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    BMC Evol Biol. 2008 Dec 3;8:327.

    Detecting coevolution without phylogenetic trees? Tree-ignorant metrics of coevolution perform as well as tree-aware metrics.

    Caporaso JG, Smit S, Easton BC, Hunter L, Huttley GA, Knight R.

    Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, CO, USA. gregcaporaso@gmail.com

    BACKGROUND: Identifying coevolving positions in protein sequences has myriad applications, ranging from understanding and predicting the structure of single molecules to generating proteome-wide predictions of interactions. Algorithms for detecting coevolving positions can be classified into two categories: tree-aware, which incorporate knowledge of phylogeny, and tree-ignorant, which do not. Tree-ignorant methods are frequently orders of magnitude faster, but are widely held to be insufficiently accurate because of a confounding of shared ancestry with coevolution. We conjectured that by using a null distribution that appropriately controls for the shared-ancestry signal, tree-ignorant methods would exhibit equivalent statistical power to tree-aware methods. Using a novel t-test transformation of coevolution metrics, we systematically compared four tree-aware and five tree-ignorant coevolution algorithms, applying them to myoglobin and myosin. We further considered the influence of sequence recoding using reduced-state amino acid alphabets, a common tactic employed in coevolutionary analyses to improve both statistical and computational performance. RESULTS: Consistent with our conjecture, the transformed tree-ignorant metrics (particularly Mutual Information) often outperformed the tree-aware metrics. Our examination of the effect of recoding suggested that charge-based alphabets were generally superior for identifying the stabilizing interactions in alpha helices. Performance was not always improved by recoding however, indicating that the choice of alphabet is critical. CONCLUSION: The results suggest that t-test transformation of tree-ignorant metrics can be sufficient to control for patterns arising from shared ancestry.

    PMID: 19055758 [PubMed - indexed for MEDLINE]

    PMCID: 2637866

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