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Mutational analysis of SARS-CoV-2 ORF8 during six months of COVID-19 pandemic.

ABSTRACT: SARS-CoV-2, the causal agent of COVID 19, is a new human pathogen that appeared in Wuhan, late December 2019. SARS-CoV-2 is a positive sense RNA virus, having four structural and six accessory proteins including that encoded by ORF8 gene known to be one of the most hypervariable and rapidly evolving genes. Thus, global characterization of mutations in this gene is important for pathogenicity and diagnostics. 240 different nonsynonymous mutations and 2 deletions were identified in 45,400 ORF8 nucleotide sequences during six months pandemic with about half of these variants were deleterious for ORF8, and the quarter of them were located in conserved amino acids. Genetic diversity analysis showed two main regions that harbor L84S and S24L. L84S is by far the most predominant mutation, followed by S24L that appeared first in USA. Phylogenetic analysis of ORF8 variants revealed the appearance of small clades with that of L84S being closer to bats. This is the first study that revealed the global nonsynonymous mutations in ORF8 from January to June 2020.

SUBMITTER: Alkhansa A

PROVIDER: S-EPMC7813478 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Mutational analysis of SARS-CoV-2 <i>ORF8</i> during six months of COVID-19 pandemic.

Alkhansa Ahmad A Lakkis Ghayas G El Zein Loubna L

Gene reports 20210117

SARS-CoV-2, the causal agent of COVID 19, is a new human pathogen that appeared in Wuhan, late December 2019. SARS-CoV-2 is a positive sense RNA virus, having four structural and six accessory proteins including that encoded by <i>ORF8</i> gene known to be one of the most hypervariable and rapidly evolving genes. Thus, global characterization of mutations in this gene is important for pathogenicity and diagnostics. 240 different nonsynonymous mutations and 2 deletions were identified in 45,400 < ...[more]

PMID: 33490718

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Project description:SARS-CoV-2 virus and its variants have proven to be a threat to global health, in part due to their capacity for rapid evolution. SARS-CoV-2 variants that emerged throughout the COVID-19 pandemic exhibited variations in virulence, leading to diminished vaccine protection and modulating disease severity. Research efforts have identified the molecular changes resulting from structural protein variants of SARS-CoV-2, particularly in Spike, that have enhanced infectivity. Yet, investigating variants of nonstructural proteins is equally critical to understand viral evolution and their role in manipulating protein-protein interactions within a host. This study focuses on nonstructural protein 3 (nsp3), a viral papain-like protease (PLpro) critical for viral polyprotein cleavage, which is also implicated in host de-ubiquitylation, ISGylation, and formation of double-membrane vesicles. Using affinity-purification mass spectrometry (AP-MS), we identify differential protein interactions caused by mutations in nsp3. Included are variants identified between 2019-2024: Alpha 20I, Beta20H, Delta21I, Delta21J, Gamma20J, Kappa21B, Lambda21G, Omicron21K, Omicron21L. A small set of amino acid substitutions in the cytosolic fragment and N-terminal region of nsp3 (nsp3.1) could be traced to increased interactions with RNA binding proteins, which are vital in viral replication. Nsp3.1 variants from Omicron 21K and 21L exhibit distinct patterns of host interactor enrichment, setting them apart from five other variants. In contrast, variants of the central region of nsp3 (nsp3.2) containing the PL2pro domain were found to share interactions with protein quality control machinery, including ER-associated degradation (ERAD). In this construct, shared trends in interactor enrichment are observed between Omicron21K and Delta21I, distinguishing them from three other variants. Our study highlights that even a small number of amino acid substitutions can significantly alter the interaction partners. Our study provides a roadmap to track the interaction changes driven by SARS-CoV-2 variant evolution, which is essential for elucidating the ongoing evolutionary arms race between the host and virus.

Dataset Information

Mutational analysis of SARS-CoV-2 ORF8 during six months of COVID-19 pandemic.

Publications

Mutational analysis of SARS-CoV-2 <i>ORF8</i> during six months of COVID-19 pandemic.

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