Modeling the intronic regulation of Alternative Splicing using Deep Convolutional Neural Nets

Sammanfattning: This paper investigates the use of deep Convolutional Neural Networks for modeling the intronic regulation of Alternative Splicing on the basis of DNA sequence. By training the CNN on massively parallel synthetic DNA libraries of Alternative 5'-splicing and Alternatively Skipped exon events, the model is capable of predicting the relative abundance of alternatively spliced mRNA isoforms on held-out library data to a very high accuracy (R2 = 0.77 for Alt. 5'-splicing). Furthermore, the CNN is shown to generalize alternative splicing across cell lines efficiently. The Convolutional Neural Net is tested against a Logistic regression model and the results show that while prediction accuracy on the synthetic library is notably higher compared to the LR model, the CNN is worse at generalizing to new intronic contexts. Tests on non-synthetic human SNP genes suggest the CNN is dependent on the relative position of the intronic region it was trained for, a problem which is alleviated with LR. The increased library prediction accuracy of the CNN compared to Logistic regression is concluded to come from the non-linearity introduced by the deep layer architecture. It adds the capacity to model complex regulatory interactions and combinatorial RBP effects which studies have shown largely affect alternative splicing. However, the architecture makes interpreting the CNN hard, as the regulatory interactions are encoded deep within the layers. Nevertheless, high-performance modeling of alternative splicing using CNNs may still prove useful in numerous Synthetic biology applications, for example to model differentially spliced genes as is done in this paper.