![]() A simple explanation of this result is that changes at the +4 and +5 sites alter the amino acid, whereas those at the +6 site may not. In contrast, the +6 site (the third codon position of the second codon) is less important. One piece of supporting evidence came from a detailed study of an influenza virus NS cDNA derivative which showed that both +4 and +5 sites were important and changes at these sites reduced protein production. It has been suggested that +4G may have little to do with initiation site recognition, but is constrained by the requirement for particular type of amino acid residue at the N-terminus of the protein. The interpretation of +4G has been controversial. Molecular biology textbooks abound with the implication that the −3R and +4G should be salient features of mRNA for highly expressed proteins. The optimal context for translation initiation in mammalian species is GCCRCCaugG (where R = purine), with the −3R and +4G being particularly important, –. While translation initiation in prokaryotes is mediated by base-paring between the Shine-Dalgarno sequence at the 5-UTR on the mRNA and the anti-Shine-Dalgarno sequence at the 3′-end of the 16S rRNA, , translation initiation in eukaryotes is mediated by the Kozak consensus –. These results are inconsistent with +4G being needed for efficient translation initiation, but consistent with the proposal of amino acid constraint hypothesis. While highly expressed genes have more +4G than lowly expressed genes, the difference is caused by GCN and GGN codons at the second codon. Among the five G-starting codons, only alanine codons (GCN), and glycine codons (GGN) to a much smaller extent, are overrepresented at the second codon, whereas the other three codons are not overrepresented. The result shows that the prevalence of +4G is not related to translation initiation. I performed a critical test of these alternative hypotheses on +4G based on 34169 human protein-coding genes and published gene expression data. Accumulated experimental and bioinformatic evidence has suggested an alternative explanation based on amino acid constraint on the second codon, i.e., amino acid Ala or Gly are needed as the second amino acid in the nascent peptide for the cleavage of the initiator Met, and the consequent overuse of Ala and Gly codons (GCN and GGN) leads to the +4G consensus. The presence of +4G has been interpreted as necessary for efficient translation initiation. The optimal context for translation initiation in mammalian species is GCCRCCaugG (where R = purine and “aug” is the initiation codon), with the -3R and +4G being particularly important. ![]()
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