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Genome-wide maps of ribosomal occupancy provide insights into adaptive evolution and regulatory roles of uORFs during Drosophila development

Jul 21,2018

Upstream open reading frames (uORFs) in the 5′ untranslated regions (UTRs) of messenger RNAs can potentially inhibit translation of the downstream regions that encode proteins by sequestering protein-making machinery the ribosome. Moreover, mutations that destroy existing uORFs or create new ones are known to cause human disease. Although mutations that create new uORFs are generally deleterious and are selected against, many uORFs are evolutionarily conserved across eukaryotic species. To resolve this dilemma, we used extensive mRNA-Seq and ribosome profiling to generate high-resolution genome-wide maps of ribosome occupancy and translational efficiency (TE) during the life cycle of the fruit fly D. melanogaster. This allowed us to identify the sequence features of uORFs that influence their ability to associate with ribosomes. We demonstrate for the first time that the majority of the newly fixed uORFs in D. melanogaster, especially the translated ones, are under positive Darwinian selection. We also show that uORFs exert widespread repressive effects on the translation of the downstream protein-coding region. We find that many uORFs are transcribed or translated in a developmental stage-, sex-, or tissue-specific manner. Our results suggest that during Drosophila development, changes in the TE of uORFs, as well as the inclusion/exclusion of uORFs, are frequently exploited to inversely influence the translation of the downstream protein-coding regions. Our study provides novel insights into the molecular mechanisms and functional consequences of uORF-mediated regulation.

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