MBE Advance Access published online on May 9, 2007
Molecular Biology and Evolution, doi:10.1093/molbev/msm093
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Research Article |
"Dual Modes of Natural Selection on Upstream Open Reading Frames"
Microbial Analysis Group, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142
1 corresponding author, Email: neafsey{at}broad.mit.edu, Ph: 617-324-5259, Fx: 617-324-4987
Received for publication December 5, 2006. Revision received April 3, 2007. Accepted for publication May 7, 2007.
Upstream open reading frames (uORFs) are common features of eukaryotic genes, occurring in 10-25% of 5' leader sequences. uORFs 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 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 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 due to 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 due to chance or due to 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 nor conservation at the amino acid level, and therefore do not likely encode bioactive peptides. Our analysis suggests that uORFs are an important and under-appreciated mechanism of post-transcriptional gene regulation in eukaryotes.
Key Words: uORF • uAUG • conservation • translation • Cryptococcus
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