Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an immediate, major threat to public health across the globe. Here we report an in-depth molecular analysis to reconstruct the evolutionary origins of the enhanced pathogenicity of SARS-CoV-2 and other coronaviruses that are severe human pathogens. Using integrated comparative genomics and machine learning techniques, we identify key genomic features that differentiate SARS-CoV-2 and the viruses behind the two previous deadly coronavirus outbreaks, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), from less pathogenic coronaviruses. These features include enhancement of the nuclear localization signals in the nucleocapsid protein and distinct inserts in the spike glycoprotein that appear to be associated with high case fatality rate of these coronaviruses as well as the host switch from animals to humans. The identified features could be crucial contributors to coronavirus pathogenicity and possible targets for diagnostics, prognostication, and interventions.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an immediate, major threat to public health across the globe
The closest known relative of SARS-CoV-2 is a bat coronavirus (Fig. 1A), but the specific route of transmission from bats to humans remains unclear. These repeated, independent zoonotic transmissions and the high associated pathogenicity call for an indepth investigation of the genomic features that contribute to coronaviruses pathogenicity and transmission, to better understand the molecular mechanisms of the high-case fatality rates (CFR) coronaviruses pathogenicity, and to be better prepared for any future coronavirus outbreaks, and potentially contribute to the development of interventions
SARS-CoV-2 has led to the most devastating pandemic since the 1918 Spanish flu, prompting an urgent need to elucidate the evolutionary history and genomic features that led to the increased pathogenicity and rampant spread of this virus as well as those coronaviruses that caused previous deadly outbreaks
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an immediate, major threat to public health across the globe. Using integrated comparative genomics and machine learning techniques, we identify key genomic features that differentiate SARS-CoV-2 and the viruses behind the two previous deadly coronavirus outbreaks, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), from less pathogenic coronaviruses. These features include enhancement of the nuclear localization signals in the nucleocapsid protein and distinct inserts in the spike glycoprotein that appear to be associated with high case fatality rate of these coronaviruses as well as the host switch from animals to humans. These repeated, independent zoonotic transmissions and the high associated pathogenicity call for an indepth investigation of the genomic features that contribute to coronaviruses pathogenicity and transmission, to better understand the molecular mechanisms of the high-CFR coronaviruses pathogenicity, and to be better prepared for any future coronavirus outbreaks, and potentially contribute to the development of interventions
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