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Keywords {🔍}

variants, uorfs, pubmed, uorf, article, translation, codons, google, scholar, cas, translated, maps, stop, utr, scores, sequences, codon, stopstrengthening, utc, fig, central, compared, association, expression, pmbb, genetic, proteincoding, gene, associations, data, downstream, set, utrs, positions, variant, human, variation, selection, missense, analysis, protein, predicted, genes, initiation, functional, uaa, nature, analyses, ukb, studies,

Topics {✒️}

io/en/latest/index nature portfolio gov/medicare/coding/icd10/2017-icd-10-cm privacy policy editing advertising plotting tools social media nonsense-mediated mrna decay reprints uorf-matched start-disrupting positions nature 536 nature 581 nature 555 nature multi-vertebrate alignment— versus utr-matched start-disrupting positions post-transcriptional protein production disrupting alternative regulatory mechanisms source data file phewas-significant stop-strengthening variant frame start-disrupting positions experimentally-determined codon-stability coefficients research design janssen research phenome-wide significant association error bars represent large-scale population data cellular-scale -omics data uorf-mediated translational regulation integrating population-scale databases phenome-wide association study significant lof-burden association aspirin-exacerbated respiratory disease phenome-wide association studies downstream protein-coding sequences26 stop-strengthening variants represent inhibiting hmg-coa reductase uorf start-disrupting positions ntg start-disrupting variants matched utr-uaa = 35%—supplementary table 2 highly-conservative bonferroni correction matched start-disrupting positions downstream protein-coding gene human protein-coding genes1 protein-coding start codons canonical protein-coding regions start-disrupting genomic positions canonical protein-coding sequences codon-optimality constrains variation

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• Edu/cgi-bin/hgTrackUi?

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         headline:Disrupting upstream translation in mRNAs is associated with human disease
         description:Ribosome-profiling has uncovered pervasive translation in non-canonical open reading frames, however the biological significance of this phenomenon remains unclear. Using genetic variation from 71,702 human genomes, we assess patterns of selection in translated upstream open reading frames (uORFs) in 5’UTRs. We show that uORF variants introducing new stop codons, or strengthening existing stop codons, are under strong negative selection comparable to protein-coding missense variants. Using these variants, we map and validate gene-disease associations in two independent biobanks containing exome sequencing from 10,900 and 32,268 individuals, respectively, and elucidate their impact on protein expression in human cells. Our results suggest translation disrupting mechanisms relating uORF variation to reduced protein expression, and demonstrate that translation at uORFs is genetically constrained in 50% of human genes. The significance of translated upstream open reading frames is not well known. Here, the authors investigate genetic variants in these regions, finding that they are under high evolutionary constraint and may contribute to disease.
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            name:University of Pennsylvania
            address:
               name:Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
               type:PostalAddress
            type:Organization
            name:University of Pennsylvania
            address:
               name:Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
               type:PostalAddress
            type:Organization
            name:University of Pennsylvania
            address:
               name:Department of Computer and Information Science, School of Engineering, University of Pennsylvania, Philadelphia, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Regeneron Genetics Center, Regeneron Pharmaceuticals, Tarrytown, USA
      name:Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia, Philadelphia, USA
      name:Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Janssen Research and Development, Spring House, USA
      name:Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
      name:Department of Computer and Information Science, School of Engineering, University of Pennsylvania, Philadelphia, USA

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