A novel bat coronavirus reveals natural insertions at the S1/S2 cleavage site of the Spike protein and a possible recombinant origin of HCoV-19

Zhou, Hong; Chen, Xing; Hu, Tao; Li, Juan; Song, Hao; Liu, Yanran; Wang, Peihan; Liu, Di; Yang, Jing; Holmes, Edward C.; Hughes, Alice C.; Bi, Yang; Shi, Weifeng

doi:10.1101/2020.03.02.974139

Cited by 45 publications

(63 citation statements)

References 21 publications

(36 reference statements)

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“…Our study provides a structural context to the S1/S2 insert, which has also been reported by others [52,62]. The presence of a distinct insert containing paired basic residues in the S1/S2 priming loop is common in many coronaviruses in Betacoronavirus lineage C (e.g.…”

Section: Discussionsupporting

confidence: 82%

Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop

Jaimes

André

Chappie

et al. 2020

Journal of Molecular Biology

453

499

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The 2019 novel coronavirus (2019-nCoV/SARS-CoV-2) originally arose as part of a major outbreak of respiratory disease centered on Hubei province, China. It is now a global pandemic and is a major public health concern. Taxonomically, SARS-CoV-2 was shown to be a Betacoronavirus (lineage B) closely related to SARS-CoV and SARS-related bat coronaviruses, and it has been reported to share a common receptor with SARS-CoV (ACE-2). Subsequently, betacoronaviruses from pangolins were identified as close relatives to SARS-CoV-2. Here, we perform structural modeling of the SARS-CoV-2 spike glycoprotein. Our data provide support for the similar receptor utilization between SARS-CoV-2 and SARS-CoV, despite a relatively low amino acid similarity in the receptor binding module. Compared to SARS-CoV and all other coronaviruses in Betacoronavirus lineage B, we identify an extended structural loop containing basic amino acids at the interface of the receptor binding (S1) and fusion (S2) domains. We suggest this loop confers fusion activation and entry properties more in line with betacoronaviruses in lineages A and C, and be a key component in the evolution of SARS-CoV-2 with this structural loop affecting virus stability and transmission.

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Section: Discussionsupporting

confidence: 82%

Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop

Jaimes

André

Chappie

et al. 2020

Journal of Molecular Biology

453

499

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“…We demonstrate that the sarbecoviruses circulating in horseshoe bats have complex recombination histories 5 / 25 permitting generation of novel viral variants, as reported by others (He et al, 2014;Hon et al, 2008;Hu et al, 2017;Li et al, 2020b;Lin et al, 2017;Wang et al, 2017;Yuan et al, 2010;Zhou et al, 2020a).…”

Section: Introductionsupporting

confidence: 76%

“…When viewing the last 7kb of the genome a clade of viruses from northeast (NE) China appears to cluster with sequences from south-central (SC) Chinese provinces, but when inspecting trees from different parts of ORF1ab the NE China clade is phylogenetically separated from the SC China clade. Individual sequences such as RpShaanxi2011, Guangxi GX2013, and two sequences from Zhejiang province (CoVZXC21/CoVZC45), as previously shown Zhou et al, 2020a), show strong phylogenetic recombination signals, as they fall on different evolutionary lineages (with bootstrap support > 80%) depending what region of the genome is being examined.…”

Section: Recombination Analysis and Identification Of Breakpoint-freementioning

confidence: 69%

“…Collectively our analyses point to bats being the primary reservoir for the SARS-CoV-2 lineage. While it is possible that pangolins may have acted as an intermediate species facilitating transmission to humans, the evidence is consistent with the virus having evolved in bats resulting in bat sarbecoviruses that can replicate in the upper respiratory tract of both humans and pangolins (Zhang and Holmes, 2020;Zhou et al, 2020a).…”

Section: Introductionmentioning

confidence: 65%

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Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic

