Hidden genomic diversity of SARS-CoV-2: implications for qRT-PCR diagnostics and transmission

Sapoval, Nicolae; Liu, Yunxi; Wang, Qi; Villapol, Sonia; Posada, David; Sedlazeck, Fritz J.

doi:10.1101/2020.07.02.184481

Cited by 25 publications

(28 citation statements)

References 54 publications

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“…Here we use a cat transmission model to show that SARS-CoV-2 genetic diversity is largely shaped by genetic drift and purifying selection. This finding is in broad agreement with recent analyses of evolutionary forces acting on SARS-CoV-2 in humans 25,[27][28][29][30][31][32] . Our results further suggest that human SARS-CoV-2 isolates are relatively well-adapted to feline hosts, and that cat models recapitulate key aspects of SARS-CoV-2 evolution in humans.…”

Section: Introductionsupporting

confidence: 92%

“…Our study found that overall genetic diversity in cats was low and signatures support prominent roles for genetic drift and purifying selection. The combination of low genetic diversity, genetic drift, and purifying selection are in line with recent estimates of human within-host diversity 25,[27][28][29][30][31][32] . Importantly, our study only evaluated three transmission pairs with an undefined mode of transmission in the context of a single human isolate.…”

Section: Discussionsupporting

confidence: 73%

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Transmission of SARS-CoV-2 in domestic cats imposes a narrow bottleneck

Braun

Moreno

Halfmann

et al. 2020

Preprint

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The evolutionary mechanisms by which SARS-CoV-2 viruses adapt to mammalian hosts and, potentially, escape human immunity depend on the ways genetic variation is generated and selected within and between individual hosts. Using domestic cats as a model, we show that SARS-CoV-2 consensus sequences remain largely unchanged over time within hosts, but dynamic sub-consensus diversity reveals processes of genetic drift and weak purifying selection. Transmission bottlenecks in this system appear narrow, with new infections being founded by fewer than ten viruses. We identify a notable variant at amino acid position 655 in Spike (H655Y) which arises rapidly in index cats and becomes fixed following transmission in two of three pairs, suggesting this site may be under positive selection in feline hosts. We speculate that narrow transmission bottlenecks and the lack of pervasive positive selection combine to constrain the pace of ongoing SARS-CoV-2 adaptive evolution in mammalian hosts.

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Section: Introductionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 73%

Transmission of SARS-CoV-2 in domestic cats imposes a narrow bottleneck

Braun

Moreno

Halfmann

et al. 2020

Preprint

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“…Due to the recent host shift and to the fact that many mutations in SARS-CoV-2 seem to be the consequence of host immune system activity, a recent significant change in mutation rates and selective pressure in SARS-CoV-2 (associated with its introduction to humans) is likely. In fact, studies have suggested that the current G→U mutation rate of SARS-CoV-2 in humans, for example, is much higher than in its reservoir hosts [ 34 , 35 ]. Specifically, [ 34 ] estimated that the G→U mutation rate in SARS-CoV-2 increased 9-fold with its introduction in humans, possibly due to difference in ROS activity between hosts.…”

Section: Resultsmentioning

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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“…The resulting intra-host diversity has been shown to affect disease progression [26], tissue tropism [27], transmission risk [28], transmission heterogeneity [29], and treatment outcome [30, 31] in various RNA viruses. Recent findings indicate that the mutation rate of SARS-CoV-2 is about as high as the one observed in the SARS-CoV genome (0.80–2.38 × 10 −3 nucleotide substitutions per site per year) [32, 33]. Although coronaviruses have evolved a proofreading capability attributed to Nonstructural protein 14 resulting in lower mutation rates than other positive-sense ssRNA viruses [34–36], the study of the intra-host genetic diversity of the novel SARS-CoV-2 virus remains important to gain a deeper understanding of its evolution and transmission dynamics and possible implications on its pathology.…”

Section: Introductionmentioning

confidence: 99%

Within-patient genetic diversity of SARS-CoV-2

Kuipers

Batavia

Jablonski

et al. 2020

Preprint

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SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, is evolving into different genetic variants by accumulating mutations as it spreads globally. In addition to this diversity of consensus genomes across patients, RNA viruses can also display genetic diversity within individual hosts, and co-existing viral variants may affect disease progression and the success of medical interventions. To systematically examine the intra-patient genetic diversity of SARS-CoV-2, we processed a large cohort of 3939 publicly-available deeply sequenced genomes with specialised bioinformatics software, along with 749 recently sequenced samples from Switzerland. We found that the distribution of diversity across patients and across genomic loci is very unbalanced with a minority of hosts and positions accounting for much of the diversity. For example, the D614G variant in the Spike gene, which is present in the consensus sequences of 67.4% of patients, is also highly diverse within hosts, with 29.7% of the public cohort being affected by this coexistence and exhibiting different variants. We also investigated the impact of several technical and epidemiological parameters on genetic heterogeneity and found that age, which is known to be correlated with poor disease outcomes, is a significant predictor of viral genetic diversity.

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Hidden genomic diversity of SARS-CoV-2: implications for qRT-PCR diagnostics and transmission

Cited by 25 publications

References 54 publications

Transmission of SARS-CoV-2 in domestic cats imposes a narrow bottleneck

Transmission of SARS-CoV-2 in domestic cats imposes a narrow bottleneck

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

Within-patient genetic diversity of SARS-CoV-2

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