Distinct evolutionary trajectories of SARS-CoV-2 interacting proteins in bats and primates identify important host determinants of COVID-19

Abstract

The COVID-19 pandemic is caused by SARS-CoV-2, a novel coronavirus that spilled from the bat reservoir. Despite numerous clinical trials and vaccines, the burden remains immense, and the host determinants of SARS-CoV-2 susceptibility and COVID-19 severity remain largely unknown. Signatures of positive selection detected by comparative functional-genetic analyses in primate and bat genomes can uncover important and specific adaptations that occurred at virus-host interfaces. Here, we performed high-throughput evolutionary analyses of 334 SARS-CoV-2 interacting proteins to identify SARS-CoV adaptive loci and uncover functional differences between modern humans, primates and bats. Using DGINN (Detection of Genetic INNovation), we identified 38 bat and 81 primate proteins with marks of positive selection. Seventeen genes, including the ACE2 receptor, present adaptive marks in both mammalian orders, suggesting common virus-host interfaces and past epidemics of coronaviruses shaping their genomes. Yet, 84 genes presented distinct adaptations in bats and primates. Notably, residues involved in ubiquitination and phosphorylation of the inflammatory RIPK1 have rapidly evolved in bats but not primates, suggesting different inflammation regulation versus humans. Furthermore, we discovered residues with typical virus-host arms-race marks in primates, such as in the entry factor TMPRSS2 or the autophagy adaptor FYCO1, pointing to host-specific in vivo important interfaces that may be drug targets. Finally, we found that FYCO1 sites under adaptation in primates are those associated with severe COVID-19, supporting their importance in pathogenesis and replication. Overall, we identified functional adaptations involved in SARS-CoV-2 infection in bats and primates, critically enlightening modern genetic determinants of virus susceptibility and severity.

Distinct evolutionary trajectories of SARS-CoV-2-interacting proteins in bats and primates identify important host determinants of COVID-19

“…Data, codes, and any information are entirely publicly available. All codes are available in https://gitbio.ens-lyon.fr/ciri/ps_sars-cov-2/2021_dginn_covid19 ( 89 ), and the DGINN pipeline is available at http://bioweb.me/DGINN-github ( 90 ). All results from the DGINN screens (DGINN full dataset) and from the detailed evolutionary analyses (DGINN genes of interest) are available through the VirHostEvol web service at https://virhostnet.prabi.fr/virhostevol/ ( 91 ).…”

“…All codes are available in https://gitbio.ens-lyon.fr/ciri/ps_sars-cov-2/2021_dginn_covid19 ( 89 ), and the DGINN pipeline is available at http://bioweb.me/DGINN-github ( 90 ). All results from the DGINN screens (DGINN full dataset) and from the detailed evolutionary analyses (DGINN genes of interest) are available through the VirHostEvol web service at https://virhostnet.prabi.fr/virhostevol/ ( 91 ). The Shiny web application open-source code is available from the IN2P3 gitlab at https://gitlab.in2p3.fr/vincent.navratil/shinyapps-virhostevol ( 92 ).…”

Adaptive duplication and functional diversification of Protein kinase R contribute to the uniqueness of bat-virus interactions

“…Bats may have evolved unique adaptations in their inflammasome components and signaling factors ( e.g . PYHIN 7 , STING 8 , IRF3 9 , RIPK1 10 ) that mitigate flight’s detrimental effects and dampen excessive inflammation, thereby presumably increasing viral tolerance. Furthermore, with more than 1,200 species and approximately 60 million years of divergence 11 , bats have co-evolved with a large diversity of viral pathogens.…”