title: 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.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Hayato
authors.initials: H
authors.lastname: Yanagida
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Gispan
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Kadouri
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shelly
authors.initials: S
authors.lastname: Rozen
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Sharon
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Naama
authors.initials: N
authors.lastname: Barkai
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Dan S
authors.initials: DS
authors.lastname: Tawfik
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D019143:Evolution, Molecular; D016368:Frameshift Mutation; D020440:Gene Duplication; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D020675:Peroxisomes / Q000201:enzymology; D010641:Phenotype; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*
chemical_list: D007521:Isocitrate Dehydrogenase; C039355:isocitrate dehydrogenase (NADP+)