Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2

Patiño-Galindo, Juan Ángel; Filip, Ioan; AlQuraishi, Mohammed; Rabadán, Raúl

doi:10.1101/2020.02.10.942748

Cited by 29 publications

(31 citation statements)

References 57 publications

(81 reference statements)

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“…In our gene-by-gene analyses of h/m ratios in Sarbecoviruses, nearly all annotated CDSs encoding subunits of the spike protein showed signs of excessive recombination, consistent with the previous phylogeny-based evidence of both ancient and recent recombination events in the spike protein in coronaviruses [2,15,22,[31][32][33][34]. By extension, recombination has recently been examined in SARS-CoV-2 and is targeted to regions encoding the spike protein [9,10,35]. Upon the initial sequencing of the SARS-CoV-2 genome, it was noted that its spike protein RBD was most similar to the RBD region of coronaviruses isolated from pangolins, although its closest relative at the whole-genome level was the SARS-like bat coronavirus, RaTG13 [3,[7][8][9]22].…”

Section: Plos Geneticssupporting

confidence: 89%

Recombination events are concentrated in the spike protein region of Betacoronaviruses

2020

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The Betacoronaviruses comprise multiple subgenera whose members have been implicated in human disease. As with SARS, MERS and now SARS-CoV-2, the origin and emergence of new variants are often attributed to events of recombination that alter host tropism or disease severity. In most cases, recombination has been detected by searches for excessively similar genomic regions in divergent strains; however, such analyses are complicated by the high mutation rates of RNA viruses, which can produce sequence similarities in distant strains by convergent mutations. By applying a genome-wide approach that examines the source of individual polymorphisms and that can be tested against null models in which recombination is absent and homoplasies can arise only by convergent mutations, we examine the extent and limits of recombination in Betacoronaviruses. We find that recombination accounts for nearly 40% of the polymorphisms circulating in populations and that gene exchange occurs almost exclusively among strains belonging to the same subgenus. Although experimental studies have shown that recombinational exchanges occur at random along the coronaviral genome, in nature, they are vastly overrepresented in regions controlling viral interaction with host cells.

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Section: Plos Geneticssupporting

confidence: 89%

Recombination events are concentrated in the spike protein region of Betacoronaviruses

2020

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“…In addition, there were 6 windows whose unique top hits are coronavirus of a SARS-CoV related lineage (Lam, et al 2020) (Supplementary Table 4). The mosaic pattern that different regions of the genome show highest identity to different virus strains is likely to have been caused by the rich recombination history of the SARS-CoV-2 lineage (Boni, et al 2020; Patiño-Galindo, et al 2020). Moreover, its unique connection with SARS-CoV related lineages in some genomic regions may suggest recombination between the ancestral lineage of SARS-CoV-2 and distantly related virus lineages, although more formal analyses are needed to determine the recombination history (see also Boni, et al 2020 for further discussion).…”

