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Literature detail

Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates.

Joana Damas1 Graham M Hughes2 Kathleen C Keough3,4 Corrie A Painter5 Nicole S Persky6 Marco Corbo1 Michael Hiller7,8,9 Klaus-Peter Koepfli10 Andreas R Pfenning11 Huabin Zhao12,13 Diane P Genereux14 Ross Swofford14 Katherine S Pollard4,15,16 Oliver A Ryder17,18 Martin T Nweeia19,20,21 Kerstin Lindblad-Toh14,22 Emma C Teeling2 Elinor K Karlsson14,23,24 Harris A Lewin25,26,27,28
Affiliations 28 institutions
  1. The Genome Center, University of California, Davis, CA 95616.
  2. School of Biology and Environmental Science, University College Dublin, Belfield, Dublin 4, Ireland.
  3. Graduate Program in Pharmaceutical Sciences and Pharmacogenomics, Quantitative Biosciences Consortium, University of California, San Francisco, CA 94117.
  4. Gladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158.
  5. Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142.
  6. Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142.
  7. Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
  8. Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany.
  9. Center for Systems Biology Dresden, 01307 Dresden, Germany.
  10. Center for Species Survival, Smithsonian Conservation Biology Institute, National Zoological Park, Front Royal, VA 22630.
  11. Department of Computational Biology, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213.
  12. Department of Ecology, Tibetan Centre for Ecology and Conservation at WHU-TU, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, China.
  13. College of Science, Tibet University, Lhasa 850000, China.
  14. Broad Institute of MIT and Harvard, Cambridge, MA 02142.
  15. Department of Epidemiology & Biostatistics, Institute for Computational Health Sciences, and Institute for Human Genetics, University of California, San Francisco, CA 94158.
  16. Chan Zuckerberg Biohub, San Francisco, CA 94158.
  17. San Diego Zoo Institute for Conservation Research, Escondido, CA 92027.
  18. Department of Evolution, Behavior, and Ecology, Division of Biology, University of California San Diego, La Jolla, CA 92093.
  19. Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA 02115.
  20. School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106.
  21. Marine Mammal Program, Department of Vertebrate Zoology, Smithsonian Institution, Washington, DC 20002.
  22. Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 751 23 Uppsala, Sweden.
  23. Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655.
  24. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655.
  25. The Genome Center, University of California, Davis, CA 95616
  26. [email protected].
  27. Department of Evolution and Ecology, University of California, Davis, CA 95616.
  28. John Muir Institute for the Environment, University of California, Davis, CA 95616.
PMID 32826334 2020 Proc Natl Acad Sci U S A eng ppublish
PubMed DOI Browse context

Article

Publication summary

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.

ACE2 comparative genomics COVID-19 SARS-CoV-2 species conservation Amino Acids Animals Betacoronavirus Binding Sites Coronavirus Infections COVID-19 Evolution, Molecular Genetic Variation Host Specificity Humans Pandemics Peptidyl-Dipeptidase A Pneumonia, Viral

Structured evidence records

Evidence records

4 total
Genomic Evolution 2 records
Genomic Evolution Extraction confidence 0.85
Key finding

Comparative sequence and structural analyses revealed signals of selection and accelerated evolution in ACE2 among mammals, particularly in bats, suggesting evolutionary adaptation relevant to SARS-CoV-2 host range.

Virus
SARS-CoV-2
Host
Mammalia
Location
Not specified
Supporting text

We utilized a unique dataset of ACE2 sequences from 410 vertebrate species to study the conservation of ACE2 and performed comparative and structural analyses, finding significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage.

Genes or proteins
ACE2; spike protein
Analysis methods
comparative genomics; protein structural analysis; selection analysis
Genomic Evolution Extraction confidence 0.85
Key finding

ACE2 coding sequence in bats shows accelerated evolution, indicating lineage-specific molecular adaptation relevant to coronavirus receptor usage.

Virus
SARS-CoV-2
Host
Chiroptera
Location
Not specified
Supporting text

We found significant signals of selection and accelerated evolution in the ACE2 coding sequence specific to the bat lineage.

Genes or proteins
ACE2
Analysis methods
comparative genomics; selection analysis
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.80
Key finding

Comparative and structural analyses revealed amino acid conservation and evolutionary selection in ACE2 across mammals, particularly bats, supporting molecular adaptation in the ACE2–spike protein interaction relevant to SARS-CoV-2 host range.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. We found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage.

Genes or proteins
ACE2; spike
Receptors
ACE2
Mechanism types
receptor_binding; host_factor_interaction; molecular_evolution
Receptor Usage 1 records
Receptor Usage Extraction confidence 0.95
Key finding

SARS-CoV-2 was predicted to bind ACE2 from various vertebrates, with mammals—especially catarrhine primates—showing conserved residues supportive of strong spike–ACE2 receptor interaction.

Virus
SARS-CoV-2
Host
Vertebrata
Location
Not specified
Supporting text

We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection.

Method
comparative sequence analysis; protein structural analysis
Receptors
ACE2