Predicting Mean Ribosome Load For 5'Utr Of Any Length Using Deep Learning

The 5' untranslated region plays a key role in regulating mRNA translation and consequently protein abundance. Therefore, accurate modeling of 5'UTR regulatory sequences shall provide insights into translational control mechanisms and help interpret genetic variants. Recently, a model was trained on a massively parallel reporter assay to predict mean ribosome load (MRL)-a proxy for translation rate-directly from 5'UTR sequence with a high degree of accuracy. However, this model is restricted to sequence lengths investigated in the reporter assay and therefore cannot be applied to the majority of human sequences without a substantial loss of information. Here, we introduced frame pooling, a novel neural network operation that enabled the development of an MRL prediction model for 5'UTRs of any length. Our model shows state-of-the-art performance on fixed length randomized sequences, while offering better generalization performance on longer sequences and on a variety of translation-related genome-wide datasets. Variant interpretation is demonstrated on a 5'UTR variant of the gene HBB associated with beta-thalassemia. Frame pooling could find applications in other bioinformatics predictive tasks. Moreover, our model, released open source, could help pinpoint pathogenic genetic variants.Author summary The human genome carries a complex code. It consists of genes, which provide blueprints to assemble proteins, and regulatory elements, which control when, where, and how often particular genes are transcribed and translated into protein. To read the genome correctly and specifically to find the causes of inherited diseases, we need to be able to find and interpret these regulatory elements. Here, we focus on particular regions of the genome, the so-called 5' untranslated regions, which play an important role in determining how often a transcribed gene is translated into protein. We develop deep learning models which can quantitatively interpret regulatory elements in human 5' untranslated regions and use this information to predict a proxy of the translation efficiency. Our model generalizes a previous model to 5' untranslated regions of any length, just as they are encountered in natural human genes. Because this model requires only the sequence as input, it can give estimates for the impact of mutations in the sequence, even if these particular mutations are very rare or entirely novel. Such estimates could help pinpoint mutations that disrupt the normal functioning of gene regulation, which could be used to better diagnose patients suffering from rare genetic disorders.