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

Jeffrey Haltom; Nidia S Trovao; Joseph Guarnieri; Pan Vincent; Urminder Singh; Sergey Tsoy; Collin A O'Leary; Yaron Bram; Gabrielle A Widjaja; Zimu Cen; Robert Meller; Stephen B Baylin; Walter N Moss; Basil J Nikolau; Francisco J Enguita; Douglas C Wallace; Afshin Beheshti; Robert Schwartz; Eve Syrkin Wurtele

doi:10.1101/2023.11.27.23298847

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

medRxiv [Preprint]. 2023 Nov 27:2023.11.27.23298847. doi: 10.1101/2023.11.27.23298847.

Authors

Jeffrey Haltom^{1

2

3}, Nidia S Trovao^{4

3}, Joseph Guarnieri^{2

3}, Pan Vincent⁴, Urminder Singh⁵, Sergey Tsoy⁶, Collin A O'Leary⁷, Yaron Bram⁶, Gabrielle A Widjaja², Zimu Cen², Robert Meller⁸, Stephen B Baylin^{9

10}, Walter N Moss^{5

7}, Basil J Nikolau^{5

7}, Francisco J Enguita¹¹, Douglas C Wallace^{2

12}, Afshin Beheshti^{3

13

14}, Robert Schwartz^{6

15

16}, Eve Syrkin Wurtele^{5

1

3}

Affiliations

¹ Department of Genetics Development and Cell Biology, Iowa State University, Ames, IA 50011, USA.
² Center for Mitochondrial and Epigenomic Medicine, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ COVID-19 International Research Team, Medford, MA 02155, USA.
⁴ Division of International Epidemiology and Population Studies, Fogarty International Center, National Institutes of Health, Bethesda, Maryland, 20892, USA.
⁵ Bioinformatics and Computational Biology Program, and Genetics Program, Iowa State University, Ames, IA 50011, USA.
⁶ Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
⁷ Roy J. Carver Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA.
⁸ Morehouse School of Medicine, Atlanta, GA , 30310-1495, USA.
⁹ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231.
¹⁰ Van Andel Research Institute, Grand Rapids, MI 49503.
¹¹ Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal.
¹² Department of Pediatrics, Division of Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA.
¹³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁴ Blue Marble Space Institute of Science, Seattle, WA, 98104 USA.
¹⁵ Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
¹⁶ Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.

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.

Keywords: COVID-19; Novel gene; ORF10; Orphan gene; Pandemic; RNA-Seq; SARS-CoV-2; Viral diversity; Viral evolution; de novo gene.

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Abstract

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