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

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

doi:10.1016/j.cell.2021.08.025

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

Cell. 2021 Sep 30;184(20):5247-5260.e19. doi: 10.1016/j.cell.2021.08.025. Epub 2021 Sep 16.

Authors

Dustin Griesemer¹, James R Xue², Steven K Reilly³, Jacob C Ulirsch⁴, Kalki Kukreja⁵, Joe R Davis⁶, Masahiro Kanai⁷, David K Yang⁸, John C Butts⁹, Mehmet H Guney¹⁰, Jeremy Luban¹¹, Stephen B Montgomery¹², Hilary K Finucane¹³, Carl D Novina¹⁴, Ryan Tewhey¹⁵, Pardis C Sabeti¹⁶

Affiliations

¹ Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA; Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02143, USA. Electronic address: jxue@broadinstitute.org.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02143, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Department of Molecular and Cell Biology, Harvard University, Cambridge, MA 02138, USA.
⁶ BigHat Biosciences, San Carlos, CA 94070, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA.
⁹ The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.
¹⁰ Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
¹² Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹⁵ The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA; Tufts University School of Medicine, Boston, MA 02111, USA.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02143, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

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.

Keywords: 3'UTR; GWAS; MPRA; evolution; functional genomics; genetic variants; regulatory genomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions / genetics*
Algorithms
Alleles
Biological Evolution*
Disease / genetics*
Gene Expression Regulation
Genes, Reporter
Genetic Variation
Genome-Wide Association Study*
Humans
Phenotype
Polymorphism, Single Nucleotide / genetics
Polyribosomes / metabolism
Quantitative Trait Loci / genetics
RNA / genetics

Substances

3' Untranslated Regions
RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding