Mapping genome variation of SARS-CoV-2 worldwide highlights the impact of COVID-19 super-spreaders

Abstract

The human pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the major pandemic of the twenty-first century. We analyzed more than 4700 SARS-CoV-2 genomes and associated metadata retrieved from public repositories. SARS-CoV-2 sequences have a high sequence identity (>99.9%), which drops to >96% when compared to bat coronavirus genome. We built a mutation-annotated reference SARS-CoV-2 phylogeny with two main macro-haplogroups, A and B, both of Asian origin, and more than 160 sub-branches representing virus strains of variable geographical origins worldwide, revealing a rather uniform mutation occurrence along branches that could have implications for diagnostics and the design of future vaccines. Identification of the root of SARS-CoV-2 genomes is not without problems, owing to conflicting interpretations derived from either using the bat coronavirus genomes as an outgroup or relying on the sampling chronology of the SARS-CoV-2 genomes and TMRCA estimates; however, the overall scenario favors haplogroup A as the ancestral node. Phylogenetic analysis indicates a TMRCA for SARS-CoV-2 genomes dating to November 12, 2019, thus matching epidemiological records. Sub-haplogroup A2 most likely originated in Europe from an Asian ancestor and gave rise to subclade A2a, which represents the major non-Asian outbreak, especially in Africa and Europe. Multiple founder effect episodes, most likely associated with super-spreader hosts, might explain COVID-19 pandemic to a large extent.

An evolutionary portrait of the progenitor SARS-CoV-2 and its dominant offshoots in COVID-19 pandemic

“…2a). This phylogeny is a rooted tree of SARS-CoV-2, which has been challenging to infer reliably [1][2][3][4][5][6][7][8] . It shows that all the early novel coronavirus lineages were established by three μ mutations, all of which were first seen in genomes sampled in China.…”

“…The early evolutionary history and order of mutational events that arose during the pandemic remain unresolved, even months after the initial detection of SARS-CoV-2 as the causal agent of COVID-19 and the acquisition of tens of thousands of genomes [1][2][3][4][5][6][7][8] . Widely-recognized impediments include a limited number of phylogenetically informative variants in genomes, the ubiquity of sequencing errors, and the lack of a closely-related outgroup sequence, all of which have complicated the inference and rooting of the SARS-CoV-2 phylogeny [1][2][3][4][5][6][7][8] . Consequently, the traditional approach to the analysis of viral spread and evolution in which a reliable genome phylogeny is first inferred, and then observed differences among sequences are mapped site-by-site, has not been able to stage the earliest mutational events in the evolution of the novel coronavirus 9,10 .…”

Assessing Uncertainty in the Rooting of the SARS-CoV-2 Phylogeny

“…However, the events leading to the early spread of the viruses are still unclear, in part because there is substantial uncertainty about the rooting of the SARS-CoV-2 phylogeny. The importance in identifying the origin of the virus has prompted other analyses on the uncertainty of rooting the phylogeny ( Gomez-Carballa et al 2020 ; Morel et al 2020 ). Previous analyses have reached different conclusions about the rooting of the phylogeny.…”

Pitfalls of barcodes in the study of worldwide SARS-CoV-2 variation and phylodynamics

“…In particular, the Global Initiative on Sharing all Individual Data (GISAID; https://www.gisaid.org/) offers full open access to SARS-CoV-2 genomic data provided by hundreds of laboratories worldwide. The scientific community can analyze the whole-genome sequences available in these resources to make inferences about SARS-CoV-2 genetic variation and its phylogenetic roots, natural selection, and phylodynamics ( Boni et al, 2020 ; Forster et al, 2020 ; Gómez-Carballa et al, 2020a , 2020b ; Gudbjartsson et al, 2020 ; Rambaut et al, 2020 ; Rockett et al, 2020 ; Van Dorp et al, 2020 ; Yu et al, 2020 ). Furthermore, the fact that the coronavirus genome is only ~30 kb allows for relatively easy computational treatment.…”

“…We propose that this redundancy could have been eliminated by simply inspecting the SARS-CoV-2 phylogeny. For instance, the phylogenetic tree skeleton in Figure 1A (inspired by Figure 3 in Gómez-Carballa et al (2020a) ), which includes the initial 20 ISMs signature, shows that: variants C8782T–T28144C together define clade B (11 nt compressed ISMs C CT GCCAAGGG in Zhao et al (2020) ); the sequence motif C241T–C3037T–A23403G characterizes clade A2 (CCCG CCA GGGG, immediate ancestral node of the most successful SARS-CoV-2 variant outside Asia, which most likely originated in Italy ( Gómez-Carballa et al, 2020a )); and G28881A–G28882A–G28883C defines haplogroup A2a4 (CCCGCCA GGG A, one of the most important sub-branches of A2 (CCCGCCAGGGG); here we favored the single multi-nucleotide polymorphism (MNP) event GGG28881AAC for nomenclature, as justified in Gómez-Carballa et al (2020a) ). In addition, their entropy-based algorithm sub-optimally prioritized positions that are diagnostic of nodes located along the same evolutionary pathway, but which add very little to the overall discrimination power of the ISMs set: A1 (CCC GC CAAGTG) makes up 4.7% of the total database, while its sub-lineage A1a (CCC TT CAAGTG) represents 4.3% and A1a3 represents 1.8% ( Figure 1A ).…”