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

Alexander L Cope, Denizhan Pak and Michael A Gilchrist

PLOS Genetics, 2026, vol. 22, issue 6, 1-29

Abstract: The process of translation is both energetically costly and relatively error-prone compared to transcription and replication. Nonsense errors during translation occur when a ribosome drops off a transcript before reaching a stop codon, resulting in energetic investment in an incomplete and likely non-functional protein. Nonsense errors impose a potentially significant energy burden on the cell, making it critical to quantify their frequency and energetic cost. Here, we present a model of ribosome movement for estimating protein production, elongation, and nonsense error rates from high-throughput ribosome profiling data. Applying this model to an exemplary ribosome profiling dataset in S. cerevisiae, we find that nonsense error rates vary substantially between codons and that these types of errors place an energetic burden on cells comparable to ribosome pausing. Overall, we present multiple lines of evidence that selection against nonsense errors is a prominent force shaping protein-coding sequence evolution and codon usage bias, in particular.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.

Date: 2026
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1012162

DOI: 10.1371/journal.pgen.1012162

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