Lucy van Dorp, Mislav Acman, Damien Richard, Liam P. Shaw, Charlotte E. Ford, Louise Ormond, Christopher J. Owen, Juanita Pang, Cedric C. S. Tan, Florencia A. T. Boshier, Arturo Torres Ortiz and François Balloux.
Emergence of genomic diversity and recurrent mutations in SARS-CoV-2.
– Phylogenetic estimates support that the COVID-2 pandemic started sometimes around 6 October 2019–11 December 2019, which corresponds to the time of the host-jump into humans.
– The diversity of SARS-CoV-2 strains in many countries recapitulates its full global diversity, consistent with multiple introductions of the virus to regions throughout the world seeding local transmission events.
– 198 sites in the SARS-CoV-2 genome appear to have already undergone recurrent, independent mutations based on a large-scale analysis of public genome assemblies.
– Detected recurrent mutations may indicate ongoing adaptation of SARS-CoV-2 to its novel human host.
-Monitoring the build-up and patterns of genetic diversity in SARS-CoV-2 has potential to inform targets for drug and vaccine development.»
SARS-CoV-2 is a SARS-like coronavirus of likely zoonotic origin first identified in December 2019 in Wuhan, the capital of China’s Hubei province. The virus has since spread globally, resulting in the currently ongoing COVID-19 pandemic. The first whole genome sequence was published on January 52,020, and thousands of genomes have been sequenced since this date. This resource allows unprecedented insights into the past demography of SARS-CoV-2 but also monitoring of how the virus is adapting to its novel human host, providing information to direct drug and vaccine design. We curated a dataset of 7666 public genome assemblies and analysed the emergence of genomic diversity over time. Our results are in line with previous estimates and point to all sequences sharing a common ancestor towards the end of 2019, supporting this as the period when SARS-CoV-2 jumped into its human host. Due to extensive transmission, the genetic diversity of the virus in several countries recapitulates a large fraction of its worldwide genetic diversity. We identify regions of the SARS-CoV-2 genome that have remained largely invariant to date, and others that have already accumulated diversity. By focusing on mutations which have emerged independently multiple times (homoplasies), we identify 198 filtered recurrent mutations in the SARS-CoV-2 genome. Nearly 80% of the recurrent mutations produced non-synonymous changes at the protein level, suggesting possible ongoing adaptation of SARS-CoV-2. Three sites in Orf1ab in the regions encoding Nsp6, Nsp11, Nsp13, and one in the Spike protein are characterised by a particularly large number of recurrent mutations (>15 events) which may signpost convergent evolution and are of particular interest in the context of adaptation of SARS-CoV-2 to the human host. We additionally provide an interactive user-friendly web-application to query the alignment of the 7666 SARS-CoV-2 genomes.»
3.1. Emergence of SARS-CoV-2 genomic diversity over time
The 7666 SARS-CoV-2 genomes offer an excellent geographical and temporal coverage of the COVID-19 pandemic ….
These 198 positions in the SARS-CoV-2 genome alignment (0.67% of all sites) were associated with 290 amino acid changes across all 7666 genomes. Of these amino acid changes, 232 comprised non-synonymous and 58 comprised synonymous mutations.»
Modern drug and vaccine development are largely based on genetic engineering and an understanding of host-pathogen interactions at a molecular level. ….
This unprecedented genomic resource has already provided strong conclusions about the pandemic. For example, analyses by multiple independent groups place the start of the COVID-19 pandemic towards the end of 2019. This rules out any scenario that assumes SARS-CoV-2 may have been in circulation long before it was identified, and hence have already infected large proportions of the population. ….
As most (but not all) pathogens capable of causing epidemic at a pandemic scale, SARS-CoV-2 is in all likelihood of zoonotic origin. ….
The vast majority of mutations observed so far in SARS-CoV-2 circulating in humans are likely neutral (Cagliani et al., 2020; Dearlove et al., 2020) or even deleterious (Nielsen et al., 2020). ….
While the immune response to SARS-CoV-2 is poorly understood at this point, key roles for CD4 T cells, which activate B cells for antibody production, and cytotoxic CD8 T cells, which kill virus-infected cells, are known to be important in mediating clearance in respiratory viral infections (Kohlmeier and Woodland, 2009). ….
However, given the crucial importance of identifying potential signatures of adaptation in SARS-CoV-2 for guiding ongoing development of vaccines and treatments, we have suggested what we believe to be a plausible approach and initial list in order to facilitate future work and interpretation of the observed patterns.»
* * * * * * *
Questo è uno studio squisitamente genetico, che volutamente non entra nelle implicanze cliniche.
Queste sono tuttavia evidenti.
Ogni mutazione genera sue proprie difese immunitarie ed anticorpi specifici. A ciò consegue l’attuale impossibilità di un uso estensivo di trattamenti con plasma di pazienti guariti, che agirebbero solo su di un determinato ceppo: ma al momento ne sono stati identificati 198.
La pluralità delle mutazioni costituisce inoltre un grande ostacolo nella messa a punto di un vaccino che possa agire in tutte le situazioni.