A previously uncharacterized gene in SARS-CoV-2 illuminates the functional dynamics and evolutionary origins of the COVID-19 pandemic

A previously uncharacterized gene in SARS-CoV-2 illuminates the functional dynamics and evolutionary origins of the COVID-19 pandemic

Understanding and preventing the emergence of novel viruses requires an accurate and
comprehensive understanding of their genomes. One under-investigated class of functional
genomic elements is overlapping genes (OLGs), which allow a single stretch of nucleotides
to encode two distinct proteins in different reading frames. Viral OLGs are common and have
been associated with the origins of pandemics, but are still widely overlooked. We
investigate de novo OLG candidates in SARS-CoV-2 and identify a new gene here named
ORF3c. ORF3c has been documented elsewhere but is unnamed, unannotated, or conflated
with ORF3b of other SARS-related betacoronaviruses (sarbecoviruses). In fact, ORF3c is
not homologous to ORF3b, as the two genes occupy different genomic positions and reading
frames. We find that ORF3c exhibits clear evidence of translation from ribosome profiling
and important immunological properties. We then conduct an evolutionary analysis of
ORF3c at three levels: between-species, between-host, and within-host. Specifically, 21
representative sarbecovirus genomes show ORF3c is also present in some pangolin-CoVs
but not more closely related bat-CoVs; 3,978 SARS-CoV-2 genomes reveal ORF3c gained a
new stop codon (G25563U) that rose drastically in frequency during the current COVID-19
pandemic; and 401 deeply sequenced samples of SARS-CoV-2 demonstrate the recurrence
of this mutation in multiple hosts. Surprisingly, the newly gained ORF3c stop codon
hitchhiked early with haplotype 241U/3037U/14408U/23403G (Spike-D614G), which
appears to drive the European pandemic spread. Our results liken ORF3c to other important
viral accessory genes recombined, lost, split, or truncated before or during outbreaks,
including ORF3b and ORF8 in sarbecoviruses. OLGs deserve considerably more attention,
as their rapid evolution may be more important than is currently appreciated in the
emergence of zoonotic viruses.

A new article by our own @Zachary_Ardern worth discussing. Congrats on getting is paper out. Looking forward to learning what you found.

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