(Hope the authorities across the globe read this paper and change their course of actions)
(Please read and if agreed pass around to the world due to the urgency of the situation)
The new coronavirus that is now popular with the title of COVID-19 around the world and boasting in spreading at a pandemic level, causing more panic than killings, is the seventh in the line of the class of coronaviruses. This family of viruses head by the common cold or flu virus that has lived in symbiosis with humans for long, and had never caused fatalities and created panic in us. Viruses such as Coronaviruses that have lived for billions of years, much longer than any other beings on the earth keep evolving for survival. This is more true for RNA viruses such as Coronaviruses that depend on hosts to survive, due to lack of DNA for independent living. So on the path of their evolution for survival, they evolve in different types invading the hosts like humans. SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome) that hit humans’ population a few years ago before COVID-19 are other types of Coronaviruses. In fact the outbreak of Coronaviruses in different forms over the past several years is a good indicator that these viruses are pushing for survival and coevolution now within the human hosts (1-7).
In this article I discuss the wise option of living with Coronaviruses in peace with no panic and resistance. This contention that might surprise many is not new in the nature as living in peace or “symbiosis” among the living creatures from plants, animals, bacteria and viruses to us humans have been a rule and part of the law of survival than exception. This has been well known in the scientific and medical circle that I will refer to here, though a call for a peace with the microbial invasions have not been forthcoming yet. The symbiosis between two livings could be obligatory or facultative (optional) that could be different on each side of the equation or relationship. For example in the case of microbes and viruses, the symbiosis on their parts is obligatory as they cannot survive without the hosts, but is optional on the hosts part to let them in or fight back and being killed.
Symbiosis and Endosymbiosis:
Symbiosis, a Greek word meaning “living together”, is any type of close and long-term biological relationship, interaction and dependency between two biological organisms in a mutualistic, commensalistic or parasitic manner. Endosymbiosis or living inside of the tissues of the hosts that most microbes, such as bacteria and viruses do, including many bacteria already living in peace within us, e.g. in our digestive system, assists with our normal living. A peaceful and healthy endosymbiosis in fact leads over time to reduction of the genome size and power of the invader or endosymbiont and lower its fatality due to the adaptation with the host. This has been a vital part of “co-evolution” in nature on earth since its living inception. In fact eukaryotes, the origin of plants, fungi and animals like us all have evolved through this symbiogenesis. Mitochondria, chloroplasts and other cellular organelles that divide and replicate independent of the cells in living creatures like us is an obvious example of such evolutionary endosymbiosis. In fact the notion of Darwinism based on competitive survival has been replaced in the modern scientific arena to the cooperative and symbiotic evolutionary survival (8-10).
One of the most impressive example of endosymbiosis in fact is the microbiota living in the mammalian guts including 100 trillion microbes living in one human’s gut. The gut microbiota is so vital for the maintenance of our immune system in fight against infections and diseases for our survival that when disrupted and not cooperated with, e.g. in the case of slow bowel movements and constipation, they could turn to pathogens and causing diseases such as colon cancers. In endosymbiosis, e.g. our guts microbiota, the relationship is not static but dynamic and plastic or flexible on both sides. Any disruption of this equilibrium takes long and many processes of negotiations, commensalism and mutualism on both parts for the sake of peace and survival, unless the terms of homeostasis is broken repeatedly or continually by one side that is mostly by the hosts. This indeed is a major lesson observed diligently in molecular biology that needs to be expanded to other symbioses and endosymbiosis around and within us. In fact the survival of our ecosystem outward and inward is heavily dependent on a full cooperation between the partners of symbiosis and endosymbiosis that hinges mostly on the hosts part like us (11-16).
