D614G mutation eventuates in all VOI and VOC in SARS-CoV-2: Is it part of the positive selection pioneered by Darwin?

Abstract

Recently, several emerging variants of SARS-CoV-2 have originated from the Wuhan strain and spread throughout the globe within one and a half years. One mutation, D614G, is very prominent in all VOI and VOC in SARS-CoV-2. This mutation might help to increase the viral fitness in all emerging variants where the mutation is present. With the help of this mutation (D614G), the SARS-CoV-2 variants have gained viral fitness to enhance viral replication and increase transmission. This paper attempts to answer the question of whether the mutation (D614G) occurs due to positive selection or not. Recently, several emerging variants of SARS-CoV-2 have originated from the Wuhan strain and spread throughout the globe within one and a half years. One mutation, D614G, is very prominent in all VOI and VOC in SARS-CoV-2. This mutation might help to increase the viral fitness in all emerging variants where the mutation is present. With the help of this mutation (D614G), the SARS-CoV-2 variants have gained viral fitness to enhance viral replication and increase transmission. This paper attempts to answer the question of whether the mutation (D614G) occurs due to positive selection or not. Scientists are trying to characterize the coronavirus disease (COVID-19) in order to develop flawless therapeutic approaches to combat the global pandemic. This RNA virus belongs to the beta coronavirus group. Like other RNA viruses, it is expeditiously evolving and transmitting, and it has killed over 3.7 million people globally. During the rapid transmission, it is common to accrue various mutations in the pathogen’s genetic structure, leading to the occurrence of more diverse and lethal forms. Especially for pathogenic viruses, decoding their evolutionary pathways will enable scientists to clarify and comprehend the precise pathogenesis or pathophysiology of the contagion. Such an approach will ultimately allow scientists to develop an effective line of treatment regimen either by creating potential vaccines or by discovering new drugs to keep the transmission in check.1Dolan P.T. Whitfield Z.J. Andino R. Mapping the evolutionary potential of RNA viruses.Cell Host Microbe. 2018; 23: 435-446Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar The RNA viruses such as the common cold, influenza, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 are inherently prone to mutations, and high rates of mutation would catalyze rapid evolution compared to their counterparts, the DNA viruses such as the herpesviruses, smallpox viruses, adenoviruses, and papillomaviruses. The faster mutation rate per se in viruses provide better prospects for natural selection to act upon instantly to perfectly shape and create distinct new strains. The vast majority of the RNA viruses that infect and kill humans tend to jump from animals.2Cleaveland S. Laurenson M.K. Taylor L.H. Diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2001; 356: 991-999Crossref PubMed Scopus (759) Google Scholar It is imperative to note that natural selection plays both the proximate and ultimate role to shape the evolutionary trajectory of viruses, and hence it could be one of the deterministic influences to configure the radiation pathways of that particular pathogen.1Dolan P.T. Whitfield Z.J. Andino R. Mapping the evolutionary potential of RNA viruses.Cell Host Microbe. 2018; 23: 435-446Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar During a viral pandemic, it was observed that natural selection favored some mutations over others and also played a deciding role in influencing their pathogenicity over time.3MacLean O.A. Lytras S. Weaver S. Singer J.B. Boni M.F. Lemey P. Kosakovsky Pond S.L. Robertson D.L. Natural selection in the evolution of SARS-CoV-2 in bats created a generalist virus and highly capable human pathogen.PLoS Biol. 2021; 19: e3001115Crossref PubMed Scopus (110) Google Scholar The SARS coronavirus 2 (SARS-CoV-2) virus infects the human cell by interacting with its spike protein on its surface where the angiotensin-converting-2 (ACE2) protein receptor presents in the cell.4Mansbach R.A. Chakraborty S. Nguyen K. Montefiori D.C. Korber B. Gnanakaran