Predicting the zoonotic capacity of mammal species for SARS-CoV-2

28 Spillback transmission from humans to animals, and secondary spillover from animal hosts back 29 into humans, have now been documented for SARS-CoV-2. In addition to threatening animal 30 health, virus variants arising from novel animal hosts have the potential to undermine global 31 COVID-19 mitigation efforts. Numerous studies have therefore investigated the zoonotic 32 capacity of various animal species for SARS-CoV-2, including predicting both species’ 33 susceptibility to infection and their capacities for onward transmission. A major bottleneck to 34 these studies is the limited number of sequences for ACE2, a key cellular receptor in chordates 35 that is required for viral cell entry. Here, we combined protein structure modeling with machine 36 learning of species’ traits to predict zoonotic capacity of SARS-CoV-2 across 5,400 mammals. 37 High accuracy model predictions were strongly corroborated by in vivo empirical studies, and 38 identify numerous mammal species across global COVID-19 hotspots that should be prioritized 39 for surveillance and experimental validation. 40 . CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted February 19, 2021. ; https://doi.org/10.1101/2021.02.18.431844 doi: bioRxiv preprint