Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Genome Aggregation Database Production Team; Genome Aggregation Database Consortium; Whiffin, Nicola; Karczewski, Konrad J.; Zhang, Xiaolei; Chothani, Sonia; Smith, Miriam J.; Evans, D. Gareth; Roberts, Angharad M.; Quaife, Nicholas M.; Schafer, Sebastian; Rackham, Owen; Alföldi, Jessica; O’Donnell-Luria, Anne H.; Francioli, Laurent C.; Armean, Irina M.; Banks, Eric; Bergelson, Louis; Cibulskis, Kristian; Collins, Ryan L.; Connolly, Kristen M.; Covarrubias, Miguel; Cummings, Beryl; Daly, Mark J.; Donnelly, Stacey; Farjoun, Yossi; Ferriera, Steven; Gabriel, Stacey; Gauthier, Laura D.; Gentry, Jeff; Gupta, Namrata; Jeandet, Thibault; Kaplan, Diane; Laricchia, Kristen M.; Llanwarne, Christopher; Minikel, Eric V.; Munshi, Ruchi; Neale, Benjamin M.; Novod, Sam; Petrillo, Nikelle; Poterba, Timothy; Roazen, David; Ruano-Rubio, Valentin; Saltzman, Andrea; Samocha, Kaitlin E.; Schleicher, Molly; Seed, Cotton; Solomonson, Matthew; Soto, Jose; Lehtimäki, Terho; Mattila, Kari M.; Suvisaari, Jaana (2020-05)
Genome Aggregation Database Production Team
Genome Aggregation Database Consortium
Whiffin, Nicola
Karczewski, Konrad J.
Zhang, Xiaolei
Chothani, Sonia
Smith, Miriam J.
Evans, D. Gareth
Roberts, Angharad M.
Quaife, Nicholas M.
Schafer, Sebastian
Rackham, Owen
Alföldi, Jessica
O’Donnell-Luria, Anne H.
Francioli, Laurent C.
Armean, Irina M.
Banks, Eric
Bergelson, Louis
Cibulskis, Kristian
Collins, Ryan L.
Connolly, Kristen M.
Covarrubias, Miguel
Cummings, Beryl
Daly, Mark J.
Donnelly, Stacey
Farjoun, Yossi
Ferriera, Steven
Gabriel, Stacey
Gauthier, Laura D.
Gentry, Jeff
Gupta, Namrata
Jeandet, Thibault
Kaplan, Diane
Laricchia, Kristen M.
Llanwarne, Christopher
Minikel, Eric V.
Munshi, Ruchi
Neale, Benjamin M.
Novod, Sam
Petrillo, Nikelle
Poterba, Timothy
Roazen, David
Ruano-Rubio, Valentin
Saltzman, Andrea
Samocha, Kaitlin E.
Schleicher, Molly
Seed, Cotton
Solomonson, Matthew
Soto, Jose
Lehtimäki, Terho
Mattila, Kari M.
Suvisaari, Jaana
05 / 2020
2523
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:tuni-202101181435
https://urn.fi/URN:NBN:fi:tuni-202101181435
Kuvaus
Peer reviewed
Tiivistelmä
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.
Kokoelmat
- TUNICRIS-julkaisut [16740]