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

Abstract

Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, was quickly identified as the cause of COVID-19 disease soon after its earliest reports. The knowledge of the contemporary evolution of SARS-CoV-2 is urgently needed not only for a retrospective on how, when, and why COVID-19 has emerged and spread, but also for creating remedies through efforts of science, technology, medicine, and public policy. Global sequencing of thousands of genomes has revealed many common genetic variants, which are the key to unraveling the early evolutionary history of SARS-CoV-2 and tracking its global spread over time. However, our knowledge of fundamental events in the evolution and spread of this coronavirus remains grossly incomplete and highly uncertain. Here, we present the heretofore cryptic mutational history, phylogeny, and dynamics of SARS-CoV-2 from an analysis of tens of thousands of high-quality genomes. The reconstructed mutational progression is highly concordant with the timing of coronavirus sampling dates. It predicts the progenitor genome whose earliest offspring without any non-synonymous mutations were still spreading worldwide months after the report of COVID-19. Over time, mutations gave rise to seven major lineages that spread episodically, some of which arose in Europe and North America after the genesis of the ancestral lineages in China. Mutational barcoding establishes that North American coronaviruses harbor very different genome signatures than coronaviruses prevalent in Europe and Asia that have converged over time. These spatiotemporal patterns continue to evolve as the pandemic progresses and can be viewed live online.

Ongoing Global and Regional Adaptive Evolution of SARS-CoV-2

“…We identified 6 principal partitions within this tree, in general agreement with other work (16,17,18) , along with two region-specific clades within partitions 3 and 6 (Fig. 1A) that, as discussed below, are important for the interpretation of the metadata.…”

Timing the SARS-CoV-2 Index Case in Hubei Province

“…It has been speculated that if SARS-CoV-2 was circulating in humans prior to the tMRCA, this time-period could have permitted the evolution of human-specific viral adaptations, specifically in the polybasic cleavage site in the Spike protein ( 13 ). Based on posterior estimates for the tMRCA, substitution rate, and number of days between index case infection and the tMRCA, we estimate that approximately 2.2 mutations (95% HPD: 0.5-3.9) occurred in SARS-CoV-2 before giving rise to the observed patterns of genetic diversity ( 23 ). This estimate is similar if we assume a relaxed molecular clock: 2.5 mutations (95% HPD: 0.1-4.3).…”

Potential Achilles heels of SARS-CoV-2 are best displayed by the base order-dependent component of RNA folding energy

“…These were obtained from the NCBI (Bethesda) and GISAID EpiCoV (Munich) databases. The Wuhan-Hu1 sequence (GenBank NC_045512.2), deemed taxonomically prototypic [17, 18], was compared (regarding base substitutions and folding potential) with 381 Chinese isolates, 430 Italian isolates, and 932 isolates from New York, USA. Our “window” starting point was base 1 of the 29,903 base prototype sequence.…”

“…The Wuhan-Hu1 sequence (GenBank NC_045512.2), deemed taxonomically prototypic [17,18], was compared (regarding base substitutions and folding potential) with 381 Chinese isolates, 430…”

“…The Wuhan-Hu1 sequence (GenBank NC_045512.2), deemed taxonomically prototypic (Kumar et al, 2020;Pipes et al, 2020), was compared (regarding base substitutions and folding potential) with 381 Chinese isolates, 430 Italian isolates, and 932 isolates from New York, USA.…”