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dc.creatorMartin, Darren P.
dc.creatorLytras, Spyros
dc.creatorLucaci, Alexander
dc.creatorMaier, Wolfgang
dc.creatorGrüning, Björn
dc.creatorShank, Stephen
dc.creatorWeaver, Steven
dc.creatorMacLean, Oscar A.
dc.creatorOrton, Richard J.
dc.creatorLemey, Philippe
dc.creatorBoni, Maciej F.
dc.creatorTegally, Houriiyah
dc.creatorHarkins, Gordon W.
dc.creatorScheepers, Cathrine
dc.creatorBhiman, Jinal N.
dc.creatorEveratt, Josie
dc.creatorAmoako, Daniel G.
dc.creatorSan, James Emmanuel
dc.creatorGiandhari, Jennifer
dc.creatorSigal, Alex
dc.creatorWilliamson, Carolyn
dc.creatorHsaio, Nei-Yuan
dc.creatorvon Gottberg, Anne
dc.creatorde Klerk, Arne
dc.creatorShafer, Robert W.
dc.creatorRobertson, David L.
dc.creatorWilkinson, Robert J.
dc.creatorSewell, B. Trevor
dc.creatorLessells, Richard
dc.creatorNekrutenko, Anton
dc.creatorGreaney, Allison J.
dc.creatorStarr, Tyler N.
dc.creatorBloom, Jesse D.
dc.creatorMurrell, Ben
dc.creatorWilkinson, Eduan
dc.creatorGupta, Ravindra K.
dc.creatorde Oliveira, Tulio
dc.creatorPond, Sergei
dc.description.abstractAmong 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.
dc.format.extent20 pages
dc.relation.ispartofFaculty/ Researcher Works
dc.relation.haspartMolecular Biology and Evolution (MBE), Vol. 39, Iss. 4
dc.relation.isreferencedbyOxford University Press (OUP)
dc.rightsAttribution CC BY
dc.subjectNegative selection
dc.subjectPositive selection
dc.titleSelection Analysis Identifies Clusters of Unusual Mutational Changes in Omicron Lineage BA.1 That Likely Impact Spike Function
dc.type.genreJournal article
dc.contributor.groupInstitute for Genomics and Evolutionary Medicine (iGEM) (Temple University)
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact
dc.description.schoolcollegeTemple University. College of Science and Technology
dc.temple.creatorLucaci, Alexander G.
dc.temple.creatorShank, Stephen D.
dc.temple.creatorWeaver, Steven
dc.temple.creatorPond, Sergei L. Kosakovsky

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