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Literature detail

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].
PMID 34289344 2021 Cell eng ppublish
PubMed DOI Browse context

Article

Publication summary

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.

COVID-19 emergence molecular virology SARS-CoV-2 selective sweep spillover viral adaptation Amino Acid Substitution Angiotensin-Converting Enzyme 2 Animals Cell Line Chiroptera Chlorocebus aethiops COVID-19 Disease Reservoirs Evolution, Molecular Genome, Viral Humans

Structured evidence records

Evidence records

3 total
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.95
Key finding

Selective sweep in the SARS-CoV-2 spike gene identified through comparative genomic analysis shows a fixation of the T372A mutation in human viruses but absence in bat and pangolin coronaviruses, indicating human-specific adaptation.

Virus
SARS-CoV-2
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). This change is present in all human SARS-CoV-2 sequences but not in closely related viruses from bats and pangolins.

Genes or proteins
spike; receptor-binding domain
Analysis methods
genome scan; comparative genomic analysis; positive selection analysis
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.98
Key finding

The SARS-CoV-2 spike mutation T372A enhances ACE2 binding and replication in human lung cells, indicating molecular adaptation to human hosts.

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

We scanned more than 182,000 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). As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays and enhanced replication in human lung cells relative to its putative ancestral variant (T372).

Genes or proteins
spike; receptor-binding domain
Receptors
ACE2
Mutations
A1114G; T372A
Mechanism types
receptor_binding; replication_efficiency; molecular_adaptation
Receptor Usage 1 records
Receptor Usage Extraction confidence 0.90
Key finding

The T372A substitution in the SARS-CoV-2 spike RBD enhances binding affinity to the human ACE2 receptor.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

We 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. As predicted, T372A RBD bound hACE2 with higher affinity in experimental binding assays.

Method
binding assay
Receptors
ACE2