  The standard genetic code is well known to be optimized for minimizing the
phenotypic effects of single nucleotide substitutions, a property that was
likely selected for during the emergence of a universal code. Given the fitness
advantage afforded by high standing genetic diversity in a population in a
dynamic environment, it is possible that selection to explore a large fraction
of the space of functional proteins also occurred. To determine whether
selection for such a property played a role during the emergence of the nearly
universal genetic code, we investigated the number of functional variants of
the Escherichia coli PhoQ protein explored at different time scales under
translation using different genetic codes. We found that the standard genetic
code is highly optimal for exploring a large fraction of the space of
functional PhoQ variants at intermediate time scales as compared to random
codes. Environmental changes, in response to which genetic diversity in a
population provides a fitness advantage, are likely to have occurred at these
intermediate time scales. Our results indicate that the ability of the standard
code to explore a large fraction of the space of functional sequence variants
arises from a balance between robustness and flexibility and is largely
independent of the property of the standard code to minimize the phenotypic
effects of mutations. We propose that selection to explore a large fraction of
the functional sequence space while minimizing the phenotypic effects of
mutations contributed towards the emergence of the standard code as the
universal genetic code.
