A pseudovirus system enables deep mutational scanning of the full SARS-CoV-2 spike

Cell, Journal Year: 2023, Volume and Issue: 186(6), P. 1263 - 1278.e20

Published: Feb. 13, 2023

A major challenge in understanding SARS-CoV-2 evolution is interpreting the antigenic and functional effects of emerging mutations viral spike protein. Here, we describe a deep mutational scanning platform based on non-replicative pseudotyped lentiviruses that directly quantifies how large numbers impact antibody neutralization pseudovirus infection. We apply this to produce libraries Omicron BA.1 Delta spikes. These each contain ∼7,000 distinct amino acid context up ∼135,000 unique mutation combinations. use these map escape from neutralizing antibodies targeting receptor-binding domain, N-terminal S2 subunit spike. Overall, work establishes high-throughput safe approach measure ∼10

Language: Английский

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Convergent Evolution in SARS-CoV-2 Spike Creates a Variant Soup from Which New COVID-19 Waves Emerge

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2264 - 2264

Published: Jan. 23, 2023

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

Language: Английский

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A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes

Nature, Journal Year: 2023, Volume and Issue: 623(7987), P. 594 - 600

Published: Sept. 25, 2023

Molnupiravir, an antiviral medication widely used against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acts by inducing mutations in the virus genome during replication. Most random are likely to be deleterious and many will lethal; thus, molnupiravir-induced elevated mutation rates reduce viral load1,2. However, if some patients treated with molnupiravir do not fully clear SARS-CoV-2 infections, there could potential for onward transmission of molnupiravir-mutated viruses. Here we show that sequencing databases contain extensive evidence mutagenesis. Using a systematic approach, find specific class long phylogenetic branches, distinguished high proportion G-to-A C-to-T mutations, found almost exclusively sequences from 2022, after introduction treatment, countries age groups widespread use drug. We identify mutational spectrum, preferred nucleotide contexts, viruses known have been its signature matches seen these cases molnupiravir-derived lineages. Finally, analyse treatment records confirm direct association between branches molnupiravir.

Language: Английский

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Fitness effects of mutations to SARS-CoV-2 proteins

Virus Evolution, Journal Year: 2023, Volume and Issue: 9(2)

Published: July 1, 2023

Knowledge of the fitness effects mutations to SARS-CoV-2 can inform assessment new variants, design therapeutics resistant escape, and understanding functions viral proteins. However, experimentally measuring is challenging: we lack tractable lab assays for many proteins, comprehensive deep mutational scanning has been applied only two Here, develop an approach that leverages millions publicly available sequences estimate mutations. We first calculate how independent occurrences each mutation are expected be observed along phylogeny in absence selection. then compare these observations actual effect mutation. These estimates correlate well with measurements. For most genes, synonymous nearly neutral, stop-codon deleterious, amino acid have a range effects. some accessory proteins under little no provide interactive visualizations all (https://jbloomlab.github.io/SARS2-mut-fitness/). The framework describe applicable any virus which number sufficiently large neutral observed.

Language: Английский

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Mutational signature dynamics indicate SARS-CoV-2’s evolutionary capacity is driven by host antiviral molecules

PLoS Computational Biology, Journal Year: 2024, Volume and Issue: 20(1), P. e1011795 - e1011795

Published: Jan. 25, 2024

The COVID-19 pandemic has been characterised by sequential variant-specific waves shaped viral, individual human and population factors. SARS-CoV-2 variants are defined their unique combinations of mutations there a clear adaptation to more efficient infection since the emergence this new coronavirus in late 2019. Here, we use machine learning models identify shared signatures, i.e., common underlying mutational processes link these subset that define concern (VOCs). First, examined global genomes associated metadata determine how viral properties public health measures have influenced magnitude waves, as measured number cases, different geographic locations using regression models. This analysis showed that, expected, both virus were with regional reported numbers impact varies geographically. We attribute intrinsic differences such vaccine coverage, testing sequencing capacity effectiveness government stringency. To assess evolutionary change, used non-negative matrix factorisation observed three distinct substitution patterns exposures from genomes. Signatures 1, 2 3 biased C→T, T→C/A→G G→T point mutations. hypothesise assignments signatures host antiviral molecules APOBEC, ADAR ROS respectively. observe shift amidst relative signature activity predominantly Signature 1 changes an increasingly high proportion consistent 2. could represent immune response interact indicates may continue generate variation future. Linkage detected VOC-defining amino acids substitutions majority SARS-CoV-2’s is likely be action rather than replication errors.