Boni

Lemey

Jiang

et al. 2020

Preprint

362

531

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There are outstanding evolutionary questions on the recent emergence of coronavirus in Hubei province that caused the COVID-19 pandemic, including (1) the relationship of the new virus to the SARS-related coronaviruses, (2) the role of bats as a reservoir species, (3) the potential role of other mammals in the emergence event, and (4) the role of recombination in viral emergence. Here, we address these questions and find that the sarbecoviruses -the viral subgenus responsible for the emergence of SARS-CoV and SARS-CoV-2 -exhibit frequent recombination, but the SARS-CoV-2 lineage itself is not a recombinant of any viruses detected to date. In order to employ phylogenetic methods to date the divergence events between SARS-CoV-2 and the bat sarbecovirus reservoir, recombinant regions of a 68-genome sarbecovirus alignment were removed with three independent methods. Bayesian evolutionary rate and divergence date estimates were consistent for all three recombination-free alignments and robust to two different prior specifications based on HCoV-OC43 and MERS-CoV evolutionary rates. Divergence dates between SARS-CoV-2 and the bat sarbecovirus reservoir were estimated as 1948 (95% HPD: 1879-1999), 1969 (95% HPD: 1930-2000), and 1982 (95% HPD: 1948-2009). Despite intensified characterization of sarbecoviruses since SARS, the lineage giving rise to SARS-CoV-2 has been circulating unnoticed for decades in bats and been transmitted to other hosts such as pangolins. The occurrence of a third significant coronavirus emergence in 17 years together with the high prevalence and virus diversity in bats implies that these viruses are likely to cross species boundaries again. : bioRxiv preprint 3 / 25 In BriefThe Betacoronavirus SARS-CoV-2 is a member of the sarbecovirus subgenus which shows frequent recombination in its evolutionary history. We characterize the extent of this genetic exchange and identify non-recombining regions of the sarbecovirus genome using three independent methods to remove the effects of recombination. Using these non-recombining genome regions and prior information on coronavirus evolutionary rates, we obtain estimates from three approaches that the most likely divergence date of SARS-CoV-2 from its most closely related available bat sequences ranges from 1948 to 1982. Key Points RaTG13 is the closest available bat virus to SARS-CoV-2; a sub-lineage of these bat viruses is able to infect humans. Two sister lineages of the RaTG13/SARS-CoV-2 lineage infect Malayan pangolins. The sarbecoviruses show a pattern of deep recombination events, indicating that there are high levels of co-infection in horseshoe bats and that the viral pool can generate novel allele combinations and substantial genetic diversity; the sarbecoviruses are efficient 'explorers' of phenotype space. The SARS-CoV-2 lineage is not a recent recombinant, at least not involving any of the bat or pangolin viruses sampled to date. Non-recombinant regions of the sarbecoviruses can be identified, allowing for phylogenetic inference and dating...

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“…This PRRA motif makes the S1/S2 cleavage in SARS-CoV-2 much more efficiently than in SARS-CoV and may expand its tropism and/or enhance its transmissibility (23). A recent study of bat CoVs in Yunnan, China, identified a three-amino acid insertion (PAA) at the same site (26). Although it is not known if this PAA motif can function like the PRRA motif, the presence of a similar insertion at the same site indicates that such insertion may already be present in the wild bat CoVs.…”

Section: Acquisition Of Receptor Binding Motif Through Recombinationmentioning

confidence: 99%

Emergence of SARS-CoV-2 through Recombination and Strong Purifying Selection

Giorgi

Marichann

et al. 2020

Preprint

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COVID-19 has become a global pandemic caused by a novel coronavirus SARS-CoV-2. Understanding the origins of SARS-CoV-2 is critical for deterring future zoonosis and for drug discovery and vaccine development. We show evidence of strong purifying selection around the receptor binding motif (RBM) in the spike gene and in other genes among bat, pangolin and human coronaviruses, indicating similar strong evolutionary constraints in different host species. We also demonstrate that SARS-CoV-2's entire RBM was introduced through recombination with coronaviruses from pangolins, possibly a critical step in the evolution of SARS-CoV-2's ability to infect humans. Similar purifying selection in different host species and frequent recombination among coronaviruses suggest a common evolutionary mechanism that could lead to new emerging human coronaviruses.

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A novel bat coronavirus reveals natural insertions at the S1/S2 cleavage site of the Spike protein and a possible recombinant origin of HCoV-19

Cited by 45 publications

References 21 publications

Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop

Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop

Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage responsible for the COVID-19 pandemic

Emergence of SARS-CoV-2 through Recombination and Strong Purifying Selection

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