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

Joana Damas; Graham M. Hughes; Kathleen C. 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 S. Pollard; Oliver A. Ryder; Martin T. Nweeia; Kerstin Lindblad-Toh; Emma C. Teeling; Elinor K. Karlsson; Harris A. Lewin

Structural analysis of variation in human ACE2 . We applied the same approach used to compare species, sequence identity and protein structural analysis, to examine the variation in ACE binding residues within humans, some of which have been proposed to alter binding affinity (18, (27) (28) (29) (30) . We integrated data from six different sources: dbSNP (31) , 1KGP (32) , Topmed (33) , UK10K (34) and CHINAMAP (28) , and identified a total of 11 variants in ten of the 25 ACE2 binding residues (Dataset S2). All variants found are rare, with allele frequency less than 0.01 in any populations, and less than 0.0007 over all populations. Three of the 11 variants were synonymous changes, seven were conservative missense variants, and one, S19P, was a semi-conservative substitution. S19P has the highest allele frequency of the 11 variants, with a global frequency of 0.0003 (17) . We evaluated, by structural homology, six missense variants. Four were neutral and two weakening (E35K, frequency=0.000016; E35D, frequency=0.000279799). S19P was not included in our structural homology assessment, but a recent study predicted it would increase binding affinity (26) . Thus, with an estimated summed frequency of 0.001, genetic variation in the ACE2 S-binding interface is overall rare, and it is unclear whether the variation that does exist increases or decreases susceptibility to infection.