Comparative Genomics and Integrated Network Approach Unveiled Undirected Phylogeny Patterns, Co-mutational Hot Spots, Functional Cross Talk, and Regulatory Interactions in SARS-CoV-2

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in 92 million cases in a span of 1 year. The study focuses on understanding population-specific variations attributing its high rate of infections in specific geographical regions particularly in the United States. Rigorous phylogenomic network analysis of complete SARS-CoV-2 genomes (245) inferred five central clades named a (ancestral), b, c, d, and e (subtypes e1 and e2). Clade d and subclade e2 were found exclusively comprised of U.S. strains. Clades were distinguished by 10 co-mutational combinations in Nsp3, ORF8, Nsp13, S, Nsp12, Nsp2, and Nsp6. Our analysis revealed that only 67.46% of single nucleotide polymorphism (SNP) mutations were at the amino acid level. T1103P mutation in Nsp3 was predicted to increase protein stability in 238 strains except for 6 strains which were marked as ancestral type, whereas co-mutation (P409L and Y446C) in Nsp13 were found in 64 genomes from the United States highlighting its 100% co-occurrence. Docking highlighted mutation (D614G) caused reduction in binding of spike proteins with angiotensin-converting enzyme 2 (ACE2), but it also showed better interaction with the TMPRSS2 receptor contributing to high transmissibility among U.S. strains. We also found host proteins, MYO5A, MYO5B, and MYO5C, that had maximum interaction with viral proteins (nucleocapsid [N], spike [S], and membrane [M] proteins). Thus, blocking the internalization pathway by inhibiting MYO5 proteins which could be an effective target for coronavirus disease 2019 (COVID-19) treatment. The functional annotations of the host-pathogen interaction (HPI) network were found to be closely associated with hypoxia and thrombotic conditions, confirming the vulnerability and severity of infection. We also screened CpG islands in Nsp1 and N conferring the ability of SARS-CoV-2 to enter and trigger zinc antiviral protein (ZAP) activity inside the host cell. IMPORTANCE In the current study, we presented a global view of mutational pattern observed in SARS-CoV-2 virus transmission. This provided a who-infect-whom geographical model since the early pandemic. This is hitherto the most comprehensive comparative genomics analysis of full-length genomes for co-mutations at different geographical regions especially in U.S. strains. Compositional structural biology results suggested that mutations have a balance of opposing forces affecting pathogenicity suggesting that only a few mutations are effective at the translation level. Novel HPI analysis and CpG predictions elucidate the proof of concept of hypoxia and thrombotic conditions in several patients. Thus, the current study focuses the understanding of population-specific variations attributing a high rate of SARS-CoV-2 infections in specific geographical regions which may eventually be vital for the most severely affected countries and regions for sharp development of custom-made vindication strategies.

Conserved molecular signatures in the spike protein provide evidence indicating the origin of SARS-CoV-2 and a Pangolin-CoV (MP789) by recombination(s) between specific lineages of Sarbecoviruses

“…Most of the studies on understanding the origin of SARS-CoV-2 and evolutionary relationships among coronaviruses/sarbecoviruses are based on phylogenetic tree constructions and sequence similarity determination for different genes/proteins from these viruses ( Li et al, 2020 ; Liu et al, 2020 ; Lu et al, 2020 ; Zhou et al, 2020b ). In addition, extensive work has been carried out on the epidemiology and evolution of different SARS-CoV-2 strains and also developing methods for identifying and predicting SARS-CoV-2 and other pathogenic viruses ( Gupta et al, 2021 ; Issa et al, 2020 ; Parlikar et al, 2020 ) ( Saha et al, 2021 ). While these studies have provided important insights into the evolution of SARS-CoV-2 and related viruses, it will be useful to carry out further studies on understanding the evolution of SARS-CoV-2, and its novel sequence characteristics, by means of other independent approaches.…”

Pharmacophore screening to identify natural origin compounds to target RNA-dependent RNA polymerase (RdRp) of SARS-CoV2

“…Genomic constituents of SARS-CoV2 have been studied extensively to understand the impact of mutation and geographical regions on the infection rate of COVID [ 58 ]. Currently, many countries have started vaccination to control this pandemic, but recent mutation reported in SARS-CoV2 can modulate its viral transmission, replication efficiency, and virulence.…”

A Bioinformatics Approach to Identifying Potential Biomarkers for Cryptosporidium parvum: A Coccidian Parasite Associated with Fetal Diarrhea

“…Using in vivo, in vitro, or ex vivo techniques, only a few studies have identified gene expression changes in C. parvum infected clinical samples. These investigations, however, have been unable to fully comprehend the role of dysregulated genes at the molecular and network levels [41][42][43]. This study investigated the epithelium's response to C. parvum infection using a series of comprehensive computational analyses.…”