BIOINFORMATICS REVCOM: A Robust Bayesian Method for Evolutionary Rate Estimation

Motivation: Evolutionary conservation estimated from a mul-tiple sequence alignment is a powerful indicator of the functio-nal significance of a residue, and helps to predict active sites, ligand binding sites, and protein interaction interfaces. Many algorithms that calculate conservation work well provided an accurate and balanced alignment is used. However, such a strong dependence on the alignment makes the results highly variable. We attempted to improve the conservation predic-tion algorithm by making it more robust and less sensitive to (i) local alignment errors, (ii) overrepresentation of sequences in some branches, and (iii) occasional presence of unrelated sequences. Results: A novel method is presented for robust constrai-ned Bayesian estimation of evolutionary rates that avoids overfitting independent rates and satisfies the above requi-rements. The method is evaluated and compared with an entropy-based conservation measure on a set of protein interfaces. We demonstrate that about % of the analyzed protein interfaces are more conserved than the remaining surface at the % significance level. A consistent method to incorporate alignment reliability is proposed and demon-strated to reduce arbitrary variation of calculated rates upon inclusion of distantly related or unrelated sequences into the alignment. Contact