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Mutations arising in SARS-CoV-2 spike on sustained human-to-human transmission and human-to-animal passage

Introduction
The proximal origins of SARS-CoV and MERS-CoV from civets and camels, respectively, are well documented. Few genetic changes in these viruses are required for the interspecies transfers to humans (Li, 2008). While precise details and timing of the evolutionary pathways remain to be elucidated, it is also apparent that SARS-CoV-2 emerged from the Sarbecovirus subgenus of the Betacoronaviruses via one or more interspecies transfers (Andersen et al., 2020; Boni et al., 2020). In contrast to SARS-CoV and MERS-CoV, SARS-CoV-2 has had an extended period of human-to-human transmission. While the evolutionary rate is not unusual for an RNA virus, mutations have occurred that appear to impact SARS-CoV-2 fitness (Kemp et al., 2020; Volz et al., 2020). For example, SARS-CoV-2 carrying G614 has replaced D614 as the predominant circulating variant (Volz et al., 2020). The D614G substitution abolishes a hydrogen-bond interaction with T859 of a neighboring monomer, which destabilizes the spike trimer and increases interaction of the receptor binding domain (RBD) with angiotension-converting enzyme 2ACE2 . By increasing viral load in the upper respiratory tract of COVID-19 patients, D614G may enhance SARS-CoV-2 transmission (Plante et al., 2020).

Recently, a SAR-CoV-2 variant emerged in the UK that has acquired 17 mutations, including 8 in spike (Rambaut et al., 2020). An apparently independent lineage emerged in South Africa that also has multiple spike mutations (Pond et al., 2020). Spike mutations have also occurred during interspecies transfers of SARS-CoV-2 from humans to animals, both during establishment of experimental models of COVID-19 and as an unintended consequence of human interactions with domestic, curated and commercial animals (Mahdy et al., 2020). Here, some of the mutations that have occurred to date in the SARS-CoV-2 spike during human-to-human transmission and following human-to-animal passage are compiled. This compilation highlights several commonly occurring natural features of coronavirus spike evolution that may be involved in interspecies transfers.

Methods
Homology modeling of the SARS-CoV-2 spike was performed in SWISS-MODEL (Waterhouse et al., 2018) using reference sequence QHD43416.1 and a closed prefusion configuration of the spike trimer pdb 6VXX (Walls et al., 2020) as template. The resulting model includes amino acids that are disordered in the spike cryoelectron microscopy structure and reverts the furin cleavage site and proline mutations used to stabilize the trimer. As in structures of all other CoV spikes, this model lacks most of the C-terminal helix (heptad repeat 2), membrane-proximal external region, transmembrane and intracellular domains.


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