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Genetic regulation of OAS1 nonsense-mediated decay underlies association with risk of severe COVID-19.

ABSTRACT: Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 OAS1 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of OAS1 . We suggest that genetically-regulated loss of OAS1 expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the OAS1 risk haplotypes.

SUBMITTER: Banday AR

PROVIDER: S-EPMC8288155 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Genetic regulation of <i>OAS1</i> nonsense-mediated decay underlies association with risk of severe COVID-19.

Banday A Rouf AR Stanifer Megan L ML Florez-Vargas Oscar O Onabajo Olusegun O OO Zahoor Muhammad A MA Papenberg Brenen W BW Ring Timothy J TJ Lee Chia-Han CH Andreakos Evangelos E Arons Evgeny E Barsh Greg G Biesecker Leslie G LG Boyle David L DL Burnett-Hartman Andrea A Carrington Mary M Chang Euijin E Choe Pyoeng Gyun PG Chrisholm Rex L RL Dalgard Clifton C Edberg Jeff J Erdmann Nathan N Feigelson Heather S HS Firestein Gary S GS Gehring Adam J AJ Ho Michelle M Holland Steven S Hutchinson Amy A AA Im Hogune H Ison Michael G MG Kim Hong Bin HB Kreitman Robert J RJ Korf Bruce R BR Mirabello Lisa L Pacheco Jennifer A JA Peluso Michael J MJ Rader Daniel J DJ Redden David T DT Ritchie Marylyn D MD Rosenbloom Brooke B Sant Anna Hanaisa P HP Savage Sharon S Siouti Eleni E Triantafyllia Vasiliki V Vargas Joselin M JM Verma Anurag A Vij Vibha V Wesemann Duane R DR Yeager Meredith M Yu Xu X Zhang Yu Y Boulant Steeve S Chanock Stephen J SJ Feld Jordan J JJ Prokunina-Olsson Ludmila L

medRxiv : the preprint server for health sciences 20210713

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 <i>OAS1</i> variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The ...[more]

PMID: 34282422

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Project description:Nonsense-mediated decay (NMD) is a host RNA control pathway that removes aberrant transcripts with long 3' untranslated regions (UTRs) due to premature termination codons (PTCs) that arise through mutation or defective splicing. To maximize coding potential, RNA viruses often contain internally located stop codons that should also be prime targets for NMD. Using an agroinfiltration-based NMD assay in Nicotiana benthamiana, we identified two segments conferring NMD-resistance in the carmovirus Turnip crinkle virus (TCV) genome. The ribosome readthrough structure just downstream of the TCV p28 termination codon stabilized an NMD-sensitive reporter as did a frameshifting element from umbravirus Pea enation mosaic virus. In addition, a 51-nt unstructured region (USR) at the beginning of the TCV 3' UTR increased NMD-resistance 3-fold when inserted into an unrelated NMD-sensitive 3' UTR. Several additional carmovirus 3' UTRs also conferred varying levels of NMD resistance depending on the construct despite no sequence similarity in the analogous region. Instead, these regions displayed a marked lack of RNA structure immediately following the NMD-targeted stop codon. NMD-resistance was only slightly reduced by conversion of 19 pyrimidines in the USR to purines, but resistance was abolished when a 2-nt mutation was introduced downstream of the USR that substantially increased the secondary structure in the USR through formation of a stable hairpin. The same 2-nt mutation also enhanced the NMD susceptibility of a subgenomic RNA expressed independently of the genomic RNA. The conserved lack of RNA structure among most carmoviruses at the 5' end of their 3' UTR could serve to enhance subgenomic RNA stability, which would increase expression of the encoded capsid protein that also functions as the RNA silencing suppressor. These results demonstrate that the TCV genome has features that are inherently NMD-resistant and these strategies could be widespread among RNA viruses and NMD-resistant host mRNAs with long 3' UTRs.

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Genetic regulation of OAS1 nonsense-mediated decay underlies association with risk of severe COVID-19.

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Genetic regulation of <i>OAS1</i> nonsense-mediated decay underlies association with risk of severe COVID-19.

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Genetic regulation of OAS1 nonsense-mediated decay underlies association with risk of severe COVID-19.

Publications

Genetic regulation of &lt;i&gt;OAS1&lt;/i&gt; nonsense-mediated decay underlies association with risk of severe COVID-19.

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OmicsDI is part of the ELIXIR infrastructure

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Genetic regulation of <i>OAS1</i> nonsense-mediated decay underlies association with risk of severe COVID-19.