Agarwal_Arnav_Introduction

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Arnav Agarwal ANTH-205/First Year Research Immersion Program Introduction Draft – COVID-19 Phylogeny Dr. Shamoon-Pour Background When the SARS-CoV-2 (COVID-19) coronavirus first emerged in Wuhan, China in early December 2019, it took researchers over a month to finally have a full genomic sequence for the novel virus, confirming its human-to-human transmission, and took even longer for it to be announced to the public that the SARS-CoV-2 virus is a potentially life threatening disease with a high rate of infectivity. Due to this slow action, the virus had a fair bit of time to move in infected hosts as people travelled across countries, and by January 2020 the first case of the SARS-CoV-2 virus emerged in the United States. The COVID-19 virus has thrown the world into a state of shock since its first emergence, with most countries initiating many lockdown and social distancing procedures in order to contain the spread of the virus. Despite this, the virus has gone onto infect nearly a million people in over 200 countries worldwide. (Dharma, et al,. 2020) The worldwide casualty of the virus is even more alarming with nearly one hundred and fifty million cases and over three million deaths. The virus seems to have varied effects on individuals with older individuals experiencing more life threatening symptoms while younger individuals generally recover with little to no problems. (Davies, et al., 2020). The virus proves to be especially dangerous due to the possibility of long term effects such as diminished smell and taste, body aches, etc. even after recovery. The coronaviridae family comprises of many viral lineages which are found in many mammals and birds, some of which are transmittable to humans such as SARS-CoV, MERS- CoV, and SARS-CoV-2. When the first cases of SARS-CoV-2 were sequenced, the virus was

characterized as a lineage-b betacoronavirus, similar to SARS-CoV- the virus responsible for an outbreak in 2003. (Jaimes, et, al., 2020). The zoonotic origins of SARS-CoV-2 are supported by its close taxonomical relationship between other SARS-related coronaviridae, many of which share bats as their natural reservoir host. (Zhou, et, al., 2020). The SARS-CoV-2 virus is a RNA based virus which means that it inherently has a very rapid rate of mutation. RNA viruses in general are known to have extremely fast mutation rates due to the fact that RNA polymerases tend to replicate much faster which results in many more errors in replication leading to many different mutations in even just one lineage of a virus. (Duffy, et al., 2008). The SARS-CoV-2 virus is not transmittable directly through air but rather by binding to respiratory droplets which travel through the air upon exit from the nose/mouth. (Deng, et al., 2021). Once inside the host body, SARS-CoV-2 enters and binds to host cells by utilizing its spike (S) protein to bind to host cells’ angiotensin converting enzyme 2 (ACE2). During active infection, the spike protein is split up into two subunits by host proteases. The S1 receptor binding subunit binds to host cell sugar receptors and the ACE2 enzyme while the S2 membrane fusion subunit undergoes structural changes within the host cell. (Shereen, et al., 2020). Once infecting an individual, SARS-CoV-2 has shown the ability to mutate relatively significantly within the host in at least five studied cases. The patients in question had longer than normal infection periods due to various immune impairments. In at least two of the five cases, the mutated variants from the patients were desensitized to neutralization by up to five times in scale. (Yesudhas, et al., 2021). As of yet there is not much more research on the virus’ intra and inter-host mutational ability however, the current data and research indicates that the virus has a high genomic plasticity fairly confidently. This may prove to be an issue in terms of

formulating treatments and vaccines for the virus as the virus itself can potentially mutate fairly easily in order to render vaccines and treatments ineffective. In infected hosts, the virus’ impact varies significantly from host to host. Most people who contract the virus exhibit little to no symptoms and recover fairly quickly from the ailment. However, symptomatic individuals have been known to experience a plethora of symptoms such as fever, sore throat, loss of taste, loss of smell, body aches, nausea, diarrhea, headache, reduced breathing ability, among various other symptoms. Symptoms may range from mild to severe depending on the individual and any possible comorbidities and the virus is potentially fatal as well. In response to the COVID-19 pandemic, the Department of Health and Human services formed the SARS-CoV-2 Interagency Group (SIG) in order to help improve efficiency in response and research of the novel coronavirus. The SIG and the CDC formulated a three tier classification for different SARS-CoV-2 variants labeled Variants of Interest (VOI), Variants of Concern (VOC), and Variants of High Consequence (VOHC). As of right now, not much research is being done into COVID-19 variants of interest and there aren’t any designated variants of high consequence in the United States, however there are five variants of concern which are being monitored and studies for genomic and expressive differences. The five variants of concern are: the B.1.1.7 lineage, P.1 lineage, B.1.351 lineage, B.1.427 lineage, and B.1.429 lineage. SARS-CoV-2 variants that belong to these viral lineages have known attributes such as anywhere from 20% to 50% increased transmissibility and minimal to significant impacts on viral antibody neutralization. (CDC, 2021). While there is not much research on the symptomatic differences between different SARS-CoV-2 strains, current research indicates that different variants may have significantly different levels of viral loads in patients, transmissibility, and resistances to antibody neutralization.

