Convergent Evolution of Multiple Mutations Improves the Viral Fitness of SARS-CoV-2 Variants by Balancing Positive and Negative Selection

Upadhyay, Vaibhav; Patrick, Casey; Lucas, Alexandra; Mallela, Krishna

doi:10.1021/acs.biochem.2c00132

Cited by 15 publications

(15 citation statements)

References 67 publications

(100 reference statements)

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“…To do this we need to choose a selection model. The circumstances in which the Omicron variant evolved are unknown, and the evolutionary fitness of the virus is more complex than its capacity to bind ACE2 – immune pressure, structural stability, and expression level also play a role, among many other factors 46 . In addition, back-mutations are common in viral evolution and selection pressure can change depending on whether the strain is switching hosts rapidly or part of a long-term infection.…”

Section: Methodsmentioning

confidence: 99%

Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

et al. 2022

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The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to the earlier SARS-CoV-2 variants, BA.1 has many mutations, some of which are known to enable antibody escape. Many of these antibody-escape mutations individually decrease the spike receptor-binding domain (RBD) affinity for ACE2, but BA.1 still binds ACE2 with high affinity. The fitness and evolution of the BA.1 lineage is therefore driven by the combined effects of numerous mutations. Here, we systematically map the epistatic interactions between the 15 mutations in the RBD of BA.1 relative to the Wuhan Hu-1 strain. Specifically, we measure the ACE2 affinity of all possible combinations of these 15 mutations (215 = 32,768 genotypes), spanning all possible evolutionary intermediates from the ancestral Wuhan Hu-1 strain to BA.1. We find that immune escape mutations in BA.1 individually reduce ACE2 affinity but are compensated by epistatic interactions with other affinity-enhancing mutations, including Q498R and N501Y. Thus, the ability of BA.1 to evade immunity while maintaining ACE2 affinity is contingent on acquiring multiple interacting mutations. Our results implicate compensatory epistasis as a key factor driving substantial evolutionary change for SARS-CoV-2 and are consistent with Omicron BA.1 arising from a chronic infection.

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Section: Methodsmentioning

confidence: 99%

Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

et al. 2022

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“…In the pre-Omicron and pre-vaccine era, variants of concern (VOCs) notably converged to mutations which resulted in the following amino acid changes: K417N, L452R, E484K, N501Y, and P681X [20]. These amino acid changes have been proposed to increase the stability of the trimeric protein [21][22][23], and they emerged in the absence of significant selective pressures by the immune system. K417N, E484A, N501Y and P681H remained hallmarks of BA.2.…”

Section: Convergent Evolutionmentioning

confidence: 99%

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Focosi¹,

Quiroga

McConnell

et al. 2022

Preprint

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The first 2 years of the COVID-19 pandemic were mainly characterized by convergent evolution of mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 across different variants of concern (Alpha, Beta, Gamma, and Delta). Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and reevaluate the potential for polyclonal therapies (such as COVID19 convalescent plasma) in immunocompromised patients.

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“…To do this we need to choose a selection model. The circumstances in which the Omicron variant evolved are unknown, and the evolutionary fitness of the virus is more complex than its capacity to bind ACE2 – immune pressure, structural stability, and expression level also play a role, among many other factors 40 . In addition, back-mutations are common in viral evolution and selection pressure can change depending on whether the strain is switching hosts rapidly or part of a long-term infection.…”

Section: Methodsmentioning

confidence: 99%

Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

Moulana

Dupic

Phillips

et al. 2022

Preprint

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The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to the ancestral Wuhan Hu-1 strain and other pre-Omicron SARS-CoV-2 variants, BA.1 has many mutations, a number of which are known to enable antibody escape. Many of these antibody-escape mutations individually decrease the spike receptor-binding domain (RBD) affinity for ACE2 in the background of early SARS-CoV-2 variants, but BA.1 still binds ACE2 with high affinity. The fitness and evolution of the BA.1 lineage is therefore driven by the combined effects of numerous mutations. Here, we systematically map the epistatic interactions between the 15 mutations in the RBD of BA.1 relative to the Wuhan Hu-1 strain. Specifically, we measure the ACE2 affinity of all possible combinations of these 15 mutations (215 = 32,768 genotypes), spanning all possible evolutionary intermediates from the ancestral Wuhan Hu-1 strain to BA.1. We find that immune escape mutations in BA.1 individually reduce ACE2 affinity but are compensated by epistatic interactions with other affinity-enhancing mutations, including Q498R and N501Y. Thus, the ability of BA.1 to evade immunity while maintaining ACE2 affinity is contingent on acquiring multiple interacting mutations. Our results implicate compensatory epistasis as a key factor driving substantial evolutionary change for SARS-CoV-2 and are consistent with Omicron BA.1 arising from a chronic infection.

show abstract

Convergent Evolution of Multiple Mutations Improves the Viral Fitness of SARS-CoV-2 Variants by Balancing Positive and Negative Selection

Cited by 15 publications

References 67 publications

Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

Convergent evolution in SARS-CoV-2 Spike creates a variant soup that causes new COVID-19 waves

Compensatory epistasis maintains ACE2 affinity in SARS-CoV-2 Omicron BA.1

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