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Abstract
Virus host shifts are generally associated with novel adaptations to exploit the cells of the new host species optimally. Surprisingly, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has apparently required little to no significant adaptation to humans since the start of the Coronavirus Disease 2019 (COVID-19) pandemic and to October 2020. Here we assess the types of natural selection taking place in Sarbecoviruses in horseshoe bats versus the early SARS-CoV-2 evolution in humans. While there is moderate evidence of diversifying positive selection in SARS-CoV-2 in humans, it is limited to the early phase of the pandemic, and purifying selection is much weaker in SARS-CoV-2 than in related bat Sarbecoviruses. In contrast, our analysis detects evidence for significant positive episodic diversifying selection acting at the base of the bat virus lineage SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in these ancestral bat hosts. The closest bat virus to SARS-CoV-2, RmYN02 (sharing an ancestor about 1976), is a recombinant with a structure that includes differential CpG content in Spike; clear evidence of coinfection and evolution in bats without involvement of other species. While an undiscovered "facilitating" intermediate species cannot be discounted, collectively, our results support the progenitor of SARS-CoV-2 being capable of efficient human-human transmission as a consequence of its adaptive evolutionary history in bats, not humans, which created a relatively generalist virus.
Highlights
In December 2019, an outbreak of pneumonia cases in the city of Wuhan, China, was linked to a novel coronavirus
We first analyse selection acting on the encoded amino acids of SARS-CoV-2 using 133,741 quality control (QC)-filtered genome sequences from the GISAID database as of 12 October 2020, representing a sample of the variants circulating in humans during the first 11 months of the pandemic
We investigated if this adaptive shift in CpG content at the base of the new coronavirus (nCoV) clade was associated with an elevation in substitution rate, which would be expected if dinucleotide mutations were being driven to fixation by positive selection
Summary
In December 2019, an outbreak of pneumonia cases in the city of Wuhan, China, was linked to a novel coronavirus. Two of the key changes which appear to have been required to generate this highly capable pathogen, the specific receptor binding domain sequence and the inserted furin cleavage site, can all be traced to bat coronaviruses [6,13,14,15] These results demonstrate that, unlike most other RNA viruses which acquire adaptations after switching to a new host species [16,17] for efficient replication and spreading as successfully as exhibited by SARS-CoV-2, the Sarbecoviruses— which already transmit frequently among bat species [18]—can exploit the generalist properties of their ACE2 binding ability, facilitating successful infection of non-bat species, including humans. We detect a shift in CpG representation on the Sarbecovirus tree, associated with the phylogenetic clade SARS-CoV-2 is found in
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