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Previous Studies Throughout the research conducted by reviewing various scientific articles regarding the SARS-CoV-2 several points of interest came up across the various articles. One of the most prevalent points of interest is regarding the D614G amino acid mutation. The D614G mutation is characterized by an A-to-G nucleotide change at position 23,403 of the genomic sequence of the original reference strain from Wuhan. The mutation was discovered somewhere in March 2020 and at the time, the mutation was very uncommon. However within a month or two, the D614G viral variant had become the dominant strain in SARS-CoV-2 cases around the world. The D614 to G614 mutation was also found to be associated with higher respiratory tract concentrations of the virus in individuals which indicates that the mutation may potentially be more infectious than other variants. This may also explain the mutations rapid dominance over other variants. (Korber, et al., 2020). Furthermore, the fact that the D614G mutation is the dominant variant indicates that it was somehow naturally selected for properties that allow the virus to spread quicker and/or withstand stressors better. The D614G mutation belongs to the B.1 lineage, of which several variants have been designated as Variants of Concern (VOC). The B.1 lineage also happens to be the most dominant lineage in SARS-CoV-2 cases around the world, indicating that viral variants that belong to the lineage may have certain mutations which make them better suited for survival. (Volz, et al., 2021). Another significant point of interest involved mutations in the viral spike (S) protein. From previous studies we know that the spike protein is the main factor in the virus’ binding to host cells. At the start of the pandemic, genomic sequencing of available SARS-CoV-2 samples did now show much genetic diversity in nonstructural proteins of the virus. This observation led researchers to hypothesize that a single sequence vaccine against the virus which targeted the

spike protein would provide sufficient immunization against other variants of the virus. However, since then, mutations in the viral spike protein have been sequenced which makes formulating a vaccine against the virus much less straightforward. (McCormick, et al,. 2021). Many of the mutations in the viral spike protein were found in the receptor binding domain which mediates the binding between the virus and host cell. An analysis of over two thousand SARS-CoV-2 genomic sequences found that there were five viral variants with mutations in the receptor binding domain with a very strong natural selection and they are as follows: A348T, V367F, G476S, V483A, and S494P. These mutations in the receptor binding domain change the virus’ binding affinity to ACE2, essentially changing the manner in which the virus binds to the host cell. (Chakraborty, et al., 2021). Further research needs to be conducted on the possible implications of changes in ACE2 binding affinity from receptor binding domain mutations. Additionally, the RNA-dependent RNA polymerase has been shown to exhibit mutations in different sequenced variants. The RNA-dependent RNA polymerase (RdRp) is an enzyme that catalyzes RNA replication from a RNA template. Mutations in the RNA-dependent RNA polymerase could prove to be significantly important as they have been found to cause differences in rate of mutation and resistance to treatments. One study which analyzed data from already sequenced SARS-CoV-2 strains showed that variants with RdRp mutations had up to a three times faster rate of mutation when compared with viral variants without RdRp mutations. (Zeng, et al,. 2021). This is likely due to the fact that many of the RdRp mutations speed up the proofreading process significantly, which causes many more errors to be made in coding viral genomic sequences which causes mutations in the virus itself. Further research needs to be conducted on the role RdRp mutations may play in impacting the virus’ transmissibility and mutation rates.

For over a year now, the world has been thrown into a state of disarray over the SARS- CoV-2 pandemic. The virus has infected and killed millions of people around the world and its extremely high rate of mutation makes treatment and prevention especially hard. RNA based viruses such as SARS-CoV-2 are very flexible in sequence preference and structural conformity which has led to different variants of the virus emerging. Variants such as the previously mentioned D614G mutation and others that belong to lineages in the VOC (Variants of Concern) designation have been shown to have increased transmissibility, infectivity, and varied resistances to vaccines and other treatments. In particular the B.1.1.7 lineage has been of great interest due to its global dominance and alarming mutations. Given the global impact that the SARS-CoV-2 outbreak has had, it is crucial that further research is conducted on genetic mutations which can potentially increase the danger the virus poses to people, specifically the B.1.1.7 lineage.

