Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans

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 repor...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 106; no. 18; pp. 7507 - 7512
Main Authors Calvo, Sarah E, Pagliarini, David J, Mootha, Vamsi K
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 05.05.2009
National Acad Sciences
Subjects
5' Untranslated Regions - genetics
Adipocytes
Base Sequence
Biochemistry
Biological Sciences
Disease - genetics
Gene expression
Genes
Genetic mutation
human diseases
Human subjects
Humans
Mammals
Messenger RNA
mice
Molecular Sequence Data
Mutation
Open Reading Frames
phenotype
Polymorphism
Polymorphism, Genetic
Protein Biosynthesis - genetics
Protein synthesis
Proteins
Receptors
Ribonucleic acid
RNA
Start codon
Stem cells
Untranslated regions
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Summary: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.
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1S.E.C. and D.J.P. contributed equally to this work.
Edited by Jonathan Weissman, University of California, San Francisco, CA, and accepted by the Editorial Board March 18, 2009
Author contributions: S.E.C., D.J.P., and V.K.M. designed research; S.E.C. and D.J.P. performed research; and S.E.C. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0810916106