Journal of Molecular Evolution

, Volume 86, Issue 6, pp 325–339 | Cite as

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

  • Shubham Tripathi
  • Michael W. Deem
Original Article


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 standard 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 toward the emergence of the standard code as the universal genetic code.


Adaptive evolution Standard genetic code Functional protein landscape Genetic heterogeneity 



This work was supported by the Center for Theoretical Biological Physics, funded by the National Science Foundation (PHY-1427654).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Authors and Affiliations

  1. 1.PhD Program in Systems, Synthetic, and Physical BiologyRice UniversityHoustonUSA
  2. 2.Center for Theoretical Biological PhysicsRice UniversityHoustonUSA
  3. 3.Department of BioengineeringRice UniversityHoustonUSA
  4. 4.Department of Physics and AstronomyRice UniversityHoustonUSA

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