OmniVira

The evolutionary history of ACE2 usage within the coronavirus subgenus Sarbecovirus.

H L Wells1 M Letko2,3 G Lasso4 B Ssebide5 J Nziza5 D K Byarugaba6,7 I Navarrete-Macias8 E Liang8 M Cranfield9,10 B A Han11 M W Tingley12 M Diuk-Wasser1 T Goldstein9 C K Johnson9 J A K Mazet9 K Chandran4 V J Munster3 K Gilardi6,9 S J Anthony13
Affiliations 13 institutions
  1. Department of Ecology, Evolution, and Environmental Biology, Columbia University, 1200 Amsterdam Ave, New York, NY 10027, USA.
  2. Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 S. 4th St, Hamilton, MT 59840, USA.
  3. Paul G. Allen School for Global Animal Health, Washington State University, 1155 College Ave, Pullman, WA 99164, USA.
  4. Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10462, USA.
  5. Gorilla Doctors, c/o MGVP, Inc., 1089 Veterinary Medicine Drive, Davis, CA 95616, USA.
  6. Makerere University Walter Reed Project, Plot 42, Nakasero Road, Kampala, Uganda.
  7. Makerere University, College of Veterinary Medicine, Living Stone Road, Kampala, Uganda.
  8. Center for Infection and Immunity, Mailman School of Public Health, Columbia University, 722 W 168th St, New York, NY 10032, USA.
  9. One Health Institute and Karen C. Drayer Wildlife Health Center, School of Veterinary Medicine, University of California Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA.
  10. Department of Microbiology and Immunology, University of North Carolina School of Medicine, 125 Mason Farm Road, Chapel Hill, NC 27599, USA.
  11. Cary Institute of Ecosystem Studies, 2801 Sharon Turnpike, Millbrook, NY 12545, USA.
  12. Department of Ecology and Evolutionary Biology, University of California Los Angeles, 612 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
  13. Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, One Shields Avenue, Davis, CA 95616, USA.
PMID33754082 DOI10.1093/ve/veab007 Year2021 Journal Virus evolution Virus Evol Languageeng Statusepublish

Abstract

Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and SARS-CoV-2 are not phylogenetically closely related; however, both use the angiotensin-converting enzyme 2 (ACE2) receptor in humans for cell entry. This is not a universal sarbecovirus trait; for example, many known sarbecoviruses related to SARS-CoV-1 have two deletions in the receptor binding domain of the spike protein that render them incapable of using human ACE2. Here, we report three sequences of a novel sarbecovirus from Rwanda and Uganda that are phylogenetically intermediate to SARS-CoV-1 and SARS-CoV-2 and demonstrate via in vitro studies that they are also unable to utilize human ACE2. Furthermore, we show that the observed pattern of ACE2 usage among sarbecoviruses is best explained by recombination not of SARS-CoV-2, but of SARS-CoV-1 and its relatives. We show that the lineage that includes SARS-CoV-2 is most likely the ancestral ACE2-using lineage, and that recombination with at least one virus from this group conferred ACE2 usage to the lineage including SARS-CoV-1 at some time in the past. We argue that alternative scenarios such as convergent evolution are much less parsimonious; we show that biogeography and patterns of host tropism support the plausibility of a recombination scenario, and we propose a competitive release hypothesis to explain how this recombination event could have occurred and why it is evolutionarily advantageous. The findings provide important insights into the natural history of ACE2 usage for both SARS-CoV-1 and SARS-CoV-2 and a greater understanding of the evolutionary mechanisms that shape zoonotic potential of coronaviruses. This study also underscores the need for increased surveillance for sarbecoviruses in southwestern China, where most ACE2-using viruses have been found to date, as well as other regions such as Africa, where these viruses have only recently been discovered.

Supporting text Virus Host Location
coronavirus 195 recombination 40 viral ecology 4 virus evolution 21

Evidence records

2 total
Genomic Evolution
2 records · 2 evidence types
Evidence type Recombination or Reassortment
1 records
OVE4643 Recombination or Reassortment
Key finding

Recombination between SARS-CoV-1 and its relatives from the ACE2‑using lineage of sarbecoviruses best explains the acquisition of ACE2‑binding capability in the SARS-CoV-1 lineage.

Virus
Severe Acute Respiratory Syndrome Coronavirus Severe acute respiratory syndrome coronavirus 2 SARS-related coronavirus
Host
Not specified
Location
Not specified
Supporting text

We show that the observed pattern of ACE2 usage among sarbecoviruses is best explained by recombination not of SARS-CoV-2, but of SARS-CoV-1 and its relatives. The lineage that includes SARS-CoV-2 is most likely the ancestral ACE2-using lineage, and recombination with at least one virus from this group conferred ACE2 usage to the lineage including SARS-CoV-1.

Event type
recombination
Genes or segments
spike gene | receptor-binding domain
Evidence type Phylogenetic Evolution
1 records
OVE4644 Phylogenetic Evolution
Key finding

Phylogenetic analysis indicates that the lineage including SARS‑CoV‑2 is the ancestral ACE2‑using sarbecovirus lineage, whereas ACE2 usage in the SARS‑CoV‑1 lineage was acquired later through recombination.

Virus
Severe acute respiratory syndrome coronavirus 2 Severe Acute Respiratory Syndrome Coronavirus
Host
Not specified
Location
Not specified
Supporting text

We show that the lineage that includes SARS‑CoV‑2 is most likely the ancestral ACE2‑using lineage, and that recombination with at least one virus from this group conferred ACE2 usage to the lineage including SARS‑CoV‑1 at some time in the past.

Genes or proteins
spike protein | receptor binding domain
Analysis methods
phylogenetic analysis | comparative genomic analysis