Viral CpG Deficiency Provides No Evidence That Dogs Were Intermediate Hosts for SARS-CoV-2

Pollock, David D.; Castoe, Todd A.; Perry, Blair W.; Lytras, Spyros; Wade, Kristen J.; Robertson, David L.; Holmes, Edward C.; Boni, Maciej F.; Pond, Sergei L. Kosakovsky; Parry, Rhys; Carlton, Elizabeth J.; Wood, James L. N.; Pennings, Pleuni S.; Goldstein, Richard A.

doi:10.1093/molbev/msaa178

Cited by 21 publications

(26 citation statements)

References 36 publications

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“…Our analyses confirmed that SARS-CoV-2 and its closely related viruses Bat-RaTG13 and Pangolin-CoV have a lower CpG content compared to other viruses (Fig. 3) (di Gioacchino, et al 2020;Pollock, et al 2020;Xia 2020). However, we show that changes in motif representation is not exclusive to CpG.…”

Section: Discussionsupporting

confidence: 79%

“…One of the unique genomic features of SARS-CoV-2 is the low abundance of CpG (di Gioacchino, et al 2020;Pollock, et al 2020;Xia 2020). CpG suppression is a well-known phenomenon in viruses particularly those with RNA genomes (Karlin, et al 1994;Rima and McFerran 1997).…”

Section: Introductionmentioning

confidence: 99%

“…A number of follow up studies have challenged Xia's methodology and conclusion. For instance, Pollock et al repeated Xia's analysis using a larger number of SARS-CoV-2 related viruses and found that CpG deficiency is not specific to dog coronaviruses or SASR-CoV-2, and it is observed in pangolin coronaviruses and to a greater extent in pangolin pestiviruses (Pollock, et al 2020). Moreover, modeling of the binding affinity of ACE2 and SARS-CoV-2 Spike protein in 410 vertebrates showed a low score of susceptibility to SARS-CoV-2 infection for dogs (Damas, et al 2020).…”

Section: Introductionmentioning

confidence: 99%

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Insight into the origin of 5’UTR and source of CpG reduction in SARS-CoV-2 genome

Afrasiabi

Alinejad‐Rokny

Lovell

et al. 2020

Preprint

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SARS-CoV-2, the causative agent of COVID-19, has an RNA genome, which is, overall, closely related to the bat coronavirus sequence RaTG13. However, the ACE2-binding domain of this virus is more similar to a coronavirus isolated from pangolin. In addition to this unique feature, the genome of SARS-CoV-2 (and its closely related coronaviruses) has a low CpG content. This has been postulated to be signature of an evolutionary pressure exerted by the host antiviral protein ZAP. Here, we analyzed the sequences of a wide range of viruses using both alignment-based and alignment free approaches to investigate the origin of SARS-CoV-2 genome. Our analyses revealed a high level of similarity between the 5UTR of SARS-CoV-2 and that of a Guangdong pangolin coronavirus. These data suggest that not only ACE2, but also the 5UTR of SARS-CoV-2 likely has a pangolin coronavirus origin. Additionally, we performed a detailed analysis of viral genome compositions as well as expression and RNA binding data of ZAP to show that the low CpG abundance in SARS-CoV-2 is not related to an evolutionary pressure from ZAP.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Insight into the origin of 5’UTR and source of CpG reduction in SARS-CoV-2 genome

Afrasiabi

Alinejad‐Rokny

Lovell

et al. 2020

Preprint

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“…Thus, a smaller or greater level of CpG depletion in particular viral lineages may be indicative of a switch in the evolutionary environment of that lineage or its ancestors. Although care must be taken to not over-interpret these results 45 .…”

Section: Patterns Of Cpg Depletion In the Ncov Clade Genome Compositmentioning

confidence: 99%

Natural selection in the evolution of SARS-CoV-2 in bats, not humans, created a highly capable human pathogen

