RT Journal Article SR Electronic T1 The origins and molecular evolution of SARS-CoV-2 lineage B.1.1.7 in the UK JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.03.08.481609 DO 10.1101/2022.03.08.481609 A1 Verity Hill A1 Louis Du Plessis A1 Thomas P. Peacock A1 Dinesh Aggarwal A1 Rachel Colquhoun A1 Alesandro M. Carabelli A1 Nicholas Ellaby A1 Eileen Gallagher A1 Natalie Groves A1 Ben Jackson A1 JT McCrone A1 Áine O’Toole A1 Anna Price A1 Theo Sanderson A1 Emily Scher A1 Joel Southgate A1 Erik Volz A1 The COVID-19 genomics UK (COG-UK) consortium A1 Wendy S. Barclay A1 Jeffrey C. Barrett A1 Meera Chand A1 Thomas Connor A1 Ian Goodfellow A1 Ravindra K. Gupta A1 Ewan M. Harrison A1 Nicholas Loman A1 Richard Myers A1 David L Robertson A1 Oliver G Pybus A1 Andrew Rambaut YR 2022 UL http://biorxiv.org/content/early/2022/03/08/2022.03.08.481609.abstract AB 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.Competing Interest StatementThe authors have declared no competing interest.