Genome-wide maps of ribosomal occupancy provide insights into adaptive evolution and regulatory roles of uORFs during Drosophila development
| Autor: | Jian Lu, Feng He, Shengqian Dou, Junjie Luo, Liping Wei, Hong Zhang |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Untranslated region Embryology Genome Insect Gene Expression Genes Insect Genome Biochemistry 0302 clinical medicine Start codon Untranslated Regions Invertebrate Genomics Melanogaster Biology (General) education.field_of_study General Neuroscience Drosophila Melanogaster Messenger RNA Eukaryota Animal Models Genomics Biological Evolution Insects Nucleic acids Experimental Organism Systems Organ Specificity Drosophila Drosophila melanogaster Cellular Structures and Organelles General Agricultural and Biological Sciences Research Article Translational efficiency Arthropoda QH301-705.5 Population Computational biology Biology Research and Analysis Methods Models Biological General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Open Reading Frames Model Organisms Genetics Animals RNA Messenger education Gene General Immunology and Microbiology Embryos Organisms Reproducibility of Results Biology and Life Sciences Cell Biology biology.organism_classification Invertebrates 030104 developmental biology Animal Genomics Protein Biosynthesis RNA Protein Translation Ribosomes 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Biology PLoS Biology, Vol 16, Iss 7, p e2003903 (2018) |
| ISSN: | 1545-7885 |
| Popis: | Upstream open reading frames (uORFs) play important roles in regulating the main coding DNA sequences (CDSs) via translational repression. Despite their prevalence in the genomes, uORFs are overall discriminated against by natural selection. However, it remains unclear why in the genomes there are so many uORFs more conserved than expected under the assumption of neutral evolution. Here, we generated genome-wide maps of translational efficiency (TE) at the codon level throughout the life cycle of Drosophila melanogaster. We identified 35,735 uORFs that were expressed, and 32,224 (90.2%) of them showed evidence of ribosome occupancy during Drosophila development. The ribosome occupancy of uORFs is determined by genomic features, such as optimized sequence contexts around their start codons, a shorter distance to CDSs, and higher coding potentials. Our population genomic analysis suggests the segregating mutations that create or disrupt uORFs are overall deleterious in D. melanogaster. However, we found for the first time that many (68.3% of) newly fixed uORFs that are associated with ribosomes in D. melanogaster are driven by positive Darwinian selection. Our findings also suggest that uORFs play a vital role in controlling the translational program in Drosophila. Moreover, we found that many uORFs are transcribed or translated in a developmental stage-, sex-, or tissue-specific manner, suggesting that selective transcription or translation of uORFs could potentially modulate the TE of the downstream CDSs during Drosophila development. Author summary 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. |
| Databáze: | OpenAIRE |
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