Bioinformatic Analysis of Defective Viral Genomes in SARS-CoV-2 and Its Impact on Population Infection Characteristics

Abstract

AbstractDVGs (Defective Viral Genomes) and SIP (Semi-Infectious Particle) are commonly present in RNA virus infections. In this study, we analyzed high-throughput sequencing data and found that DVGs or SIPs are also widely present in SARS-CoV-2. Comparison of SARS-CoV-2 with various DNA viruses revealed that the SARS-CoV-2 genome is more susceptible to damage and has greater sequencing sample heterogeneity. Variability analysis at the whole-genome sequencing depth showed a higher coefficient of variation for SARS-CoV-2, and DVG analysis indicated a high proportion of splicing sites, suggesting significant genome heterogeneity and implying that most virus particles assembled are enveloped with incomplete RNA sequences. We further analyzed the characteristics of different strains in terms of sequencing depth and DVG content differences and found that as the virus evolves, the proportion of intact genomes in virus particles increases, which can be significantly reflected in third-generation sequencing data, while the proportion of DVG gradually decreases. Specifically, the proportion of intact genome of Omicron was greater than that of Delta and Alpha strains. This can well explain why Omicron strain is more infectious than Delta and Alpha strains. We also speculate that this improvement in completeness is due to the enhancement of virus assembly ability, as the Omicron strain can quickly realize the binding of RNA and capsid protein, thereby shortening the exposure time of exposed virus RNA in the host environment and greatly reducing its degradation level. Finally, by using mathematical modeling, we simulated how DVG effects under different environmental factors affect the infection characteristics and evolution of the population. We can explain well why the severity of symptoms is closely related to the amount of virus invasion and why the same strain causes huge differences in population infection characteristics under different environmental conditions. Our study provides a new approach for future virus research and vaccine development.