Another impressive well know example of endosymbiosis between us and microbes is the bacterial communities present in the vagina of reproductive-aged women as a cornerstone of a multifaceted antimicrobial defense system. The vaginal microbiota play a significant role in the prevention of bacterial vaginosis, yeast and sexually transmitted infections, urinary tract and HIV infections among others. The lactic acid–producing bacteria (mainly Lactobacillus sp.), common colonizing bacteria in the human vagina, are the key players in maintaining homeostasis of this microbiota endosymbiosis. Like the gut, depending on the sexual activity, menstrual cycle, and other environmental factors, there are periods of community-wide stability as well as periods of extreme variability. The stability or healthy symbiosis and instability or dysbiosis in vagina depends heavily on the host and her sexual/hygienic/reproductive behaviours (17-20).
Viruses not antagonistisc but essentials:
While the roles of bacteria have been known for long in endosymbiosis of the hosts well-being like us, the role of viruses traditionally and still out of scientific arena in endosymbiosis has not been appreciated until about a decade ago. Indeed viruses due to their much minute sizes and its cellular structures, particularly RNA or particle viruses that cannot survive independently, have much more endosymbiotic roles not only in the large size beings, but even within bacteria. This mutualistic relationship has been explored in detail recently pointing to the vitality of viral endosymbiosis not for short-term survival but for long-terms and in the hosts’ evolution as they are the major partners in the hosts’ genomes. In fact the viral symbiogenesis seems to be the most important factor in the evolution of all life on earth (21-24).
Viruses that have been until recently associated with diseases and studied as such, are the most abundant and diverse biological entities on the planet. Recent biodiversity surveys in desert, ocean, soil, animals and plants have revealed the vital roles of viruses in every ecosystem. Due to their obligatory existence as endosymbiont within all other beings larger than themselves, the viruses had to possess evolutionary plasticity to form and maintain the most excellent models of symbiotic relationships. Moreover and most importantly the viruses are the main force behind the genome diversities and genetic evolutions across all species. In fact majority of virus-host interactions all around are commensal or friendly. But even in the case of antagonistic interactions, when there is resistance from the host by fighting the virus through its immune armamentarium, the plasticity and obligation of the virus for endosymbiosis living and evolutionary genetic diversification, assists the survival of the host at the end of the arm race, as the end of life of the host would be the end of life of the virus (25-34)
A great example of such co-evolution and assistance in survival is the “interferon”, a master regulator of the immune system and cell metabolism found in nearly all cell types that has evolved within lives through viral interactions. Another impressive example observed in the interaction between a bacterium and lytic virus and also in the killer viruses of yeast by the virus protection against the lytic phage (virus fighting against its own killing machine) for the survival of the host, ultimately leading to the endosymbiosis or dependency of the host onto the virus for living. Studies on plants that were first to appreciate the importance of viral interactions and symbiosis in ecosystem, diversity and evolution of the plants, have also shown how viruses assist the plants in coping with their adverse environments such as drought, thermal tolerance and adversarial invasions (34-43).
In human studies, GB virus C has been shown to fight against HIV through down-regulation of cell receptors for entry, reduced replication, promoting interferon and interactions with interleukin immune pathways. Latent herpes virus and cytomegalovirus have also been shown to enhance the T cells immune response to influenza and other fatal microbial invasions. Endogenous retroviruses that make up at least 8% of human genomes and non-retroviral endogenous viruses have been revealed in recent years that have been contributing for million of years to the genetic evolution and diversities of all living forms on earth. This so-called endogenization of viral elements has sculpted the evolution of extant genomes in all domains of life. The significance of the contribution of viral interactions in the evolution of their hosts’ genetic make-up, diversity and survival became possible only since the sequencing and analysis of hosts genomes such as humans in the recent years. In brief, viruses that have until recently been considered fatal and antagonistic to life, at least in the field of virology, genetics, evolution, ecosystem and biodiversity, have been appreciated as the most important vital elements of life on the planet (44-63).
What about the aggressive viruses?
