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Comprehensive In Vivo Interrogation Reveals Phenotypic Impact of Human Enhancer Variants.

Authors
  • Kvon, Evgeny Z1
  • Zhu, Yiwen1
  • Kelman, Guy1
  • Novak, Catherine S1
  • Plajzer-Frick, Ingrid1
  • Kato, Momoe1
  • Garvin, Tyler H1
  • Pham, Quan1
  • Harrington, Anne N1
  • Hunter, Riana D1
  • Godoy, Janeth1
  • Meky, Eman M1
  • Akiyama, Jennifer A1
  • Afzal, Veena1
  • Tran, Stella1
  • Escande, Fabienne2
  • Gilbert-Dussardier, Brigitte3
  • Jean-Marçais, Nolwenn4
  • Hudaiberdiev, Sanjarbek5
  • Ovcharenko, Ivan5
  • And 7 more
  • 1 Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
  • 2 CHU Lille, University of Lille, EA7364, F-59000, Lille, France. , (France)
  • 3 CHU Poitiers, University of Poitiers, EA3808, F-86000, Poitiers, France. , (France)
  • 4 CHU Dijon Bourgogne, Department of Clinical Genetics, F-21000, Dijon, France. , (France)
  • 5 Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20892, USA.
  • 6 Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 7 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 8 Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Berkeley, CA 94720, USA; School of Natural Sciences, University of California, Merced, CA 95343, USA. Electronic address: [email protected]
  • 9 Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: [email protected]
  • 10 Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Berkeley, CA 94720, USA; Comparative Biochemistry Program, University of California, Berkeley, CA 94720, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cell
Publication Date
Mar 19, 2020
Volume
180
Issue
6
Identifiers
DOI: 10.1016/j.cell.2020.02.031
PMID: 32169219
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here, we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential of human enhancer variants in vivo and examine nearly a thousand variants in an enhancer repeatedly linked to polydactyly. We show that 71% of all rare non-coding variants previously proposed as causal lead to reporter gene expression in a pattern consistent with their pathogenic role. Variants observed to alter enhancer activity were further confirmed to cause polydactyly in knockin mice. We also used combinatorial and single-nucleotide mutagenesis to evaluate the in vivo impact of mutations affecting all positions of the enhancer and identified additional functional substitutions, including potentially pathogenic variants hitherto not observed in humans. Our results uncover the functional consequences of hundreds of mutations in a phenotype-associated enhancer and establish a widely applicable strategy for systematic in vivo evaluation of human enhancer variants. Published by Elsevier Inc.

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