TY - JOUR
AU - Martin, Darren P.
AU - Lytras, Spyros
AU - Lucaci, Alexander G.
AU - Maier, Wolfgang
AU - Grüning, Björn
AU - Shank, Stephen D.
AU - Weaver, Steven
AU - MacLean, Oscar A.
AU - Orton, Richard J.
AU - Lemey, Philippe
AU - Boni, Maciej F.
AU - Tegally, Houriiyah
AU - Harkins, Gordon W.
AU - Scheepers, Cathrine
AU - Bhiman, Jinal N.
AU - Everatt, Josie
AU - Amoako, Daniel G.
AU - San, James Emmanuel
AU - Giandhari, Jennifer
AU - Sigal, Alex
AU - Williamson, Carolyn
AU - Hsiao, Nei-yuan
AU - von Gottberg, Anne
AU - de Klerk, Arné
AU - Shafer, Robert W
AU - Robertson, David L.
AU - Wilkinson, Robert J
AU - Sewell, B Trevor
AU - Lessells, Richard J.
AU - Nekrutenko, Anton
AU - Greaney, Allison J
AU - Starr, Tyler N
AU - Bloom, Jesse D
AU - Murrell, Ben
AU - Wilkinson, Eduan
AU - Gupta, Ravindra K.
AU - De Oliveira, Tulio
AU - Kosakovsky Pond, Sergei L.
PY - 2022
DA - April
TI - Selection analysis identifies clusters of unusual mutational changes in Omicron lineage BA.1 that likely impact Spike function
JO - Molecular Biology and Evolution
VL - 39
IS - 4
DO - http://dx.doi.org/10.1093/molbev/msac061
AB - Among the 30 nonsynonymous 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 (1) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (2) interactions of Spike with ACE2 receptors, and (3) 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 virus 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, in combination with other mutations, adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron overall 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.
PB - Oxford University Press
UR - http://eprints.gla.ac.uk/268456/
KW - Coronavirus (COVID-19)
ER