results also imply that the standard genetic code can be improved in this respect by a quite small number of changes, which are in fact realized in its variants. It would mean that the tendency to minimize mutational errors was not the main force that drove the evolution of the SGC.