key: cord-0774168-sgmt6gja authors: Laiton-Donato, K.; Usme-Ciro, J. A.; Franco-Munoz, C.; Alvarez-Diaz, D. A.; Ruiz-Moreno, H. A.; Reales-Gonzalez, J.; Prada, D. A.; Corchuelo, S.; Herrera-Sepulveda, M. T.; Naizaque, J.; Santamaria, G.; Wiesner, M.; Walteros, D. M.; Ospina Martinez, M. L.; Marcela Mercado-Reyes, M. title: Novel highly divergent SARS-CoV-2 lineage with the Spike substitutions L249S and E484K date: 2021-03-15 journal: nan DOI: 10.1101/2021.03.12.21253000 sha: b2442455dbc329306d26e6151a13674de6dc6ccc doc_id: 774168 cord_uid: sgmt6gja COVID-19 pandemics has led to genetic diversification of SARS-CoV-2 and the appearance of variants with potential impact in transmissibility and viral escape from acquired immunity. We report a new lineage containing ten amino acid changes across the genome. Further studies are required for monitoring its epidemiologic impact. COVID-19 continues challenging the health system abroad. After the emergence of SARS-CoV-2 in China in late 2019 and despite the rapid international response once the WHO declared it as a Public Health Emergency of International Concern (PHEIC), the virus rapidly crossed the borders, started autochthonous transmission in every country and spread locally despite the strict lockdown measures (1) . The enormous population size of SARS-CoV-2 at the global level and its RNA nature has led to the rapid accumulation of genetic variability as more than 800 lineages (2, 3) . Some lineages or genetic variants have special attention due to the rapid increase in frequency in some areas (4) , abnormally high mutation accumulation across the genome, most amino acid changes affecting the spike protein, evidence for evolutionary convergence of some critical changes and increasing evidence for virus escape to the antibody-mediated immunity (5) . As the genomic information is being deposited in public databases, more lineages of special attention are being reported (https://github.com/cov-lineages/pango-designation/issues) and a very high and increasing number of lineages containing the E484K substitution in the Spike protein have been reported to emerge independently at least 68 times and worldwide (Table 2) . Further studies are required to assess the functional role of these mutations and to monitor their epidemiologic impact. In Colombia, SARS-CoV-2 genomic surveillance was established early during the pandemic, leading to the identification of the importation of at least 12 lineages before international flight cancellation and during lockdown. A 48% of SARS-CoV-2 sequences were assigned the B.1 parental lineage with little or no shared mutations accumulated . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Here we report a novel and highly divergent lineage with 21 characteristic The large list of distinctive mutations at the nucleotide and protein levels ( Table 1) are consistent with the existence of a common recent ancestor for the Colombian sequences and three other reported sequences from USA (2 sequences) and Belgium (1 sequence). The intra-lineage and between-lineages p-distances suggest a drastic divergence of the new lineage from the most closely related lineages (Appendix 2 Table S1 ). While increasing the sample size could help to reconstruct the gradual accumulation of mutations leading to divergence from the B.1.111 ancestor, a plausible explanation for the origin of this new lineage could also be the existence of a strong selection pressure on the virus population in an unknown context (e.g., natural infection in a population reaching herd immunity, convalescent plasma or monoclonal antibodies treatment, chronic infection in immunocompromised patients, replication in a different vertebrate species, etc.) (5, (7) (8) (9) . The result of the analysis by IFEL and MEME (using a . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 2 Table S2 ). The presence of E484K located at the receptor binding domain (RBD) is of special relevance as it has been associated to the phenotypic properties of two well described lineages, B.1.1.28 and B.1.351 and it is being suggested to be responsible for a considerably lower neutralizing activity in vitro from convalescent plasma (8, 10, 11) , although the cell-mediated immunity could not be affected by the distinctive mutations (12). In the same way, S249L is located at the N-terminal domain (NTD), the second domain most frequently targeted by neutralizing antibodies (11) . The potential impact of other changes in critical proteins for viral replication (e.g., Helicase, 2'-O-ribose methyltransferase, etc.) is to be determined. Despite increasing effort in the routine genomic surveillance in Colombia, the new lineage has only been detected from samples collected during late December to mid-January mainly from the Caribbean region of the country, which supposes a major effort is necessary to determine the epidemiologic contribution in the different cities. An obligatory question that arises from the current analysis of the novel lineage and the evidence of 68 lineages with the evolutionary convergence at the Spike amino acid E484K is related to the context of the emergence of highly divergent lineages, and the selection of specific substitutions. The fact that some amino acid changes have appeared independently in these lineages is not plausibly explained by chance, but probably by the result of a selective immune pressure. Many hypotheses have been raised without conclusive support. One of them is related to the chronic infection in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 15, 2021. ; https://doi.org/10.1101/2021.03.12.21253000 doi: medRxiv preprint immunocompromised patients and the administration of under-neutralizing antibody titers during convalescent plasma or monoclonal antibody therapies (7, (13) (14) (15) ). In the context of pandemic spread of the virus, an enormous virus population size is expected, as it is also the emergence of virus variants that could also make possible the emergence of antibody-resistant mutants in the context of natural infection in immunocompetent people. It is necessary to evaluate the impact of this genetic background in the neutralization efficacy of convalescent sera/plasma from acquired immunity. In The authors thank the National Laboratory Network for routine virologic surveillance of SARS-CoV-2 in Colombia. We also thank all researchers who deposited genomes in GISAID's EpiCoV Database contributing to genomic diversity and phylogenetic relationship of SARS-CoV-2. We thank Rotary International and Charlie Rut Castro for . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 15, 2021. ; https://doi.org/10.1101/2021.03.12.21253000 doi: medRxiv preprint equipment's donation. Finally, we thank red RENATA and Universidad Industrial de Santander for the bioinformatic assistance. This work was funded by the Project CEMIN-4-2020 Instituto Nacional de Salud. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 15, 2021. ; https://doi.org/10.1101/2021.03.12.21253000 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted March 15, 2021. ; https://doi.org/10.1101/2021.03.12.21253000 doi: medRxiv preprint Global coordination on crossborder travel and trade measures crucial to COVID-19 response A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology Center for Infectious Disease Research and Policy (CIDRAP) Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants Respiratory Syndrome Coronavirus 2, Colombia. Emerg Infect Dis The impact of Spike mutations on SARS-CoV-2 neutralization 1 Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies. bioRxiv SARS-CoV-2 evolution during treatment of chronic infection Escape of SARS-CoV-2 501Y.V2 variants from neutralization by convalescent plasma. medRxiv SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma South Africa 2020-10-06 B.1.486 USA 2020-10-22 the author/funder, who has granted medRxiv a license to display the preprint in perpetuity Analysis performed for the sequences available up to February 14 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 15, 2021. ; https://doi.org/10.1101/2021.03.12.21253000 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted March 15, 2021. ; https://doi.org/10.1101/2021.03.12.21253000 doi: medRxiv preprint