As early as mid-80s it has been argued that the virulence of a microbial invasion such as viral infections could be favored by the natural selection and lead more to co-evolution, when pathology enhances genetic transmission, better adaptation and evolution (64). This has also been shown in the case of coronavirus as early as mid-90s, when it was shown that mouse hepatitis virus strain A59 (MHV-A59) a member of the family of coronaviruses, containing a single-stranded positive-polarity RNA genome, similar to other coronaviruses, e.g. SARS and COVID-19, that the co-evolution between the mouse and the virus favors virulence. In a vitro (lab study), Wan Chen and Ralph Baric in 1996 showed the resistant host cells of the mouse that impede the vertical transmission of the virus created a genetic bottleneck for the subsequent selection of a more virulent variants viruses (65).
The virulent coronaviruses such as SARS, MERS and now COVID-19 that once long ago were circumlocated to the wild life mostly bats and one genu have rapidly spread intra-species (e.g. between different genu of bats) and recently inter-species even to humans. This rapid spread of this class of virus with its high virulence is a hallmark of the coronavirus rapid evolution (66). Most recently Letko and colleagues in 2018 have shown that how MERS-CoV by altering the surface charge of its spike (or crown where the name of Corona derives from) surpasses the host cell receptor resistance for entry (67). Koonpaew et al. (68) in 2019 have also shown another coronavirus, Enteropathogenic porcine epidemic diarrhea virus (PEDV) and porcine delta coronavirus (PDCoV) that cause diarrhea in neonatal pigs in the past decade, how circumvent or subvert the host’s first line of defense for entry.
The Evolutionary Pathway of Coronavirus:
Most impressive Wertheim and colleagues in 2013 argued and showed that coronaviruses infecting mammals (alpha-and-beta coronaviruses) and gamma-and-delta coronaviruses infecting birds have co-existed and evolved with these ancient species between 190 to 489 million years ago (69). By analysis of the nucleotide sequences of these coronaviruses at the non-recombinant regions of their genomes and estimation of the branch length of the inferred maximum likelihood of their phylogenies, these researchers were able to extrapolate the lineage of Coronaviruses being as ancient as their hosts, back to an average of 300 million years ago. More recently it has also been shown that the human coronavirus OC43 involved in the common cold or flu, that’s a beta coronavirus type 1, similar to the one infecting cattle (BCoV) has been spilled over from bovine to our homo sapiens ancestor after the first contact with their respiratory tracts (70).
The coronavirus spillover once again has emerged in the recent years with full force of the new types of beta coronavirus infections such as SARS, MERS and now COVID-19. Such pathogen emergence is driven by ecological, genetic factors and codon usage at the service of adaptation of the viruse to the hosts, through natural selection based on translation efficiency and drift according to the genomic mutation pressure. On the path of its evolution and adaptation to its host and breaking any resistance, the human coronavirus OC43 has evolved and changed to many genotypes and variants that had already been shown in the human samples in France and China among other places. What we have seen and suffered by the novel coronaviruses of SARS, MERS and now COVID-19 in the recent years are all the tips of an iceberg of biodiversity and power of co-evolution of the coronaviruses deep down in the ocean of a universal ecosystem on earth (71-81).
An Enemy that was never:
The human coronaviruses that evolved almost a million year ago with our homo sapiens ancestor and lived with us since as a peaceful common cold or flu in our respiratory system has been striking back in the recent years. Our current knowledge despite the vast and fast progress in the field of virology and bridging with genetics, evolution and ecosystem, is still in it infancy, lest to resist the entry of our own coronavirus with its diversity and unbreakable armamentarium. Despite our current and ongoing all global panic over COVID-19, the virus has been fatal only in the elderly and persons with underlying severe medical conditions with poor immune system to adapt to the virus. According to the WHO data, almost 20% of the fatalities have been in the age group of over 80 years old with decreasing drastically by decade down the ladder of life, so 10% in the age group of 70-79, less than 5% in the age group of 60-69 and just over 1% in the age group of 50-59 with rare to almost no mortality in any age group under 50 years old (less than 1% in all age groups of 0-49).
