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

Nicola Whiffin (), Konrad J. Karczewski, Xiaolei Zhang, Sonia Chothani, Miriam J. Smith, D. Gareth Evans, Angharad M. Roberts, Nicholas M. Quaife, Sebastian Schafer, Owen Rackham, Jessica Alföldi, Anne H. O’Donnell-Luria, Laurent C. Francioli, Stuart A. Cook, Paul J. R. Barton, Daniel G. MacArthur and James S. Ware
Additional contact information
Nicola Whiffin: Imperial College London
Konrad J. Karczewski: Broad Institute of MIT and Harvard
Xiaolei Zhang: Imperial College London
Sonia Chothani: Duke-NUS Medical School
Miriam J. Smith: University of Manchester
D. Gareth Evans: University of Manchester
Angharad M. Roberts: Imperial College London
Nicholas M. Quaife: Imperial College London
Sebastian Schafer: Duke-NUS Medical School
Owen Rackham: Duke-NUS Medical School
Jessica Alföldi: Broad Institute of MIT and Harvard
Anne H. O’Donnell-Luria: Broad Institute of MIT and Harvard
Laurent C. Francioli: Broad Institute of MIT and Harvard
Stuart A. Cook: Imperial College London
Paul J. R. Barton: Imperial College London
Daniel G. MacArthur: Broad Institute of MIT and Harvard
James S. Ware: Imperial College London

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-10717-9

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