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Modes of evolution of stop codons in protein-coding genes, especially the conservation of UAA, have been debated for many years. We reconstructed the evolution of stop codons in 40 groups of closely related prokaryotic and eukaryotic genomes. The results indicate that the UAA codons are maintained by purifying selection in all domains of life. In contrast, positive selection appears to drive switches from UAG to other stop codons in prokaryotes but not in eukaryotes. Changes in stop codons are significantly associated with increased substitution frequency immediately downstream of the stop. These positions are otherwise more strongly conserved in evolution compared to sites farther downstream, suggesting that such substitutions are compensatory. Although GC content has a major impact on stop codon frequencies, its contribution to the decreased frequency of UAA differs between bacteria and archaea, presumably, due to differences in their translation termination mechanisms.

Purifying and positive selection in the evolution of stop codons