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 in | Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 18; pp. 7507 - 7512 |
|---|---|
| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
05.05.2009
National Acad Sciences |
| Subjects | |
| Online Access | Get full text |
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| 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. |
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| AbstractList | 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. 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. [PUBLICATION ABSTRACT] |
| Author | Calvo, Sarah E Pagliarini, David J Mootha, Vamsi K |
| Author_xml | – sequence: 1 fullname: Calvo, Sarah E – sequence: 2 fullname: Pagliarini, David J – sequence: 3 fullname: Mootha, Vamsi K |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/19372376$$D View this record in MEDLINE/PubMed |
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| PublicationYear | 2009 |
| Publisher | National Academy of Sciences National Acad Sciences |
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| Snippet | 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... 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... |
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| SubjectTerms | 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 |
| Title | Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans |
| URI | https://www.jstor.org/stable/40483303 http://www.pnas.org/content/106/18/7507.abstract https://www.ncbi.nlm.nih.gov/pubmed/19372376 https://www.proquest.com/docview/201416403 https://www.proquest.com/docview/20243794 https://www.proquest.com/docview/46246754 https://www.proquest.com/docview/67210536 https://pubmed.ncbi.nlm.nih.gov/PMC2669787 |
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