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Disrupting upstream translation in mRNAs leads to loss-of-function associated with human disease

By David S.M. Lee, Joseph Park, Andrew Kromer, Regeneron Genetics Center, Daniel Rader, Marylyn D. Ritchie, Louis R. Ghanem, Yoseph Barash

Posted 12 Sep 2020
bioRxiv DOI: 10.1101/2020.09.09.287912

Ribosome-profiling has uncovered pervasive translation in 5’UTRs, 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 new gene-disease associations in two independent biobanks containing exome sequencing from 10,900 and 32,268 individuals respectively, and demonstrate their impact on gene expression in human cells. Our results establish new mechanisms relating uORF variation to loss-of-function of downstream genes, and demonstrate that translated uORFs are genetically constrained regulatory elements in 40% of human genes. ### Competing Interest Statement The authors have declared no competing interest.

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