The above factual data is an evidence that the virus is not antagonistic and against our survival, but an endosymbiont and a part of the co-evolution and ecosystem that needs to be with us. While the interaction or invasion of the coronavirus on the surface seems to be unilateral and opportunist with no benefit for us, our scarce knowledge in the very field cautions us to the contrary. Unlike the antagonistic and destructive viruses such as HIV and HPV, the cornoviruses like many so other good viruses have never caused the extinction of their other bovine and avian hosts and not even our own human CoV-OC43 over million years of cohabitation has not harmed us seriously. Therefore it is obvious that our human coronavirus in its different variants, even the current ongoing COVID-19 is a mutual partner that most probably is on the mission of evolving us or helping us to adapt to the current and the future environment. The virulence of the new variants of the human coronavirus as detailed in other viral cases is not a sign against mutual cohabitation or symbiosis and co-evolution but it speaks of the urgency for the need of entry at the service of genomic diversity and evolution. The fatalities of elderly and immune compromised population not withstanding this entry and adaptation for a healthier future is not the fault of the virus. Any resistance to the virus entry, specially at the current time of its utmost urgent virulence for entry will lead to another later more aggressive entry through another more fatal pandemic outbreak.
The current universal panic about the COVID-19 has been so far the worst pandemic event befalling on the humans globally. Although there have been epidemics and pandemics across the human history such as plague and Spanish Flu, none has been this extensive crossing all the waters and lands. While at the onset, all the blames were on China and its Wuhan province where the outbreak started, there has been rarely any place on the face of earth to have skipped this microbial invasion. This universal entry of the coronavirus, this time after the recent SARS and MERS with its powerful virulence is a strong evidence of the natural selection obligation that the virus has for maintenance of our longer-term survival.
Our lack of knowledge and ignorance about the significance of symbiosis with other beings such as viruses that have been the backbones of life like other vital elements making this planet, has been the cause of our world-wide panic never seen before. While even in the scientific arena viruses until recently were thought as antagonistic and pathogens, we need to come to the realization and appreciation of the role of viruses in every single life form from plants to bacteria and larger animals like us. Symbiosis and endosymbiosis is a vital part of life and has existed from the inception of life on the planet with no exceptions, even for us. Our brains and logic that makes us different from the other forms of livings, and was evolved to understand our environment has obviously failed us by our greed and panic.
To get to the point hastily for the urgency of the situation world-wide if there are any common sense and understanding left, the human coronavirus OC43 that has spilled over almost a million year ago from bovines to our homo sapience ancestor has been living with us in peaceful endosymbiosis causing only a mild flu or common cold since. The recent aggressive invasion of the virulent variants of the virus, e.g. SARS, MERS and now COVID-19 does not mean that the virus agenda has changed from a peaceful cohabitation and co-evolution to wipe us out! In fact the current understanding and appreciation in the scientific field is that the virulence and aggression of the virus for entry is not antagonistic to life, but at the service of an urgent entry for maintaining survival, natural selection and evolution on both sides of the equation, the virus and the host. Any resistance and fighting back would lead to the future more aggressive and fatal entry of the virus as history has repeated itself with the outbreak of the current and ongoing COVID-19 that has been much more virulent and lethal than his sisters SARS & MERS.
First and most of all the current coronavirus invasion is not an invasion of an enemy to panic and put us in a defensive mode to fight it back foolishly with our weapons and economic power. The virus has obviously defeated us financially, mentally and physically and has been still proceeding with full force causing more morbidities and mortalities. The fear and damage will not end by COVID-19 that its course as like other coronaviruses will end as a winter virus by the end of season. But more future outbreaks of its more virulent and aggressive type will be our upcoming nightmares. Therefore it is imperative for our survival and maintenance of the balance in our ecosystem, if wish to be a part, and also for our future evolution and survival, to step back and proceed with the following recommendations:
1-Since the COVID-19 has obviously killed the elderly and compromised immune populations, we need to protect this population all over the world with quarantine, vaccination and fostering their immunity.
2- Since the COVID-19 has not and will not kill the younger age groups and immune healthy populations, these age groups do not need at any rate to panic and be quarantined or isolated. If we look well around, the virus has caused no to mild and tolerable symptoms in our young and healthy population that after the infection will leave them a future immunity from the next more virulent outbreaks.