MacLean

Lytras

Weaver

et al. 2020

Preprint

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RNA viruses are proficient at switching to novel host species due to their fast mutation rates. Implicit in this assumption is the need to evolve adaptations in the new host species to exploit their cells efficiently. However, SARS-CoV-2 has required no significant adaptation to humans since the pandemic began, with no observed selective sweeps to date. Here we contrast the role of positive selection and recombination in the Sarbecoviruses in horseshoe bats to SARS-CoV-2 evolution in humans. While methods can detect some evidence for positive selection in SARS-CoV-2, we demonstrate these are mostly due to recombination and sequencing artefacts.Purifying selection is also substantially weaker in SARS-CoV-2 than in the related bat Sarbecoviruses. In comparison, our results show evidence for positive, specifically episodic selection, acting on the bat virus lineage SARS-CoV-2 emerged from. This signature of selection can also be observed among synonymous substitutions, for example, linked to ancestral CpG depletion on this bat lineage. We show the bat virus RmYN02 has recombinant CpG content in Spike pointing to coinfection and evolution in bats without involvement of other species. Our results suggest the non-human progenitor of SARS-CoV-2 was capable of humanhuman transmission as a consequence of its natural evolution in bats. Main textIn December 2019, a novel coronavirus emerged in the city of Wuhan, China, causing coronavirus disease-2019 (COVID-19) characterised by respiratory or gastrointestinal viral symptoms, and in severe cases, additionally, acute respiratory distress syndrome, cardiovascular dysfunction, thrombosis and other symptoms 1 . Evolutionary analysis placed this new human virus in the same subgenus of Betacoronavirus, the Sarbecoviruses (Figure 1A), that SARS emerged from 2 , and it was named SARS-CoV-2 3 -the seventh known humaninfecting member of the Coronaviridae. The initial outbreak of human cases of the virus was connected to the Huanan Seafood Wholesale Market in Wuhan 4 , and while related viruses have been found in horseshoe bats 5 and pangolins 6 , their divergence represents decades of evolution 7 leaving the direct origin of the pandemic unknown. In addition to the importance of understanding the route from animals to humans, key questions for assessing future risk of emergence are: what is the extent of evolution required to permit a bat virus to transmit to humans, and what subsequent evolution needs to occur for efficient transmission once the virus is established within the human population?While both the first SARS virus outbreak in 2002/2003, causing approximately 8,000 infections, and a re-emergence in late 2003, causing four infections, were linked to Himalayan palm civets and raccoon dogs in marketplaces in Guangdong province 8,9 , it became clear that these animals were conduits for spillover to humans and not true viral reservoirs 10 . Extensive surveillance work subsequently identified related viruses circulating in horseshoe bats in China some of which can replicate rea...

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“…Furthermore, the enzyme APOBEC3G in the viral hosts is known to deaminate cytosine to uracil nucleotides, particularly those present in the single-stranded RNA [ 14 , 15 , 17 ]. Investigating the dinucleotide patterns of SARS-CoV-2 genomes revealed that the CpG dinucleotides were severely reduced in these viral genomes [ 14 , 17 , 18 , 19 , 20 ]. Zinc finger antiviral protein (ZAP) protects cells from viral infections and this protein identifies viral genomes based on their CpG dinucleotide content (CpG content) [ 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

The Long-Term Evolutionary History of Gradual Reduction of CpG Dinucleotides in the SARS-CoV-2 Lineage

Subramanian

2021

Biology

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Recent studies suggested that the fraction of CG dinucleotides (CpG) is severely reduced in the genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The CpG deficiency was predicted to be the adaptive response of the virus to evade degradation of the viral RNA by the antiviral zinc finger protein that specifically binds to CpG nucleotides. By comparing all representative genomes belonging to the genus Betacoronavirus, this study examined the potential time of origin of CpG depletion. The results of this investigation revealed a highly significant correlation between the proportions of CpG nucleotide (CpG content) of the betacoronavirus species and their times of divergence from SARS-CoV-2. Species that are distantly related to SARS-CoV-2 had much higher CpG contents than that of SARS-CoV-2. Conversely, closely related species had low CpG contents that are similar to or slightly higher than that of SARS-CoV-2. These results suggest a systematic and continuous reduction in the CpG content in the SARS-CoV-2 lineage that might have started since the Sarbecovirus + Hibecovirus clade separated from Nobecovirus, which was estimated to be 1213 years ago. This depletion was not found to be mediated by the GC contents of the genomes. Our results also showed that the depletion of CpG occurred at neutral positions of the genome as well as those under selection. The latter is evident from the progressive reduction in the proportion of arginine amino acid (coded by CpG dinucleotides) in the SARS-CoV-2 lineage over time. The results of this study suggest that shedding CpG nucleotides from their genome is a continuing process in this viral lineage, potentially to escape from their host defense mechanisms.

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Viral CpG Deficiency Provides No Evidence That Dogs Were Intermediate Hosts for SARS-CoV-2

Cited by 21 publications

References 36 publications

Insight into the origin of 5’UTR and source of CpG reduction in SARS-CoV-2 genome

Insight into the origin of 5’UTR and source of CpG reduction in SARS-CoV-2 genome

Natural selection in the evolution of SARS-CoV-2 in bats, not humans, created a highly capable human pathogen

The Long-Term Evolutionary History of Gradual Reduction of CpG Dinucleotides in the SARS-CoV-2 Lineage

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