Multi-modality imaging on track

Editorial commentary.Radiation, Radionuclides and ReactorsApplied Science

Genome-wide functional screen of 3\u27UTR variants uncovers causal variants for human disease and evolution.

3\u27 untranslated region (3\u27UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3\u27UTRs (MPRAu) to sensitively assay 12,173 3\u27UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3\u27UTR function, suggesting that simple sequences predominately explain 3\u27UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3\u27UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration