Stop Codon Usage as a Window into Genome Evolution: Mutation, Selection, Biased Gene Conversion and the TAG Paradox

Alexander T. Ho, Laurence D. Hurst

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2 Citations (SciVal)


Protein coding genes terminate with one of three stop codons (TAA, TGA, or TAG) that, like synonymous codons, are not employed equally. With TGA and TAG having identical nucleotide content, analysis of their differential usage provides an unusual window into the forces operating on what are ostensibly functionally identical residues. Across genomes and between isochores within the human genome, TGA usage increases with G + C content but, with a common G + C → A + T mutation bias, this cannot be explained by mutation bias-drift equilibrium. Increased usage of TGA in G + C-rich genomes or genomic regions is also unlikely to reflect selection for the optimal stop codon, as TAA appears to be universally optimal, probably because it has the lowest read-through rate. Despite TAA being favored by selection and mutation bias, as with codon usage bias G + C pressure is the prime determinant of between-species TGA usage trends. In species with strong G + C-biased gene conversion (gBGC), such as mammals and birds, the high usage and conservation of TGA is best explained by an A + T → G + C repair bias. How to explain TGA enrichment in other G + C-rich genomes is less clear. Enigmatically, across bacterial and archaeal species and between human isochores TAG usage is mostly unresponsive to G + C pressure. This unresponsiveness we dub the TAG paradox as currently no mutational, selective, or gBGC model provides a well-supported explanation. That TAG does increase with G + C usage across eukaryotes makes the usage elsewhere yet more enigmatic. We suggest resolution of the TAG paradox may provide insights into either an unknown but common selective preference (probably at the DNA/RNA level) or an unrecognized complexity to the action of gBGC.

Original languageEnglish
Article numberevac115
JournalGenome biology and evolution
Issue number8
Early online date22 Jul 2022
Publication statusPublished - 3 Aug 2022

Bibliographical note

We thank Adam Eyre-Walker and colleagues for sharing their G + C equilibrium data and providing permission to replot these. This work was supported by the European Research Council (grant EvoGenMed ERC-2014-ADG 669207 to L.D.H.).


  • genome evolution
  • molecular evolution
  • stop codon read-through
  • stop codon usage
  • translation termination
  • translational read-through

ASJC Scopus subject areas

  • General Medicine


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