Exploration of sequence space as the basis of viral RNA genome segmentation.
The mechanisms of viral RNA genome segmentation are unknown. On extensive passage of foot-and-mouth disease virus in baby hamster kidney-21 cells, the virus accumulated multiple point mutations and underwent a transition akin to genome segmentation. The standard single RNA genome molecule was replaced by genomes harboring internal in-frame deletions affecting the L- or capsid-coding region. These genomes were infectious and killed cells by complementation. Here we show that the point mutations in the nonstructural protein-coding region (P2, P3) that accumulated in the standard genome before segmentation increased the relative fitness of the segmented version relative to the standard genome. Fitness increase was documented by intracellular expression of virus-coded proteins and infectious progeny production by RNAs with the internal deletions placed in the sequence context of the parental and evolved genome. The complementation activity involved several viral proteins, one of them being the leader proteinase L. Thus, a history of genetic drift with accumulation of point mutations was needed to allow a major variation in the structure of a viral genome. Thus, exploration of sequence space by a viral genome (in this case an unsegmented RNA) can reach a point of the space in which a totally different genome structure (in this case, a segmented RNA) is favored over the form that performed the exploration.
Department of Virology and Microbiology, Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid, Spain.
Elena
E
Moreno
Samuel
S
Ojosnegros
Juan
J
García-Arriaza
Cristina
C
Escarmís
Esteban
E
Domingo
Celia
C
Perales
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D006224:Cricetinae; D010450:Endopeptidases / Q000235:genetics; D019143:Evolution, Molecular; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D005816:Genetic Complementation Test; D040961:Genetic Drift; D016679:Genome, Viral; D008969:Molecular Sequence Data; D017354:Point Mutation; D012367:RNA, Viral / Q000235:genetics*; D012641:Selection, Genetic; D017384:Sequence Deletion; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
D012367:RNA, Viral; D014764:Viral Proteins; D010450:Endopeptidases; C088747:leader proteinase, foot-and-mouth disease virus
RNA virus evolution; evolutionary transition; mutant spectrum; quasi-species; viral emergence