Section: Resultsmentioning

confidence: 99%

Synonymous mutations and the molecular evolution of SARS-Cov-2 origins

Wang

Pipes

Nielsen

2020

Preprint

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1Human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is most closely 2 related, by average genetic distance, to two coronaviruses isolated from bats, RaTG13 and 3 RmYN02. However, there is a segment of high amino acid similarity between human CoV-2 and a pangolin isolated strain, GD410721, in the receptor binding domain (RBD) of 5 the spike protein, a pattern that can be caused by either recombination or by convergent 6 amino acid evolution driven by natural selection. We perform a detailed analysis of the 7 synonymous divergence, which is less likely to be affected by selection than amino acid 8 divergence, between human SARS-CoV-2 and related strains. We show that the 9 synonymous divergence between the bat derived viruses and SARS-CoV-2 is larger than 10 between GD410721 and SARS-CoV-2 in the RBD, providing strong additional support for 11 the recombination hypothesis. However, the synonymous divergence between pangolin 12 strain and SARS-CoV-2 is also relatively high, which is not consistent with a recent 13 recombination between them, instead it suggests a recombination into RaTG13. We also 14 find a 14-fold increase in the d N /d S ratio from the lineage leading to SARS-CoV-2 to the 15 strains of the current pandemic, suggesting that the vast majority of non-synonymous 16 mutations currently segregating within the human strains have a negative impact on viral 17fitness. Finally, we estimate that the time to the most recent common ancestor of SARS-18CoV-2 and RaTG13 or RmYN02 based on synonymous divergence, is 51.71 years (95% 19 C.I., 28.11-75.31) and 37.02 years (95% C.I., 18.19-55.85), respectively. 20 21 a coronavirus (Lu, et al. 2020; Zhang and Holmes 2020), Severe acute respiratory syndrome 1 coronavirus 2 (SARS-CoV-2), an RNA virus with a 29,891 bp genome consisting of four major 2 structural genes (Wu, et al. 2020; Zhou, Yang, et al. 2020). Of particular relevance to this study 3 is the spike protein which is responsible for binding to the primary receptor for the virus, 4 angiotensin-converting enzyme 2 (ACE2) (Wan, et al. 2020; Wu, et al. 2020; Zhou, Yang, et al. 5 2020). 6Human SARS-CoV-2 is related to a coronavirus (RaTG13) isolated from the bat 7Rhinolophus affinis from Yunnan province of China (Zhou, Yang, et al. 2020). RaTG13 and the 8 human strain reference sequence (Genbank accession number MN996532) are 96.2% identical 9and it was first argued that, throughout the genome, RaTG13 is the closest relative to human 10 SARS-CoV-2 (Zhou, et al. 2020). Zhang, et al. 2020 showed that RaTG13 and SARS-CoV-2 11 were 91.02% and 90.55% identical ,respectively, to coronaviruses isolated from pangolins 12 (Pangolin-CoV), which therefore form a close outgroup to the SARS-CoV-2+RaTG13 clade . 13 Furthermore, five key amino acids in the receptor-binding domain (RBD) of spike were identical 14 between SARS-CoV-2 and Pangolin-CoV, but differed between those two strains and RaTG13. 15 (Lam, et al. 2020) independently made similar observations and additionally showed that when 16 analyzing...

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“…Parallel and/convergent evolution, which occur through point mutation, could contribute to our observed evolutionary convergence, but it could not account for the unusually high incidence of convergent sites observed in this study, representing a rare finding in previous studies [20][21][22][23][24][25][26] . Recent studies have shown a relatively high likelihood of occurrence of homologous recombination in spike protein 7,34,35 , and especially, it is considered that the RBD of 2019-nCov may be derived from a recombination event between that of human SARS-CoV and another (unsampled) SARS-like CoV 35 . If this is the case, the homologous recombination, if any, may have occurred between the ancestors (branches C and K) of SARS-related CoV and COVID-19-related CoV, accounting for their unusually high incidence of convergent sites observed in this study.…”

Section: Resultsmentioning

confidence: 99%

Strong evolutionary convergence of receptor-binding protein spike between COVID-19 and SARS-related coronaviruses

2020

Preprint

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Coronavirus Disease 2019 and severe acute respiratory syndrome (SARS)-related coronaviruses (e.g., 2019-nCoV and SARS-CoV) are phylogenetically distantly related, but both are capable of infecting human hosts via the same receptor, angiotensin-converting enzyme 2, and cause similar clinical and pathological features, suggesting their phenotypic convergence. Yet, the molecular basis that underlies their phenotypic convergence remains unknown. Here, we used a recently developed molecular phyloecological approach to examine the molecular basis leading to their phenotypic convergence. Our genome-level analyses show that the spike protein, which is responsible for receptor binding, has undergone significant Darwinian selection along the branches related to 2019-nCoV and SARS-CoV. Further examination shows an unusually high proportion of evolutionary convergent amino acid sites in the receptor binding domain (RBD) of the spike protein between COVID-19 and SARS-related CoV clades, leading to the phylogenetic uniting of their RBD protein sequences. In addition to the spike protein, we also find the evolutionary convergence of its partner protein, ORF3a, suggesting their possible co-evolutionary convergence. Our results demonstrate a strong adaptive evolutionary convergence between COVID-19 and SARS-related CoV, possibly facilitating their adaptation to similar or identical receptors. Finally, it should be noted that many observed bat SARS-like CoVs that have an evolutionary convergent RBD sequence with 2019-nCoV and SARS-CoV may be preadapted to human host receptor ACE2, and hence would be potential new coronavirus sources to infect humans in the future.

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Recombination and lineage-specific mutations linked to the emergence of SARS-CoV-2

Cited by 29 publications

References 57 publications

Recombination events are concentrated in the spike protein region of Betacoronaviruses

Recombination events are concentrated in the spike protein region of Betacoronaviruses

Synonymous mutations and the molecular evolution of SARS-Cov-2 origins

Strong evolutionary convergence of receptor-binding protein spike between COVID-19 and SARS-related coronaviruses

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