RT Journal Article
SR Electronic
T1 Disrupting upstream translation in mRNAs leads to loss-of-function associated with human disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.09.287912
DO 10.1101/2020.09.09.287912
A1 David S.M. Lee
A1 Joseph Park
A1 Andrew Kromer
A1 Regeneron Genetics Center
A1 Daniel J. Rader
A1 Marylyn D. Ritchie
A1 Louis R. Ghanem
A1 Yoseph Barash
YR 2020
UL http://biorxiv.org/content/early/2020/09/12/2020.09.09.287912.abstract
AB 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 StatementThe authors have declared no competing interest.