title: A small reservoir of disabled ORFs in the yeast genome and its implications for the dynamics of proteome evolution.
abstract: We surveyed the sequenced Saccharomyces cerevisiae genome (strain S288C) comprehensively for open reading frames (ORFs) that could encode full-length proteins but contain obvious mid-sequence disablements (frameshifts or premature stop codons). These pseudogenic features are termed disabled ORFs (dORFs). Using homology to annotated yeast ORFs and non-yeast proteins plus a simple region extension procedure, we have found 183 dORFs. Combined with the 38 existing annotations for potential dORFs, we have a total pool of up to 221 dORFs, corresponding to less than approximately 3% of the proteome. Additionally, we found 20 pairs of annotated ORFs for yeast that could be merged into a single ORF (termed a mORF) by read-through of the intervening stop codon, and may comprise a complete ORF in other yeast strains. Focussing on a core pool of 98 dORFs with a verifying protein homology, we find that most dORFs are substantially decayed, with approximately 90% having two or more disablements, and approximately 60% having four or more. dORFs are much more yeast-proteome specific than live yeast genes (having about half the chance that they are related to a non-yeast protein). They show a dramatically increased density at the telomeres of chromosomes, relative to genes. A microarray study shows that some dORFs are expressed even though they carry multiple disablements, and thus may be more resistant to nonsense-mediated decay. Many of the dORFs may be involved in responding to environmental stresses, as the largest functional groups include growth inhibition, flocculation, and the SRP/TIP1 family. Our results have important implications for proteome evolution. The characteristics of the dORF population suggest the sorts of genes that are likely to fall in and out of usage (and vary in copy number) in a strain-specific way and highlight the role of subtelomeric regions in engendering this diversity. Our results also have important implications for the effects of the [PSI+] prion. The dORFs disabled by only a single stop and the mORFs (together totalling 35) provide an estimate for the extent of the sequence population that can be resurrected readily through the demonstrated ability of the [PSI+] prion to cause nonsense-codon read-through. Also, the dORFs and mORFs that we find have properties (e.g. growth inhibition, flocculation, vanadate resistance, stress response) that are potentially related to the ability of [PSI+] to engender substantial phenotypic variation in yeast strains under different environmental conditions. (See genecensus.org/pseudogene for further information.)
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8114, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Harrison
authors.forename: Anuj
authors.initials: A
authors.lastname: Kumar
authors.forename: Ning
authors.initials: N
authors.lastname: Lan
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Echols
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.forename: Mark
authors.initials: M
authors.lastname: Gerstein
mesh_terms: D015825:Chromosomes, Fungal / Q000235:genetics; D018388:Codon, Terminator / Q000235:genetics*; D019295:Computational Biology; D019143:Evolution, Molecular; D016368:Frameshift Mutation / Q000235:genetics*; D005800:Genes, Fungal / Q000235:genetics; D016681:Genome, Fungal; D016366:Open Reading Frames / Q000235:genetics*; D011328:Prions / Q000235:genetics; D020543:Proteome; D011544:Pseudogenes / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D013045:Species Specificity; D016615:Telomere / Q000235:genetics
chemical_list: D018388:Codon, Terminator; D011328:Prions; D020543:Proteome