There is an increased interest in the determination of RNA structures in vivo as it is now possible to probe them in a high-throughput manner, e.g. using SHAPE protocols. By now, there exist a range of computational methods that integrate experimental SHAPE-probing evidence into computational RNA secondary structure prediction. The state-of-the-art in this field is currently provided by computational methods that employ the minimum-free energy strategy for prediction RNA secondary structures with SHAPE-probing evidence. These methods, however, rely on the assumption that transcripts in vivo fold into the thermodynamically most stable configuration and ignore evolutionary evidence for conserved RNA structure features. We here present a new computational method, ShapeSorter, that predicts RNA structure features without employing the thermodynamic strategy. Instead, ShapeSorter employs a fully probabilistic framework to identify RNA structure features that are supported by evolutionary and SHAPE-probing evidence. Our method can capture RNA structure heterogeneity, pseudo-knotted RNA structures as well as transient and mutually exclusive RNA structure features. Moreover, it estimates P-values for the predicted RNA structure features which allows for easy filtering and ranking. We investigate the merits of our method in a comprehensive performance benchmarking and conclude that ShapeSorter has a significantly superior performance for predicting base-pairs than the existing state-of-the-art methods.
