{
  "abstract": "In this work, we aimed to synthesize the analyses we conducted during the SARS-CoV-2 epidemic, which was associated with the largest number of viral genome sequences ever generated, with a particular focus on the evolution of the SARS-CoV-2 Spike protein. Indeed, during previous epidemics caused by emerging viruses, very few genomic sequences were generated and published. In the context of COVID-19, our ability to monitor both the clinical course of patients and the genomic evolution of the viruses responsible for successive epidemic waves over time, owing to patient recruitment at our institute (IHU) and our capacity to perform high-throughput sequencing in real time with >60,000 SARS-CoV-2 genomes obtained between February 2020 and October 2022, led us to revisit several concepts using figurative terminology of our own, which had been clearly defined in previous publications (“Red queen model”, “Court Jester model”, “Cheshire cat paradigm,” “Mistigri,” “wild bunch”, “democratic” versus “non-democratic”, “fertile” and “outlaw” mutations, “boomerang effect”, “selective sweep”, and “Interventionist therapy” hypothesis). These terms (Box 1) were intended not merely as memorable labels, but as conceptual tools to help communicate evolutionary phenomena that are otherwise often described through highly specialized genetic terminology, such as intrahost single-nucleotide variants, purifying selection, positive selection, epistatic fitness, spillover, spillback and evolutionary bottlenecks), thereby making these concepts accessible to a broader audience and provide an intuitive entry point into these dynamics. This work synthesizes the various conceptual developments arising from the full range of evolutionary changes we were able to observe through this unique experience with an emerging virus and challenged several conventional assumptions about how SARS-CoV-2 adapt and spread. The successive waves of SARS-CoV-2 do not reflect a static pathogen spreading through a uniform human population, but an evolving virus navigating in genetically diverse human and animal species and frequently shifting of biological environments (which refers to «the circulation theory»). It is worth noting, that most SARS-CoV-2 genomes available in public databases represent democratic (consensus) sequences and therefore are virtual genomes bioinformatically generated from next-generation sequencing reads far shorter than the genome length and consisting of a succession of the most prevalent nucleotides harbored by those reads at each position of the reconstructed genome. However, one should not neglect the «minority reports», consisting of genomes harboring less prevalent nucleotides but that contributes to the diversity of the intra-host viral quasispecies, a «wild bunch» of viruses that truly supports the evolution of viral lineage. Leveraging ultra–high-throughput sequencing, we analyzed both consensus and low- abundance (non-democratic) genomes across the COVID-19 pandemic and identified a small subset of «hyperfertile and fertile» mutations that generate, by selective sweep, disproportionately large viral lineages spreading worldwide. We also reported «neutral» or «weakly deleterious» mutations that arise within viral genomes without conferring a selective advantage to the virus but that, in contrast, will promote lineage disappearance when approximately 7-8 of such mutations had accumulated. Finally, we described «outlaw» mutations (never observed in the democratic sequences) that are dead ends for virus lineages for which they occur. We further show that successful mutations preferentially arise in RNA loop regions, implicating RNA secondary structure as a key determinant of evolutionary success. In fact, some synonymous mutations can confer be deleterious or advantageous for viruses. These findings highlight the central role of hidden viral diversity (non-democratic individual genomes found within quasispecies) in shaping SARS-CoV-2 evolutionary dynamics. In a shifting landscape, the evolution of SARS-CoV-2 has been profoundly shaped by selective pressures in each infected individual (ACE2 polymorphism, anti-spike immune response, interferon responses, monoclonal antibodies, vaccine, antiviral treatment) and cross-species transmission allowing the virus to explore alternative adaptive pathways before potential reintroduction into new human subpopulations (the «boomerang effect theory») leading to emergence of new variants monitored over time in different epidemics waves in humans. Importantly, mutations preexist to selection. Every infection thus represents a unique ecosystem and minority variants in one host may become majority ones in another host if they confer higher fitness in this new ecosystem. Variants such as B.1.160, Alpha, Delta, or Omicron emerged within specific epidemiological and immunological contexts that favored their mutation profiles. Thus, pandemic waves represent transient equilibria in a multilevel evolutionary system that defines a Go/No-Go model for each mutant viral genome within a complex ecosystem. Viral fitness is relational, shaped by host genetics, immune pressures, cross-species transmission, and ongoing ecological change.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "name": "Christian A Devaux"
    },
    {
      "name": "Philippe Colson"
    },
    {
      "name": "Jacques Fantini"
    },
    {
      "name": "Didier Raoult"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0b5kc1syy2bwq.bib",
  "cited_by": 0,
  "doi": null,
  "fulltext_url": null,
  "id": "0b5kc1syy2bwq",
  "issns": [],
  "landing_url": "https://amu.hal.science/hal-05696667v2",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://amu.hal.science/hal-05696667/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-26",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/0b5kc1syy2bwq.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:01Z",
      "native_id": "hal-05696667",
      "source": "hal",
      "url": "https://amu.hal.science/hal-05696667v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "hal:0.sdv",
      "subfield": "general"
    }
  ],
  "title": "The evolutionary dynamics of SARS-CoV-2 and their spikes: personal views",
  "title_text": "The evolutionary dynamics of SARS-CoV-2 and their spikes: personal views",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:01Z",
  "url": "https://research.draconitic.com/paper/0b5kc1syy2bwq",
  "venue": "HAL",
  "versions": []
}