The evolutionary consequences of erroneous protein synthesis

Abstract

Errors in protein synthesis disrupt cellular fitness, cause disease phenotypes and shape gene and genome evolution. Experimental and theoretical results on this topic have accumulated rapidly in disparate fields, such as neurobiology, protein biosynthesis and degradation and molecular evolution, but with limited communication among disciplines. Here, we review studies of error frequencies, the cellular and organismal consequences of errors and the attendant long-range evolutionary responses to errors. We emphasize major areas in which little is known, such as the failure rates of protein folding, in addition to areas in which technological innovations may enable imminent gains, such as the elucidation of translational missense error frequencies. Evolutionary responses to errors fall into two broad categories: adaptations that minimize errors and their attendant costs and adaptations that exploit errors for the organism's benefit.

Figure 1

Sources of errors in eukaryotic gene expression.

Figure 2

Alternative strategies to reduce protein misfolding. (A) Proteins are poor folders and misfold readily. A highly accurate translational apparatus produces few proteins with translation errors and thus limits the total amount of misfolded protein. (B) An error-prone translation system produces many proteins with errors. But proteins are excellent folders and tend not to misfold even when mistranslated.

Figure 3

Evolutionary exploitation of synthesis errors. (A) A frameshift regulates gene expression. Ornithine decarboxylase (ODC) catalyzes the synthesis of putrescine. ODC is inhibited by ornithine decarboxylase antizyme (OAZ), which binds to ODC and causes it to be degraded by the proteasome. Proper expression of functional (OAZ) requires a +1 frameshift. The frameshift occurs readily at high concentration of polyamines such as putrescine and its derivatives spermine and spermidine. (B) Translation of cryptic genetic variation. In the absence of the yeast prion ([psi−]), the protein Sup35p is readily available to form translation-termination complexes (TTCs). Consequently, stop codons are recognized reliably. In the presence of the yeast prion ([PSI+]), much Sup35p is sequestered, and there are too few TTCs for reliable translation termination. As a consequence, cryptic genetic variation (indicated in red) is expressed.