Deep learning prediction of ribosome profiling with Translatomer reveals translational regulation and interprets disease variants

Abstract

Gene expression involves transcription and translation. Despite large datasets and increasingly powerful methods devoted to calculating genetic variants’ effects on transcription, discrepancy between messenger RNA and protein levels hinders the systematic interpretation of the regulatory effects of disease-associated variants. Accurate models of the sequence determinants of translation are needed to close this gap and to interpret disease-associated variants that act on translation. Here we present Translatomer, a multimodal transformer framework that predicts cell-type-specific translation from messenger RNA expression and gene sequence. We train the Translatomer on 33 tissues and cell lines, and show that the inclusion of sequence improves the prediction of ribosome profiling signal, indicating that the Translatomer captures sequence-dependent translational regulatory information. The Translatomer achieves accuracies of 0.72 to 0.80 for the de novo prediction of cell-type-specific ribosome profiling. We develop an in silico mutagenesis tool to estimate mutational effects on translation and demonstrate that variants associated with translation regulation are evolutionarily constrained, both in the human population and across species. In particular, we identify cell-type-specific translational regulatory mechanisms independent of the expression quantitative trait loci for 3,041 non-coding and synonymous variants associated with complex diseases, including Alzheimer’s disease, schizophrenia and congenital heart disease. The Translatomer accurately models the genetic underpinnings of translation, bridging the gap between messenger RNA and protein levels as well as providing valuable mechanistic insights for uninterpreted disease variants. A transformer-based approach called Translatomer is presented, which models cell-type-specific translation from messenger RNA expression and gene sequence, bridging the gap between messenger RNA and protein levels as well as providing a mechanistic insight into the genetic regulation of translation.