The standard genetic code facilitates exploration of the space of functional nucleotide sequences

TL;DR

This study shows that the standard genetic code is optimized for exploring diverse functional protein variants, balancing robustness and flexibility, which may have influenced its emergence as the universal code.

Contribution

It demonstrates that the standard genetic code facilitates exploration of functional protein variants more effectively than random codes, especially at intermediate evolutionary time scales.

Findings

Standard genetic code is highly optimal for exploring functional PhoQ variants.

Environmental changes at intermediate time scales favor genetic diversity.

The code's exploration ability is independent of mutation minimization properties.

Abstract

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.