Synthesis of a functional protein from genetic information is strikingly error-prone. For example, amino-acid misincorporations during translation are estimated to occur once in every 1,000 to 10,000 codons translated1,2
. At this error rate, 15% of average-length protein molecules will contain at least one misincorporated amino acid. Polypeptide errors can induce protein misfolding, aggregation, and cell death (e.g. Ref. 3
). Misfolded proteins underlie a broad array of neurogenerative diseases, and misincorporation of amino acids during translation may be a causative factor in the pathology of multiple sclerosis and ALS4,5
. Conversely, global defects in protein synthesis produce tissue-specific neurodegeneration linked to production of misfolded proteins3,6
We define erroneous protein synthesis as any disruption in the conversion of a coding sequence into a functioning protein. Besides amino-acid misincorporations, sources of errors are transcription errors, aberrant splicing, premature termination, faulty posttranslational modifications, and kinetic missteps during folding (). This definition explicitly includes correctly synthesized polypeptides that fail to fold into a functional protein.
Sources of errors in eukaryotic gene expression.
We have previously hypothesized that major patterns of coding sequence evolution, conserved from bacteria to humans, arise from the selective pressure to minimize the cost of erroneous protein synthesis, including the failure of properly synthesized polypeptides to fold5
. Such selection would act most strongly on highly expressed genes and, in animals, on genes expressed in neural tissues. Mathematical modeling and computer simulations predict biophysical adaptations that reduce this cost5,7–9
, and several of these predictions have now been verified in a recent experimental evolution study10
Together, these studies illuminate a pathway leading from the fidelity of protein production through cellular dysfunction and organismal fitness defects—exemplified by neurodegeneration—to adaptations whose imprints are visible in the evolution of coding sequences across taxa.
Here, we first review what is known about the frequencies of errors in the production of functional proteins, from transcription to protein folding. We do not attempt a comprehensive review of all measurements. Instead, we aim to create perspective and to motivate much-needed future studies by highlighting the diverse set of approaches taken. We then review the many ways in which organisms may have evolved to cope with errors in synthesis, either by selectively reducing error rates or by evolving tolerance to errors. Next, we examine how organisms exploit errors in synthesis to achieve biological and evolutionary ends that are inaccessible when synthesis is error-free. We conclude with a discussion of implications for future research.