Comparative ACE2 variation and primate COVID-19 risk

Amanda D. Melin; Mareike C. Janiak; Frank Marrone; Paramjit S. Arora; James P. Higham

Substitutions at binding sites might be at least partially protective against COVID-19 in these mammals. For example, the limited experimental evidence to date suggests that while catswhich have the same residue as humans at site 34 -are not strongly symptomatic, they present lung lesions, while dogs -which have a substitution at this site -do not 22 . The amino acid residue at site 24 differs from primates in all other mammalian species examined. However, our models suggest that the variant residues may confer relatively minor reductions in binding affinity. Other sources of variation, including residues affecting ACE2 protein stability 20 . Our results are also consistent with previous reports that ACE2 genetic diversity is greater among bats than that observed among mammals susceptible to SARS-CoV-type viruses. This variation has been suggested to indicate that bat species may act as a reservoir of SARS-CoV viruses or their More generally, if adhering to the precautionary principle, then our results highlighting higher risks to some species should be taken with greater gravity than our results that predict potential lower risks to others. Another limitation of our study is that we have looked at only 27 primate species, albeit with broad taxonomic scope. Analysis of additional species is important, especially among . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.09.034967 doi: bioRxiv preprint strepsirrhine species, where our coverage is relatively scant. In particular, the almost identical residue sequences of Coquerel's sifaka to those of catarrhines suggests a need to assess the residue sequences of a wider diversity of lemur species. It is also important to remember that our study assesses only the potential for initial binding of the virus to the target site. Downstream consequences of infection may differ drastically based on species-specific proteases, genomic variants, metabolism, and immune system responses 38, 39 . In humans, the development of COVID-19 can lead to a pro-inflammatory cytokine storm of hyperinflammation, which may lead to some of the more severe impacts of infection 40, 41 .