title: Interspecific adaptation by binary choice at de novo polyomavirus T antigen site through accelerated codon-constrained Val-Ala toggling within an intrinsically disordered region.
abstract: It is common knowledge that conserved residues evolve slowly. We challenge generality of this central tenet of molecular biology by describing the fast evolution of a conserved nucleotide position that is located in the overlap of two open reading frames (ORFs) of polyomaviruses. The de novo ORF is expressed through either the ALTO protein or the Middle T antigen (MT/ALTO), while the ancestral ORF encodes the N-terminal domain of helicase-containing Large T (LT) antigen. In the latter domain the conserved Cys codon of the LXCXE pRB-binding motif constrains codon evolution in the overlapping MT/ALTO ORF to a binary choice between Val and Ala codons, termed here as codon-constrained Val-Ala (COCO-VA) toggling. We found the rate of COCO-VA toggling to approach the speciation rate and to be significantly accelerated compared to the baseline rate of chance substitution in a large monophyletic lineage including all viruses encoding MT/ALTO and three others. Importantly, the COCO-VA site is located in a short linear motif (SLiM) of an intrinsically disordered region, a typical characteristic of adaptive responders. These findings provide evidence that the COCO-VA toggling is under positive selection in many polyomaviruses, implying its critical role in interspecific adaptation, which is unprecedented for conserved residues.
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, 2300-RC Leiden, The Netherlands Institute for Medical Informatics and Biometry, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Lauber
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, 2300-RC Leiden, The Netherlands.
authors.forename: Siamaque
authors.initials: S
authors.lastname: Kazem
authors.affiliation: Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Kravchenko
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, 2300-RC Leiden, The Netherlands.
authors.forename: Mariet C W
authors.initials: MC
authors.lastname: Feltkamp
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, 2300-RC Leiden, The Netherlands Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119899 Moscow, Russia a.e.gorbalenya@lumc.nl.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Gorbalenya
mesh_terms: D000220:Adaptation, Biological; D000409:Alanine / Q000235:genetics; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D003062:Codon; D019143:Evolution, Molecular; D064267:Intrinsically Disordered Proteins / Q000235:genetics; D016366:Open Reading Frames; D010802:Phylogeny; D011120:Polyomavirus / Q000145:classification / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: D000952:Antigens, Polyomavirus Transforming; D003062:Codon; D064267:Intrinsically Disordered Proteins; D014633:Valine; D000409:Alanine