S. The SARS-CoV-2 spike variant D614G favors an open conformational state.Sci. Adv. 2021; 7: eabf3671Crossref PubMed Scopus (109) Google Scholar The spike protein consists of three protomers, and when they interact with the ACE2 receptor, it promotes the entry of the virus into a host cell.4Mansbach R.A. Chakraborty S. Nguyen K. Montefiori D.C. Korber B. Gnanakaran S. The SARS-CoV-2 spike variant D614G favors an open conformational state.Sci. Adv. 2021; 7: eabf3671Crossref PubMed Scopus (109) Google Scholar Thus, the spike protein has become a specific target for scientists to formulate therapeutic approaches, and therefore, the molecular structure of the spike protein has been characterized recently.4Mansbach R.A. Chakraborty S. Nguyen K. Montefiori D.C. Korber B. Gnanakaran S. The SARS-CoV-2 spike variant D614G favors an open conformational state.Sci. Adv. 2021; 7: eabf3671Crossref PubMed Scopus (109) Google Scholar,5Zhang J. Cai Y. Xiao T. Lu J. Peng H. Sterling S.M. Walsh Jr., R.M. Rits-Volloch S. Zhu H. Woosley A.N. et al.Structural impact on SARS-CoV-2 spike protein by D614G substitution.Science. 2021; 372: 525-530Crossref PubMed Scopus (256) Google Scholar The chemistry of interaction between the spike protein and its receptor has also been explored.6Kirchdoerfer R.N. Wang N. Pallesen J. Wrapp D. Turner H.L. Cottrell C.A. Corbett K.S. Graham B.S. McLellan J.S. Ward A.B. Stabilized coronavirus spikes are resistant to conformational changes induced by receptor recognition or proteolysis.Sci. Rep. 2018; 8: 15701Crossref PubMed Scopus (314) Google Scholar,7Henderson R. Edwards R.J. Mansouri K. Janowska K. Stalls V. Gobeil S.M.C. Kopp M. Li D. Parks R. Hsu A.L. et al.Controlling the SARS-CoV-2 spike glycoprotein conformation.Nat. Struct. Mol. Biol. 2020; 27: 925-933Crossref PubMed Scopus (263) Google Scholar Despite the fact that the rapid mutation rate is not all that unusual for RNA viruses like SARS-CoV-2, the outstanding concern is whether or not the mutated strains alter viral properties. A classic example is the D614G mutated variant of SARS-CoV-2 that has become so dominant in all variants of concern (VOC) and variants of interest (VOI) globally (Figure 1).8Chakraborty C. Bhattacharya M. Sharma A.R. Present variants of concern and variants of interest of severe acute respiratory syndrome coronavirus 2: their significant mutations in S-glycoprotein, infectivity, re-infectivity, immune escape and vaccines activity.Rev. Med. Virol. 2021; 2207https://doi.org/10.1002/rmv.2270Crossref Scopus (77) Google Scholar Reports have confirmed the mutation of a particular SARS-CoV-2 variant at any geographical level and the distribution of that specific mutation occurring both regionally and globally (Figures 2 and 3).9Korber B. Fischer W.M. Gnanakaran S. Yoon H. Theiler J. Abfalterer W. Hengartner N. Giorgi E.E. Bhattacharya T. Foley B. et al.Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus.Cell. 2020; 182: 812-827.e19Abstract Full Text Full Text PDF PubMed Scopus (2714) Google Scholar This mutated variant has been transmitted worldwide with high infectious rate compared to its original counterpart (Figure 4).9Korber B. Fischer W.M. Gnanakaran S. Yoon H. Theiler J. Abfalterer W. Hengartner N. Giorgi E.E. Bhattacharya T. Foley B. et al.Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus.Cell. 2020; 182: 812-827.e19Abstract Full Text Full Text PDF PubMed Scopus (2714) Google Scholar,10Volz E. Hill V. McCrone J.T. Price A. Jorgensen D. O’Toole Á. Southgate J. Johnson R. Jackson B. Nascimento F.F. et al.Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity.Cell. 2021; 184: 64-75.e11Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar It is therefore imperative to mention that higher viral loads in the upper respiratory tract of humans have been associated with the mutated variant, suggesting a particular alteration that increases the efficiency of the virus entering the host cell while boosting the binding affinity of spike protein to its cognate ACE2 receptor.11Ozono S. Zhang Y. Ode H. Sano K. Tan T.S. Imai K. Miyoshi K. Kishigami S. Ueno T. Iwatani Y.S. et al.SARS-CoV-2 D614G spike mutation increases entry efficiency with enhanced ACE2-binding affinity.Nat. Commun. 