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Rare Codons Cluster Thomas F. Clarke IV, Patricia L. Clark* Department of Chemistry Biochemistry, University of Notre Dame, Notre Dame, Indiana, United States of America Abstract 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. Citation: Clarke TF IV, Clark PL (2008) Rare Codons Cluster. PLoS ONE 3(10): e3412. doi:10.1371/journal.pone.0003412 Editor: Dong-Yan Jin, University of Hong Kong, China Received September 12, 2008; Accepted September 19, 2008; Published October 15, 2008 Copyright: 2008 Clarke IV et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use