The Evolutionary Potential of Phenotypic Mutations

Abstract

Errors in protein synthesis, so-called phenotypic mutations, are orders-of-magnitude more frequent than genetic mutations. Here, we provide direct evidence that alternative protein forms and phenotypic variability derived from translational errors paved the path to genetic, evolutionary adaptations via gene duplication. We explored the evolutionary origins of Saccharomyces cerevisiae IDP3 - an NADP-dependent isocitrate dehydrogenase mediating fatty acids ß-oxidation in the peroxisome. Following the yeast whole genome duplication, IDP3 diverged from a cytosolic ancestral gene by acquisition of a C-terminal peroxisomal targeting signal. We discovered that the pre-duplicated cytosolic IDPs are partially localized to the peroxisome owing to +1 translational frameshifts that bypass the stop codon and unveil cryptic peroxisomal targeting signals within the 3’-UTR. Exploring putative cryptic signals in all 3’-UTRs of yeast genomes, we found that other enzymes related to NADPH production such as pyruvate carboxylase 1 ( PYC1) might be prone to peroxisomal localization via cryptic signals. Using laboratory evolution we found that these translational frameshifts are rapidly imprinted via genetic single base deletions occurring within the very same gene location. Further, as exemplified here, the sequences that promote translational frameshifts are also more prone to genetic deletions. Thus, genotypes conferring higher phenotypic variability not only meet immediate challenges by unveiling cryptic 3’-UTR sequences, but also boost the potential for future genetic adaptations.

Author Summary

The rarity of genetic mutations limits the likelihood of adaptation. However, transcriptional and translational errors, so-called phenotypic mutations, are >10 ⁵-fold more frequent, thus generating protein mutants from unmodified genes. We provide the first evidence that phenotypic mutations paved the path to what later, after gene duplication, became newly compartmentalized enzymes. Thus, gene duplication followed rather than initiated the divergence of this new trait. Our findings also show that translational infidelity and phenotypic variability comprise the origins of evolutionary innovations, and how selection for enhanced phenotypic variability also promotes the appearance of genetic mutations that lead to the very same outcome.