Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans
Name
Calvo-2009-Upstream open readin.pdf
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Author(s)
Calvo, Sarah E.
Pagliarini, David J.
Mootha, Vamsi K.
Date Issued
April 2009
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences
Citation
Calvo, Sarah E, David J Pagliarini, and Vamsi K Mootha. “Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans.” Proceedings of the National Academy of Sciences 106.18 (2009): 7507-7512.
Version
Final published version
Abstract
Upstream ORFs (uORFs) are mRNA elements defined by a start codon in the 5′ UTR that is out-of-frame with the main coding sequence. Although uORFs are present in approximately half of human and mouse transcripts, no study has investigated their global impact on protein expression. Here, we report that uORFs correlate with significantly reduced protein expression of the downstream ORF, based on analysis of 11,649 matched mRNA and protein measurements from 4 published mammalian studies. Using reporter constructs to test 25 selected uORFs, we estimate that uORFs typically reduce protein expression by 30–80%, with a modest impact on mRNA levels. We additionally identify polymorphisms that alter uORF presence in 509 human genes. Finally, we report that 5 uORF-altering mutations, detected within genes previously linked to human diseases, dramatically silence expression of the downstream protein. Together, our results suggest that uORFs influence the protein expression of thousands of mammalian genes and that variation in these elements can influence human phenotype and disease.
MIT Department
Broad Institute of MIT and Harvard
Harvard University--MIT Division of Health Sciences and Technology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
http://dx.doi.org/10.1073/pnas.0810916106
