A correlation between the type of the start codon and the presence of the SD sequence has been reported: genes with an AUG start are more likely to possess an SD sequence than genes with alternative starts 18. In addition to the start codon, an important translation initiation signal is the Shine-Dalgarno (SD) sequence, also known as the ribosome-binding site, which base pairs with a complementary sequence near the 3′-terminus of the 16 S rRNA and increases the efficiency of initiation 17. In prokaryotes, the start codon is one of the major translation initiation determinants: replacement of AUG with an alternative start codon, such as GUG, typically leads to a several-fold drop in the translation efficiency 10, 11, 12, 13, 14, 15, 16. Recognition of the start codons and discrimination between the initiator and elongation tRNAs depends on the translation initiation factor IF3 that helps to position the correct start codon in the ribosomal P-site before binding the aminoacyl-tRNA 9, 10. Furthermore, in some bacteria, such as Bacillus, UUG is more prevalent and leads to higher levels of protein production than GUG 5.Īll start codons are apparently recognized by the dedicated initiator N-Formyl methionyl-tRNA with a CAU anticodon 6, 7, 8. This is generally the case for genes in other bacteria as well 3 although it has been shown that GC content affects the frequency of genes starting with GUG compared with AUG 2. In accord with this ranking of the start codons, genes starting with AUG are, on average, expressed at significantly higher levels than genes that start with GUG, and the latter are expressed at higher levels than genes starting with UUG 3, 4. Recently, it has been shown that, under specific conditions, many different start codons can be used for initiation of translation in Escherichia coli although most of these are employed only rarely, whereas AUG, followed by GUG and then by UUG, remain the principal start signals 3. Over the years, however, many studies have demonstrated that alternative start codons, such as GUG, could be utilized for translation initiation with non-negligible frequencies, i.e. The standard genetic code table contains one start codon, AUG. Together, all these findings indicate that in prokaryotes, translation start signals are subject to weak but significant selection for maximization of initiation rate and, consequently, protein production. Mutation of the start codon to a sub-optimal form (GUG or UUG) tends to be compensated by mutations in the Shine-Dalgarno sequence towards a stronger translation initiation signal. Selection on start codons is most pronounced in evolutionarily conserved, highly expressed genes. The only exception is the AUG to UUG switch that is strongly selected against among start codons. However, purifying selection on start codons is significantly weaker than the selection on the same codons in coding sequences, although the switches between the codons result in conservative amino acid substitutions. Thus, AUG is the optimal start codon that is actively maintained by purifying selection. The AUG starts are replaced by GUG and especially UUG significantly less frequently than expected under the neutral expectation derived from the frequencies of the respective nucleotide triplet substitutions in non-coding regions and in 4-fold degenerate sites. Reconstruction of the evolution of start codons in 36 groups of closely related bacterial and archaeal genomes reveals purifying selection affecting AUG codons.
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