Peer-Reviewed Publication
Cell2021;184(20):5247-5260.e19.September 30, 2021Journal Article
Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution.
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
1Broad 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.
2Broad 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.
3Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02143, USA.
4Broad 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.
5Department of Molecular and Cell Biology, Harvard University, Cambridge, MA 02138, USA.
6BigHat Biosciences, San Carlos, CA 94070, USA.
7Broad 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.
8Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA.
9The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.
10Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
11Broad 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.
12Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
13Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
14Broad 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.
15The 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.
16Broad 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 ad…
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