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Genetic code flexibility in microorganisms: novel mechanisms and impact on physiology

  • Review Article
  • Published:

From Nature Reviews Microbiology

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Key Points

  • The genetic code is not frozen.

  • Genetic code variations found in microorganisms include codon bias, codon reassignment, ambiguous decoding and natural genetic code expansion.

  • Codon bias, which is present in all sequenced genomes, modulates the rate of protein synthesis, which in turn regulates many biological processes.

  • Codon reassignment involves distinct mechanisms to completely redefine codon meaning.

  • Ambiguous decoding, which is detrimental at high levels, can be advantageous under stress conditions by increasing proteome diversity and activating stress responses.

  • Natural genetic code expansion with selenocysteine and pyrrolysine enables certain organisms to synthesize proteins with 21 or 22 amino acids, with consequences for enzymatic and metabolic efficiency that are just beginning to be understood.

  • The impact of genetic code evolution on microbial physiology is an emerging field, which is ripe for new discoveries.

Abstract

The genetic code, initially thought to be universal and immutable, is now known to contain many variations, including biased codon usage, codon reassignment, ambiguous decoding and recoding. As a result of recent advances in the areas of genome sequencing, biochemistry, bioinformatics and structural biology, our understanding of genetic code flexibility has advanced substantially in the past decade. In this Review, we highlight the prevalence, evolution and mechanistic basis of genetic code variations in microorganisms, and we discuss how this flexibility of the genetic code affects microbial physiology.

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Figure 1: Mechanisms of genetic code flexibility.
Figure 2: Biased codon usage.
Figure 3: Codon reassignment.
Figure 4: Ambiguous decoding.
Figure 5: Expanding the genetic code with Sec and Pyl.

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Acknowledgements

Work in the authors' laboratories was supported by grants from the US National Institute of General Medical Sciences (GM022854 to D.S.; and GM115431 to J.L.), from the Natural Sciences and Engineering Research Council of Canada (RGPIN 04282–2014 to P.O.), from the Canadian Institutes of Health Research Tier 2 Canada Research Chair (950-229917 to P.O.), and from The University of Texas Health Science Center at Houston start-up fund (to J.L.). The authors are grateful to I. Heinemann for discussions and a critical reading of the manuscript.

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  1. Jiqiang Ling and Patrick O'Donoghue: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Molecular Genetics, University of Texas Health Science Center, Houston, 77030, Texas, USA

    Jiqiang Ling

  2. Department of Biochemistry, The University of Western Ontario, London, N6A 5C1, Ontario, Canada

    Patrick O'Donoghue

  3. Department of Chemistry, The University of Western Ontario, London, N6A 5C1, Ontario, Canada

    Patrick O'Donoghue

  4. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, 06520–8114, Connecticut, USA

    Dieter Söll

  5. Department of Chemistry, Yale University, New Haven, 06520–8114, Connecticut, USA

    Dieter Söll

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  1. Jiqiang Ling
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Correspondence to Dieter Söll.

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Glossary

Aminoacyl-tRNA

(aa-tRNA). A tRNA molecule with an amino acid attached to the 3′ end. It is used as a substrate by the ribosome to synthesize proteins.

Codon–anticodon pairing

During translation, the bases of the mRNA codon and the tRNA anticodon need to match each other. Watson–Crick pairing (A–U and G–C) in the first and second positions of the codon is required for efficient decoding, whereas the third position allows more flexible pairing, for example, between G and U or using modified bases.

Synonymous codons

Different triplet nucleotide sequences that decode the same amino acid.

tRNA isoacceptors

Different tRNA species recognized by the same aminoacyl-tRNA synthetase and ligated with the same amino acid.

Misacylation

Incorrect pairing of an amino acid and tRNA by an aminoacyl-tRNA synthetase. Errors resulting from misacylation, if left uncorrected, reduce the overall translational fidelity.

Frameshifting

Change in the reading frame during translation due to mutations in the DNA, errors during transcription or translation or specific mRNA structures, leading to new protein sequences.

Shine–Dalgarno-like sequences

mRNA sequences that share high similarity with the Shine–Dalgarno sequence, which pairs with the anti-Shine–Dalgarno sequence of the ribosomal RNA.

Codon adaptation index

A method for analysing usage bias of synonymous codons using a set of highly expressed genes from a species as a reference to assign a score to each gene.

Wobble position

The third position of a codon, which is more flexibly recognized by the tRNA compared with other positions.

Phages

(Also called bacteriophages). Viruses that infect and propagate within bacteria. Phages contain their own genome but hijack the translational machinery of the bacterial host for protein synthesis.

RpoB

The β-subunit of the bacterial RNA polymerase and target of the antibiotic rifampicin.

Nucleophilicity

The property to donate an electron in chemical reactions.

Elongation factor Tu

(EF-Tu). A bacterial elongation factor that delivers aminoacyl-tRNAs to the ribosome during peptide synthesis. The counterpart of EF-Tu in archaea and eukaryotes is EF-1A.

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Ling, J., O'Donoghue, P. & Söll, D. Genetic code flexibility in microorganisms: novel mechanisms and impact on physiology. Nat Rev Microbiol 13, 707–721 (2015). https://doi.org/10.1038/nrmicro3568

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