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Open Access Highly Accessed Methodology article

Detecting groups of coevolving positions in a molecule: a clustering approach

Julien Dutheil* and Nicolas Galtier

Author Affiliations

Institut des Sciences de l'Évolution (UM2-CNRS) Université Montpellier 2 Place Eugéne Bataillon, CC064, 34 095 Montpellier cedex 5, France

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BMC Evolutionary Biology 2007, 7:242  doi:10.1186/1471-2148-7-242

Published: 30 November 2007



Although the patterns of co-substitutions in RNA is now well characterized, detection of coevolving positions in proteins remains a difficult task. It has been recognized that the signal is typically weak, due to the fact that (i) amino-acid are characterized by various biochemical properties, so that distinct amino acids changes are not functionally equivalent, and (ii) a given mutation can be compensated by more than one mutation, at more than one position.


We present a new method based on phylogenetic substitution mapping. The two above-mentioned problems are addressed by (i) the introduction of a weighted mapping, which accounts for the biochemical effects (volume, polarity, charge) of amino-acid changes, (ii) the use of a clustering approach to detect groups of coevolving sites of virtually any size, and (iii) the distinction between biochemical compensation and other coevolutionary mechanisms. We apply this methodology to a previously studied data set of bacterial ribosomal RNA, and to three protein data sets (myoglobin of vertebrates, S-locus Receptor Kinase and Methionine Amino-Peptidase).


We succeed in detecting groups of sites which significantly depart the null hypothesis of independence. Group sizes range from pairs to groups of size ≃ 10, depending on the substitution weights used. The structural and functional relevance of these groups of sites are assessed, and the various evolutionary processes potentially generating correlated substitution patterns are discussed.