Elisabeth R M Tillier1, Thomas W H Lui. 1. Ontario Cancer Institute, University Health Network, Suite 703, 620 University Avenue, Toronto, Ontario, Canada M5G 2M9. e.tillier@utoronto.ca
Abstract
MOTIVATION: Multiple sequence alignments of homologous proteins are useful for inferring their phylogenetic history and to reveal functionally important regions in the proteins. Functional constraints may lead to co-variation of two or more amino acids in the sequence, such that a substitution at one site is accompanied by compensatory substitutions at another site. It is not sufficient to find the statistical correlations between sites in the alignment because these may be the result of several undetermined causes. In particular, phylogenetic clustering will lead to many strong correlations. RESULTS: A procedure is developed to detect statistical correlations stemming from functional interaction by removing the strong phylogenetic signal that leads to the correlations of each site with many others in the sequence. Our method relies upon the accuracy of the alignment but it does not require any assumptions about the phylogeny or the substitution process. The effectiveness of the method was verified using computer simulations and then applied to predict functional interactions between amino acids in the Pfam database of alignments.
MOTIVATION: Multiple sequence alignments of homologous proteins are useful for inferring their phylogenetic history and to reveal functionally important regions in the proteins. Functional constraints may lead to co-variation of two or more amino acids in the sequence, such that a substitution at one site is accompanied by compensatory substitutions at another site. It is not sufficient to find the statistical correlations between sites in the alignment because these may be the result of several undetermined causes. In particular, phylogenetic clustering will lead to many strong correlations. RESULTS: A procedure is developed to detect statistical correlations stemming from functional interaction by removing the strong phylogenetic signal that leads to the correlations of each site with many others in the sequence. Our method relies upon the accuracy of the alignment but it does not require any assumptions about the phylogeny or the substitution process. The effectiveness of the method was verified using computer simulations and then applied to predict functional interactions between amino acids in the Pfam database of alignments.
Authors: Faruck Morcos; Andrea Pagnani; Bryan Lunt; Arianna Bertolino; Debora S Marks; Chris Sander; Riccardo Zecchina; José N Onuchic; Terence Hwa; Martin Weigt Journal: Proc Natl Acad Sci U S A Date: 2011-11-21 Impact factor: 11.205