Abstract
Reconstruction of the evolution of start codons in 36 groups of closely related bacterial and archaeal genomes reveals purifying selection affecting AUG codons. 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. Thus, AUG is the optimal start codon that is actively maintained by purifying selection. 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. The only exception is the AUG to UUG switch that is strongly selected against among start codons. Selection on start codons is most pronounced in evolutionarily conserved, highly expressed genes. 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. 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.
Highlights
The standard genetic code table contains one start codon, AUG
These findings indicate that the start codon in itself is a key translation initiation signal that is recognized by the initiation machinery, in particular the ribosomal small subunit, in a tRNA-independent manner, and interacts with other initiation signals
We further demonstrated that the difference in the frequencies of switch to an AUG and from an AUG start codon was significant in each of the individual prokaryotic phyla except for γ-proteobacteria, where the difference between the frequencies of the AUG to UUG and UUG to AUG switches was found not to be significant (Table 2)
Summary
The standard genetic code table contains one start codon, AUG. Over the years, many studies have demonstrated that alternative start codons, such as GUG, could be utilized for translation initiation with non-negligible frequencies, i.e. up to 20% non-AUG starts[1,2]. Translation of leaderless mRNAs that lack the SD sequence appears to require an AUG start codon, and this requirement does not depend on the anticodon complementarity to the start codon because compensatory modification of the anticodon does not restore translation of leaderless mRNAs with alternative start codons[19] In addition to the start codon and the SD sequences, other sequences in the vicinity of the translation start site can affect the efficiency of initiation, in particular, several nucleotides immediately downstream of the start codon; compensatory relationships between such signals and the SD have been demonstrated[25,26,27] These findings indicate that the start codon in itself is a key translation initiation signal that is recognized by the initiation machinery, in particular the ribosomal small subunit, in a tRNA-independent manner, and interacts with other initiation signals. We identified significant associations between start codon switches and substitutions in the upstream SD sequence and in positions −1 to −3
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