Using Phylogenetics and Mutual Information to Identify Coevolving Sites in Protein Families
by
Christopher DeHaan
The University of Western Ontario
Coauthors: Lindi Wahl, Andrew Fernandes

Proteins with similar functions found in different organisms can be aligned in a multiple sequence alignment (MSA), and standard techniques are now available to infer the phylogenetic tree which relates these sequences in evolutionary history. A number of recent papers have elucidated the use of Mutual Information (MI) in identifying positions within such a protein family which co-evolve or are in contact in the folded structure. However, to date, none of these MI methods have made use of the phylogenetic history of the proteins in the MSA. I have used the inferred phylogeny of an MSA to simulate realistic random protein sequences, but with no interdependence on any of the individual positions. Initial amino acid distributions and their mutation probabilities are based on observed data (a contingency table). This allows the computation of a distribution of MI in the absence of interdependence, which serves as a null distribution which is specific to a particular MSA. Positions in the real MSA which share significantly more MI than the simulated null distribution can then be identified with some certainty. This method leads to more accurate identification of protein active sites and sites which are in contact, both of which are critical in determining the protein mechanism and structure.

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Date received: May 13, 2008