3-Since the majority of the population will be safe even by exposure to the virus and being infected with a future natural immunization that is better than any man-made vaccinations, we need to stop running away from the virus and insulting it with sanitations and isolations.
4-Therefore it is very urgent to return to our normal manners of life as soon as possible and open what have been closed and start running whatever have been halted and welcome the virus in a friendly manner and in peace.
5-Since the universal spread of the COVID-19 is an obvious sign of the urgency of the virus for a global entry into the human race, the welcoming of the virus has to be a world-wide effort with no resistance.
Hope the above recommendations will be appreciated and put in place urgently before the worse future outbreaks befall on us.
Dr.Mostafa Showraki, MD, FRCPC Lecturer, School of Medicine, University of Toronto
- Dandekar, A; Perlman, S. 2005. “Immunopathogenesis of coronavirus infections: implications for SARS”. Nat Rev Immunol 5 (12): 917–927.
- Su S, Wong G, Shi W, Liu J, Lai AC, Zhou J, Liu W, Bi Y, Gao GF. 2016. Epidemiology, Genetic Recombination, and Pathogenesis of Coronaviruses.Trends Microbiol. pii: S0966-842X(16)00071-8.
- Zumla, A; Hui, DS; Perlman, S. 2015. “Middle East respiratory syndrome.”. Lancet (London, England) 386: 995–1007.
- Chan JF, Lau SK, To KK, Cheng VC, Woo PC, Yuen KY. 2015. “Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease”. Clin Microbiol Rev 28 (2): 465–522.
- Reid CR, Airo AM, Hobman TC. 2015. The Virus-Host Interplay: Biogenesis of +RNA Replication Complexes. Viruses. 7(8):4385-413.
- Benvenuto et al. 2020. The 2019 new Coronavirus epidemic: evidence for virus evolution. bioRxiv.2020.01.24.915157.
7.Hui DS, et al. 2020. The continuing 2019-nCoV epidemic threat of novel coronavirus outbreak in Wuhan, China. Int J Infect Dis. 14;91:264-266.
- Martin, Bradford D.; Schwab, Ernest. 2012. “Symbiosis: ‘Living together’ in chaos”, Studies in the History of Biology, 4 (4): 7–25.
9.Latorre, A.; Durban, A.; Moya, A.; Pereto, J. 2011. The role of symbiosis in eukaryotic evolution. Origins and evolution of life – An astrobiological perspective. pp. 326–339.
- Wernegreen, J.J. 2002. “Genome evolution in bacterial endosymbionts of insects”. Nature Reviews Genetics. 3 (11): 850–861.
- Artis D. 2008. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol. 8:411–420.
- Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. 2005. Host–bacterial mutualism in the human intestine. Science. 307:1915–1920.
- Benson A, Pifer R, Behrendt CL, Hooper LV, Yarovinsky F. 2009. Gut commensal bacteria direct a protective immune response against Toxoplasma gondii. Cell Host Microbe. 6:187–196.
- Bry L, Falk PG, Midtvedt T, Gordon JI. 1996. A model of host–microbial interactions in an open mammalian ecosystem. Science. 273:1380–1383.
- Dethlefsen L, McFall-Ngai M, Relman DA. 2007. An ecological and evolutionary perspective on human–microbe mutualism and disease. Nature. 449:811–818. 16. Edwards D. 2009. The roles of tolerance in the evolution, maintenance and breakdown of mutualism. Naturwissenschaften. 96:1137–1145.
- Ravel J, Gajer P, Abdo Z, et al. 2011. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci USA. 108:4680–87.
- Donders GG, Bosmans E, Dekeersmaecker A, et al. 2000. Pathogenesis of abnormal vaginal bacterial flora. Am J Obstet Gynecol. 182:872–78.
