Incipient functional SARS-CoV-2 diversification identified through neural network haplotype maps

Author:

Delgado Soledad1,Somovilla Pilar23,Ferrer-Orta Cristina4,Martínez-González Brenda56,Vázquez-Monteagudo Sergi4,Muñoz-Flores Javier7,Soria María Eugenia26,García-Crespo Carlos2ORCID,de Ávila Ana Isabel2,Durán-Pastor Antoni5,Gadea Ignacio6,López-Galíndez Cecilio8,Moran Federico9,Lorenzo-Redondo Ramon10,Verdaguer Nuria4ORCID,Perales Celia56,Domingo Esteban2ORCID

Affiliation:

1. Departamento de Sistemas Informáticos, Escuela Técnica Superior de Ingeniería de Sistemas Informáticos, Universidad Politécnica de Madrid, Madrid 28031, Spain

2. Microbes in Health and Welfare Program, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain

3. Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid 28049, Spain

4. Structural and Molecular Biology Department, Institut de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona 08028, Spain

5. Department of Molecular and Cell Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid 28049, Spain

6. Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, Madrid 28040, Spain

7. Global Management Solutions S.L., Torre Picasso, Madrid 28020, Spain

8. Unidad de Virología Molecular, Laboratorio de Referencia e Investigación en retrovirus, Centro Nacional de Microbiología, Instituto de salud Carlos III, Majadahonda 28222, Spain

9. Departamento de Bioquímica y Biología Molecular, Universidad Complutense de Madrid, Madrid 28040, Spain

10. Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Center for Pathogen Genomics and Microbial Evolution, Northwestern University Havey Institute for Global Health, Chicago, IL 60611

Abstract

Since its introduction in the human population, SARS-CoV-2 has evolved into multiple clades, but the events in its intrahost diversification are not well understood. Here, we compare three-dimensional (3D) self-organized neural haplotype maps (SOMs) of SARS-CoV-2 from thirty individual nasopharyngeal diagnostic samples obtained within a 19-day interval in Madrid (Spain), at the time of transition between clades 19 and 20. SOMs have been trained with the haplotype repertoire present in the mutant spectra of the nsp12- and spike (S)-coding regions. Each SOM consisted of a dominant neuron (displaying the maximum frequency), surrounded by a low-frequency neuron cloud. The sequence of the master (dominant) neuron was either identical to that of the reference Wuhan-Hu-1 genome or differed from it at one nucleotide position. Six different deviant haplotype sequences were identified among the master neurons. Some of the substitutions in the neural clouds affected critical sites of the nsp12-nsp8-nsp7 polymerase complex and resulted in altered kinetics of RNA synthesis in an in vitro primer extension assay. Thus, the analysis has identified mutations that are relevant to modification of viral RNA synthesis, present in the mutant clouds of SARS-CoV-2 quasispecies. These mutations most likely occurred during intrahost diversification in several COVID-19 patients, during an initial stage of the pandemic, and within a brief time period.

Funder

Ministerio de Ciencia e Innovación

MEC | Instituto de Salud Carlos III

Ministerio de Ciencia e Innovacion

Comunidad de Madrid

Fundació la Marató de TV3

MINECO

Ministerio de Ciencia, Innovación y Universidades

Publisher

Proceedings of the National Academy of Sciences

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