The importance of nonsense errors: Estimating the rates and implications of ribosome drop-off during protein synthesis

Author summary The process of translating mRNA into a protein is both energetically expensive and relatively error-prone. As such, natural selection is thought to shape the evolution of protein-coding genes to reduce the cost of these errors when they occur. Nonsense errors (NSEs) occur when a ribosome stops translation before completing a functional protein, resulting in wasted energy on a non-functional product. Despite their functional consequences, NSEs and their effects on coding sequence evolution are generally understudied compared to other types of translation errors. This is in part due to the challenge of quantifying these errors from omics-scale data. We present a model for quantifying codon-specific estimates of elongation and NSE rates from ribosome profiling data, which gives a snapshot of the actively translating ribosomes in a cell. Although it is well-established that sense codons vary in their elongation rates, we find evidence that codons also vary in their NSE rates. Using our parameter estimates, we find multiple lines of evidence for selection against NSEs shaping patterns of codon usage bias. Our results suggest the cost of NSEs is comparable to the cost of ribosome pausing, and thus may play a greater role in coding sequence evolution than previously appreciated.