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Phylogenetic profiling methods can achieve good accuracy in predicting protein-protein interactions, especially in prokaryotes. Recent studies have shown that the choice of reference taxa (RT) is critical for accurate prediction, but with more than 2500 fully sequenced taxa publicly available, identifying the most-informative RT is becoming increasingly difficult. Previous studies on the selection of RT have provided guidelines for manual taxon selection, and for eliminating closely related taxa. However, no general strategy for automatic selection of RT is currently available.

Automatic selection of reference taxa for protein–protein interaction prediction with phylogenetic profiling