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Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution.
Griesemer, Dustin; Xue, James R; Reilly, Steven K; Ulirsch, Jacob C; Kukreja, Kalki; Davis, Joe R; Kanai, Masahiro; Yang, David K; Butts, John C; Guney, Mehmet H; Luban, Jeremy; Montgomery, Stephen B; Finucane, Hilary K; Novina, Carl D; Tewhey, Ryan; Sabeti, Pardis C.
Afiliação
  • Griesemer D; 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.
  • Xue JR; 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.
  • Reilly SK; Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Department Of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02143, USA.
  • Ulirsch JC; 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.
  • Kukreja K; Department of Molecular and Cell Biology, Harvard University, Cambridge, MA 02138, USA.
  • Davis JR; BigHat Biosciences, San Carlos, CA 94070, USA.
  • Kanai M; 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.
  • Yang DK; Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA.
  • Butts JC; The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.
  • Guney MH; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
  • Luban J; 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.
  • Montgomery SB; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Finucane HK; Broad Institute of MIT and Harvard, Cambridge, MA 02143, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Novina CD; 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.
  • Tewhey R; 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.
  • Sabeti PC; 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.
Cell ; 184(20): 5247-5260.e19, 2021 09 30.
Article em En | MEDLINE | ID: mdl-34534445
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença / Regiões 3' não Traduzidas / Evolução Biológica / Estudo de Associação Genômica Ampla Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doença / Regiões 3' não Traduzidas / Evolução Biológica / Estudo de Associação Genômica Ampla Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Cell Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos