What is SARS-CoV2 from Genetics perspective and how did it evolve from animal to human?
by PQE Group’s Infodemic Research Team
Valentina Izzo, Project Manager
Madan Lal, Consultant
The most significant component of a virus is its DNA/RNA, as it is essential for carrying information, its replication and survival in the host. Understanding the genome of SARS-CoV 2 becomes a priority among researchers, since it can give information about its mechanisms of action, which in turn might lead to the treatment of the resulting infection and its related complications but also to the possible development of effective vaccines.
ACE2 Receptor on human cells are normally expressed on the epithelium of many internal organs, such as heart, blood vessels and lungs, especially on some epithelial cells of pulmonary alveoli, where the gas exchanges occur. It is likely the way the virus infects humans. Earliest known cases of infection had a link to a wholesale live food market in Wuhan City in China, suggesting that this specific place could have been the source of this outbreak, where the virus probably spilled over from an animal to a human. Knowing how the virus genome evolved and became a threat for humans is puzzling the researchers all over the world, since knowing how a pandemic starts is a key to prevent the next one. Genetic similarity of SARSCoV-2 to Bat SARS-CoV-like coronaviruses, indicates the likelihood of bats as reservoir hosts for its progenitor. However, SARSCoV-2 passed through an intermediary animal, as the outbreak in 2002 did, from horseshoe bats to civet cats and then humans.
Besides this, different possible explanations of SARS-CoV-2 origins and transmission to human from animals are here presented.
ACE (Angiotensin-Converting Enzyme) RBD (Receptor Binding Domain) RaTG13 (one of the bat SARS-related coronaviruses).
What is SARS-CoV2 from a Genetics Perspective?
SARS-CoV 2 mechanisms of action is dependent on the presence of angiotensin-converting enzyme 2 (ACE2 Receptor) on human cells.
ACE2 is normally expressed on the epithelium of many internal organs, such as lungs, heart and blood vessels and it is normally involved in critical biochemical pathways such as blood pressure regulation, wound healing and inflammation. In particular, ACE2 is highly expressed on pneumocytes which are the epithelium cells of pulmonary alveoli, where the exchange between oxygen and carbon dioxide takes place.
Once in human body, it has been shown that SARS-CoV 2 can specifically bind ACE2 receptor on the surface of epithelial cells using the protein called “Spike”, thus entering into the cell and starting the infection. A specific section of Spike called RBD, is responsible for the modulation of the interaction with ACE2 receptor. In fact this is the most variable part of the coronavirus genome, and the amino acids (building block of proteins) of this section have been shown to be critical for binding to ACE2 receptors and for determining the host susceptibility.
The mechanism is similar to a Key and Lock interaction: while Spike protein is the key, the ACE2 Receptor is the lock to enter human cells. Then the infection triggers an impairment of processes normally mediated through the receptor, precipitates inflammatory processes and alveoli cells death, eventually reducing the amount of oxygen brought into the body, as shown in Figure 1 and Figure 2. In Coronaviruses, Spike gene is not only very important as the most variable part of the viral genome, but it can be used to better classify the viruses. In fact, even a small mutation to Spike gene can determine a big change in the protein structure, changing how the viral particle attaches to receptors in human cells (hence the specificity towards a particular cell). Analyses of SARS-CoV 2 Spike gene have demonstrated that its unique structure creates bonds with the human receptor four times stronger than those of other coronaviruses, which could be one of the reasons why the new coronavirus is so highly contagious .
Understanding SARS-CoV-2 genome is crucial to understand its mechanisms of action, not only to possibly fight the resulting infection and related complications, but also to develop potentially effective vaccines.
Europe has recently funded the GEFACOVID project (Analysis of Genetic Factors influencing infection with SARS-CoV 2 and progression of COVID-19). A consortium of universities, and private companies from Europe, China, India and other countries, will investigate SARS-CoV 2 genome and the human genetic characteristics influencing host susceptibility to the infection, the involvement of immune response and the risk of life-threatening complication.
Mutations in the receptor-binding domain of SARS-CoV 2
As above mentioned, the RBD portion of the Spike protein is the most variable part of the coronavirus genome. Computational analyses predicted that the interaction between RBD of SARS-CoV 2 and human ACE2 is not ideal and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding. Thus, the high-affinity binding of the SARS-CoV-2 Spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This evidence supports that SARS-CoV-2 is not the product of purposeful manipulation .
How did SARS-CoV2 evolve from animal to human?
First reported case of SARS-CoV2 by officials in Wuhan City, China, was on December 26th 2019. Earliest known cases had a link to a wholesale food market in Wuhan. Many of the initial patients were either stall owners, market employees, or regular visitors to this market .
Possible mechanism of SARS-CoV-2 origins and transmission from market animals to human could be:
Natural selection in an animal host before zoonotic transfer.
Genetic studies have revealed similarity of SARS-Cov-2 to bat SARS-CoV-like coronaviruses like RaTG13. Hence there is a high probability that bats serve as reservoir hosts for its progenitor. Although RaTG13 is ~96% identical to SARS-CoV-2, its Spike deviates in region RBD of the protein, which suggests that it may not bind efficiently to human ACE2 , .
On the other hand, it has been shown that Malayan pangolins illegally imported in China contain coronaviruses similar to SARS CoV-2, especially between their RBD region and SARS-CoV-2 one ,.
RaTG13 virus still remains the closest to SARS-CoV-2, nevertheless similarly with pangolin coronavirus suggest that the SARS-CoV-2 spike protein increased affinity to human-like ACE2 may be the result of natural selection. Further mutations might occur in the Spike protein by a natural evolutionary processed, among which a particular region, called polybasic cleavage site, is shown to be mutated and play a role in determining viral infectivity and host range.
Natural selection in humans after zoonotic transfer.
The possible progenitor of SARS-CoV-2 then jumped into humans, acquiring the genomic features through adaptation during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off and produce a sufficiently large cluster of cases to trigger the surveillance system which detected it. Further serological studies should be conducted to determine the extent of prior human exposure to SARS-CoV-2.
Selection during passage.
Basic research been ongoing for many years across the world, therefore possibility of an inadvertent laboratory release of SARS-CoV-2 cannot be ruled out completely. In theory, it is possible that SARS-CoV-2 acquired RBD mutations during adaptation to passage in cell culture. Although possible, the finding of pangolin SARS-CoV like viruses with nearly identical RBDs, would suggest otherwise, requiring a more meaningful explanation of how SARS-CoV-2 acquired these RBD via in-vitro recombination or mutation . Furthermore, a hypothetical generation of SARS-CoV-2 by cell culture or animal passage would have required prior isolation of a progenitor virus with very high genetic similarity, which has not been described .
Other research suggested SARS-CoV2 was the recombinant virus of bat coronavirus and snake coronavirus, by comparison in conjunction with relative synonymous codon usage bias among different animal species.
As the virus is new to the world and the outbreak of SARS-CoV-2 has caused severe damages at all levels, understanding its genetics, origin, evolution and transmission to humans becomes a prime necessity. Based on available data there is no specific evidence available to prove the exact origin of SARS-CoV-2. Further investigation is required to have a broader and deeper knowledge. Investigation shall be focused on ‘how and why’ it happened, not on “what” happened. Country leaders should pay more attention, share more initial information about the origin and be more inclusive in the fight against such a virus. Only working together with proper knowledge, scientists all over the word could identify origin’s virus, and, in this way, the process of a vaccine development could be speed up.
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