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Open Access Research article

Topology of evolving, mutagenized viral populations: quasispecies expansion, compression, and operation of negative selection

Samuel Ojosnegros1, Rubén Agudo1, Macarena Sierra1, Carlos Briones23, Saleta Sierra14, Claudia González- López15, Esteban Domingo123* and Juan Cristina16

Author Affiliations

1 Centro de Biología Molecular "Severo Ochoa", UAM-CSIC. Campus de Cantoblanco, 28049, Madrid, Spain

2 Laboratorio de Evolución Molecular, Centro de Astrobiología (CSIC/INTA), Instituto Nacional de Técnica Aeroespacial, Ctra de Torrejón a Ajalvir, km 4, 28850 Torrejón de Ardoz, Madrid, Spain

3 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain

4 Institute of Virology, University of Cologne, Fuerst-Pueckler Str. 56, D-50935 Cologne, Germany

5 MRC Laboratory for Molecular Cell Biology & Cell Biology Unit, University College London, Gower Street, London, WC1E 6BT, UK

6 Laboratorio de Virología Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay

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BMC Evolutionary Biology 2008, 8:207  doi:10.1186/1471-2148-8-207

Published: 17 July 2008

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.

Conclusion

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.