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Broad Host Range of SARS-CoV-2 Predicted by Comparative and Structural Analysis of ACE2 in Vertebrates.

  • Damas, Joana1
  • Hughes, Graham M2
  • Keough, Kathleen C3, 4
  • Painter, Corrie A5, 6
  • Persky, Nicole S5, 7
  • Corbo, Marco1
  • Hiller, Michael8, 9, 10
  • Koepfli, Klaus-Peter11
  • Pfenning, Andreas R12
  • Zhao, Huabin13
  • Genereux, Diane P5
  • Swofford, Ross5
  • Pollard, Katherine S3, 4, 14
  • Ryder, Oliver A15, 16
  • Nweeia, Martin T17, 18, 19
  • Lindblad-Toh, Kerstin5, 20
  • Teeling, Emma C2
  • Karlsson, Elinor K5, 21, 22
  • Lewin, Harris A1, 23, 24
  • 1 The Genome Center, University of California Davis, Davis, CA 95616, USA.
  • 2 School of Biology and Environmental Science, University College Dublin, Belfield, Dublin 4, Ireland. , (Ireland)
  • 3 University of California San Francisco, San Francisco, CA 94117, USA.
  • 4 Gladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA.
  • 5 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 6 Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 7 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 8 Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany. , (Germany)
  • 9 Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany. , (Germany)
  • 10 Center for Systems Biology Dresden, 01307 Dresden, Germany. , (Germany)
  • 11 Smithsonian Conservation Biology Institute, Center for Species Survival, National Zoological Park, Front Royal, VA 22630, Washington, DC 20008 USA.
  • 12 Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
  • 13 Department of Ecology and Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China. , (China)
  • 14 Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
  • 15 San Diego Zoo Institute for Conservation Research, Escondido, CA 92027, USA.
  • 16 Department of Evolution, Behavior, and Ecology, Division of Biology, University of California San Diego, La Jolla, CA 92093, USA.
  • 17 Harvard School of Dental Medicine, Boston, MA 02115, USA.
  • 18 Case Western Reserve University School of Dental Medicine, Cleveland, OH 44106, USA.
  • 19 Marine Mammal Program, Department of Vertebrate Zoology, Smithsonian Institution, Washington, DC 20002, USA.
  • 20 Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, 751 23, Sweden. , (Sweden)
  • 21 Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
  • 22 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
  • 23 Department of Evolution and Ecology, University of California Davis, Davis, CA 95616, USA.
  • 24 John Muir Institute for the Environment, University of California Davis, Davis, CA 95616, USA.
Published Article
bioRxiv : the preprint server for biology
Publication Date
Apr 18, 2020
DOI: 10.1101/2020.04.16.045302
PMID: 32511356


The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species from very high to very low. Only mammals fell into the medium to very high categories, and only catarrhine primates in the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (<0.1%) variants in 10/25 binding sites. In addition, we observed evidence of positive selection in ACE2 in multiple species, including bats. Utilized appropriately, our results may lead to the identification of intermediate host species for SARS-CoV-2, justify the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.

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