title: Topology of evolving, mutagenized viral populations: quasispecies expansion, compression, and operation of negative selection.
abstract: BACKGROUND
  The molecular events and evolutionary forces underlying lethal mutagenesis of virus (or virus extinction through an excess of mutations) are not well understood. Here we apply for the first time phylogenetic methods and Partition Analysis of Quasispecies (PAQ) to monitor genetic distances and intra-population structures of mutant spectra of foot-and-mouth disease virus (FMDV) quasispecies subjected to mutagenesis by base and nucleoside analogues.
  
  
  RESULTS
  Phylogenetic and PAQ analyses have revealed a highly dynamic variation of intrapopulation diversity of FMDV quasispecies. The population diversity first suffers striking expansions in the presence of mutagens and then compressions either when the presence of the mutagenic analogue was discontinued or when a mutation that decreased sensitivity to a mutagen was selected. The pattern of mutations found in the populations was in agreement with the behavior of the corresponding nucleotide analogues with FMDV in vitro. Mutations accumulated at preferred genomic sites, and dn/ds ratios indicate the operation of negative (or purifying) selection in populations subjected to mutagenesis. No evidence of unusually elevated genetic distances has been obtained for FMDV populations approaching extinction.
  
  
  CONCLUSIONS
  Phylogenetic and PAQ analysis provide adequate procedures to describe the evolution of viral sequences subjected to lethal mutagenesis. These methods define the changes of intra-population structure more precisely than mutation frequencies and Shannon entropies. PAQ is very sensitive to variations of intrapopulation genetic distances. Strong negative (or purifying) selection operates in FMDV populations subjected to enhanced mutagenesis. The quantifications provide evidence that extinction does not imply unusual increases of intrapopulation complexity, in support of the lethal defection model of virus extinction.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, UAM-CSIC, Campus de Cantoblanco, 28049, Madrid, Spain. sojosnegros@cbm.uam.es
authors.forename: Samuel
authors.initials: S
authors.lastname: Ojosnegros
authors.forename: Rubén
authors.initials: R
authors.lastname: Agudo
authors.forename: Macarena
authors.initials: M
authors.lastname: Sierra
authors.forename: Carlos
authors.initials: C
authors.lastname: Briones
authors.forename: Saleta
authors.initials: S
authors.lastname: Sierra
authors.forename: Claudia
authors.initials: C
authors.lastname: González-López
authors.forename: Esteban
authors.initials: E
authors.lastname: Domingo
authors.forename: Juan
authors.initials: J
authors.lastname: Cristina
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D019143:Evolution, Molecular; D029544:Foot-and-Mouth Disease Virus / Q000187:drug effects / Q000235:genetics*; D016679:Genome, Viral; D016013:Likelihood Functions; D008954:Models, Biological; D016296:Mutagenesis; D009153:Mutagens; D009154:Mutation; D010802:Phylogeny; D012367:RNA, Viral / Q000235:genetics; D012254:Ribavirin / Q000494:pharmacology; D012641:Selection, Genetic
chemical_list: D009153:Mutagens; D012367:RNA, Viral; D012254:Ribavirin