Investigating the evolutionary origins of the first three SARS-CoV-2 variants of concern

Ghafari, Mahan; Liu, Qihan; Dhillon, Arushi; Weissman, Daniel B.

doi:10.1101/2022.05.09.491227

Cited by 8 publications

(9 citation statements)

References 59 publications

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Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections may act as viral reservoirs that could seed future outbreaks [1][2][3][4][5] , give rise to highly divergent lineages [6][7][8] , and contribute to cases with post-acute Coronavirus disease 2019 (COVID-19) sequelae (Long Covid) 9,10 . However, the population prevalence of persistent infections, their viral load kinetics, and evolutionary dynamics over the course of infections remain largely unknown.

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mentioning

confidence: 99%

High number of SARS-CoV-2 persistent infections uncovered through genetic analysis of samples from a large community-based surveillance study

Ghafari

Hall

Golubchik

et al. 2023

Preprint

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Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections may act as viral reservoirs that could seed future outbreaks1–5, give rise to highly divergent lineages6–8, and contribute to cases with post-acute Coronavirus disease 2019 (COVID-19) sequelae (Long Covid)9,10. However, the population prevalence of persistent infections, their viral load kinetics, and evolutionary dynamics over the course of infections remain largely unknown. We identified 381 infections lasting at least 30 days, of which 54 lasted at least 60 days. These persistently infected individuals had more than 50% higher odds of self-reporting Long Covid compared to the infected controls, and we estimate that 0.09-0.5% of SARS-CoV-2 infections can become persistent and last for at least 60 days. In nearly 70% of the persistent infections we identified, there were long periods during which there were no consensus changes in virus sequences, consistent with prolonged presence of non-replicating virus. Our findings also suggest reinfections with the same major lineage are rare and that many persistent infections are characterised by relapsing viral load dynamics. Furthermore, we found a strong signal for positive selection during persistent infections, with multiple amino acid substitutions in the Spike and ORF1ab genes emerging independently in different individuals, including mutations that are lineage-defining for SARS-CoV-2 variants, at target sites for several monoclonal antibodies, and commonly found in immunocompromised patients11–14. This work has significant implications for understanding and characterising SARS-CoV-2 infection, epidemiology, and evolution.

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mentioning

confidence: 99%

High number of SARS-CoV-2 persistent infections uncovered through genetic analysis of samples from a large community-based surveillance study

Ghafari

Hall

Golubchik

et al. 2023

Preprint

Self Cite

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“…Whereas other lineages may evolve through non-selective mechanisms, such as genetic drift, the existing VOC have exhibited strong signals of prior positive selection at the time of their emergence 16,[48][49][50] . The tight bottlenecks identified here will limit the development of highly mutated VOC in transmission chains of acutely infected individuals, adding to the evidence that selection over prolonged infections in immunocompromised patients may drive the evolution of SARS-CoV-2 variants of concern 6,15,51,52 .…”

Section: Discussionmentioning

confidence: 81%

Rapid transmission and tight bottlenecks constrain the evolution of highly transmissible SARS-CoV-2 variants

et al. 2023

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Transmission bottlenecks limit the spread of novel mutations and reduce the efficiency of selection along a transmission chain. While increased force of infection, receptor binding, or immune evasion may influence bottleneck size, the relationship between transmissibility and the transmission bottleneck is unclear. Here we compare the transmission bottleneck of non-VOC SARS-CoV-2 lineages to those of Alpha, Delta, and Omicron. We sequenced viruses from 168 individuals in 65 households. Most virus populations had 0–1 single nucleotide variants (iSNV). From 64 transmission pairs with detectable iSNV, we identify a per clade bottleneck of 1 (95% CI 1–1) for Alpha, Delta, and Omicron and 2 (95% CI 2–2) for non-VOC. These tight bottlenecks reflect the low diversity at the time of transmission, which may be more pronounced in rapidly transmissible variants. Tight bottlenecks will limit the development of highly mutated VOC in transmission chains, adding to the evidence that selection over prolonged infections may drive their evolution.

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“…Whereas other lineages may evolve through non-selective mechanisms, such as genetic drift, the existing VOC have exhibited strong signals of prior positive selection at the time of their emergence (16)(54–56). The tight bottlenecks identified here will limit the development of highly mutated VOC in typical transmission chains, adding to the evidence that selection over prolonged infections in immunocompromised patients may drive the evolution of SARS-CoV-2 variants of concern (6, 15, 57, 58).…”

Section: Discussionmentioning

confidence: 82%

Rapid transmission and tight bottlenecks constrain the evolution of highly transmissible SARS-CoV-2 variants

Bendall

Callear

Getz

et al. 2022

Preprint

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Transmission bottlenecks limit the spread of novel mutations and reduce the efficiency of natural selection along a transmission chain. Many viruses exhibit tight bottlenecks, and studies of early SARS-CoV-2 lineages identified a bottleneck of 1-3 infectious virions. While increased force of infection, host receptor binding, or immune evasion may influence bottleneck size, the relationship between transmissibility and the transmission bottleneck is unclear. Here, we compare the transmission bottleneck of non-variant-of-concern (non-VOC) SARS-CoV-2 lineages to those of the Alpha, Delta, and Omicron variants. We sequenced viruses from 168 individuals in 65 multiply infected households in duplicate to high depth of coverage. In 110 specimens collected close to the time of transmission, within-host diversity was extremely low. At a 2% frequency threshold, 51% had no intrahost single nucleotide variants (iSNV), and 42% had 1-2 iSNV. In 64 possible transmission pairs with detectable iSNV, we identified a bottleneck of 1 infectious virion (95% CI 1-1) for Alpha, Delta, and Omicron lineages and 2 (95% CI 2-2) in non-VOC lineages. The latter was driven by a single iSNV shared in one non-VOC household. The tight transmission bottleneck in SARS-CoV-2 is due to low genetic diversity at the time of transmission, a relationship that may be more pronounced in rapidly transmissible variants. The tight bottlenecks identified here will limit the development of highly mutated VOC in typical transmission chains, adding to the evidence that selection over prolonged infections in immunocompromised patients may drive their evolution.

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Investigating the evolutionary origins of the first three SARS-CoV-2 variants of concern

Cited by 8 publications

References 59 publications

High number of SARS-CoV-2 persistent infections uncovered through genetic analysis of samples from a large community-based surveillance study

High number of SARS-CoV-2 persistent infections uncovered through genetic analysis of samples from a large community-based surveillance study

Rapid transmission and tight bottlenecks constrain the evolution of highly transmissible SARS-CoV-2 variants

Rapid transmission and tight bottlenecks constrain the evolution of highly transmissible SARS-CoV-2 variants

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