Coronavirus Genetics

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Coronaviruses, so named because they look like halos (known as coronas) when viewed under the electron microscope, are a large family of RNA viruses. The typical generic coronavirus genome is a single strand of RNA, 32 kilobases long, and is the largest known RNA virus genome. Coronaviruses have the highest known frequency of recombination of any positive-strand RNA virus, promiscuously combining genetic information from different sources when a host is infected with multiple coronaviruses. In other words, these viruses mutate and change at a high rate, which can create havoc for both diagnostic detection as well as therapy (and vaccine) regimens.

Coronaviruses have an unusual replication process, which involves a 2-step replication mechanism. Many RNA virus genomes contain a single open reading frame (ORF) which is then translated as a single polyprotein that is then catalytically cleaved into smaller functional viral proteins, but coronaviruses can contain up to 10 separate ORFs. Most ribosomes translate the biggest one of these ORFs, called replicase, which alone is twice the size of many other RNA viral genomes. The replicase gene encodes a series of enzymes that use the rest of the genome as a template to produce a set of smaller, overlapping messenger RNA molecules, which are then translated into the structural proteins -- the building blocks of new viral particles.

Coronaviruses mainly cause respiratory and gastrointestinal tract infections and are genetically classified into four major genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (Li, 2016). The former two genera primarily infect mammals, whereas the latter two predominantly infect birds (Tang et al., 2015). Six kinds of human CoVs have been previously identified. These include HCoV-NL63 and HCoV-229E, which belong to the Alphacoronavirus genus; and HCoV-OC43, HCoV-HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV), which belong to the Betacoronavirus genus (Tang et al., 2015). Coronaviruses did not attract worldwide attention until the 2003 SARS pandemic, followed by the 2012 MERS and, most recently, the 2019-nCoV outbreaks (China CDC, 2020, Song et al., 2019). SARS-CoV and MERS-CoV are considered highly pathogenic (Cui et al., 2019), and it is very likely that both SARS-CoV and MERS-CoV were transmitted from bats to palm civets (Guan et al., 2003) or dromedary camels (Drosten et al., 2014), and finally to humans (Cui et al., 2019).


The genome of coronaviruses, whose size ranges between approximately 26,000 and 32,000 bases, includes a variable number (from 6 to 11) of open reading frames (ORFs) (Song et al., 2019). The first ORF representing approximately 67% of the entire genome encodes 16 non-structural proteins (nsps), while the remaining ORFs encode accessory proteins and structural proteins (Cui et al., 2019). The four major structural proteins are the spike surface glycoprotein (S), small envelope protein (E), matrix protein (M), and nucleocapsid protein (N). The spike surface glycoprotein plays an essential role in binding to receptors on the host cell and determines host tropism (Li, 2016, Zhu et al., 2018). The spike proteins of SARS-CoV and MERS-CoV bind to different host receptors via different receptor-binding domains (RBDs). SARS-CoV uses angiotensin-converting enzyme 2 (ACE2) as one of the main receptors (Ge et al., 2013) with CD209L as an alternative receptor (Jeffers et al., 2004), whereas MERS-CoV uses dipeptidyl peptidase 4 (DPP4, also known as CD26) as the primary receptor. Initial analysis suggested that 2019-nCoV has a close evolutionary association with the SARS-like bat coronaviruses (Zhou et al., 2020). Here, based on the first three determined genomes of the novel coronavirus (2019-nCoV), namely Wuhan/IVDC-HB-01/2019 (GISAID accession ID: EPI_ISL_402119) (HB01), Wuhan/IVDC-HB-04/2019 (EPI_ISL_402120) (HB04), and Wuhan/IVDC-HB-05/2019 (EPI_ISL_402121) (HB05), an in-depth genome annotation of this virus was performed with a comparison to related coronaviruses, including 1,008 human SARS-CoV, 338 bat SARS-like CoV, and 3,131 human MERS-CoV, whose genomes were published before January 12, 2020 (release date: September 12, 2019) from Virus Pathogen Database and Analysis Resource (ViPR) (http://www.viprbrc.org/) and NCBI.


Comparison of genomes of these three strains showed that they are almost identical, with only five nucleotide differences in the genome of ~29.8 kb nucleotides (Figure S1). The 2019-nCoV genome was annotated to possess 14 ORFs encoding 27 proteins (Figure 1A and Tables S1A and S1B). The orf1ab and orf1a genes located at the 5′-terminus of the genome respectively encode the pp1ab and pp1a proteins, respectively. They together comprise 15 nsps including nsp1 to nsp10 and nsp12 to nsp16 (Figure 1A and Table S1B). The 3′-terminus of the genome contains four structural proteins (S, E, M, and N) and eight accessory proteins (3a, 3b, p6, 7a, 7b, 8b, 9b, and orf14). At the amino acid level, the 2019-nCoV is quite similar to that of SARS-CoV, but there are some notable differences. For example, the 8a protein is present in SARS-CoV and absent in 2019-nCoV; the 8b protein is 84 amino acids in SARS-CoV, but longer in 2019-nCoV, with 121 amino acids; the 3b protein is 154 amino acids in SARS-CoV, but shorter in 2019-nCoV, with only 22 amino acids (Table S1A). Further studies are needed to characterize how these differences affect the functionality and pathogenesis of 2019-nCoV.

Genome composition and phylogenetic tree for 2019-nCoV

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