Protein covariance networks reveal interactions important to the emergence of SARS coronaviruses as human pathogens

Abstract

SARS-CoV-2 is one of three recognized coronaviruses (CoVs) that have caused epidemics or pandemics in the 21 st century and that have likely emerged from animal reservoirs based on genomic similarities to bat and other animal viruses. Here we report the analysis of conserved interactions between amino acid residues in proteins encoded by SARS-CoV-related viruses. We identified pairs and networks of residue variants that exhibited statistically high frequencies of covariance with each other. While these interactions are likely key to both protein structure and other protein-protein interactions, we have also found that they can be used to provide a new computational approach (CoVariance-based Phylogeny Analysis) for understanding viral evolution and adaptation. Our data provide evidence that the evolutionary processes that converted a bat virus into human pathogen occurred through recombination with other viruses in combination with new adaptive mutations important for entry into human cells.

Covariance predicts conserved protein residue interactions important to the emergence and continued evolution of SARS-CoV-2 as a human pathogen

“…These could inform about epitopes and antigenic regions that are possibly vulnerable to enriched mutations also in part due to covariance such as specific regions in the Spike NTD. Furthermore, these may reveal key residues that contribute to yet undiscovered interactions between viral proteins of SARS-CoV-2 including Spike and ORF3a as discussed in an earlier description of our initial results 55 .…”

“…Furthermore, these may reveal key residues that contribute to yet undiscovered interactions between viral proteins of SARS-CoV-2 including Spike and ORF3a as discussed in an earlier description of our initial results 55 .…”

“…Because covariant AA residues change in concert with each other, they can define critical AA-AA residue interactions within a protein or in homologous or heterologous protein-protein pairs or instead indicate phylogenetic relatedness based on their co-existence 37,38 . These putative residue interactions may provide new insights into the evolution and relatedness of the CoV family of viruses 55 . To survey the frequency of covariance among a reference collection CoVs, we identified correlative pairs and also assembled groups of three or more (here designated as 'clusters') of covarying amino acid residues using a correlating tandem model 56 .…”

Covariance predicts conserved protein residue interactions important for the emergence and continued evolution of SARS-CoV-2 as a human pathogen

“…Detected residues in new lineages that are likewise found to be significantly covariant with other residues that have been demonstrated to increase virulence, stability, transmission, or immunity evasion can then inform about such issues regarding vaccine efficacy and even clinical outcomes. Furthermore, these may reveal key residues that contribute to yet undiscovered interactions between all viral proteins of SARS-CoV-2 including spike and ORF3a as discussed in an earlier description of our initial results [ 59 ].…”

“…Because covariant AA residues change in concert with each other, they can define critical AA-AA residue interactions within a protein or in homologous or heterologous protein-protein pairs or instead indicate phylogenetic relatedness based on their co-existence [ 43 , 44 ]. These putative residue interactions may provide new insights into the evolution and relatedness of the CoV family of viruses [ 59 ]. To survey the frequency of covariance among a reference collection CoVs, we identified correlative pairs and also assembled groups of three or more (here designated as ‘clusters’) of covarying amino acid residues using a correlating tandem model [ 60 ].…”