- Martin HL, Richardson BA, Nyange PM, et al. 1999. Vaginal lactobacilli, microbial flora, and risk of human immunodeficiency virus type 1and sexually transmitted disease acquisition. J Infect Dis. 180:1863–68.
- Watts DH, Fazzari M, Minkoff H, et al. 2005. Effects of bacterial vaginosis and other genital infections on the natural history of human papillomavirus infection in HIV-1-infected and high-risk HIV-1-uninfected women. J Infect Dis. 191:1129–39.
- Bao X, Roossinck MJ. 2013. A life history view of mutualistic viral symbioses: quantity or quality forcooperation?Curr. Opin. Microbiol.16:514–18.
- Zablocki O, Ardriaenssens EM, Cowan D. 2016. Diversity and ecology of viruses in hyperarid desertsoils. Appl. Environ. Microbiol.82:770–77.
- Breitbart M, Rohwer F. 2005. Here a virus, there a virus, everywhere the same virus?Trends Microbiol.13:278–84.
- Cavalier-Smith T. 2013. Symbiogenesis: mechanisms, evolutionary consequences, and systemic implications. Annu. Rev. Ecol. Evol. Syst.44:145–72.
- Williamson KE, Radosevich M, Wommack KE. 2005. Abundance and diversity of viruses in six Delaware soils. Appl. Environ. Microbiol.71:3119–25.
- Cowan DA, Makhalanyane TP, Dennis PG, Hopkins DW. 2014. Microbial ecology and biogeochemistry of continental Antarctic soils. Front. Microbiol.5:154.
- Hoffmann HH, Schneider WM, Rice CM. 2015. Interferons and viruses: an evolutionary arms race of molecular interactions.Trends Immunol. 36:124–3.
- 40. Koonin EV, Dolja VV. 2013. A virocentric perspective on the evolution of life. Curr. Opin. Virol.3:546–57.
- Chen X. 2012. Small RNAs in development—insights from plants. Curr. Opin. Genet. Dev.22:361–67.
- Castel SE, Martienssen RA. 2013. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat. Rev. Genet.14:100–12.
- Hembry DH, Yoder JB, Goodman KR. 2014. Coevolution and the diversification of life. Am. Nat.184:425–38.
- Suttle CA. 2013. Viruses: unlocking the greatest biodiversity on Earth. Genome56:542–44.
- Martiny JBH, Riemann L, Marston MF, Middelboe M. 2014. Antagonistic coevolution of marine plank-tonic viruses and their hosts. Annu. Rev. Mar. Sci.6:391–414.
- Dennehy JJ. 2012. What can phages tell us about host-pathogen coevolution? Int. J. Evol. Biol.2012:39616535.
- Engelberg-Kulka H, Glaser G. 1999. Addiction modules and programmed cell death and anti-death in bacterial cultures. Annu. Rev. Microbiol.53:43–70.
- Schmitt MJ, Breinig F. 2006. Yeast viral killer toxins: lethality and self-protection.Nat.Rev.Microbiol.4:212–21.
- Keen EC, Bliskovsky VV, Malagon F, Baker JD, Prince JS, et al. 2017. Novel “superspreader” bacterio-phages promote horizontal gene transfer by transformation.mBio8:e02115-16.
- Gilbert C, Peccoud J, Chateigner A, Moumen B, Cordauz R, Herniou EA. 2016. Continuous influx of genetic material from host to virus populations. PLOS Genet. 12:e1005838.
- Wang X, Kim Y, Ma Q, Hong SH, Polusaeva K, et al. 2010. Cryptic prophages help bacteria cope with adverse environments. Nat. Commun.1:147.
- Obeng N, Pratama AA, van Elsas JD. 2016. The significance of mutualistic phages for bacterial ecology and evolution. Trends Microbiol. 24:440–49.
- Xu P, Chen F, Mannas JP, Feldman T, Sumner LW, Roossinck MJ. 2008. Virus infection improves drought tolerance. New Phytol. 180:911–21.
- M ́arquez LM, Redman RS, Rodriguez RJ, Roossinck MJ. 2007. A virus in a fungus in a plant—three-ways symbiosis required for thermal tolerance.Science315:513–15.
