SARS-CoV-2 Orphan Gene ORF10 Contributes to More Severe COVID-19 Disease

The orphan gene of SARS-CoV-2, ORF10, is the least studied gene in the virus responsible for the COVID-19 pandemic. Recent experimentation indicated ORF10 expression moderates innate immunity in vitro. However, whether ORF10 affects COVID-19 in humans remained unknown. We determine that the ORF10 se...

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Published inmedRxiv : the preprint server for health sciences
Main Authors Haltom, Jeffrey, Trovao, Nidia S, Guarnieri, Joseph, Vincent, Pan, Singh, Urminder, Tsoy, Sergey, O'Leary, Collin A, Bram, Yaron, Widjaja, Gabrielle A, Cen, Zimu, Meller, Robert, Baylin, Stephen B, Moss, Walter N, Nikolau, Basil J, Enguita, Francisco J, Wallace, Douglas C, Beheshti, Afshin, Schwartz, Robert, Wurtele, Eve Syrkin
Format Journal Article
LanguageEnglish
Published United States 27.11.2023
Subjects
COVID-19
Novel gene
SARS-CoV-2
RNA-Seq
Viral evolution
Viral diversity
Pandemic
Orphan gene
ORF10
de novo gene
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Summary:The orphan gene of SARS-CoV-2, ORF10, is the least studied gene in the virus responsible for the COVID-19 pandemic. Recent experimentation indicated ORF10 expression moderates innate immunity in vitro. However, whether ORF10 affects COVID-19 in humans remained unknown. We determine that the ORF10 sequence is identical to the Wuhan-Hu-1 ancestral haplotype in 95% of genomes across five variants of concern (VOC). Four ORF10 variants are associated with less virulent clinical outcomes in the human host: three of these affect ORF10 protein structure, one affects ORF10 RNA structural dynamics. RNA-Seq data from 2070 samples from diverse human cells and tissues reveals ORF10 accumulation is conditionally discordant from that of other SARS-CoV-2 transcripts. Expression of ORF10 in A549 and HEK293 cells perturbs immune-related gene expression networks, alters expression of the majority of mitochondrially-encoded genes of oxidative respiration, and leads to large shifts in levels of 14 newly-identified transcripts. We conclude ORF10 contributes to more severe COVID-19 clinical outcomes in the human host.