Mary Wilson
Well-known member
Posted: 26 Sep 2024
https://ssrn.com/abstract=4965918 or http://dx.doi.org/10.2139/ssrn.4965918
Haltom, Jeffrey Allen and Trovão, Nídia Sequeira and Guarnieri, Joseph W. and Pan, Vincent and Singh, Urminder and Tsoy, Sergey and O'Leary, Collin A. and Bram, Yaron and Widjaja, Gabrielle A. and Cen, Zimu and Meller, Robert and Baylin, Stephen and Moss, Walter N. and Nikolau, Basil J. and Enguita, Francisco J. and Wallace, Douglas C. and Beheshti, Afshin and Schwartz, Robert E. and Wurtele, Eve
Abstract
SARS-CoV-2 ORF10 encodes a unique orphan protein, the function of which is both unclear and understudied. Recent experimentation indicates that ORF10 expression moderates innate immunity \textit{in vitro}. However, whether ORF10 affects COVID-19 in humans had remained unknown. Here, we assess millions of sequences from the Global Initiative on Sharing All Influenza Data (GSAID) and determine that, across the entire pandemic, 95\% of the ORF10 nucleotide sequences are identical to the Wuhan-Hu-1 (WT) ancestral haplotype. In each of the five SARS-CoV-2 variants of concern (VOC), fewer than 5\% of ORF10 sequences bear even a single mutation. Despite the low statistical power due to the sparsity of mutated sequences, we were able to identify four ORF10 mutations that are associated with less virulent clinical outcomes in humans than the WT in COVID-19 patients: three affect ORF10 protein structure, one affects ORF10 RNA structural dynamics. No mutations were associated with more severe outcomes. Data from diverse cell and tissue samples reveals that ORF10 transcript accumulation is conditionally discordant from other SARS-CoV2 transcripts. Expression of ORF10 in A549 and 293T human cells massively decreases expression of genes of oxidative respiration (OXPHOS), impedes immune-related gene expression networks, and leads to large shifts in levels of 14 newly-identified transcripts. We propose that ORF10 contributes to more severe clinical outcomes in humans, a finding with critical implications for the development of therapeutics and other mitigation strategies. These results highlight the importance of assessing the role of orphan genes in emerging viral threats.
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4965918
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Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com.
https://ssrn.com/abstract=4965918 or http://dx.doi.org/10.2139/ssrn.4965918
Haltom, Jeffrey Allen and Trovão, Nídia Sequeira and Guarnieri, Joseph W. and Pan, Vincent and Singh, Urminder and Tsoy, Sergey and O'Leary, Collin A. and Bram, Yaron and Widjaja, Gabrielle A. and Cen, Zimu and Meller, Robert and Baylin, Stephen and Moss, Walter N. and Nikolau, Basil J. and Enguita, Francisco J. and Wallace, Douglas C. and Beheshti, Afshin and Schwartz, Robert E. and Wurtele, Eve
Abstract
SARS-CoV-2 ORF10 encodes a unique orphan protein, the function of which is both unclear and understudied. Recent experimentation indicates that ORF10 expression moderates innate immunity \textit{in vitro}. However, whether ORF10 affects COVID-19 in humans had remained unknown. Here, we assess millions of sequences from the Global Initiative on Sharing All Influenza Data (GSAID) and determine that, across the entire pandemic, 95\% of the ORF10 nucleotide sequences are identical to the Wuhan-Hu-1 (WT) ancestral haplotype. In each of the five SARS-CoV-2 variants of concern (VOC), fewer than 5\% of ORF10 sequences bear even a single mutation. Despite the low statistical power due to the sparsity of mutated sequences, we were able to identify four ORF10 mutations that are associated with less virulent clinical outcomes in humans than the WT in COVID-19 patients: three affect ORF10 protein structure, one affects ORF10 RNA structural dynamics. No mutations were associated with more severe outcomes. Data from diverse cell and tissue samples reveals that ORF10 transcript accumulation is conditionally discordant from other SARS-CoV2 transcripts. Expression of ORF10 in A549 and 293T human cells massively decreases expression of genes of oxidative respiration (OXPHOS), impedes immune-related gene expression networks, and leads to large shifts in levels of 14 newly-identified transcripts. We propose that ORF10 contributes to more severe clinical outcomes in humans, a finding with critical implications for the development of therapeutics and other mitigation strategies. These results highlight the importance of assessing the role of orphan genes in emerging viral threats.
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4965918
__________________________________________________ _____________________________
Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com.