SARS-CoV-2 Orphan Gene ORF10 Contributes to More Severe COVID-19 Disease
Haltom, J. A.; Trovao, N. S.; Guarnieri, J.; Vincent, P.; Singh, U.; Tsoy, S.; O'Leary, C. A.; Bram, Y.; Widjaja, G. A.; Cen, Z.; Meller, R.; Baylin, S. B.; Moss, W. N.; Nikolau, B. J.; Enguita, F. J.; Wallace, D. C.; Beheshti, A.; Schwartz, R.; Wurtele, E. S.
Show abstract
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.
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