Horizontal gene transfer and recombination analysis of SARS-CoV-2 genes helps discover its close relatives and shed light on its origin

Abstract

Background The SARS-CoV-2 pandemic is one of the greatest global medical and social challenges that have emerged in recent history. Human coronavirus strains discovered during previous SARS outbreaks have been hypothesized to pass from bats to humans using intermediate hosts, e.g. civets for SARS-CoV and camels for MERS-CoV. The discovery of an intermediate host of SARS-CoV-2 and the identification of specific mechanism of its emergence in humans are topics of primary evolutionary importance. In this study we investigate the evolutionary patterns of 11 main genes of SARS-CoV-2. Previous studies suggested that the genome of SARS-CoV-2 is highly similar to the horseshoe bat coronavirus RaTG13 for most of the genes and to some Malayan pangolin coronavirus (CoV) strains for the receptor binding (RB) domain of the spike protein. Results We provide a detailed list of statistically significant horizontal gene transfer and recombination events (both intergenic and intragenic) inferred for each of 11 main genes of the SARS-CoV-2 genome. Our analysis reveals that two continuous regions of genes S and N of SARS-CoV-2 may result from intragenic recombination between RaTG13 and Guangdong (GD) Pangolin CoVs. Statistically significant gene transfer-recombination events between RaTG13 and GD Pangolin CoV have been identified in region [1215–1425] of gene S and region [534–727] of gene N. Moreover, some statistically significant recombination events between the ancestors of SARS-CoV-2, RaTG13, GD Pangolin CoV and bat CoV ZC45-ZXC21 coronaviruses have been identified in genes ORF1ab, S, ORF3a, ORF7a, ORF8 and N. Furthermore, topology-based clustering of gene trees inferred for 25 CoV organisms revealed a three-way evolution of coronavirus genes, with gene phylogenies of ORF1ab, S and N forming the first cluster, gene phylogenies of ORF3a, E, M, ORF6, ORF7a, ORF7b and ORF8 forming the second cluster, and phylogeny of gene ORF10 forming the third cluster. Conclusions The results of our horizontal gene transfer and recombination analysis suggest that SARS-CoV-2 could not only be a chimera virus resulting from recombination of the bat RaTG13 and Guangdong pangolin coronaviruses but also a close relative of the bat CoV ZC45 and ZXC21 strains. They also indicate that a GD pangolin may be an intermediate host of this dangerous virus.

What we know and what we need to know about the origin of SARS-CoV-2

“…According to these authors, not only pangolins, but also other mammals -such as small carnivores-would be candidates. With respect specifically to pangolins, Makarenkov et al (2021) provided arguments supporting the hypothesis of the SARS-CoV-2 origin, according to which, the SARS-CoV-2 genome was a chimera of the RaTG13 and pangolin coronaviruses. Moreover, the results of their horizontal gene transfer and recombination analysis suggested that SARS-CoV-2 could not only be a chimera virus resulting from recombination of the bat RaTG13 and pangolin coronaviruses, but also a close relative of the bat CoV ZC45 and ZXC21 strains.…”

Phylogenetic reconciliation reveals extensive ancestral recombination in Sarbecoviruses and the SARS-CoV-2 lineage

“…There have been two recent investigations of HGT and recombination in coronaviruses using phylogenetic reconciliation approaches [14,29] (performed independently in parallel to the current work). Fu et al [14] used DTL reconciliation to infer inter-host HGT events using approximately 400 coronavirus genomes, including alpha, beta, delta, and gamma coronaviruses from a variety of host species.…”

“…The resulting reconciliations were used to identify the host species that were most likely to engage in cross-host-species recombination of coronaviruses. Makarenkov et al [29] used phylogenetic techniques to investigate patterns of HGT and recombination in 11 gene families from Sarbecoviruses. In particular, the authors use the HGT detection program T-Rex [6], based on bipartition dissimilarity between a strain tree and gene trees, to identify partial-and full-gene HGTs.…”

“…Lastly, we identify and discuss the strengths and limitations of the proposed reconciliation-based approach, contrast virDTL with widely-used sequence-similarity based approaches such as SimPlot [28] and RDP [30], and compare our protocol against two recent approaches used to investigate recombination in coronaviruses using phylogenetic reconciliation, developed in parallel and independently from this work [14,29] (Discussion).…”

SARS-CoV-2 Portrayed against HIV: Contrary Viral Strategies in Similar Disguise

“…Pangolin-CoV is identical to SARS-CoV-2 in all five critical residues for receptor binding of the RBD but has only 92% whole-genome nucleotide identity [ 117 ]. Analysis of horizontal gene transfer and recombination lends support for intragenic recombination of the spike genes between RaTG13 and Pangolin-CoV, which could have given rise to the chimeric SARS-CoV-2 [ 118 ]. However, neither RaTG13 nor Pangolin-CoV contain the polybasic furin cleavage site at the S1/S2 junction, which is present within the spike protein of SARS-CoV-2 and greatly contributes to the virus’s tropism and pathogenicity [ 119 ].…”