The origins and molecular evolution of SARS-CoV-2 lineage B.1.1.7 in the UK

Abstract

The first SARS-CoV-2 variant of concern (VOC) to be designated was lineage B.1.1.7, later labelled by the World Health Organisation (WHO) as Alpha. Originating in early Autumn but discovered in December 2020, it spread rapidly and caused large waves of infections worldwide. The Alpha variant is notable for being defined by a long ancestral phylogenetic branch with an increased evolutionary rate, along which only two sequences have been sampled. Alpha genomes comprise a well-supported monophyletic clade within which the evolutionary rate is more typical of SARS-CoV-2. The Alpha epidemic continued to grow despite the continued restrictions on social mixing across the UK, and the imposition of new restrictions, in particular the English national lockdown in November 2020. While these interventions succeeded in reducing the absolute number of cases, the impact of these non-pharmaceutical interventions was predominantly to drive the decline of the SARS-CoV-2 lineages which preceded Alpha. We investigate the only two sampled sequences that fall on the branch ancestral to Alpha. We find that one is likely to be a true intermediate sequence, providing information about the order of mutational events that led to Alpha. We explore alternate hypotheses that can explain how Alpha acquired a large number of mutations yet remained largely unobserved in a region of high genomic surveillance: an under-sampled geographical location, a non-human animal population, or a chronically-infected individual. We conclude that the last hypothesis provides the best explanation of the observed behaviour and dynamics of the variant, although we find that the individual need not be immunocompromised, as persistently-infected immunocompetent hosts also display a higher within-host rate of evolution. Finally, we compare the ancestral branches and mutation profiles of other VOCs to each other, and identify that Delta appears to be an outlier both in terms of the genomic locations of its defining mutations, and its lack of rapid evolutionary rate on the ancestral branch. As new variants, such as Omicron, continue to evolve (potentially through similar mechanisms) it remains important to investigate the origins of other variants to identify ways to potentially disrupt their evolution and emergence.

Replacement of the Alpha variant of SARS-CoV-2 by the Delta variant in Lebanon between April and June 2021

“…The terminal substitution rates using a relaxed molecular clock model were estimated at 7.6×10 −4 (±2.2×10 −4 ) substitutions per site per year for the Alpha samples sequenced as part of this study, against 6.2×10 −4 (±2.8×10 −4 ) substitutions per site per year for the global Alpha sequences included in the present analysis. This is in agreement with other estimates, which show no noticeable differences in rates except for episodic events leading to new lineages [34]. The overall estimated rates may also be influenced by the analysis time span and model choice, which explains subtle differences between publications [35].…”

“…This model allows for the individual rates to vary between samples, while the particular mean rate chosen reflects the timespan of the analysis [29]. Variants of concern are associated with episodic increases in the evolutionary rate, however sustained changes in the overall rate haven"t been observed so far [30].…”

Genetic Diversity and Evolutionary Convergence of Cryptic SARS-CoV-2 Lineages Detected Via Wastewater Sequencing

“…Regardless of the origins and dynamics of cryptic variant shedding, our results highlight the ability of wastewater-based epidemiology to more completely monitor SARS-CoV-2 transmission and genetic diversity than can patient based sampling, at scale and at a greatly reduced cost. Given that multiple VOCs may have gone undetected until suddenly appearing, highly mutated, in apparently single evolutionary leaps [12], it is crucial to the early detection of the next variant of concern that novel SARS-CoV-2 genotypes are monitored for evidence of significant expansion. Importantly, patient sampling efforts, despite occurring with an intensity not seen in any prior epidemic, were unable to identify intermediary forms of most VOCs.…”

Spike protein cleavage-activation mediated by the SARS-CoV-2 P681R mutation: a case-study from its first appearance in variant of interest (VOI) A.23.1 identified in Uganda

“…The A.23.1 variant pre-dated the B.1.617 lineage as a P681R-containing VOC/VOI by several months. It is interesting to note that B.1.617.2 (Delta) has been shown to be a genetic outlier compared to other VOCs (29), raising the question of whether P681R (found in A.23.1 and B.1.617) ultimately results in a more successful viral variant compared to P681H, found in B.1.1.7 (Alpha) and B.1.529 (Omicron BA.1/BA.2). It is important to note that both lineages that have temporarily dominated Uganda have encoded the spike P681R substitution, but in combination with distinct changes in the spike protein.…”