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

By Joana Damas, Graham M. Hughes, Kathleen Keough, Corrie A. Painter, Nicole S. Persky, Marco Corbo, Michael Hiller, Klaus-Peter Koepfli, Andreas R Pfenning, Huabin Zhao, Diane P. Genereux, Ross Swofford, Katherine Pollard, Oliver A Ryder, Martin T. Nweeia, Kerstin Lindblad-Toh, Emma C. Teeling, Elinor K. Karlsson, Harris A. Lewin

Posted 18 Apr 2020
bioRxiv DOI: 10.1101/2020.04.16.045302 (published DOI: 10.1073/pnas.2010146117)

The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). As for other coronaviruses, there is transmission between animals and humans. 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 scheme 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 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 risk classification. 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. ### Competing Interest Statement The authors have declared no competing interest.

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