Generative modeling for RNA splicing predictions and design.

Alternative splicing (AS) of pre-mRNA plays a crucial role in tissue-specific gene regulation, with disease implications due to splicing defects. Predicting and manipulating AS can therefore uncover new regulatory mechanisms and aid in therapeutics design. We introduce TrASPr+BOS, a generative AI model with Bayesian Optimization for predicting and designing RNA for tissue-specific splicing outcomes. TrASPr is a multi-transformer model that can handle different types of AS events and generalize to unseen cellular conditions. It then serves as an oracle, generating labeled data to train a Bayesian Optimization for Splicing (BOS) algorithm to design RNA for condition-specific splicing outcomes. We show TrASPr+BOS outperforms existing methods, enhancing tissue-specific AUPRC by up to 2.4 fold and capturing tissue-specific regulatory elements. We validate hundreds of predicted novel tissue-specific splicing variations and confirm new regulatory elements using dCas13. We envision TrASPr+BOS as a light yet accurate method researchers can probe or adopt for specific tasks.