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Nat Commun. 2016 May 24;7:11663. doi: 10.1038/ncomms11663.

Conservation of uORF repressiveness and sequence features in mouse, human and zebrafish.

Chew GL1, Pauli A1, Schier AF1,2,3,4,5.

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Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA.
FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA.
Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.


Upstream open reading frames (uORFs) are ubiquitous repressive genetic elements in vertebrate mRNAs. While much is known about the regulation of individual genes by their uORFs, the range of uORF-mediated translational repression in vertebrate genomes is largely unexplored. Moreover, it is unclear whether the repressive effects of uORFs are conserved across species. To address these questions, we analyse transcript sequences and ribosome profiling data from human, mouse and zebrafish. We find that uORFs are depleted near coding sequences (CDSes) and have initiation contexts that diminish their translation. Linear modelling reveals that sequence features at both uORFs and CDSes modulate the translation of CDSes. Moreover, the ratio of translation over 5' leaders and CDSes is conserved between human and mouse, and correlates with the number of uORFs. These observations suggest that the prevalence of vertebrate uORFs may be explained by their conserved role in repressing CDS translation.

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