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

Document Type

Article

Publication Date

9-30-2021

Publication Title

Cell

Keywords

JMG

JAX Source

Cell 2021 Sep 30; 184(20):5247-5260.e19

Volume

184

Issue

20

First Page

5247

Last Page

5260

ISSN

1097-4172

PMID

34534445

DOI

https://doi.org/10.1016/j.cell.2021.08.025

Grant

HG008179

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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