Unique protein features of SARS-CoV-2 relative to otherSarbecoviruses

Defining the unique properties of SARS-CoV-2 protein sequences, has potential to explain the range of Coronavirus Disease 2019 (COVID-19) severity. To achieve this we compared proteins encoded by allSarbecovirusesusing profile Hidden Markov Model similarities to identify protein features unique to SARS-CoV-2. Consistent with previous reports, a small set of bat and pangolin-derivedSarbecovirusesshow the greatest similarity to SARS-CoV-2 but unlikely to be the direct source of SARS-CoV-2. Three proteins (nsp3, spike and orf9) showed differing regions between the batSarbecovirusesand SARS-CoV-2 and indicate virus protein features that might have evolved to support human infection and/or transmission. Spike analysis identified all regions of the protein that have tolerated change and revealed that the current SARS-CoV-2 variants of concern (VOCs) have sampled only a fraction (~31%) of the possible spike domain changes which have occurred historically inSarbecovirusevolution. This result emphasises the evolvability of these coronaviruses and potential for further change in virus replication and transmission properties over the coming years.