Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike...

Area of Science:

• Virology
• Genomics
• Molecular Biology

Background:

• The Omicron variant of SARS-CoV-2 possesses 30 non-synonymous nucleotide substitutions in its Spike (S)-gene, with 13 mutations rarely observed in previous strains.
• These mutations are concentrated in three critical functional regions of the S-gene, potentially impacting Spike protein trimerization, ACE2 receptor binding, and membrane fusion.

Approach:

• Analysis of mutation rarity in intrapatient sequencing reads.
• Examination of selection patterns at codon sites across SARS-CoV-2 and related sarbecoviruses.
• Inference of pre-emergence fitness costs and adaptive functional alterations.

Key Points:

• Prior to Omicron's emergence, these 13 mutations were predicted to decrease genomic fitness.
• The mutations likely interact cooperatively to mitigate individual fitness costs and adapt Spike function.
• The rapid spread of Omicron suggests significant adaptive advantages conferred by these S-gene mutations.

Conclusions:

• Understanding the assembly of Omicron's complex S-gene mutations is crucial for predicting future viral evolution.
• The undetected early stages of Omicron's S-gene mutation accumulation highlight gaps in global genomic surveillance.
• Further research is needed to elucidate the mechanisms behind Omicron's adaptive evolution and undetected emergence.