Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
Abstract 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.
Evans D Gareth、Rackham Owen、Alf?ldi Jessica、O?ˉDonnell-Luria Anne H、Genome Aggregation Database (gnomAD) Consortium、MacArthur Daniel G、Whiffin Nicola、Karczewski Konrad J、Smith Miriam J、Cook Stuart A、Genome Aggregation Database (gnomAD) Production Team、Schafer Sebastian、Zhang Xiaolei、Francioli Laurent C、Roberts Angharad M、Quaife Nicholas M、Ware James S、Barton Paul J R、Chothani Sonia
NW Genomic Laboratory Hub, Centre for Genomic Medicine, Division of Evolution and Genomic Science, University of Manchester, St Mary?ˉs HospitalProgram in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolMedical and Population Genetics, Broad Institute of MIT and Harvard||Analytical and Translational Genetics Unit, Massachusetts General HospitalMedical and Population Genetics, Broad Institute of MIT and Harvard||Analytical and Translational Genetics Unit, Massachusetts General HospitalMedical and Population Genetics, Broad Institute of MIT and Harvard||Analytical and Translational Genetics Unit, Massachusetts General HospitalNational Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London||NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust||Medical and Population Genetics, Broad Institute of MIT and HarvardMedical and Population Genetics, Broad Institute of MIT and Harvard||Analytical and Translational Genetics Unit, Massachusetts General HospitalNW Genomic Laboratory Hub, Centre for Genomic Medicine, Division of Evolution and Genomic Science, University of Manchester, St Mary?ˉs HospitalNational Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London||Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School||National Heart Centre SingaporeProgram in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School||National Heart Centre SingaporeNational Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London||NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation TrustMedical and Population Genetics, Broad Institute of MIT and Harvard||Analytical and Translational Genetics Unit, Massachusetts General HospitalNational Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London||NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation TrustNational Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London||NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation TrustNational Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London||NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust||Medical and Population Genetics, Broad Institute of MIT and HarvardNational Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London||NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation TrustProgram in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School
基础医学遗传学分子生物学
Evans D Gareth,Rackham Owen,Alf?ldi Jessica,O?ˉDonnell-Luria Anne H,Genome Aggregation Database (gnomAD) Consortium,MacArthur Daniel G,Whiffin Nicola,Karczewski Konrad J,Smith Miriam J,Cook Stuart A,Genome Aggregation Database (gnomAD) Production Team,Schafer Sebastian,Zhang Xiaolei,Francioli Laurent C,Roberts Angharad M,Quaife Nicholas M,Ware James S,Barton Paul J R,Chothani Sonia.Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals[EB/OL].(2025-03-28)[2025-07-20].https://www.biorxiv.org/content/10.1101/543504.点此复制
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