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Disrupting upstream translation in mRNAs is associated with human disease

Author

Listed:
  • David S. M. Lee

    (University of Pennsylvania
    University of Pennsylvania)

  • Joseph Park

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Andrew Kromer

    (University of Pennsylvania)

  • Aris Baras

    (Regeneron Genetics Center, Regeneron Pharmaceuticals)

  • Daniel J. Rader

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Marylyn D. Ritchie

    (University of Pennsylvania
    University of Pennsylvania)

  • Louis R. Ghanem

    (Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of Philadelphia
    University of Pennsylvania
    Janssen Research and Development)

  • Yoseph Barash

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

Abstract

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.

Suggested Citation

  • David S. M. Lee & Joseph Park & Andrew Kromer & Aris Baras & Daniel J. Rader & Marylyn D. Ritchie & Louis R. Ghanem & Yoseph Barash, 2021. "Disrupting upstream translation in mRNAs is associated with human disease," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21812-1
    DOI: 10.1038/s41467-021-21812-1
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