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Works Cited CDC. (2021, March 14). SARS-CoV-2 Variant Classifications and Definitions. Retrieved from https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html Chakraborty S. (2021). Evolutionary and structural analysis elucidates mutations on SARS- CoV2 spike protein with altered human ACE2 binding affinity. Biochemical and biophysical research communications, 538, 97–103. https://doi.org/10.1016/j.bbrc.2021.01.035 Davies NG, Klepac P, Liu Y, Prem K, Jit M, Eggo RM. 2020. Age-dependent effects in the transmission and control of COVID-19 epidemics. Nature Medicine 26:1205–1211. Deng, X., Gong, G., He, X., Shi, X., & Mo, L. (2021). Control of exhaled SARS-CoV-2-laden aerosols in the interpersonal breathing microenvironment in a ventilated room with limited space air stability. Journal of Environmental Sciences (China), 108, 175–187. https://doi.org/10.1016/j.jes.2021.01.025 Dhama K, Patel SK, Sharun K, Pathak M, Tiwari R, Yatoo MI, Malik YS, Sah R, Rabaan AA, Panwar PK, Singh KP, Michalak I, Chaicumpa W, Martinez-Pulgarin DF, Bonilla-Aldana DK, Rodriguez-Morales AJ. 2020. SARS-CoV-2 jumping the species barrier: Zoonotic lessons from SARS, MERS and recent advances to combat this pandemic virus. Travel Medicine and Infectious Disease 37:101830. Duffy S. (2018). Why are RNA virus mutation rates so damn high?. PLoS biology, 16(8), e3000003. https://doi.org/10.1371/journal.pbio.3000003 Shereen, M. A., Khan, S., Kazmi, A., Bashir, N., & Siddique, R. (2020). COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. Journal of advanced research, 24, 91–98. https://doi.org/10.1016/j.jare.2020.03.005 Jaimes JA, André NM, Chappie JS, Millet JK, Whittaker GR. 2020. Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop. Journal of Molecular Biology 432:3309–3325. Korber, B., Fischer, W. M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Hengartner, N., Giorgi, E. E., Bhattacharya, T., Foley, B., Hastie, K. M., Parker, M. D., Partridge, D. G., Evans, C. M., Freeman, T. M., de Silva, T. I., Sheffield COVID-19 Genomics Group, McDanal, C., Perez, L. G., Tang, H., … Montefiori, D. C. (2020). Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell, 182(4), 812–827.e19. https://doi.org/10.1016/j.cell.2020.06.043 McCormick, K. D., Jacobs, J. L., & Mellors, J. W. (2021). The emerging plasticity of SARS- CoV-2. Science (New York, N.Y.), 371(6536), 1306–1308. https://doi.org/10.1126/science.abg4493 R., Jesudason, N., Li, K., Jarrett, R., … Connor, T. R. (2021). Evaluating the Effects of SARS- CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity. Cell, 184(1), 64–75.e11. https://doi.org/10.1016/j.cell.2020.11.020

Zeng, L., Li, D., Tong, W., Shi, T., & Ning, B. (2021). Biochemical features and mutations of key proteins in SARS-CoV-2 and their impacts on RNA therapeutics. Biochemical pharmacology, 114424. Advance online publication. https://doi.org/10.1016/j.bcp.2021.114424 Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, Si H-R, Zhu Y, Li B, Huang C-L, Chen H-D, Chen J, Luo Y, Guo H, Jiang R-D, Liu M-Q, Chen Y, Shen X-R, Wang X, Zheng X-S, Zhao K, Chen Q-J, Deng F, Liu L-L, Yan B, Zhan F-X, Wang Y-Y, Xiao G-F, Shi Z-L. 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579:270– 273. Volz, E., Hill, V., McCrone, J. T., Price, A., Jorgensen, D., O'Toole, Á., Southgate, J., Johnson, R., Jackson, B., Nascimento, F. F., Rey, S. M., Nicholls, S. M., Colquhoun, R. M., da Silva Filipe, A., Shepherd, J., Pascall, D. J., Shah, R., Jesudason, N., Li, K., Jarrett, R., … Connor, T. R. (2021). Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity. Cell, 184(1), 64–75.e11. https://doi.org/10.1016/j.cell.2020.11.020 Yesudhas, D., Srivastava, A., & Gromiha, M. M. (2021). COVID-19 outbreak: history, mechanism, transmission, structural studies and therapeutics. Infection, 49(2), 199–213. https://doi.org/10.1007/s15010-020-01516-2

Agarwal_Arnav_Introduction

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