Language: Английский

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Fitness effects of mutations to SARS-CoV-2 proteins

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 31, 2023

Knowledge of the fitness effects mutations to SARS-CoV-2 can inform assessment new variants, design therapeutics resistant escape, and understanding functions viral proteins. However, experimentally measuring is challenging: we lack tractable lab assays for many proteins, comprehensive deep mutational scanning has been applied only two Here develop an approach that leverages millions publicly available sequences estimate mutations. We first calculate how independent occurrences each mutation are expected be observed along phylogeny in absence selection. then compare these observations actual effect mutation. These estimates correlate well with measurements. For most genes, synonymous nearly neutral, stop-codon deleterious, amino-acid have a range effects. some accessory proteins under little no provide interactive visualizations all (https://jbloomlab.github.io/SARS2-mut-fitness/). The framework describe applicable any virus which number sufficiently large neutral observed.

Language: Английский

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Effect of molnupiravir on SARS-CoV-2 evolution in immunocompromised patients: a retrospective observational study

The Lancet Microbe, Journal Year: 2024, Volume and Issue: 5(5), P. e452 - e458

Published: March 22, 2024

IntroductionContinued SARS-CoV-2 infection among immunocompromised individuals is likely to play a role in generating genomic diversity and the emergence of novel variants. Antiviral treatments such as molnupiravir are used mitigate severe COVID-19 outcomes, but extended effects these drugs on viral evolution patients with chronic infections remain uncertain. This study investigates how affects prolonged infections.MethodsThe included five treated four not (two two non-immunocompromised). We selected who had been infected by similar variants high-quality genomes across timepoints allow comparison between groups. Throat nasopharyngeal samples were collected up 44 days post treatment sequenced using tiled amplicon sequencing followed variant calling. The UShER pipeline University California Santa Cruz genome viewer provided insights into global context Treated untreated compared, mutation profiles visualised understand impact evolution.FindingsPatients showed large increase low-to-mid-frequency little 10 after treatment, whereas no change was observed patients. Some became fixed population, including non-synonymous mutations spike protein. distributed unique commonly found omicron genomes. Notably, G-to-A C-to-T dominated mutational profile patients, persisting treatment.InterpretationMolnupiravir led accumulation distinctive pattern beyond recommended 5 treatment. maintained persistent PCR positivity for duration monitoring, indicating clear potential transmission subsequent variants.FundingAustralian Research Council.

Language: Английский

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The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Abstract RNA viruses like SARS-CoV-2 have a high mutation rate, which contributes to their rapid evolution. The rate of mutations depends on the type (e.g., A → C , G etc.) and can vary between sites in viral genome. Understanding this variation shed light mutational processes at play, is crucial for quantitative modeling Using millions available full-genome sequences, we estimate rates synonymous all 12 possible nucleotide types examine how much these sites. We find surprisingly level variability several striking patterns: four suddenly increase one two gene boundaries; most strongly depend site’s local sequence context, with up 56-fold differences contexts; consistent previous study, some are lower engaged secondary structure. simple log-linear model features explains ∼15-60% fold-variation sites, depending type; more complex models only modestly improve predictive power out sample. fitness effect each based number times it actually occurs versus expected occur model. identify small regions genome where or noncoding less often than expected, indicative strong purifying selection that independent protein sequence. Overall, work expands our basic understanding SARS-CoV-2’s evolution by characterizing virus’s process individual uncovering patterns arise from unknown mechanisms.

Language: Английский

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Genomic Tools in Biological Invasions: Current State and Future Frontiers

Genome Biology and Evolution, Journal Year: 2023, Volume and Issue: 16(1)

Published: Dec. 18, 2023

Human activities are accelerating rates of biological invasions and climate-driven range expansions globally, yet we understand little how genomic processes facilitate the invasion process. Although most literature has focused on underlying phenotypic correlates invasiveness, advances in technologies showing a strong link between variation success. Here, consider ability tools to (i) inform mechanistic understanding (ii) solve real-world issues predicting managing invasions. For both, examine current state field discuss genomics can be leveraged future. In addition, make recommendations pertinent broader research issues, such as data sovereignty, metadata standards, collaboration, science communication best practices that will require concerted efforts from global community.

Language: Английский

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A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 27, 2023

Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication. Most random are likely to be deleterious virus, and many will lethal, so molnupiravir-induced elevated mutation rates reduce viral load 2,3 . However, if some patients treated with molnupiravir do not fully clear SARS-CoV-2 infections, there could potential for onward transmission of molnupiravir-mutated viruses. Here we show sequencing databases contain extensive evidence mutagenesis. Using a systematic approach, find specific class long phylogenetic branches, distinguished high proportion G-to-A C-to-T mutations, appear almost exclusively sequences from 2022, after introduction treatment, countries age-groups widespread usage drug. We identify mutational spectrum, preferred nucleotide contexts, viruses known have its signature matches seen these cases onwards molnupiravir-derived lineages. Finally, analyse treatment records confirm direct association between branches use molnupiravir.

Language: Английский

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