OmniVira

A selective sweep in the Spike gene has driven SARS-CoV-2 human adaptation.

Lin Kang1,2 Guijuan He3 Amanda K Sharp4 Xiaofeng Wang3 Anne M Brown5,6,7 Pawel Michalak1,8,9 James Weger-Lucarelli10
Affiliations 10 institutions
  1. Edward Via College of Osteopathic Medicine, Monroe, LA 71203, USA
  2. Department of Biomedical Sciences and Pathobiology, VA-MD Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA.
  3. School of Plant and Environmental Sciences, Virginia Tech, Blacksburg, VA 24061, USA.
  4. Program in Genetics, Bioinformatics, and Computational Biology (GBCB), Virginia Tech, Blacksburg, VA 24061, USA.
  5. Program in Genetics, Bioinformatics, and Computational Biology (GBCB), Virginia Tech, Blacksburg, VA 24061, USA
  6. Research and Informatics, University Libraries, Virginia Tech, Blacksburg, VA 24061, USA
  7. Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA.
  8. Center for One Health Research, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA 24060, USA
  9. Institute of Evolution, University of Haifa, Haifa 3498838, Israel. Electronic address: [email protected].
  10. Department of Biomedical Sciences and Pathobiology, VA-MD Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24060, USA. Electronic address: [email protected].
PMID34289344 DOI10.1016/j.cell.2021.07.007 Year2021 Journal Cell Languageeng Statusppublish

Abstract

The coronavirus disease 2019 (COVID-19) pandemic underscores the need to better understand animal-to-human transmission of coronaviruses and adaptive evolution within new hosts. We scanned more than 182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signatures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and increase binding to human ACE2 (hACE2), the cellular receptor. This change is present in all human SARS-CoV-2 sequences but not in closely related viruses from bats and pangolins. As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays. We engineered the reversion mutant (A372T) and found that A372 (wild-type [WT]-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect that was 20 times greater than the well-known D614G mutation. Our findings suggest that this mutation likely contributed to SARS-CoV-2 emergence from animal reservoirs or enabled sustained human-to-human transmission.

Supporting text Virus Host Location
COVID-19 467 emergence 10 molecular virology 1 SARS-CoV-2 550 selective sweep 1 spillover 105 viral adaptation 5 Amino Acid Substitution 81 Angiotensin-Converting Enzyme 2 177 Animals 1948 Cell Line 158 Chiroptera 371 Chlorocebus aethiops 70 COVID-19 425 Disease Reservoirs 149 Evolution, Molecular 176 Genome, Viral 317 Humans 1440 Models, Molecular 99 Mutation 209 Phylogeny 805 SARS-CoV-2 453 Spike Glycoprotein, Coronavirus 274 Vero Cells 55

Evidence records

2 total
Functional Mechanism
1 records · 1 evidence types
Evidence type Molecular Adaptation
1 records
OVE5002 Molecular Adaptation
Key finding

The T372A substitution in the SARS-CoV-2 spike receptor-binding domain removes glycosylation and enhances replication in human lung cells, indicating molecular adaptation to human infection.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

We engineered the reversion mutant (A372T) and found that A372 (wild-type [WT]-SARS-CoV-2) enhanced replication in human lung cells relative to its putative ancestral variant (T372), an effect that was 20 times greater than the well-known D614G mutation.

Genes or proteins
spike protein | receptor-binding domain
Receptors
human ACE2
Mutations
T372A
Mechanism types
receptor binding | replication adaptation | host-range expansion
Genomic Evolution
1 records · 1 evidence types
Evidence type Phylogenetic Evolution
1 records
OVE5000 Phylogenetic Evolution
Key finding

Genome-wide scan of over 182,000 SARS-CoV-2 genomes revealed a selective sweep and positive selection around spike mutation A1114G (T372A), associated with adaptation to humans.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
human Homo sapiens Natural host
Location
Not specified
Supporting text

We scanned more than 182,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes for selective sweep signatures and found a distinct footprint of positive selection located around a non-synonymous change (A1114G; T372A) within the spike protein receptor-binding domain (RBD), predicted to remove glycosylation and increase binding to human ACE2 (hACE2), the cellular receptor.

Genes or proteins
spike protein | receptor-binding domain (RBD)
Analysis methods
selective sweep analysis | genome-wide scan for positive selection