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.