Genome-wide Functional Screen of 3'UTR Variants Uncovers Causal Variants for Human Disease and Evolution

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 Sep 17

PMID 34534445

Citations 78

Authors

Dustin Griesemer

James R Xue

Steven K Reilly

Jacob C Ulirsch

Kalki Kukreja

Joe R Davis

Masahiro Kanai

David K Yang

John C Butts

Mehmet H Guney

Jeremy Luban

Stephen B Montgomery

Hilary K Finucane

Carl D Novina

Ryan Tewhey

Pardis C Sabeti

Affiliations

Soon will be listed here.

Abstract

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 simple sequences predominately explain 3'UTR 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'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.

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