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Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals


Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.

Type Journal
ISBN 2041-1723 (Electronic) 2041-1723 (Linking)
Authors Whiffin, N.; Karczewski, K. J.; Zhang, X.; Chothani, S.; Smith, M. J.; Evans, D. G.; Roberts, A. M.; Quaife, N. M.; Schafer, S.; Rackham, O.; Alfoldi, J.; O'Donnell-Luria, A. H.; Francioli, L. C.; Genome Aggregation Database Production, Team; Genome Aggregation Database, Consortium; Cook, S. A.; Barton, P. J. R.; MacArthur, D. G.; Ware, J. S.
Responsible Garvan Author Prof Daniel MacArthur
Publisher Name Nature Communications
Published Date 2020-05-27
Published Volume 11
Published Issue 1
Published Pages 2523
Status Published in-print
DOI 10.1038/s41467-019-10717-9
URL link to publisher's version