Long read RNA sequencing reveals subgenomic RNAs as molecular indicators of asymptomatic SARS-CoV-2 infection

In coronaviridae such as SARS-CoV-2, subgenomic RNAs (sgRNA) are replicative intermediates, therefore, their abundance and structures could infer viral replication activity and severity of host infection. Now, researchers from the Jackson Laboratory for Genomic Medicine systematically characterized the sgRNA expression and their structural variation in 81 clinical specimens collected from symptomatic and asymptomatic individuals with a goal of assessing viral genomic signatures of disease severity. The researchers demonstrated the highly coordinated and consistent expression of sgRNAs from individuals with robust infections that results in symptoms, and found their expression is significantly repressed in the asymptomatic infections, indicating that the ratio of sgRNAs to genomic RNA (sgRNA/gRNA) is highly correlated with the severity of the disease. Using long read sequencing technologies to characterize full-length sgRNA structures, they also observed widespread deletions in viral RNAs, and identified unique sets of deletions preferentially found primarily in symptomatic individuals, with many likely to confer changes in SARS-CoV-2 virulence and host responses. Furthermore, based on the sgRNA structures, the frequently occurred structural variants in SARS-CoV-2 genomes serves as a mechanism to further induce SARS-CoV-2 proteome complexity. Taken together, these results show that differential sgRNA expression and structural mutational burden both appear to be correlated with the clinical severity of SARS-CoV-2 infection. Longitudinally monitoring sgRNA expression and structural diversity could further guide treatment responses, testing strategies, and vaccine development.

SARS-CoV-2 transcriptome diversity

a. Proposed models of the origins of SARS-CoV-2 genomic deletions resulted from the lack of accurate replications of viral gRNAs (Right) or transcription of viral sgRNA (Left). b. Assignment of full-length (FL) transcript units (TUs) revealed by long-read Iso-seq into viral sgRNAs (n=1,114), gRNAs (n=4,591) or undefined (n=9,539) based on their spans across Transcription regulatory sequence (TRS) -Leader/-Body (TRS-L/TRSB) junctions. c. The distribution of FL TUs assigned to different sgRNA species based on their corresponding TRS-B sites.

Wong C H et al. (2021) Subgenomic RNAs as molecular indicators of asymptomatic SARS-CoV-2 infection. bioRXiv [online preprint]. [abstract]

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