RNA secondary structure prediction using an ensemble of two-dimensional deep neural networks and transfer learning

The majority of our human genome transcribes into noncoding RNAs with unknown structures and functions. Obtaining functional clues for noncoding RNAs requires accurate base-pairing or secondary-structure prediction. However, the performance of such predictions by current folding-based algorithms has been stagnated for more than a decade. Here, we propose the use of deep contextual learning for base-pair prediction including those noncanonical and non-nested (pseudoknot) base pairs stabilized by tertiary interactions. Since only < 250 nonredundant, high-resolution RNA structures are available for model training, we utilize transfer learning from a model initially trained with a recent high-quality bpRNA dataset of > 10,000 nonredundant RNAs made available through comparative analysis. The resulting method achieves large, statistically significant improvement in predicting all base pairs, noncanonical and non-nested base pairs in particular. The proposed method (SPOT-RNA), with a freely available server and standalone software, should be useful for improving RNA structure modeling, sequence alignment, and functional annotations. The limited availability of high-resolution 3D RNA structures for model training limits RNA secondary structure prediction. Here, the authors overcome this challenge by pre-training a DNN on a large set of predicted RNA structures and using transfer learning with high-resolution structures.