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

A recent mutagenesis screen using a synthetic human ACE2 mutant library identified variants that either increased or decreased its binding to SARS-CoV-2 Sprotein (Procko, 2020) . Using a sequencing-based enrichment assay, the fold enrichment or depletion of the mutant sequences was measured in this study (Procko, 2020) . Mapping the enrichment z-scores from this study (Procko, 2020) to the spectrum of natural ACE2 polymorphisms, we identified several rare ACE2 variants (Figure 1c) that likely alter their binding to the SARS-CoV-2 S-protein and thereby protect or render individuals more susceptible to the virus(Supplementary Table 2 ). The majority of the variants that were predicted to alter the interaction between ACE2 and the virus Sprotein were clustered around the N-terminal region of ACE2 that interacts with the Sprotein (Figure 1b) .