Ancestral sequence reconstruction analysis indicates the S1/S2 insertion in the SARS-CoV-2 spike gene likely...

Area of Science:

• Virology
• Genomics
• Molecular Biology

Background:

• The SARS-CoV-2 genome features a 12-nucleotide insertion at the S1/S2 junction of the spike protein, creating a furin cleavage site.
• This insertion's precise genomic location is debated, with previous observations suggesting it aligns within a codon.

Purpose of the Study:

• To determine the ancestral S1/S2 junction sequence of SARS-CoV-2.
• To ascertain whether the spike protein insertion occurred within or between codons.

Main Methods:

• Ancestral sequence reconstruction of coronaviruses.
• Comparative genomic analysis of SARS-CoV-2 and related coronaviruses (e.g., RaTG13, BANAL-20-52).

Main Results:

• The most recent common ancestor of SARS-CoV-2 likely shared its S1/S2 junction sequence with related coronaviruses.
• Analysis indicates that mutations enabling a clean, between-codon insertion are improbable within the SARS-CoV-2 lineage.
• The 12-nucleotide insertion most likely interrupted an existing codon.

Conclusions:

• The unique furin cleavage site in SARS-CoV-2 likely arose from an insertion that interrupted a codon.
• This finding provides insight into the evolutionary origins of SARS-CoV-2's spike protein structure.