A phylogenetic model for the detection of epistatic interactions.

Paired epistatic interactions, such as those in the stem regions of RNA, play an important role in many biological processes. However, unlike protein-coding regions, paired epistatic interactions have lacked the appropriate statistical tools for the detection of departures from selective neutrality. Here, a model is presented for the analysis of paired epistatic regions that draws upon the population genetics of the compensatory substitution process to detect the relative strength of natural selection acting against deleterious combinations of alleles. The method is based upon the relative rates of double and single substitution, and can differentiate between nonindependent interactions and negatively epistatic ones. The model is implemented in a fully Bayesian framework for parameter estimation and is demonstrated using a 5S rRNA data set. In addition to the detection of selection, modeling the double and single substitution processes in this manner inherently accounts for a substantial proportion of rate variation among stem positions.