Adenine Enrichment at the Fourth CDS Residue in Bacterial Genes Is Consistent with Error Proofing for +1 Frameshifts

• Published in: Molecular Biology and Evolution Vol. 34; no. 12; pp. 3064 - 3080
• Main Authors: Abrahams, Liam, Hurst, Laurence D
• Format: Journal Article Web Resource
• Language: English
• Published: United States Oxford University Press 01.12.2017
• Subjects: Adenine - metabolism; Bacteria - genetics; Base Sequence; Codon - metabolism; Codon, Initiator - genetics; Codon, Terminator - genetics; Discoveries; Evolution, Molecular; Frameshift Mutation - genetics; Genes, Bacterial - genetics; Genome, Bacterial - genetics; Ribosomes - metabolism; RNA Stability - genetics; RNA, Messenger - genetics; error mitigation, dual coding; translation initiation; frameshift; fourth site
• ISSN: 0737-4038; 1537-1719
• DOI: 10.1093/molbev/msx223

Beyond selection for optimal protein functioning, coding sequences (CDSs) are under selection at the RNA and DNA levels. Here, we identify a possible signature of "dual-coding," namely extensive adenine (A) enrichment at bacterial CDS fourth sites. In 99.07% of studied bacterial genomes, fourth site A use is greater than expected given genomic A-starting codon use. Arguing for nucleotide level selection, A-starting serine and arginine second codons are heavily utilized when compared with their non-A starting synonyms. Several models have the ability to explain some of this trend. In part, A-enrichment likely reduces 5' mRNA stability, promoting translation initiation. However T/U, which may also reduce stability, is avoided. Further, +1 frameshifts on the initiating ATG encode a stop codon (TGA) provided A is the fourth residue, acting either as a frameshift "catch and destroy" or a frameshift stop and adjust mechanism and hence implicated in translation initiation. Consistent with both, genomes lacking TGA stop codons exhibit weaker fourth site A-enrichment. Sequences lacking a Shine-Dalgarno sequence and those without upstream leader genes, that may be more error prone during initiation, have greater utilization of A, again suggesting a role in initiation. The frameshift correction model is consistent with the notion that many genomic features are error-mitigation factors and provides the first evidence for site-specific out of frame stop codon selection. We conjecture that the NTG universal start codon may have evolved as a consequence of TGA being a stop codon and the ability of NTGA to rapidly terminate or adjust a ribosome.