TY - JOUR
T1 - Characterising the loss-of-function impact of 5' untranslated region variants in 15,708 individuals
AU - Genome Aggregation Database (gnomAD) Production Team
AU - Genome Aggregation Database (gnomAD) 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 - Cook, Stuart A.
AU - Barton, Paul J.R.
AU - MacArthur, Daniel G.
AU - Ware, James S.
AU - Alföldi, Jessica
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 - Francioli, Laurent
AU - Gabriel, Stacey
AU - Gauthier, Laura D.
AU - Gentry, Jeff
AU - Gupta, Namrata
AU - Jeandet, Thibault
AU - Kaplan, Diane
AU - Karczewski, Konrad J.
AU - Laricchia, Kristen M.
AU - Llanwarne, Christopher
AU - Minikel, Eric V.
AU - Munshi, Ruchi
AU - Neale, Benjamin M.
AU - Novod, Sam
AU - O'Donnell-Luria, Anne H.
AU - Petrillo, Nikelle
AU - Poterba, Timothy
AU - Roazen, David
AU - Ruano-Rubio, Valentin
AU - Pulver, Ann E.
N1 - Publisher Copyright:
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2019/2/7
Y1 - 2019/2/7
N2 - Upstream open reading frames (uORFs) are important tissue-specific cis-regulators of protein translation. Although isolated case reports have shown that variants that create or disrupt uORFs can cause disease, genetic sequencing approaches typically focus on protein-coding regions and ignore these variants. Here, we describe a systematic genome-wide study of variants that create and disrupt human uORFs, and explore their role in human disease using 15,708 whole genome sequences collected by the Genome Aggregation Database (gnomAD) project. We show that 14,897 variants that create new start codons upstream of the canonical coding sequence (CDS), and 2,406 variants disrupting the stop site of existing uORFs, are under strong negative selection. Furthermore, variants creating uORFs that overlap the CDS show signals of selection equivalent to coding missense variants, and uORF-perturbing variants are under strong selection when arising upstream of known disease genes and genes intolerant to loss-of-function variants. Finally, we identify specific genes where perturbation of uORFs is likely to represent an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in families with neurofibromatosis. Our results highlight uORF-perturbing variants as an important and under-recognised functional class that can contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data to study the deleteriousness of specific classes of non-coding variants.
AB - Upstream open reading frames (uORFs) are important tissue-specific cis-regulators of protein translation. Although isolated case reports have shown that variants that create or disrupt uORFs can cause disease, genetic sequencing approaches typically focus on protein-coding regions and ignore these variants. Here, we describe a systematic genome-wide study of variants that create and disrupt human uORFs, and explore their role in human disease using 15,708 whole genome sequences collected by the Genome Aggregation Database (gnomAD) project. We show that 14,897 variants that create new start codons upstream of the canonical coding sequence (CDS), and 2,406 variants disrupting the stop site of existing uORFs, are under strong negative selection. Furthermore, variants creating uORFs that overlap the CDS show signals of selection equivalent to coding missense variants, and uORF-perturbing variants are under strong selection when arising upstream of known disease genes and genes intolerant to loss-of-function variants. Finally, we identify specific genes where perturbation of uORFs is likely to represent an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in families with neurofibromatosis. Our results highlight uORF-perturbing variants as an important and under-recognised functional class that can contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data to study the deleteriousness of specific classes of non-coding variants.
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U2 - 10.1101/543504
DO - 10.1101/543504
M3 - Article
AN - SCOPUS:85095355513
SN - 0309-1708
JO - Unknown Journal
JF - Unknown Journal
ER -