- Belliure B, Sabelis MW, Janssen A. 2010. Vector and virus induce plant responses that benefit a non-vector herbivore. Basic Appl. Ecol.11:162–69.
- Barton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M, et al. 2007. Herpes virus latency confers symbiotic protection from bacterial infection. Nature447:326–30.
- White DW, Keppel CR, Schnieder SE, Reese TA, Coler J, et al. 2010. Latent herpes virus infection arms NK cells.Blood115:4377–83.
- Furman D, Jojic V, Sharma S, Shen-Orr SS, Angel CJ, et al. 2015. Cytomegalovirus infection improves the immune responses to influenza. Sci. Transl. Med.7:281ra43.
- Sandalova E, Laccabue D, Boni C, Tan AT, Fink K, et al. 2010. Contribution of herpes virus specific CD8 T cells to antiviral T cell response in humans. PLOS Pathog. 6:e1001051.
- Patel MR, Emerman M, Malik HS. 2011. Paleovirology—ghosts and gifts of viruses past. Curr. Opin.Virol.1:304–9.
- Katzourakis A. 2013. Paleovirology: inferring viral evolution from host genome sequence data. Philos.Trans. R. Soc. B369:20120493.
- Strand MR, Burke GR. 2015. Polydnaviruses: from discovery to current insights.Virology479–80:393–402.
- Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, et al. 2001. Initial sequencing and analysis of the human genome.Nature409:860–921.
52.Stoye JP. 2012. Studies of endogenous retroviruses reveal a continuing evolutionary saga. Nat. Rev.Microbiol.10:395.
53.Johnson WE. 2015. Endogenous retroviruses in the genomics era. Annu. Rev. Virol.2:135–59.
54.Chuong EB, Elde NC, Feschotte C. 2016. Regulatory evolution of innate immunity through co-option of endogenous retroviruses.Science351:1083–87.
- Malfavon-Borja R, Feschotte C. 2015. Fighting fire with fire: endogenous retrovirus envelopes as restriction factors. J. Virol.89:4047–50.
- Liu H, Fu Y, Jiang D, Li G, Xie J, et al. 2010. Widespread horizontal gene transfer from double-stranded RNA viruses to eukaryotic nuclear genomes. J.Virol.84:11879–87.
57.Belyi VA, Levine AJ, Skalka AM. 2010. Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: The Parvoviridae and Circoviridaeare more than 40 to 50 million years old. J. Virol.84:12458–62.
- Aiewsakun P, Katzourakis A. 2015. Endogenous viruses: connecting recent and ancient viral evolution.Virology479–80:26–37.
- Feschotte C, Gilbert C. 2012. Endogenous viruses: insights into viral evolution and impact on host biology. Nat. Rev. Genet.13:283–96.
- Koonin EV. 2006. On the origin of cells and viruses: a comparative-genomic perspective. Isr. J. Ecol.Evol.52:299–318.
- Guerrero R, Margulis L, Berlanga M. 2013. Symbiogenesis: the holobiont as a unit of evolution.Int.Microbiol.16:133–43.
- Meyerson NR, Sawyer SL. 2011. Two-stepping through time: mammals and viruses. Trends Microbiol.19:286–9425.
- Li C, Shi M, Tian J, Lin X, Kang Y, et al. 2015. Unprecedented genomic diversity of RNA viruses in arthropods reveals the ancestor of negative sense RNA viruses.eLife4:e05378.
64.Johnson, R. B.1986. Human disease and the evolution of pathogen virulence. J. Theor. Biol.122:19–24.
- Chen W, Baric RS. 1996. Molecular anatomy of mouse hepatitis virus persistence: coevolution of increased host cell resistance and virus virulence. J Virol. 70(6):3947–3960.
