Dual modes of natural selection on upstream open reading frames.
نویسندگان
چکیده
Upstream open reading frames (uORFs) are common features of eukaryotic genes, occurring in 10%-25% of 5' leader sequences. Upstream ORFs that have been subjected to experimental analysis have been generally found to decrease translational efficiency of the downstream coding sequence. Previous investigations of uORFs in mammals and yeast have detected uORFs conserved over long evolutionary distances, prompting speculation about the nature and cause of the natural selection underlying such conservation. We have analyzed uORFs in the basidiomycetous fungal pathogen Cryptococcus neoformans to discern the properties of this purifying selection. We find that uORFs in the Cryptococcus species complex are conserved at twice the expected rate, and we report 122 uORFs that are conserved among all four sequenced Cryptococcus strains. A significantly greater proportion of uORF losses occur via direct mutation to the uORF start codon than expected. This observation suggests that mutational disruption of a uORF that leaves the start codon intact may be selectively disadvantageous, perhaps because of the risk of premature translation initiation. Accounting for this constrained mode of loss and comparing the relative conservation of uORFs between the 5' leader and control sequences enables us to calculate that at least a third of uORFs may be conserved for their effects on translational efficiency. The remaining fraction may be conserved either by chance or as a result of selective pressure to prevent premature translation initiation from the uORF start codon. We find that the majority of conserved uORFs do not exhibit codon usage bias or conservation at the amino acid level, and therefore they do not likely encode bioactive peptides. Our analysis suggests that uORFs are an important and underappreciated mechanism of post-transcriptional gene regulation in eukaryotes.
منابع مشابه
Upstream ORFs are prevalent translational repressors in vertebrates.
Regulation of gene expression is fundamental in establishing cellular diversity and a target of natural selection. Untranslated mRNA regions (UTRs) are key mediators of post-transcriptional regulation. Previous studies have predicted thousands of ORFs in 5'UTRs, the vast majority of which have unknown function. Here, we present a systematic analysis of the translation and function of upstream o...
متن کاملDual Short Upstream Open Reading Frames Control Translation of a Herpesviral Polycistronic mRNA
The Kaposi's sarcoma-associated herpesvirus (KSHV) protein kinase, encoded by ORF36, functions to phosphorylate cellular and viral targets important in the KSHV lifecycle and to activate the anti-viral prodrug ganciclovir. Unlike the vast majority of mapped KSHV genes, no viral transcript has been identified with ORF36 positioned as the 5'-proximal gene. Here we report that ORF36 is robustly tr...
متن کاملSuppressors of translation initiation defect in hem12 locus of Saccharomyces cerevisiae.
A system for the positive selection of transational initiation suppressors in S. cerevisiae has been developed. A mutant with an ATA initiation codon in the HEM12 gene, encoding uroporphyrinogen decarboxylase, was used to select cis- and trans-acting suppressors. These suppressors partially restore growth on nonfermentable carbon sources, such as glycerol, but still allow the accumulation of po...
متن کاملTranslational Control via Protein-Regulated Upstream Open Reading Frames
Analysis of the regulation of msl-2 mRNA by Sex lethal (SXL), which is critical for dosage compensation in Drosophila, has uncovered a mode of translational control based on common 5' untranslated region elements, upstream open reading frames (uORFs), and interaction sites for RNA-binding proteins. We show that SXL binding downstream of a short uORF imposes a strong negative effect on major rea...
متن کاملBAIUCAS: a novel BLAST-based algorithm for the identification of upstream open reading frames with conserved amino acid sequences and its application to the Arabidopsis thaliana genome
MOTIVATION Upstream open reading frames (uORFs) are often found in the 5'-untranslated regions of eukaryotic messenger RNAs. Some uORFs have been shown to encode functional peptides involved in the translational regulation of the downstream main ORFs. Comparative genomic approaches have been used in genome-wide searches for uORFs encoding bioactive peptides, and by comparing uORF sequences betw...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Molecular biology and evolution
دوره 24 8 شماره
صفحات -
تاریخ انتشار 2007