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Open Access Research article

Analysis of the distribution of functionally relevant rare codons

Michael Widmann1, Marie Clairo2, Jürgen Dippon2 and Jürgen Pleiss1*

Author Affiliations

1 Institute of Technical Biochemistry, Allmandring 31, 70569 Stuttgart, Germany

2 Institut für Stochastik und Anwendungen, Pfaffenwaldring 57, 70569 Stuttgart, Germany

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BMC Genomics 2008, 9:207  doi:10.1186/1471-2164-9-207

Published: 5 May 2008



The substitution of rare codons with more frequent codons is a commonly applied method in heterologous gene expression to increase protein yields. However, in some cases these substitutions lead to a decrease of protein solubility or activity. To predict these functionally relevant rare codons, a method was developed which is based on an analysis of multisequence alignments of homologous protein families.


The method successfully predicts functionally relevant codons in fatty acid binding protein and chloramphenicol acetyltransferase which had been experimentally determined. However, the analysis of 16 homologous protein families belonging to the α/β hydrolase fold showed that functionally rare codons share no common location in respect to the tertiary and secondary structure.


A systematic analysis of multisequence alignments of homologous protein families can be used to predict rare codons with a potential impact on protein expression. Our analysis showed that most genes contain at least one putative rare codon rich region. Rare codons located near to those regions should be excluded in an approach of improving protein expression by an exchange of rare codons by more frequent codons.