SARS-CoV-2-Encoded Proteome and Human Genetics: From Interaction-Based to Ribosomal Biology Impact on Disease and Risk Processes

Abstract

SARS-CoV-2 (COVID-19) has infected millions of people worldwide, with lethality in hundreds of thousands. The rapid publication of information, both regarding the clinical course and the viral biology, has yielded incredible knowledge of the virus. In this review, we address the insights gained for the SARS-CoV-2 proteome, which we have integrated into the Viral Integrated Structural Evolution Dynamic Database, a publicly available resource. Integrating evolutionary, structural, and interaction data with human proteins, we present how the SARS-CoV-2 proteome interacts with human disorders and risk factors ranging from cytokine storm, hyperferritinemic septic, coagulopathic, cardiac, immune, and rare disease-based genetics. The most noteworthy human genetic potential of SARS-CoV-2 is that of the nucleocapsid protein, where it is known to contribute to the inhibition of the biological process known as nonsense-mediated decay. This inhibition has the potential to not only regulate about 10% of all biological transcripts through altered ribosomal biology but also associate with viral-induced genetics, where suppressed human variants are activated to drive dominant, negative outcomes within cells. As we understand more of the dynamic and complex biological pathways that the proteome of SARS-CoV-2 utilizes for entry into cells, for replication, and for release from human cells, we can understand more risk factors for severe/lethal outcomes in patients and novel pharmaceutical interventions that may mitigate future pandemics.

Functional and tissue enrichment analyses suggest that SARS-CoV-2 infection affects host metabolism and catabolism mediated by interference on host proteins

“…Viruses can manipulate and regulate many steps in gene expression: transcription, mRNA processing, mRNA export from the nucleus, regulation of mRNA stability, and translation [ 35 ]. SARS-CoV-2 N protein interacts with UPF1 and PABPC1 proteins interfering with host cellular processes of mRNA degradation [ 36 ]. Both host proteins interfered by SARS-CoV-2 are associated with transcriptional processes shown in enrichment analysis results (supplementary table 2 ).…”

CCR5 and Biological Complexity: The Need for Data Integration and Educational Materials to Address Genetic/Biological Reductionism at the Interface of Ethical, Legal, and Social Implications

“…We have expanded these tools to clinical variants from the HudsonAlpha genomic sequencing projects to help explain complex Variants of Uncertain Significance (VUS), including MED13 ( 131 ) and RALA ( 132 ) that can be found at prokoplab.com/educational-resources/. At the outbreak of the SARS-CoV-2 pandemic, we also used this same workflow to establish critical and rapid insights on the viral encoded proteins and their interactions with host proteins utilizing CODE as a distributed research network to gain faster insights of proteins ( 133 , 134 ). Expanding these tools to additional projects and collaboration will open a door for educational information in the needed area of genomics and genomic medicine.…”

Multi-ancestry omic Mendelian randomization revealing putative drug targets of COVID-19 severity

“…PLOD2, located on chromosome 3, is found in the endoplasmic reticulum and functions to catalyse the hydroxylation of lysyl residues in collagenlike peptides. Its protein, PLOD2, was revealed to interact with the SARS-CoV-2 protein open reading frame 8 (ORF8) (62), which was identified as containing the most pathogenic variants of all coronavirus proteins (63). Another gene (SRP72) located on chromosome 4, is the only subunit of the signal recognition particle (SRP) that can be phosphorylated.…”