Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility

Eric W. Stawiski; Devan Diwanji; Kushal Suryamohan; Ravi Gupta; Frederic A. Fellouse; J. Fah Sathirapongsasuti; Jiang Liu; Ying-Ping Jiang; Aakrosh Ratan; Monika Mis; Devi Santhosh; Sneha Somasekar; Sangeetha Mohan; Sameer Phalke; Boney Kuriakose; Aju Antony; Jagath R. Junutula; Stephan C. Schuster; Natalia Jura; Somasekar Seshagiri

Thus far, the role of variations in human ACE2 receptor in susceptibility to both SARS CoVs had not been comprehensively examined. A recent study analyzed a limited ACE2 population variation data set and concluded that these polymorphisms did not confer resistance to the virus (Cao et al., 2020a) . In this study, we have examined human ACE2 variation data compiled from multiple data sets and identified polymorphisms that will either likely render individuals more susceptible to the SARS-CoV-2 or protect them from the virus. Using structural predictions based on published protein structures and data from an elegant mutagenesis screen that used deep sequencing to assess enrichment or depletion of S-protein binding ACE2 variants, we classified the variants identified in this study for the effects on susceptibility to SARS-CoV (Procko, 2020; Shang et al., 2020; Walls et al., 2020; Wrapp et al., 2020; . In particular, human ACE2 variants K26R, S16P, T27A, K31R, H34R, E35K, E37K, D38V, N51S, N64K, K68E, F72V, T921, Q102P, G326E, G352V, D355N, H378R, Q388L, and D509Y are predicted to increase the susceptibility of the individuals carrying these variations. It is interesting to note that the T921I ACE2 variant is part of the consensus NxS/T N-glycosylation motif and is predicted to abolish glycosylation of the conserved N90 residue. Our structural investigation suggests that this mutation will favor improved viral S-protein binding. A previous study showed that the ACE2 N90 renders human cells resistant to Civet CoV (Li et al., 2005b) . Recently, N90 and T92 ACE2 mutations were enriched in a screen for CoV-2 S-protein binding (Procko, 2020) .