TY - JOUR
T1 - Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
AU - Genome Aggregation Database Production Team
AU - Genome Aggregation Database Consortium
AU - Whiffin, Nicola
AU - Karczewski, Konrad J.
AU - Zhang, Xiaolei
AU - Chothani, Sonia
AU - Smith, Miriam J.
AU - Evans, D. Gareth
AU - Roberts, Angharad M.
AU - Quaife, Nicholas M.
AU - Schafer, Sebastian
AU - Rackham, Owen
AU - Alföldi, Jessica
AU - O’Donnell-Luria, Anne H.
AU - Francioli, Laurent C.
AU - Armean, Irina M.
AU - Banks, Eric
AU - Bergelson, Louis
AU - Cibulskis, Kristian
AU - Collins, Ryan L.
AU - Connolly, Kristen M.
AU - Covarrubias, Miguel
AU - Cummings, Beryl
AU - Daly, Mark J.
AU - Donnelly, Stacey
AU - Farjoun, Yossi
AU - Ferriera, Steven
AU - Gabriel, Stacey
AU - Gauthier, Laura D.
AU - Gentry, Jeff
AU - Gupta, Namrata
AU - Jeandet, Thibault
AU - Kaplan, Diane
AU - Laricchia, Kristen M.
AU - Llanwarne, Christopher
AU - Minikel, Eric V.
AU - Munshi, Ruchi
AU - Neale, Benjamin M.
AU - Novod, Sam
AU - Petrillo, Nikelle
AU - Poterba, Timothy
AU - Roazen, David
AU - Ruano-Rubio, Valentin
AU - Saltzman, Andrea
AU - Samocha, Kaitlin E.
AU - Schleicher, Molly
AU - Seed, Cotton
AU - Solomonson, Matthew
AU - Soto, Jose
AU - Tiao, Grace
AU - Tibbetts, Kathleen
AU - Turner, Dan
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085581111&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10717-9
DO - 10.1038/s41467-019-10717-9
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C2 - 32461616
AN - SCOPUS:85085581111
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2523
ER -