RT Journal Article
SR Electronic
T1 Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.14.476382
DO 10.1101/2022.01.14.476382
A1 Darren P Martin
A1 Spyros Lytras
A1 Alexander G Lucaci
A1 Wolfgang Maier
A1 Björn Grüning
A1 Stephen D Shank
A1 Steven Weaver
A1 Oscar A MacLean
A1 Richard J Orton
A1 Philippe Lemey
A1 Maciej F Boni
A1 Houriiyah Tegally
A1 Gordon Harkins
A1 Cathrine Scheepers
A1 Jinal N Bhiman
A1 Josie Everatt
A1 Daniel G Amoako
A1 James Emmanuel San
A1 Jennifer Giandhari
A1 Alex Sigal
A1 NGS-SA
A1 Carolyn Williamson
A1 Nei-yuan Hsiao
A1 Anne von Gottberg
A1 Arne De Klerk
A1 Robert W Shafer
A1 David L Robertson
A1 Robert J Wilkinson
A1 B Trevor Sewell
A1 Richard Lessells
A1 Anton Nekrutenko
A1 Allison J. Greaney
A1 Tyler N. Starr
A1 Jesse D. Bloom
A1 Ben Murrell
A1 Eduan Wilkinson
A1 Ravindra K Gupta
A1 Tulio de Oliveira
A1 Sergei L Kosakovsky Pond
YR 2022
UL http://biorxiv.org/content/early/2022/01/18/2022.01.14.476382.abstract
AB Among the 30 non-synonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (i) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (ii) interactions of Spike with ACE2 receptors, and (iii) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any genomes within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron over all previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected.Competing Interest StatementJDB consults for Moderna, Flagship Labs 77, and Oncorus. JDB, AJG, and TNS are inventors on Fred Hutch licensed patents related to deep mutational scanning of viral proteins.