Fabienne F. V. Chevance and Kelly T. Hughes

GENETICS

Significance

The genetic code for life is a triplet base code. It is known that adjacent codons can influence translation of a given codon and that codon pair biases occur throughout nature. We show that mRNA translation at a given codon can be affected by the two previous codons. Data presented here support a model in which the evolutionary selection pressure on a single codon is over five successive codons, including synonymous codons. This work provides a foundation for the interpretation of how single DNA base changes might affect translation over multiple codons and should be considered in the characterization of the effects of DNA base changes on human disease.

Abstract

The efficiency of codon translation in vivo is controlled by many factors, including codon context. At a site early in the Salmonella flgM gene, the effects on translation of replacing codons Thr6 and Pro8 of flgM with synonymous alternates produced a 600-fold range in FlgM activity. Synonymous changes at Thr6 and Leu9 resulted in a twofold range in FlgM activity. The level of FlgM activity produced by any codon arrangement was directly proportional to the degree of in vivo ribosome stalling at synonymous codons. Synonymous codon suppressors that corrected the effect of a translation-defective synonymous flgM allele were restricted to two codons flanking the translation-defective codon. The various codon arrangements had no apparent effects on flgM mRNA stability or predicted mRNA secondary structures. Our data suggest that efficient mRNA translation is determined by a triplet-of-triplet genetic code. That is, the efficiency of translating a particular codon is influenced by the nature of the immediately adjacent flanking codons. A model explains these codon-context effects by suggesting that codon recognition by elongation factor-bound aminoacyl-tRNA is initiated by hydrogen bond interactions between the first two nucleotides of the codon and anticodon and then is stabilized by base-stacking energy over three successive codons.

See http://www.pnas.org/content/114/18/4745.abstract.html?etoc

PNAS May 2 2017; vol.114; no.18: 4745–4750

Figure 1: A model showing the effect of Watson–Crick base pairing and the influence of base stacking with bases in the anticodon loop and adjacent bases in the mRNA sequence on codon–anticodon stabilization in the accommodation step in translation and showing how translation can be affected by codons adjacent to the codon being translated (context).