Predicting the translation efficiency of messenger RNA in mammalian cells

The degree to which translational control is specified by mRNA sequence is poorly understood in mammalian cells. Here, we constructed and leveraged a compendium of 3,819 ribosomal profiling datasets, distilling them into a transcriptome-wide atlas of translation efficiency (TE) measurements encompassing >140 human and mouse cell types. We subsequently developed RiboNN, a multitask deep convolutional neural network, and classic machine learning models to predict TEs in hundreds of cell types from sequence-encoded mRNA features, achieving state-of-the-art performance (r=0.79 in human and r=0.78 in mouse for mean TE across cell types). While the majority of earlier models solely considered 5' UTR sequence¹, RiboNN integrates contributions from the full-length mRNA sequence, learning that the 5' UTR, CDS, and 3' UTR respectively possess ~67%, 31%, and 2% per-nucleotide information density in the specification of mammalian TEs. Interpretation of RiboNN revealed that the spatial positioning of low-level di- and tri-nucleotide features (i.e., including codons) largely explain model performance, capturing mechanistic principles such as how ribosomal processivity and tRNA abundance control translational output. RiboNN is predictive of the translational behavior of base-modified therapeutic RNA, and can explain evolutionary selection pressures in human 5' UTRs. Finally, it detects a common language governing mRNA regulatory control and highlights the interconnectedness of mRNA translation, stability, and localization in mammalian organisms.