Genetics and genomics of SARS-CoV-2: A review of the literature with the special focus on genetic diversity and SARS-CoV-2 genome detection

Abstract

The outbreak of 2019-novel coronavirus disease (COVID-19), caused by SARS-CoV-2, started in late 2019; in a short time, it has spread rapidly all over the world. Although some possible antiviral and anti-inflammatory medications are available, thousands of people are dying daily. Well-understanding of the SARS-CoV-2 genome is not only essential for the development of new treatments/vaccines, but it also can be used for improving the sensitivity and specificity of current approaches for virus detection. Accordingly, we reviewed the most critical findings related to the genetics of the SARS-CoV-2, with a specific focus on genetic diversity and reported mutations, molecular-based diagnosis assays, using interfering RNA technology for the treatment of patients, and genetic-related vaccination strategies. Additionally, considering the unanswered questions or uncertainties in these regards, different topics were discussed.

Keywords: COVID-19; Coronavirus; Genetics; Molecular diagnosis; SARS-CoV-2; Treatment; Vaccine.

Fig. 1

Schematic presentation of structure and genome organization of SARS-CoV-2 based on reference sequence (EPI_ISL_412026). (A) The virion is covered by the spike (S) proteins as well as the membrane (M) and envelope (E) proteins are placed among the S proteins in the virus envelope. The genomic RNA is surrounded by phosphorylated nucleocapsid (N) proteins inside phospholipid bilayers. (B) The SARS-CoV-2 genome (29903 nucleotides) comprises of the 5′ UTR, ORF1a/b encoding 16 nsps for replication, four genes that encode structural proteins including S, E, M, and N proteins, six accessory genes that encode six accessory proteins such as ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10, as well as the 3′ UTR. The location of the seventeen high-frequency mutations and co-mutations reported in the literature are shown on the genome by vertical red lines and circles with similar color, respectively. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; 5′ UTR, 5′ untranslated region; OFR, open reading frame; nsp, non-structural protein. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Antiviral applications of RNAi against SARS-CoV-2. Generally, RNAi can either be induced by transfection of chemically synthesized siRNAs or the intracellular expression of double-stranded siRNA precursors stably or temporary. After transcription of pri-miRNA from the corresponding miRNA gene by RNA Pol II/III, and then processed by Drosha to construct pre-miRNA in the nucleus, double-stranded siRNA precursors (shRNA, lhRNA or pre-miRNA) are exported to the cytoplasm and processed into mature siRNAs using Dicer. Subsequently, the antisense strand of the siRNAs/miRNAs load into the RISC. The complex can finally cleave the target mRNA. The siRNA-based strategies against the SARS-CoV-2 can either be directed against the SARS-CoV-2 itself or against the ACE2 receptor or TMPRSS2, whose silencing will inhibit virus entry into the cell. Following the interaction of the SARS-CoV-2 spike protein with the human ACE2 receptor after spike protein activation by TMPRSS2, the virus is endocytosed. Then, the virion releases its RNA for translation into proteins by the cell’s machinery. Abbreviations: RNAi, RNA interference; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; siRNA, small interfering RNA; pri-miRNA, primary miRNA; RNA Pol II/III, RNA polymerase II/III; pre-miRNA, precursor-miRNA; shRNA, short hairpin RNA; lhRNA, long hairpin RNA; RISC, RNA-induced silencing complex; ACE2, angiotensin-converting enzyme-2; TMPRSS2, transmembrane protease serine-2.