Most amino acids are encoded by more than one codon. These synonymous codons are not used with equal frequency: in every organism, some codons are used more commonly, while others are more rare. Though the encoded protein sequence is identical, selective pressures favor more common codons for enhanced translation speed and fidelity. However, rare codons persist, presumably due to neutral drift. Here, we determine whether other, unknown factors, beyond neutral drift, affect the selection and/or distribution of rare codons. We have developed a novel algorithm that evaluates the relative rareness of a nucleotide sequence used to produce a given protein sequence. We show that rare codons, rather than being randomly scattered across genes, often occur in large clusters. These clusters occur in numerous eukaryotic and prokaryotic genomes, and are not confined to unusual or rarely expressed genes: many highly expressed genes, including genes for ribosomal proteins, contain rare codon clusters. A rare codon cluster can impede ribosome translation of the rare codon sequence. These results indicate additional selective pressures govern the use of synonymous codons, and specifically that local pauses in translation can be beneficial for protein biogenesis.

BackgroundThe process of translation can be affected by the use of rare versus common codons within the mRNA transcript.ResultsHere, we show that rare codons are enriched at the 5' and 3' termini of genes from E. coli and other prokaryotes. Genes predicted to be secreted show significant enrichment in 5' rare codon clusters, but not 3' rare codon clusters. Surprisingly, no correlation between 5' mRNA structure and rare codon usage was observed.ConclusionsPotential functional roles for the enrichment of rare codons at terminal positions are explored.

While in vitro experiments have contributed much to our understanding of protein folding, we know much less about how proteins fold in the more complex environment of the cell. This review summarizes our current knowledge of the earliest in vivo folding intermediates: the conformations adopted by nascent polypeptides during synthesis by the ribosome. The challenges related to successful folding in the cellular environment, including off-pathway aggregation and macromolecular crowding, are also discussed.

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