Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals
By N. Whiffin, Konrad J. Karczewski, Xiaolei Zhang, S. Chothani, M. Smith, D. Evans, Angharad M. Roberts, N. Quaife, S. Schafer, O. Rackham and 157 more. 2019
162 citations recorded by the source corpus.
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. Upstream open reading frames (uORFs), located in 5’ untranslated regions, are regulators of downstream protein translation. Here, Whiffin et al. use the genomes of 15,708 individuals in the Genome Aggregation Database (gnomAD) to systematically assess the deleteriousness of variants creating or disrupting uORFs.
Subfields: Genetics, Molecular Biology
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In Molecular Biology
Citations in the corpus
- Human 5′ UTR design and variant effect prediction from a massively parallel translation assay (2018, background): “Intriguingly, variants within the 50-nucleotide window directly adjacent to the start codon are under stronger negative selection than those further upstream 16 , providing another motivation to focus on this window.”