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Omicron, South Africa on November 24th, 2021 Omicron diverged from the B.1.1 lineage roughly in mid-2020 Mutations not found in: Alpha, Beta, Gamma, and Delta SARS-CoV-2 variants isolated from three chronically infected patients The B.1.1 variants showed the highest sequence similarities to Omicron Normal rate of mutations in spike protein RNA ∼0.45 mutations per month During missing time for Omicron 27 mutations accumulated in spike protein RNA (in Branch O) during 18 months ∼1.5 mutations per month ∼3.3 times faster than the average rate of other variants First hypothesis Omicron could have “cryptically spread” and circulated in a population Second hypothesis Omicron could have evolved in a chronically infected COVID-19 patient Third hypothesis Omicron could have accumulated mutations in a nonhuman host and then jumped into humans Mice Evidence for a mouse origin of the SARS-CoV-2 Omicron variant https://www.sciencedirect.com/science/article/pii/S1673852721003738 The rapid accumulation of mutations Omicron Proximal origin occurred in humans or another mammalian host? Omicron, 45 point mutations that Omicron acquired since divergence from the B.1.1 lineage Significantly different from the spectrum for viruses that evolved in human patients Omicron spike protein sequence, stronger positive selection than that of any previous variants Suggesting a possibility of host-jumping Resembled the spectra associated with virus evolution in a mouse cellular environment Mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts (through enhanced spike protein binding affinity for the mouse cell entry receptor) So Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak Fortunately Evolved to increase binging to mouse ACE2 receptors Consistent with human immune escape Consistent with upper airway adsorption © 2021 The Authors. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press.

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