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

View ORCID ProfileDustin Griesemer, View ORCID ProfileJames R Xue, View ORCID ProfileSteven K Reilly, View ORCID ProfileJacob C Ulirsch, View ORCID ProfileKalki Kukreja, View ORCID ProfileJoe Davis, View ORCID ProfileMasahiro Kanai, David K Yang, View ORCID ProfileStephen B Montgomery, View ORCID ProfileCarl D Novina, View ORCID ProfileRyan Tewhey, View ORCID ProfilePardis C Sabeti
doi: https://doi.org/10.1101/2021.01.13.424697
Dustin Griesemer
1Broad Institute of MIT and Harvard, Cambridge, MA, 02143
2Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, 02115
3Brigham and Women’s Hospital, Boston, MA, 02115
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James R Xue
1Broad Institute of MIT and Harvard, Cambridge, MA, 02143
4Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, 02143
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  • For correspondence: jxue@broadinstitute.org
Steven K Reilly
1Broad Institute of MIT and Harvard, Cambridge, MA, 02143
4Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, 02143
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Jacob C Ulirsch
1Broad Institute of MIT and Harvard, Cambridge, MA, 02143
5Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115
6Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114
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Kalki Kukreja
7Department of Molecular and Cell Biology, Harvard University, Cambridge, MA, 02138
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Joe Davis
8Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305
9Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305
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Masahiro Kanai
1Broad Institute of MIT and Harvard, Cambridge, MA, 02143
2Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, 02115
6Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114
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David K Yang
1Broad Institute of MIT and Harvard, Cambridge, MA, 02143
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Stephen B Montgomery
8Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305
9Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305
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Carl D Novina
1Broad Institute of MIT and Harvard, Cambridge, MA, 02143
10Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02115
11Department of Medicine, Harvard Medical School, Boston, MA, 02115
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Ryan Tewhey
12The Jackson Laboratory, Bar Harbor, ME, 04609
13Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME, 04469
14Tufts University School of Medicine, Boston, MA, 02111
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Pardis C Sabeti
1Broad Institute of MIT and Harvard, Cambridge, MA, 02143
4Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, 02143
15Howard Hughes Medical Institute, Chevy Chase, Maryland, 20815
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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 low-complexity sequences predominately explain 3’UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base-pair resolution, including an 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.

Competing Interest Statement

P.C.S. is a co-founder of and consultant to Sherlock Biosciences and Board Member of Danaher Corporation.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 13, 2021.
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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 Davis, Masahiro Kanai, David K Yang, Stephen B Montgomery, Carl D Novina, Ryan Tewhey, Pardis C Sabeti
bioRxiv 2021.01.13.424697; doi: https://doi.org/10.1101/2021.01.13.424697
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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 Davis, Masahiro Kanai, David K Yang, Stephen B Montgomery, Carl D Novina, Ryan Tewhey, Pardis C Sabeti
bioRxiv 2021.01.13.424697; doi: https://doi.org/10.1101/2021.01.13.424697

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