Transformers significantly improve splice site prediction.

Mutations that affect RNA splicing significantly impact human diversity and disease. Here we present a method using transformers, a type of machine learning model, to detect splicing from raw 45,000-nucleotide sequences. We generate embeddings with residual neural networks and apply hard attention to select splice site candidates, enabling efficient training on long sequences. Our method surpasses the leading tool, SpliceAI, in detecting splice sites in GENCODE and ENSEMBL annotations. Using extensive RNA sequencing data from an Icelandic cohort of 17,848 individuals and the Genotype-Tissue Expression (GTEx) project, our method demonstrates superior performance in detecting splice junctions compared to SpliceAI-10k (PR-AUC = 0.834 vs. PR-AUC = 0.820) and is more effective at identifying disease-related splice variants in ClinVar (PR-AUC = 0.997 vs. PR-AUC = 0.996). These advancements hold promise for improving genetic research and clinical diagnostics, potentially leading to better understanding and treatment of splicing-related diseases.