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Identification of Evolutionary Trajectories Shared across Human Betacoronaviruses

Escalera-Zamudio, Marina; Kosakovsky Pond, Sergei L; Martínez de la Viña, Natalia; Gutiérrez, Bernardo; Inward, Rhys P D; Thézé, Julien; van Dorp, Lucy; Castelán-Sánchez, Hugo G; Bowden, Thomas A; Pybus, Oliver G; Hulswit, Ruben J G


Marina Escalera-Zamudio

Sergei L Kosakovsky Pond

Natalia Martínez de la Viña

Bernardo Gutiérrez

Rhys P D Inward

Julien Thézé

Lucy van Dorp

Hugo G Castelán-Sánchez

Thomas A Bowden

Oliver G Pybus

Ruben J G Hulswit


Adam Eyre-Walker


Comparing the evolution of distantly related viruses can provide insights into common adaptive processes related to shared ecological niches. Phylogenetic approaches, coupled with other molecular evolution tools, can help identify mutations informative on adaptation, although the structural contextualization of these to functional sites of proteins may help gain insight into their biological properties. Two zoonotic betacoronaviruses capable of sustained human-to-human transmission have caused pandemics in recent times (SARS-CoV-1 and SARS-CoV-2), although a third virus (MERS-CoV) is responsible for sporadic outbreaks linked to animal infections. Moreover, two other betacoronaviruses have circulated endemically in humans for decades (HKU1 and OC43). To search for evidence of adaptive convergence between established and emerging betacoronaviruses capable of sustained human-to-human transmission (HKU1, OC43, SARS-CoV-1, and SARS-CoV-2), we developed a methodological pipeline to classify shared nonsynonymous mutations as putatively denoting homoplasy (repeated mutations that do not share direct common ancestry) or stepwise evolution (sequential mutations leading towards a novel genotype). In parallel, we look for evidence of positive selection and draw upon protein structure data to identify potential biological implications. We find 30 candidate mutations, from which 4 (codon sites 18121 [nsp14/residue 28], 21623 [spike/21], 21635 [spike/25], and 23948 [spike/796]; SARS-CoV-2 genome numbering) further display evolution under positive selection and proximity to functional protein regions. Our findings shed light on potential mechanisms underlying betacoronavirus adaptation to the human host and pinpoint common mutational pathways that may occur during establishment of human endemicity.


Escalera-Zamudio, M., Kosakovsky Pond, S. L., Martínez de la Viña, N., Gutiérrez, B., Inward, R. P. D., Thézé, J., …Hulswit, R. J. G. (2023). Identification of Evolutionary Trajectories Shared across Human Betacoronaviruses. Genome Biology and Evolution, 15(6),

Journal Article Type Article
Acceptance Date Apr 21, 2023
Online Publication Date May 23, 2023
Publication Date Jun 1, 2023
Deposit Date Jul 10, 2024
Publicly Available Date Jul 10, 2024
Journal Genome Biology and Evolution
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 15
Issue 6
Keywords molecular evolution, phylogenomics, convergence, adaptation, betacoronaviruses


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