TY - JOUR T1 - Genome-wide functional screen of 3’UTR variants uncovers causal variants for human disease and evolution JF - bioRxiv DO - 10.1101/2021.01.13.424697 SP - 2021.01.13.424697 AU - Dustin Griesemer AU - James R Xue AU - Steven K Reilly AU - Jacob C Ulirsch AU - Kalki Kukreja AU - Joe Davis AU - Masahiro Kanai AU - David K Yang AU - Stephen B Montgomery AU - Carl D Novina AU - Ryan Tewhey AU - Pardis C Sabeti Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/13/2021.01.13.424697.abstract N2 - 3’ untranslated region (3’UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the Massively Parallel Reporter Assay for 3’UTRs (MPRAu) to sensitively assay 12,173 3’UTR 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’UTR function, suggesting that low-complexity sequences predominately explain 3’UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base-pair resolution, including an AU-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3’UTR 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.Competing Interest StatementP.C.S. is a co-founder of and consultant to Sherlock Biosciences and Board Member of Danaher Corporation. ER -