In an article published March 26 in Cell, Professor Yongzhen Zhang of the Fudan University Clinical Center for Public Health and co-author Professor Edward Holmes of the University of Sydney reveal what the genetic data of the virus tell us and the gap in knowledge about the origin of the outbreak. The authors hypothesize that the New Coronavirus epidemic may have undergone a period of “recessive” transmission in the population before a large outbreak, with early cases of pneumonia going unnoticed due to asymptomatic, mild, or sporadic infections until the virus acquired mutations at key loci that better adapted to the human host. The article also suggests that the new coronavirus may be a recombinant virus whose high replication rate makes the mutation rate seem insignificant, but should still be taken seriously. It took 20 years for the virus to evolve from bat to human The authors of the paper review the pre-tracing work on the new coronavirus pointing out that the closest genetic sequence match to the new coronavirus so far is a coronavirus found in bats in Yunnan, more than 1,500 kilometers from Wuhan. “The simple inference from this is that our sampling of bat viruses is strongly biased against certain geographic locations. This needs to be corrected in future studies.” The study authors said. In particular, the authors emphasize that even though the coronavirus from the Yunnan bats described above has 96% -97% sequence similarity to the new coronavirus, this may represent more than 20 years of evolutionary sequence. The article infers, “What cannot be ruled out is that the virus acquired some key mutations during its ‘recessive’ transmission in the population prior to its first discovery in December 2019.” For the virus to evolve highly adaptively in humans, it had to acquire mutations in key RBD (receptor binding region) sites, as well as insertional mutations in the Furin protease excision site, which is unique to the new coronavirus. The authors speculate that the virus may have been well adapted to the human host after a period of transmission in the population prior to the rapid outbreak in a short period of time. The authors suggest that during the initial period of “recessive” transmission, when the virus was first introduced to humans, it may have gone undetected due to asymptomatic infections (only mild respiratory symptoms but no pneumonia) or small, localized outbreaks that were not reported to the standard system. Instead, during the ongoing human-to-human transmission, the virus gradually evolved key mutations such as the aforementioned protease cleavage site and thus became fully adapted to humans. To test the validity of these speculations, the researchers suggest that backtracking samples from patients with respiratory symptoms before December 2019 could help unravel the mystery of how the virus spreads “insidiously,” but also raises the difficulty of doing so. The authors say, “Retrospective serologic or macrogenomic studies of respiratory infections would help determine whether this is true, although such early cases may never be detected.” Another issue of great concern noted in the paper is whether the new coronavirus is a recombinant virus. Recombination events of viruses can accelerate large outbreaks and therefore should not be underestimated. Yet trying to determine the exact pattern and genomic origin of recombination events is difficult. “Especially because many of the recombination regions may be small and small mutations may have occurred as we sample more viruses associated with neo-crown.” The authors said. To address these issues, the authors concluded that it would be necessary to sample the viral diversity in animal populations more extensively again, but this would be equally difficult. “Unfortunately, the apparent lack of direct animal samples in the South China seafood market may mean that it is difficult, if not impossible, to accurately identify any animal hosts in this location.” The authors said. The authors also urge that limiting our exposure to animal pathogens as much as possible may be the easiest and most cost-effective way to reduce the risk of future outbreaks, given the enormous diversity of viruses in the wild and their ongoing evolution. Low viral mutation rates may be an illusion As COVID-19 becomes more prevalent, more viral genomes are being sequenced. The authors suggest that although the current mutation rate of new crowns appears to be low, this may be masked by the high replication rate of the virus in the host. It remains unclear whether the ability of the virus to mutate plays a role in viral transmissibility and virulence, so continued attention to viral mutations that cause phenotypic changes is necessary in the current context of widespread transmission. The authors suggest that the earliest virus samples from Wuhan contain less genetic diversity and that these virus samples all share the same recent common ancestor, which may hinder detailed phylogenetic and phylogeographic inferences of virus evolution. Nonetheless, the authors concluded that the Wuhan Public Health Department did an excellent job in identifying the first cases of pneumonia. The investigators argue that while the accumulation of genetic diversity means that it is now possible to detect different phylogenetic clusters of new coronavirus sequences, it is difficult to determine by genomic comparison alone whether the virus fixed important phenotypic mutations as it spread through the global population, and any such claim requires careful experimental validation. On the other hand, given the high mutation rate of RNA viruses, the researchers believe that more mutations will appear in the viral genome. “This will help us track the spread of new coronaviruses. However, as the outbreak spreads, our sequence sample size may be so small relative to the total number of cases that it will be difficult to detect individual strands of transmission. Therefore, caution must always be exercised when trying to infer the exact transmission event. ” the authors said. Professors Yongzhen Zhang and Holmes released the first complete genome sequence of a novel coronavirus to the world on the Open Virology website back in early January, a strain from an unidentified pneumonia patient admitted to Wuhan in late December. There are now about 200 publicly released novel coronavirus genome sequences from patients in multiple regions of the world. The authors of the article also note that with the rapid spread of neo-coronaviruses worldwide, reference to the number of confirmed cases should be avoided because mild or asymptomatic infections are often excluded from the counts and the true number of cases is likely to be much larger than reported. Furthermore, although these uncertainties may not be resolved without large-scale serologic investigations, the current data suggest that the morbidity and mortality rates of neo-crown disease are likely to be higher than those of seasonal influenza but lower than those of SARS and MERS viruses. Content source: Firstrade