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MBE Advance Access published online on April 6, 2009
Molecular Biology and Evolution, doi:10.1093/molbev/msp070
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© The Author 2009. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Research Article

Translationally optimal codons associate with structurally sensitive sites in proteins

Tong Zhou1,2, Mason Weems3 and Claus O. Wilke1,2,3,*

1 Center for Computational Biology and Bioinformatics, University of Texas at Austin, Austin, TX 78731, USA
2 Section of Integrative Biology, University of Texas at Austin, Austin, TX 78731, USA
3 Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, TX 78731, USA

* Corresponding author Email: cwilke{at}mail.utexas.edu, Phone: +1 512 471 6028

Received for publication December 9, 2008. Revision received February 16, 2009. Accepted for publication March 27, 2009.

The mistranslation-induced-protein-misfolding hypothesis predicts that selection should prefer high-fidelity codons at sites at which translation errors are structurally disruptive and lead to protein misfolding and aggregation. To test this hypothesis, we analyzed the relationship between codon usage bias and protein structure in the genomes of four model organisms, E. coli, yeast, fly, and mouse. Using both the Mantel-Haenszel procedure, which applies to categorical data, and a newly developed association test for continuous variables, we find that translationally optimal codons associate with buried residues and also with residues at sites where mutations lead to large changes in free energy ({Delta}{Delta}G). In each species, only a subset of all amino acids show this signal, but most amino acids show the signal in at least one species. By repeating the analysis on a reduced data set that excludes inter-domain linkers, we show that our results are not caused by an association of rare codons with solvent-accessible linker regions. Finally, we find that our results depend weakly on expression level; the association between optimal codons and buried sites exists at all expression levels, but increases in strength as expression level increases.

Key Words: codon usage bias • optimal codon • protein structure • protein evolution • translational accuracy selection


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