Alternative Transcription of Protein Coding Genes underlie COVID-19 Disease Severity

Like single-stranded RNA viruses, SARS-CoOV-2 hijacks the host transcriptional machinery for its own replication. Numerous traditional differential gene expression-based investigations have examined the diverse clinical symptoms caused by SARS-CoV-2. However, the virus also alters the host splicing machinery, causing transcriptional dysregulation which can lead to diverse clinical outcomes. In this study, we performed transcriptome sequencing of 125 hospital admitted COVID-19 patients to understand the different severity sub-phenotypes (Mild, Moderate, Severe and Mortality). Our differential transcript expression (DTE) analysis showed evidence of diminished transcriptional diversity as well as altered promoter site usage pattern in differentially expressed protein coding transcripts in COVID-19 mortality patients. We also looked at the possible mechanisms driving the alternate splicing and discovered a differential enrichment of repeats in the promoter region and splice sites of differentially expressed transcripts. These findings suggested a repeat-mediated plausible regulation of alternative splicing and potential modulation of COVID-19 disease severity.