Within-patient genetic diversity of SARS-CoV-2

Kuipers, Jack; Batavia, Aashil A.; Jablonski, Kim Philipp; Bayer, Fritz M.; Borgsmüller, Nico; Dondi, Arthur; Drăgan, M; Ferreira, Pedro; Jahn, Katharina; Lamberti, Lisa; Pirkl, Martin; Posada-Céspedes, Susana; Topolsky, Ivan; Nissen, Ina; Santacroce, Natascha; Burcklen, Elodie; Schär, Tobias; Capece, Vincenzo; Beckmann, Christiane; Kobel, Olivier; Noppen, Christoph; Redondo, Maurice; Nadeau, Sarah; Seidel, Sophie; Souza, Noemi Santamaria de; Beisel, Christian; Stadler, Tanja; Beerenwinkel, Niko

doi:10.1101/2020.10.12.335919

Cited by 20 publications

(31 citation statements)

References 59 publications

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“…In a similar way as selection is expected to decrease the frequency of deleterious SARS-CoV-2 alleles at the human population level, the same is true at the within-host levels, as selection is expected to act on within-host deleterious mutations and often prevent them from reaching high frequency and transmit further on. While within-patient genetic diversity data can indeed be very informative of the SARS-CoV-2 evolutionary patterns [ 13 , 14 , 45 ], it is important to consider that such data is also more prone to sequencing, read processing, and RNA degradation issues. These issues cause some errors in consensus sequences [ 23 , 22 ] but they are expected to be even more problematic at the level of detected within-host variation.…”

Section: Discussionmentioning

confidence: 99%

Mutation rates and selection on synonymous mutations in SARS-CoV-2

Maio

Walker

Turakhia

et al. 2021

Preprint

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The COVID-19 pandemic has seen an unprecedented response from the sequencing community. Leveraging the sequence data from more than 140,000 SARS-CoV-2 genomes, we study mutation rates and selective pressures affecting the virus. Understanding the processes and effects of mutation and selection has profound implications for the study of viral evolution, for vaccine design, and for the tracking of viral spread. We highlight and address some common genome sequence analysis pitfalls that can lead to inaccurate inference of mutation rates and selection, such as ignoring skews in the genetic code, not accounting for recurrent mutations, and assuming evolutionary equilibrium. We find that two particular mutation rates, G→U and C→U, are similarly elevated and considerably higher than all other mutation rates, causing the majority of mutations in the SARS-CoV-2 genome, and are possibly the result of APOBEC and ROS activity. These mutations also tend to occur many times at the same genome positions along the global SARS-CoV-2 phylogeny (i.e., they are very homoplasic). We observe an effect of genomic context on mutation rates, but the effect of the context is overall limited. While previous studies have suggested selection acting to decrease U content at synonymous sites, we bring forward evidence suggesting the opposite.

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Section: Discussionmentioning

confidence: 99%

Mutation rates and selection on synonymous mutations in SARS-CoV-2

Maio

Walker

Turakhia

et al. 2021

Preprint

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“…It was shown that patients with severe COVID-19 symptoms present a more important intra-host diversity than patients with mild symptoms [ 70 ]. Furthermore, Kuipers et al established that age is significantly associated with intra-host viral genetic diversity [ 71 ]. The identification of these factors inducing new diversity is worth exploring in an in-depth analysis of existing genomic data integrated with extensive epidemiological and clinical information.…”

Section: Discussionmentioning

confidence: 99%

Intra-Host Diversity of SARS-Cov-2 Should Not Be Neglected: Case of the State of Victoria, Australia

Armero

Berthet

Avarre

2021

Viruses

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Since the identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the etiological agent of the current COVID-19 pandemic, a rapid and massive effort has been made to obtain the genomic sequences of this virus to monitor (in near real time) the phylodynamic and diversity of this new pathogen. However, less attention has been given to the assessment of intra-host diversity. RNA viruses such as SARS-CoV-2 inhabit the host as a population of variants called quasispecies. We studied the quasispecies diversity in four of the main SARS-CoV-2 genes (ORF1a, ORF1b, S and N genes), using a dataset consisting of 210 next-generation sequencing (NGS) samples collected between January and early April of 2020 in the State of Victoria, Australia. We found evidence of quasispecies diversity in 68% of the samples, 76% of which was nonsynonymous variants with a higher density in the spike (S) glycoprotein and ORF1a genes. About one-third of the nonsynonymous intra-host variants were shared among the samples, suggesting host-to-host transmission. Quasispecies diversity changed over time. Phylogenetic analysis showed that some of the intra-host single-nucleotide variants (iSNVs) were restricted to specific lineages, highlighting their potential importance in the epidemiology of this virus. A greater effort must be made to determine the magnitude of the genetic bottleneck during transmission and the epidemiological and/or evolutionary factors that may play a role in the changes in the diversity of quasispecies over time.

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“…The early evolutionary events that shaped the epistatic network conceivably laid the foundation for the diversification of the virus relevant to virulence, immune evasion, and transmission. Recent analysis of within-patient genetic diversity has shown that the most common mutations are highly diverse within individuals (37) . Such diversity could either result from multiple infections, or otherwise, could present evidence of an even greater role of positive selection affecting a larger number of sites than inferred from our tree (Fig.…”

Section: Mainmentioning

confidence: 99%

Ongoing Global and Regional Adaptive Evolution of SARS-CoV-2

Rochman

Wolf

Faure

et al. 2020

Preprint

106

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Unprecedented sequencing efforts have, as of October 2020, produced over 100,000 genomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the ongoing COVID-19 crisis. Understanding the trends in SARS-CoV-2 evolution is paramount to control the pandemic. Although this extensive data availability quickly facilitated the development of vaccine candidates1, major challenges in the analysis of this enormous dataset persist, limiting the ability of public health officials to translate science into policy. Having evolved over a short period of time, the SARS-CoV-2 isolates show low diversity, necessitating analysis of trees built from genome-scale data. Here we provide a complete ancestral genome reconstruction for SARS-CoV-2 leveraging Fitch Traceback2. We show that the ongoing evolution of SARS-CoV-2 over the course of the pandemic is characterized primarily by purifying selection. However, a small set of sites, including the extensively studied spike 6143, harbor mutations which recurred on multiple, independent occasions, indicative of positive selection. These mutations form a strongly connected network of apparent epistatic interactions. The phylogenetic tree of SARS-CoV-2 consists of 7 major clades which show distinct global and temporal dynamics. Periods of regional diversification of SARS-CoV-2 are short and, despite dramatically reduced travel4, globalization of the virus is apparent.

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Within-patient genetic diversity of SARS-CoV-2

Cited by 20 publications

References 59 publications

Mutation rates and selection on synonymous mutations in SARS-CoV-2

Mutation rates and selection on synonymous mutations in SARS-CoV-2

Intra-Host Diversity of SARS-Cov-2 Should Not Be Neglected: Case of the State of Victoria, Australia

Ongoing Global and Regional Adaptive Evolution of SARS-CoV-2

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