2021; 12: 848Crossref PubMed Scopus (316) Google Scholar This particular mutated variant is dangerously communicable as it infects multiple human cell types.12Daniloski Z. Jordan T.X. Ilmain J.K. Guo X. Bhabha G. tenOever B.R. Sanjana N.E. The spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types.eLife. 2021; 10: e65365Crossref PubMed Scopus (124) Google Scholar Plante et al.13Plante J.A. Liu Y. Liu J. Xia H. Johnson B.A. Lokugamage K.G. Zhang X. Muruato A.E. Zou J. Fontes-Garfias C.R. et al.Spike mutation D614G alters SARS-CoV-2 fitness.Nature. 2021; 592: 116-121Crossref PubMed Scopus (992) Google Scholar reported that the D614G mutation might alter the viral fitness of SARS-CoV-2. With the help of the mutation (D614G), the SARS-CoV-2 variants are gaining viral fitness to improve replication and increase transmission.Figure 3Through positive selection, D614G mutation emerges in all VOI and VOC and spreads worldwideShow full captionThis figure shows that the variants of SARS-CoV-2 with D614G mutation have spread in different parts of the world other than the United States. It also shows the phylodynamics of the variants with D614G mutation in different parts of the world other than the United States. (A) The transmission pattern of the variants of SARS-CoV-2 with D614G mutation in Asia. (B) Phylodynamics of the variants of SARS-CoV-2 with D614G mutation in Asia. (C) Transmission pattern of the variants of SARS-CoV-2 with D614G mutation in Latin America and the Caribbean. (D) Phylodynamics of the variants of SARS-CoV-2 with D614G mutation in Latin America and the Caribbean. (E) Transmission pattern of the variants of SARS-CoV-2 with D614G mutation in West Africa. (F) Phylodynamics of the variants of SARS-CoV-2 with D614G mutation in West Africa. Map of the transmission pattern of all regions with the variants of SARS-CoV-2 with D614G mutation and their phylodynamics of all area-specific variants showing D614G mutation circulating worldwide. Map of the transmission pattern of all regions and phylodynamics of all variants of a specific area was developed before July 7, 2021, using GISAID data.18Shu Y. McCauley J. GISAID: Global initiative on sharing all influenza data—from vision to reality.Euro Surveill. 2017; 22: 30494Crossref PubMed Scopus (1680) Google ScholarView Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4The hypothetical diagram illustrates the positive selection of the D614G mutation. From our previous analysis (Figure 1, Figure 2, Figure 3), finally, we have concluded by stating D614G mutation occurrence in all the emerging variants of concern (VOC) and interest (VOI) of SARS-CoV-2 with the highest frequency and circulating throughout the World.View Large Image Figure ViewerDownload Hi-res image Download (PPT) This figure shows that the variants of SARS-CoV-2 with D614G mutation have spread in different parts of the world other than the United States. It also shows the phylodynamics of the variants with D614G mutation in different parts of the world other than the United States. (A) The transmission pattern of the variants of SARS-CoV-2 with D614G mutation in Asia. (B) Phylodynamics of the variants of SARS-CoV-2 with D614G mutation in Asia. (C) Transmission pattern of the variants of SARS-CoV-2 with D614G mutation in Latin America and the Caribbean. (D) Phylodynamics of the variants of SARS-CoV-2 with D614G mutation in Latin America and the Caribbean. (E) Transmission pattern of the variants of SARS-CoV-2 with D614G mutation in West Africa. (F) Phylodynamics of the variants of SARS-CoV-2 with D614G mutation in West Africa. Map of the transmission pattern of all regions with the variants of SARS-CoV-2 with D614G mutation and their phylodynamics of all area-specific variants showing D614G mutation circulating worldwide. Map of the transmission pattern of all regions and phylodynamics of all variants of a specific area was developed before July 7, 2021, using GISAID data.18Shu Y. McCauley J. GISAID: Global initiative on sharing all influenza data—from vision to reality.Euro Surveill. 2017; 22: 30494Crossref PubMed Scopus (1680) Google Scholar The natural selection favors some mutations over others, and a higher fitness advantage could be one of the reasons catalyzing the faster replication of a specific type. That is why the new mutant variant has become more infections with faster communicable potential compared to its ancestral form in terms of disease progression.9Korber B. Fischer W.M. Gnanakaran S. Yoon H. Theiler J. Abfalterer W. Hengartner N. Giorgi E.E. Bhattacharya T. Foley B. et al.Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus.Cell. 2020; 182: 812-827.e19Abstract Full Text Full Text PDF PubMed Scopus (2714) Google Scholar The expansion of a particular viral mutation is regulated by various evolutionary factors that include founder effect, population bottleneck, genetic drift, range expansion, population growth, and ultimately natural selection. The variant with faster mutation capacity may persist in population for an extended period with a higher frequency as it is evolutionarily advantageous for the pathogen.10Volz E. Hill V. McCrone J.T. Price A. Jorgensen D. O’Toole Á. Southgate J. Johnson R. Jackson B. Nascimento F.F. et al.Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity.Cell. 2021; 184: 64-75.e11Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar Natural selection plays a pivotal role in removing deleterious short-lived viral variants from a population by imposing positive selection, which is the rule of thumb to shape the selection progression of viral replication and evolution.14Elena S. Moya A. Rate of deleterious mutation and the distribution of its effects on fitness in vesicular stomatitis virus.J. Evol. Biol. 1999; 12: 1078-1088Crossref Scopus (73) Google Scholar Ideally, pathogenic microorganisms should opt for a reduced level of virulence in evolution since greater virulence associated with microscopic pathogens can lead to extinction not only of its host, but also for itself. Thus, natural selection favors the level of virulence maximizing the rate of increase in the pathogenic population to optimize the evolutionary trajectory by establishing a potential relationship between transmissibility and outcome of that particular virus on host mortality.15Lenski R.E. May R.M. The evolution of virulence in parasites and pathogens: reconciliation between two competing hypotheses.J. Theor. Biol. 1994; 169: 253-265Crossref PubMed Scopus (286) Google Scholar Trucchi et al.16Trucchi E. Gratton P. Mafessoni F. Motta S. Cicconardi F. Mancia F. Bertorelle G. D’Annessa I. Di Marino D. Population dynamics and structural effects at short and long range support the hypothesis of the selective advantage of the G614 SARS-CoV-2 spike variant.Mol. Biol. Evol. 2021; 38: 1966-1979Crossref PubMed Scopus (19) Google Scholar proposed a hypothesis that the D614G variants got a selective advantage due to structural changes in the furin-like domain in S-glycoprotein. The mutation helps to change the conformational plasticity in this domain, which further helps to increase the volume of the cavity of this domain and its surrounding cleavage site in S-glycoprotein. This structural change favors the virus to interact with the host, and it appears to be the evolutionary strength of the virus. It is well proven that positive selection is one of the foremost causes for molecular evolution. Some may consider that natural selection through random genetic drift could play a role in triggering an array of variants.17Booker T.R. Jackson B.C. Keightley P.D. Detecting positive selection in the genome.BMC Biol. 2017; 15: 98Crossref PubMed Scopus (71) Google Scholar However, we conclude from our analysis that the D614G mutation is not at all a vibrant outcome of genetic drift, and instead, it appears to be part of positive selection. Thus, further exploration of D614G mutation will certainly contribute to better understanding of the molecular evolution of emerging variants of SARS-CoV-2. The authors confirm that the data supporting the findings of this study are available within the article. We are thankful to Bacterial and Viral Bioinformatics Resource Center (BV-BRC) and GISAID database and their researcher who developed these web servers/databases. Conceptualization, C.C.; Writing – Original Draft, C.C., A.S., and G.A.; Writing – Review and Editing, C.C., A.R.S., and M.B.; Validation and Formal Analysis, A.R.S. and M.B.; Supervision and Funding, S.-S.L. and C.C. The authors declare no competing interests.

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