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

Li, Xiaojun; Giorgi, Elena E.; Marichann, Manukumar Honnayakanahalli; Foley, Brian; Xiao, Chuan; Kong, Xiang‐Peng; Chen, Yue; Korber, Bette T.; Gao, Feng

doi:10.1101/2020.03.20.000885

Cited by 62 publications

(36 citation statements)

References 43 publications

(81 reference statements)

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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%

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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Section: Introductionsupporting

confidence: 76%

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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“…Human SARS-CoV-2 strains were identified as potential parental sequences recombining with pangolin-SARS-CoV-2 isolated in 2019 and bat-SARS-CoV-2 strains; with a recombination event involving the region of the S glycoprotein that binds to the cell receptor (Table 1). This finding matches the previous observation that ACE2 binding residues are shared between pangolin and human, and the recent analysis by Li et al 26 . While our analysis could not confidently discern the recombinant from the parent sequences, signature pattern analysis (Figure 1a) and a Maximum likelihood tree calculated using this recombinant region only (data not shown), clearly showed pangolin and COV-2 clustering together.…”

Section: Mainsupporting

confidence: 93%

“…Recombination was a critical factor in the emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 from bat reservoirs 22,23 . There is currently conflicting evidence on whether or not the new coronavirus originated from recombination events 24-26 . Since the human lineages is 96% identical to bat-SARS-CoV-2 1 , but ACE2 binding residues F486, Q493, S494 and N501 (Figure 1a) are conserved between pangolin-SARS-CoV-2 lineage b strains, we investigated the evolutionary relationships among available full genome sequences (bat and pangolin-related SARS-CoV-2 strains, bat-SL-CoVs, SARS-CoV-1 and SARS-like strains) using a neighbor network (NNet) based algorithm 27 .…”

Section: Mainmentioning

confidence: 99%

Recombination and purifying selection preserves covariant movements of mosaic SARS-CoV-2 protein S

Tagliamonte

Abid

Ostrov

et al. 2020

Preprint

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22Following the recent report of a furin-like cleavage site unique to SARS-CoV-2, we characterized 23 additional amino acid residues, positioned within the crown of the spike (S) glycoprotein, under 24 diversifying selection along the ancestral lineage of currently circulating pandemic strains, and 25 affecting enhanced ability to infect host cells. Molecular dynamic simulations revealed long-26 range covariant movements of SARS-CoV-2 S glycoprotein monomer in pre-fusion conformation 27 with furin cleavage, and residue T333, under purifying selection, hinge of such movement. 28Evolutionary analysis revealed that the current human lineage likely emerged after a 29 recombination event between ancestors in bat and pangolin. Recombination impacted residues

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“…Instead, variation in the region is comparable to numerous other conserved regions of the spike and to the viral genome as a whole. While Wong et al (19) and others (21)(22)(23)(24)(25)(26)(27)(28) raised the model that recombination occurred in the RBD region in the derivation of SARS-CoV-2, the lack of a singular dip in the landscape of pangolin-SARS-CoV-2 variation in the region would seem counterintuitive were SARS-CoV-2 a result of a localized recombination between a close relative of RaTG13 and a close relative of the putative pangolin coronaviruses under consideration. Thus alternative models for the observed sequence variation seem important to consider and indeed parsimonious, including that of selection acting on the RaTG13 sequences in bats or another intermediate host resulting in a rapid variation of the amino acids at the highly critical virus-receptor interface.…”

Section: Bat Virus Ratg13mentioning

confidence: 99%

“…A number of literature contributions now discuss the potential role for bats, pangolins, and other possible progenitor/intermediate species in derivation of SARS-CoV-2 from different approaches and perspectives, with a diversity of approaches and interpretations in understanding the origin of the virus. In particular, there has been extensive discussion and debate about the possible pangolin origin of SARS-CoV-2 (19,(21)(22)(23)(24)(25)(26)(27)(28)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). These studies provide useful insights into the evolution of SARS-CoV-2 but have limitations and uncertainty in drawing conclusions regarding the viral origin, as most studies were mainly performed through sequence-based comparison and simulation.…”

Section: Bat Virus Ratg13mentioning

confidence: 99%

An Extensive Meta-Metagenomic Search Identifies SARS-CoV-2-Homologous Sequences in Pangolin Lung Viromes

Wahba

Jain

Fire

et al. 2020

mSphere

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In numerous instances, tracking the biological significance of a nucleic acid sequence can be augmented through the identification of environmental niches in which the sequence of interest is present. Many metagenomic data sets are now available, with deep sequencing of samples from diverse biological niches. While any individual metagenomic data set can be readily queried using web-based tools, meta-searches through all such data sets are less accessible. In this brief communication, we demonstrate such a meta-metagenomic approach, examining close matches to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in all high-throughput sequencing data sets in the NCBI Sequence Read Archive accessible with the "virome" keyword. In addition to the homology to bat coronaviruses observed in descriptions of the SARS-CoV-2 sequence (F. Wu, S. Zhao, B. Yu, Y. M. Chen, et al., Nature 579:265-269, 2020, https://doi., et al., Nature 579:270 -273, 2020, https://doi.org/ 10.1038/s41586-020-2012-7), we note a strong homology to numerous sequence reads in metavirome data sets generated from the lungs of deceased pangolins reported by Liu et al. (P. Liu, W. Chen, and J. P. Chen, Viruses 11:979, 2019, https://doi.org/10.3390/ v11110979). While analysis of these reads indicates the presence of a similar viral sequence in pangolin lung, the similarity is not sufficient to either confirm or rule out a role for pangolins as an intermediate host in the recent emergence of SARS-CoV-2. In addition to the implications for SARS-CoV-2 emergence, this study illustrates the utility and limitations of meta-metagenomic search tools in effective and rapid characterization of potentially significant nucleic acid sequences. IMPORTANCE Meta-metagenomic searches allow for high-speed, low-cost identification of potentially significant biological niches for sequences of interest. extensive meta-metagenomic search identifies SARS-CoV-2-homologous sequences in pangolin lung viromes. mSphere 5:e00160-20.

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

Cited by 62 publications

References 43 publications

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

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

Recombination and purifying selection preserves covariant movements of mosaic SARS-CoV-2 protein S

An Extensive Meta-Metagenomic Search Identifies SARS-CoV-2-Homologous Sequences in Pangolin Lung Viromes

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