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

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.

Keywords

Affiliated Institutions

• Columbia University Irving Medical Center US
• Harvard University US
• Assistance Publique – Hôpitaux de Paris FR
• Helsinki University Hospital FI
• University of Manchester GB
• Sorbonne Université FR
• Colorado School of Public Health US
• Hospital Del Mar ES
• Broad Institute US
• Icahn School of Medicine at Mount Sinai US
• Wake Forest University US
• Karolinska Institutet SE
• National Human Genome Research Institute US
• St Mary's Hospital GB
• Massachusetts General Hospital US
• Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán MX
• University of Leicester GB
• University of Mississippi Medical Center US
• Christian-Albrechts-Universität zu Kiel DE
• Institute for Molecular Medicine Finland FI
• Cleveland Clinic Lerner College of Medicine US
• Universitat de Vic - Universitat Central de Catalunya ES
• Columbia University US
• Imperial College London GB
• University of Helsinki FI
• Albert Einstein College of Medicine US
• Instituto Nacional de Salud Pública MX
• Brigham and Women's Hospital US
• Duke-NUS Medical School SG
• Framingham Heart Study US
• University of Illinois Chicago US
• University of Parma IT
• The University of Texas Health Science Center at Houston US
• NIHR Royal Brompton Cardiovascular Biomedical Research Unit GB
• Hadassah Medical Center IL
• Hôpital Saint-Antoine FR
• Boston University US
• Lund University SE
• National Health Service GB
• Glenfield Hospital GB
• University of Haifa IL
• National Institutes of Health US
• Cleveland Clinic US
• University of Eastern Finland FI
• Hospital del Mar Research Institute ES
• University of Michigan US
• NIHR Leicester Biomedical Research Centre GB
• Jackson Memorial Hospital US
• University of Lübeck DE
• Peninsula College of Medicine and Dentistry GB
• Chinese University of Hong Kong HK
• National Heart Lung and Blood Institute US
• Wellcome Sanger Institute GB
• University of Tartu EE
• MRC London Institute of Medical Sciences GB
• Texas Biomedical Research Institute US
• SUNY Upstate Medical University US

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