Explore the evolutionary trajectory of SARS-CoV-2 interacting proteins in bats and primates

In a recent study posted on bioRxiv* Preprint server, researchers have found that the high throughput of genes encoding the 334 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral interaction proteins (VIPs) in modern humans, primates, and bats. Perform evolutionary analysis, followed by comprehensive function-gene analysis of the seven VIPs of interest.

Background

During infection, SARS-CoV-2 interacts with the VIP to quickly counter viral infections and settle in the host population. In response, the host induces the VIP into a periodic reverse adaptation cycle, forming an arms race between the virus and the host.

The arms race is characterized by accelerated evolutionary speeds or signs of aggressive choice. Therefore, comparative functional genomics is a powerful approach for identifying VIPs with positive selection signatures and discovering host viral interfaces that regulate bat reservoirs and primate host infections.

Several In vitro Approaches such as clustered, regularly spaced short CRISPR / gene knockout (KO) screens, complementary DNA (cDNA) library screens, or mass spectrometry (MS) analysis are available to researchers. Helped identify hundreds of SARS-CoV-2 VIPs. However, research has not elucidated the role of the identified SARS-CoV-2 VIP. In vivo..

About research

In this study, researchers identified VIPs with signs of adaptive evolution accumulated in the VIP gene due to past epidemics. They also mapped VIPs with similar different evolutions and genetics in humans and zoonoses hosts.

The team is working on the Detection of Genetic INNovation (DGINN) bioinformatics pipeline to perform positive selection analysis across large datasets of bat and primate homologs from the National Center for Biotechnology Information (NCBI) database. Was used.

DGINN automatically acquired data and combined several methods for analysis, screening for duplicate events, gene orthologs and potential paralogs, and identification of recombinant events. In addition, DGINN curated the coding sequence, performed codon alignment, and subsequently performed a phylogenetic reconstruction.

Researchers compared the omega parameters of each VIP of primates and bats, measured codon substitution rates, and estimated whether the entire gene or codons were evolving under a positive selection. Finally, they uploaded the results of sequence alignment, phylogenetic tree, and gene and site-specific positive selections to the open access web application VirHostNet 2.0.

Investigation result

Overall, there were 81 primates and 38 bat VIPs identified by evidence of positive selection. The authors also found that genes with elevated omega parameters in primates evolved rapidly overall in bats.In addition, pathway enrichment analysis showed that positively selected VIPs were strongly associated with cell cycle regulation, indicating that cell division regulation and centrosome regulatory cell polarization were required by SARS-CoV. rice field In vivo..

Among the positively selected VIPs, 17 VIP-encoded genes, including angiotensin converting enzyme 2 (ACE2), integrin beta 1 (ITGN1), and POLA1, are core SARS-CoV- with indication marks in both mammalian order. Represents 2 VIP. , And primates. This indicates that past SARS-CoV epidemics occurred during the evolution of both bats and primates.

In addition, the authors identified 84 genes that evolved through well-defined strain-specific adaptations, of which 64 VIPs were under positive selection only in primates and 20 were bats. These VIPs containing transmembrane serine protease 2 (TMPRSS2), Receptor Interaction Serin / Threonine Protein Kinase 1 (RIPK1), FYVE and Coiled Coil Domain Autophagy Adapter 1 (FYCO1), Zinc Finger Protein 318 (ZNF318), and prim-pol Primase Complex-in a variety of mammalian hosts CoV pathogenic.

The authors observed that the amino acid (aa) residues involved in the phosphorylation and ubiquitination of inflammatory RIPK1 evolved rapidly in bats rather than primates, demonstrating different inflammatory regulation in bats and humans.In addition, aa residues with a typical viral host arms race mark in primates such as TMPRSS2 and FYCO1 showed significant host specificity. In vivo An interface that can be a drug discovery target.

In particular, FYCO1 received a positive selection in primates, but not in bats, as confirmed by a comprehensive positive selection analysis. The FYCO1 site being indicated in primates is associated with severe coronavirus disease (COVID-19) in 2019, demonstrating their importance in etiology and replication.

Conclusion

This study showed that some host factors are similar and different between bat reservoirs and primate hosts. In vivo Viral host determinants and drug discovery targets. More importantly, this study identified essentially different interactomes in distant SARSs-coronavirus (SARS-CoV) Hosts, bats, and primates caused by the ancient epidemic of pathogenic SARS-CoV. In other words, the core VIP and past CoV epidemics have shaped the universal SARS-CoV-host molecular arms race.

Therefore, SARS-CoV may have evolved different cellular proteins in primates and bats. For example, the recent SARS-CoV-2 Mutant Concern (VOC) Omicron has adapted to enter human hosts via TMPRSS2-dependent and independent pathways, demonstrating intrahost plasticity at these interfaces. increase.

Functional adaptation with SARS-CoV-2 reveals differences in susceptibility to SARS-CoV-2 infection and a major determinant of the severity of COVID-19 in modern humans.

*Important Notices

bioRxiv publishes unpeer-reviewed preliminary scientific reports and should not be considered definitive, guide clinical / health-related behaviors, or be treated as established information.