Rapid threat detection in SARS-CoV-2

This paper presents a novel virus surveillance framework, completely independent of phylogeny-based methods. The framework issues timely alerts with an accuracy exceeding 85% that are based on the co-evolutionary relations between sites of the viral multiple sequence array (MSA). This set of relations is formalized via a motif complex, whose dynamics contains key information about the emergence of viral threats without the referencing of strain prevalence. Our notion of threat is centered at the emergence of a certain type of critical cluster consisting of key co-evolving sites. We present three case studies, based on GISAID data from UK, US and New York, where we perform our surveillance. We alert on May 16, 2022, based on GISAID data from New York, to a critical cluster of co-evolving sites mapping to the Pango-designation, BA.5. The alert specifies a cluster of seven genomic sites, one of which exhibits D3N on the M (membrane) protein–the distinguishing mutation of BA.5, three encoding ORF6:D61L and the remaining three exhibiting the synonymous mutations C26858T, C27889T and A27259C. New insight is obtained: when projected onto sequences, this cluster splits into two, mutually exclusive blocks of co-evolving sites (m:D3N,nuc:C27889T) linked to the five reverse mutations (nuc:C26858T,nuc:A27259C,ORF6:D61L). We furthermore provide an in depth analysis of all major signaled threats, during which we discover a specific signature concerning linked reverse mutation in the critical cluster. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was partially supported by the VDH Grant PV-BII VDH COVID-19 Modeling Program VDH-21-501-0135. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors