The Standard Genetic Code Facilitates Exploration of the Space of Functional Nucleotide Sequences
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.
KeywordsAdaptive 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).
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Conflict of interest
The authors declare that they have no conflict of interest.
- Alberts B, Hunt T, Johnson A et al (2008) Cells and genomes. In: Molecular biology of the cell, 5th edn. Garland Science, New York, pp 1–44Google Scholar
- Berg JM, Tymoczko JL, Stryer L (2002) Protein structure and function. In: Biochemistry, 5th edn, W H Freeman, New YorkGoogle Scholar
- Freeland SJ, Knight RD, Landweber LF, Hurst LD (2000) Early fixation of an optimal genetic code. Mol Biol Evol 17:511–518. https://doi.org/10.1093/oxfordjournals.molbev.a026331 CrossRefPubMedGoogle Scholar
- Giulio MD (2016) The lack of foundation in the mechanism on which are based the physico-chemical theories for the origin of the genetic code is counterposed to the credible and natural mechanism suggested by the coevolution theory. J Theor Biol 399:134–140. https://doi.org/10.1016/j.jtbi.2016.04.005 CrossRefPubMedGoogle Scholar
- Griffiths A, Miller J, Suzuki D et al (2000) An introduction to genetic analysis, 7th edn. W H Freeman, New YorkGoogle Scholar
- Koonin EV, Novozhilov AS (2017) Origin and evolution of the universal genetic code. Annu Rev Genet 51:45–62. https://doi.org/10.1146/annurev-genet-120116-024713 CrossRefPubMedGoogle Scholar
- Polyansky AA, Hlevnjak M, Zagrovic B (2013) Proteome-wide analysis reveals clues of complementary interactions between mRNAs and their cognate proteins as the physicochemical foundation of the genetic code. RNA Biol 10:1248–1254. https://doi.org/10.4161/rna.25977 CrossRefPubMedPubMedCentralGoogle Scholar
- Woese CR (1967) The genetic code: the molecular basis for genetic expression. Harper & Row, New YorkGoogle Scholar