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Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution.
- Source :
-
Cell [Cell] 2021 Sep 30; Vol. 184 (20), pp. 5247-5260.e19. Date of Electronic Publication: 2021 Sep 16. - Publication Year :
- 2021
-
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.<br />Competing Interests: Declaration of interests P.C.S. is a co-founder of and consultant to Sherlock Biosciences and Board Member of Danaher Corporation. She is a shareholder in both companies.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Algorithms
Alleles
Gene Expression Regulation
Genes, Reporter
Genetic Variation
Humans
Phenotype
Polymorphism, Single Nucleotide genetics
Polyribosomes metabolism
Quantitative Trait Loci genetics
RNA genetics
3' Untranslated Regions genetics
Biological Evolution
Disease genetics
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 184
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 34534445
- Full Text :
- https://doi.org/10.1016/j.cell.2021.08.025