Modeling ribosome dwell times and relationships with tRNA loading and codon usage in mammals

Protein translation depends on mRNA-specific initiation, elongation and termination rates. While the regulation of ribosome elongation is well studied in bacteria and yeast, less is known in higher eukaryotes. Here, we combined ribosome and tRNA profiling to investigate the relations between ribosome elongation rates, (aminoacyl-) tRNA levels and codon usage in mammals. We modeled codon-specific ribosome dwell times and translation fluxes from ribosome profiling, considering pair-interactions between ribosome sites. In mouse liver, the model revealed site and codon specific dwell times, as well as codon pair-interactions clustering by amino acids. While translation fluxes varied significantly across diurnal time and feeding regimen, codon dwell times were highly stable, and conserved in human. Fasting had no effect on codon dwell times in mouse liver. Profiling of total and aminoacyl-tRNAs revealed highly heterogeneous levels that correlated with codon usage and showed specific isoacceptor patterns. tRNAs for several amino acids were lowly loaded, which was conserved in fasted mice. Finally, codons with low levels of charged tRNAs and high codon usage relative to tRNA abundance exhibited long dwell times. Together, these analyses pave the way towards understanding the complex interactions between tRNA loading, codon usage and ribosome dwell times in mammals.