- Ar Gouilh M, Puechmaille SJ, Diancourt L, Vandenbogaert M, Serra-Cobo
J, Lopez Roïg M, Brown P, Moutou F, Caro V, Vabret A,Manuguerra JC; EPICOREM consortium. 2018. SARS-CoV related Betacoronavirus and diverse Alphacoronavirus members found in western old-world. Virology. 517:88-97.
- Letko M, Miazgowicz K, McMinn R, Seifert SN, Sola I, Enjuanes
L, Carmody A, van Doremalen N, Munster V. 2018. Adaptive Evolution of MERS-CoV to Species Variation in DPP4. Cell Rep. 24(7):1730-1737.
- Koonpaew S, Teeravechyan S, Frantz PN, Chailangkarn T, Jongkaewwattana A. 2019. PEDV and PDCoV Pathogenesis: The Interplay Between Host Innate Immune Responses and Porcine Enteric Coronaviruses. Front Vet Sci. 6:34.
- Wertheim JO, Chu DK, Peiris JS, Kosakovsky Pond SL, Poon LL. 2013. A case for the ancient origin of coronaviruses. J Virol. 87(12):7039–7045.
- Brandão PE. 2018. Could human coronavirus OC43 have co-evolved with early humans?. Genet Mol Biol. 41(3):692–698.
- Bahir I, Fromer M, Prat Y, Linial M. 2009. Viral adaptation to host: a proteome-based analysis of codon usage and amino acid preferences. Mol Syst Biol. 5:311.
- Bidokhti MR, Tråvén M, Krishna NK, Munir M, Belák S, Alenius S, Cortey M. 2013. Evolutionary dynamics of bovine coronaviruses: Natural selection pattern of the spike gene implies adaptive evolution of the strains. J Gen Virol. 94:2036–2049.
- Borucki MK, Allen JE, Chen-Harris H, Zemla A, Vanier G, Mabery S, Torres C, Hullinger P, Slezak T. 2013. The role of viral population diversity in adaptation of bovine coronavirus to new host environments. PLoS One. 8:e52752.
- Denison MR, Graham RL, Donaldson EF, Eckerle LD, Baric RS. 2011. Coronaviruses: An RNA proofreading machine regulates replication fidelity and diversity. RNA Biol. 8:270–279.
- Gandon S, Hochberg ME, Holt RD, Day T. 2013. What limits the evolutionary emergence of pathogens? Philos Trans R Soc Lond B Biol Sci. 368:20120086.
- Snijder EJ, Bredenbeek PJ, Dobbe JC, Thiel V, Ziebuhr J, Poon LL, Guan Y, Rozanov M, Spaan WJ, Gorbalenya AE. 2003. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol. 331:991–1004.
- Vabret A, Dina J, Mourez T, Gouarin S, Petitjean J, van der Werf S, Freymuth F. 2006. Inter- and intra-variant genetic heterogeneity of human coronavirus OC43 strains in France. J Gen Virol. 87:3349–3353.
- Vijgen L, Keyaerts E, Lemey P, Moës E, Li S, Vandamme AM, Van Ranst M. 2005a. Circulation of genetically distinct contemporary human coronavirus OC43 strains. Virology. 337:85–92.
- Vijgen L, Keyaerts E, Moës E, Thoelen I, Wollants E, Lemey P, Vandamme AM, Van Ranst M. 2005b. Complete genomic sequence of human coronavirus OC43: Molecular clock analysis suggests a relatively recent zoonotic coronavirus transmission event. J Virol. 79:1595–1604.
- Kin N, Miszczak F, Lin W, Gouilh MA, Vabret A; EPICOREM Consortium. 2015. Genomic Analysis of 15 Human Coronaviruses OC43 (HCoV-OC43s) Circulating in France from 2001 to 2013 Reveals a High Intra-Specific Diversity with New Recombinant Genotypes. Viruses. 7(5):2358–2377. Published 2015 May 7.
- Hu Q, Lu R, Peng K, et al. 2014. Prevalence and genetic diversity analysis of human coronavirus OC43 among adult patients with acute respiratory infections in Beijing, 2012. PLoS One. 9(7):e100781.