The Evolutionary Potential of Phenotypic Mutations.

Hayato Yanagida,Ariel Gispan,Shelly Rozen,Noam Kadouri,Naama Barkai,Dan S Tawfik,Michal Sharon,Mark D Rausher

doi:10.1371/journal.pgen.1005445

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.

Highlights

Latent, promiscuous protein functions serve as starting points for evolving new functions, resolving the evolutionary ‘catch’ of no new trait can evolve unless it already exists and can confer an immediate survival benefit [1,2,3]
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
We provide the first evidence that phenotypic mutations paved the path to what later, after gene duplication, became newly compartmentalized enzymes

Summary

Introduction

Promiscuous protein functions serve as starting points for evolving new functions, resolving the evolutionary ‘catch’ of no new trait can evolve unless it already exists and can confer an immediate survival benefit [1,2,3]. It has been proposed that other forms of molecular infidelity, such as transcriptional and translational errors, may underlie the evolution of new protein traits [4,5,6] These so-called ‘phenotypic mutations’ yield protein variability from an unmutated gene and are up to 105 times more frequent than genetic mutations [7,8,9]. Phenotypic mutations may bridge the crucial and relatively long time gap between the appearance of a new challenge and the emergence and fixation of changes in genotype, i.e., evolutionary adaptations as often manifested in new, paraloguous genes. Duplication may occur at a much later stage, allowing the two functions to be split between two paraloguous genes (sub-functionalization)

Methods

Results

Discussion

Conclusion