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Dual modes of natural selection on upstream open reading frames
Daniel E Neafsey1, James E Galagan
1Microbial Analysis Group, Broad Institute of MIT and Harvard, Cambridge, MA, USA. neafsey@broad.mit.edu
Molecular Biology and Evolution
|May 12, 2007
Summary
Upstream open reading frames (uORFs) are conserved in fungi, suggesting they regulate gene translation. Many uORFs are lost by mutating start codons, indicating selection against disrupting them.
Area of Science:
- * Molecular Biology
- * Genetics
- * Evolutionary Biology
Background:
- * Upstream open reading frames (uORFs) are prevalent in eukaryotic 5' leader sequences (10-25%).
- * Experimentally, uORFs often reduce the translational efficiency of downstream coding sequences.
- * Conserved uORFs in mammals and yeast hint at evolutionary selection pressures.
Purpose of the Study:
- * To investigate the evolutionary conservation and functional significance of uORFs in Cryptococcus neoformans.
- * To determine the properties of purifying selection acting on uORFs in this fungal pathogen.
Main Methods:
- * Comparative genomic analysis of uORFs across four sequenced Cryptococcus strains.
- * Statistical analysis of uORF conservation rates and loss mechanisms.
- * Evaluation of codon usage bias and amino acid conservation for uORFs.
Main Results:
- * uORFs in the Cryptococcus species complex are conserved at twice the expected rate.
- * 122 uORFs are conserved across all four sequenced strains.
- * A higher proportion of uORF losses occur via start codon mutation than expected, suggesting selection against disruption.
- * At least one-third of uORFs may be conserved for their translational efficiency effects.
- * Most conserved uORFs lack codon usage bias or amino acid conservation, indicating they likely do not encode peptides.
Conclusions:
- * uORFs in Cryptococcus are under significant purifying selection.
- * Selection may act to maintain translational efficiency or prevent premature translation initiation.
- * uORFs represent an underappreciated mechanism for post-transcriptional gene regulation in eukaryotes.
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