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

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 rep

SUBMITTER: Whiffin N 

PROVIDER: S-EPMC7253449 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature