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 report tha...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences
2009
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| Online Access: | http://hdl.handle.net/1721.1/50259 |
| _version_ | 1826202735721054208 |
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| author | Calvo, Sarah E. Pagliarini, David J. Mootha, Vamsi K. |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Calvo, Sarah E. Pagliarini, David J. Mootha, Vamsi K. |
| author_sort | Calvo, Sarah E. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T12:15:38Z |
| format | Article |
| id | mit-1721.1/50259 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:15:38Z |
| publishDate | 2009 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/502592022-10-01T08:49:58Z Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans Calvo, Sarah E. Pagliarini, David J. Mootha, Vamsi K. Broad Institute of MIT and Harvard Harvard University--MIT Division of Health Sciences and Technology Calvo, Sarah E. Calvo, Sarah E. Pagliarini, David J. Mootha, Vamsi K. 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. National Institute of General Medical Science 2009-12-28T18:52:38Z 2009-12-28T18:52:38Z 2009-04 2008-10 Article http://purl.org/eprint/type/JournalArticle 0027-8424 http://hdl.handle.net/1721.1/50259 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. 19372376 en_US http://dx.doi.org/10.1073/pnas.0810916106 Proceedings of the National Academy of Sciences of the United States of America 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. application/pdf National Academy of Sciences PNAS |
| spellingShingle | Calvo, Sarah E. Pagliarini, David J. Mootha, Vamsi K. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans |
| title | Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans |
| title_full | Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans |
| title_fullStr | Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans |
| title_full_unstemmed | Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans |
| title_short | Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans |
| title_sort | upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans |
| url | http://hdl.handle.net/1721.1/50259 |
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