Researchers Link Orphan Gene in SARS-CoV-2 Virus to More Severe Cases of COVID-19

The international research findings could contribute to better therapies as well as more information to plan for future pandemics

AMES, Iowa and NEW YORK and PHILADELPHIA, Oct. 21, 2025 /PRNewswire/ -- An international team of researchers led by scientists at Iowa State University, Weill Cornell Medicine and Children's Hospital of Philadelphia (CHOP) has found that an orphan gene in the SARS-CoV-2 virus is responsible for exacerbating COVID-19 severity. The findings not only present a potential target for future therapeutic interventions for COVID-19 but also underscore the importance of orphan genes in viral evolution and how that information may inform the study of future pandemics. The findings were recently published in the journal Molecular Biology and Evolution.

Orphan genes are only found in a specific species or group of closely related species and are rarely studied in detail. Prior studies have identified orphan gene, ORF10, in SARS-CoV-2, the virus responsible for COVID-19. However, the role ORF10 played in COVID-19 outcomes in humans remained unknown.

As part of the work being done by the COVID-19 International Research Team (COV-IRT), this study combined lab experiments, analysis of thousands of patient samples, and genetic data from millions of SARS-CoV-2 sequences. Together, these efforts revealed how ORF10 has evolved, how it affects mitochondria and the immune system, how it is turned on in different tissues and cell types, and that patients with certain ORF10 structure altering mutations tended to have milder cases of COVID-19.

"While many orphan genes remain understudied, we know that thousands of orphan genes have contributed to more dangerous and deadly organisms and viruses," said first study author Jeffrey Haltom, PhD, a bioinformatic scientist with the Center for Mitochondrial and Epigenomic Medicine at CHOP who began this research at Iowa State University. "Since we are beginning to learn more about the evolution of viruses via their orphan genes, we wanted to apply that line of questioning to SARS-CoV-2 to determine whether its orphan gene could provide us with clues about what makes the virus so dangerous to humans."

The study found that millions of ORF10 sequences of SARS-CoV-2, from the Alpha to Omicron variants of concern (VOC), are identical to their ancestral Wuhan-Hu-1 haplotype, the strain of the virus that was first identified in Wuhan, China in 2019. When studying the VOC – the variants of SARS-CoV-2 that were responsible for more infections, hospitalizations and deaths – the researchers found that less than 5% of genomes carried any mutations of the ORF10 orphan gene, meaning that the gene was mostly preserved as the virus evolved and continued to infect humans. In fact, four ORF10 mutations were associated with less severe clinical outcomes in COVID-19 patients, and no mutations were linked to increased severity.

Researchers also found that ORF10 transcript levels can differ from other SARS-CoV-2 genes depending on the tissue, and was linked to disruptions of gene expression related to oxidative phosphorylation (OXPHOS) – the key process by which mitochondria generate cellular energy – as well as immune network disruptions. Additionally, fully functional ORF10 is present in multiple SARS-CoV strains but absent from less severe SARS-CoV-1-like strains, suggesting a stronger connection to more severe strains of the virus.

This study was supported by the National Science Foundation award IOS 1546858, National Institutes of Health grants NIAID 2R01AI107301, NIDDK R01DK121072, R01GM133810 the American Heart Association, the Irma Hirschl Trust Research Award Scholar, Department of Defense grant W81XWH-21-1-0128, the Gates Foundation Grant INV-046722, and Extreme Science and Engineering Discovery Environment (XSEDE) supported by National Science Foundation ACI-1548562, through Bridges HPC environment TG-MCB190098 and TG-MCB200123.

Haltom et al, "Importance of de novo gene evolution to emerging viral threats: the ORF10 strain-restricted orphan gene of SARS-CoV-2 promotes pathogenesis." Mol Biol Evol. Online October 1, 2025. DOI: 10.1093/molbev/msaf211.

About Children's Hospital of Philadelphia: 
A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.

Contact: Ben Leach
Children's Hospital of Philadelphia
609-634-7906
leachb@chop.edu

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