MOTIVATION: An increasing amount of evidence from experimental and computational 
analysis suggests that rare codon clusters are functionally important for 
protein activity. Most of the studies on rare codon clusters were performed on a 
limited number of proteins or protein families. In the present study, we present 
the Sherlocc program and how it can be used for large scale protein family 
analysis of evolutionarily conserved rare codon clusters and their relation to 
protein function and structure. This large-scale analysis was performed using 
the whole Pfam database covering over 70% of the known protein sequence 
universe. Our program Sherlocc, detects statistically relevant conserved rare 
codon clusters and produces a user-friendly HTML output.
RESULTS: Statistically significant rare codon clusters were detected in a 
multitude of Pfam protein families. The most statistically significant rare 
codon clusters were predominantly identified in N-terminal Pfam families. Many 
of the longest rare codon clusters are found in membrane-related proteins which 
are required to interact with other proteins as part of their function, for 
example in targeting or insertion. We identified some cases where rare codon 
clusters can play a regulating role in the folding of catalytically important 
domains. Our results support the existence of a widespread functional role for 
rare codon clusters across species. Finally, we developed an online filter-based 
search interface that provides access to Sherlocc results for all Pfam families.
AVAILABILITY: The Sherlocc program and search interface are open access and are 
available at http://bcb.med.usherbrooke.ca