Could SARS-CoV-2 be extinct in India due to high mutation rates?

As the pandemic of COVID-19 continues to cause economic and social disruption in addition to infection and death, it changed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads across different regions. Is gradually becoming apparent. This tendency is caused by spontaneous adaptive mutations shaped by different environmental conditions and different selective pressures exerted by the host. This is reinforced by the adoption of lockdowns and other social distance measures. New research now published on preprint server bioRxiv*In August 2020, we show the importance of revealing virus dynamics with particular attention to geographic variation.

Current research has focused on finding and interpreting the links between the evolution of SARS-CoV-2 and Indian environmental and host status.

Increased spike mutations, decreased viral fitness

Researchers said that the virus spike Glycoprotein This showed a mutation-derived difference as it is a key to viral binding, fusion, and cell entry leading to host cell infection. This is an important virulence feature that distinguishes it from previous virulence Coronavirus SARS-CoV and MERS-CoV. It also has the two most important genetic characteristics of the virus.

As a result, researchers say, “By investigating the structure and mechanism of spike glycoproteins, we can clarify the susceptibility of the virus and predict the facts that will help us discover SARS-CoV-2 antidotes.”

They used the genomic sequences of 630 Indian isolates obtained from the GISAID database. Tracking these mutations Spike protein The subspecies followed two pathways starting from two ancestral lines, Wuhan-Hu-1/2019 and its D614G variant.

The Wuhan-Hu-1 / 2019 strain gave rise to the D614G variant, but it has evolved into yet another 20 variants, one of which led to three more. The other ancestor strain D614G produced 47 variants, 9 of which resulted in additional variants. Although the two ancestral lines predominate, there were 16 detectable spike protein variants detected in multiple isolates with different levels of spike receptor stability. Surprisingly, several mutations occurred independently at the same position among the 8 variants that were not phylogenetically linked.

More than half of the subspecies were found only in India, but more than two-thirds were less spike receptor stable than their ancestral lines. This should be expected in regions where new rapidly mutating viruses try to adapt to the host while doing so. In the absence of genetic recombination mechanisms, both positive and deleterious mutations can occur without reversion.

Schematic of diversity of circulating spike protein variants in India using maximum likelihood based phylogenetic reconstruction. Each node represents a particular spiked protein variant, and the internal node size and number represent the frequency of that variant. The red or green color of each arrow indicates whether the stability index of the SR complex for each variant is higher or lower than the major variant of the ancestor (ancestor 1 or ancestor 2). Black arrows lead to variants for which the docking score could not be determined because there is at least one variation outside the template region available for docking (18, 42), or because of an isolated fictitious fictional isolate. Nodes with the H1083Q mutation shown in increasingly black. This black node shows variants with no isolates in the dataset, but there were two derivative variants, H1083Q:R78M and H1083Q:E583D, which were available.

The implication is that, despite the ever-increasing rate of mutations, this rapid accumulation of mutations in recent strains leads to loss of compatibility compared to ancestors. The researchers called Muller’s ratchet, a hypothesis that the irreversible accumulation of harmful mutations in asexual reproduction gradually kills the species.

Interestingly, scientists recognize that SARS-CoV-2’s ability to jump species barriers and infect humans is due to certain mutations. This is an RNA virus that inherently results in high mutation rates. Understanding how this occurs at the molecular level will help us understand how it causes disease and how it can be suppressed.

Heatmap distribution across four Indian states with more than 50 sequenced isolates based on the average stability index. The Mean Stability Index for a particular state indicates the mean value of the docking score/HADDOCK score of the SR complex for all circulating variants. The average stability index and mortality values ​​in Indian states are plotted to fit an exponential function (R2 = 0.96).

Reduced mortality due to reduced stability

The most important spike protein diversity was in Maharashtra, Orissa, West Bengal, and Gujarat, but it is limited by the fact that many other states have very few isolates. This diversity may be due to the positive selection pressure that allows proteins, the primary immune targets, to evade the host’s immunity and enter the cell. This can affect the binding of spike receptors. They found 41 and 22 mutations in the S1 and S2 subunits of the spike, respectively.

Next, a study of the average spike-receptor complex stability in each state based on the individual stability index of the variant in that state’s circulation, using the docking score of the S1 subunit with receptor I ran it. We have searched this index in Maharashtra, Delhi, Gujarat and Telangana, limiting only those isolates with more than 50 sequenced isolates. These make up 70% of all isolates and cover a wide variety.

The average stability of the spike receptor complex across these subspecies was strongly and exponentially correlated with mortality (mortality: recovered cases) across the Indian subcontinent. Mortality has dropped sevenfold between April 11, 2020 and June 28, 2020. Terangana and Delhi showed similar average stability with a mortality rate of 7%.

They say this suggests [is] A potential marker for assessing the severity of the disease. “They suggest that further research at the population level is needed to ly verify this. In particular, the actual parameter used (docking score) has so far not been directly correlated with mortality.

Implication

Researchers have published the theory that this loss of stability may be responsible for the decline in national mortality. In India, it peaked at 38% on April 11, 2020, after an initial phase of steadily increasing mortality for four weeks, until it reached 5% on June 28, 2020, when researchers last joined. I got their data, which decreased sharply. However, the mutation rate increased during this period from March to May 2020.

They wonder, “Can Muller’s ratchet be a player in shaping SARS-CoV-2 evolutionary dynamics in India?” In other words, the virus is naturally owing to its rapid rate of mutation. The selection washout process may not be able to compensate and may gradually extinguish itself under the weight of the accumulation of harmful mutations. This corrects deleterious mutations in the viral population, and this accumulation can cause “mutational meltdown.”

According to the researchers, a short period of research precludes a definitive answer, but trends may be seen. It also facilitates the meltdown process by inducing more deleterious mutations and helps evolve better therapeutic approaches. This requires extensive genomic research to answer the questions, which helps improve public health surveillance and prevention programs.

The researchers put it together as follows. “Overall, while proposing the potential stability of the SR complex to track disease severity, there is an urgent need to investigate whether SARS CoV 2 approaches mutation meltdown in India. there is.”

*Important Notices

bioRxiv It publishes preliminary, non-peer reviewed scientific reports and should not be considered conclusive and should not guide clinical practice/health-related behavior or be treated as established information.