Implications of SARS-CoV-2 Mutations for Genomic RNA Structure and Host microRNA Targeting

Abstract

<jats:p>The SARS-CoV-2 virus is a recently-emerged zoonotic pathogen already well adapted to transmission and replication in humans. Although the mutation rate is limited, recently introduced mutations in SARS-CoV-2 have the potential to alter viral fitness. In addition to amino acid changes, mutations could affect RNA secondary structure critical to viral life cycle, or interfere with sequences targeted by host miRNAs. We have analysed subsets of genomes from SARS-CoV-2 isolates from around the globe and show that several mutations introduce changes in Watson–Crick pairing, with resultant changes in predicted secondary structure. Filtering to targets matching miRNAs expressed in SARS-CoV-2-permissive host cells, we identified ten separate target sequences in the SARS-CoV-2 genome; three of these targets have been lost through conserved mutations. A genomic site targeted by the highly abundant miR-197-5p, overexpressed in patients with cardiovascular disease, is lost by a conserved mutation. Our results are compatible with a model that SARS-CoV-2 replication within the human host is constrained by host miRNA defences. The impact of these and further mutations on secondary structures, miRNA targets or potential splice sites offers a new context in which to view future SARS-CoV-2 evolution, and a potential platform for engineering conditional attenuation to vaccine development, as well as providing a better understanding of viral tropism and pathogenesis.</jats:p>

Effects of SARS-CoV-2 Mutations on Protein Structures and Intraviral Protein-Protein Interactions

“…But there were some mutations, such as T85I in nsp2 and P323L in nsp12, found no significant impact on integral protein structure according to our results. However, their high frequency prompt us to further investigate whether they could affect virus characteristics via altering RNA second structure [20], protein stability [21] or partial structure [22]. For instance, experimental research reported that D614G in S could lead to virus infectivity increased by eliminating side-chain hydrogen bond which was only a tiny change in overall protein structure [23], and our data also showed small structural difference between D614G mutant and control (RMSD = 2.33 Å).…”

High affinity of host human microRNAs to SARS-CoV-2 genome: An in silico analysis

“…Several studies have predicted possible binding sites for miRNAs on the SARS-CoV-2 genome from the beginning of the COVID-19 pandemic [ [22] , [23] , [24] , [25] , [26] ]. Arisan et al (2020) identified seven miRNAs including miR-8066, miR-5197, miR-3611, miR-1307-3p, miR-3691-3p, miR-3934-3p, and miR-1468-5p, which bind to SARS-CoV-2 genome [ 25 ].…”

“…Arisan et al (2020) identified seven miRNAs including miR-8066, miR-5197, miR-3611, miR-1307-3p, miR-3691-3p, miR-3934-3p, and miR-1468-5p, which bind to SARS-CoV-2 genome [ 25 ]. In another study by D. McLellan et al (2020), ten microRNAs expressed in the SARS-CoV-2 target cells were filtered according to databases and published data and mutations within the binging sites of these miRNAs on the SARS-CoV-2 genome were investigated [ 26 ]. They identified eight mutations and hypothesized that these mutations might affect the host miRNA antiviral defenses.…”

COVID-19: fighting the invisible enemy with microRNAs

“…Another study of a sequence analysis of SARS-CoV-2 genome has identified that out of 10, 3 targets have been lost. This includes miR 197-5p [65].…”