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

Additional files: Additional file 1: Neighbour-joining, maximum likelihood and maximum parsimony analysis of populations RAp35 and RA0p35. Additional file 2: Maximum likelihood phylogenetic analysis of mutagenized populations of FMDV. Additional file 3: Standard errors.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.Work at Centro de Biología Molecular "Severo Ochoa" was supported by grants BFU2006-00863 from MEC, 36558/06 from FIPSE, and Fundación R.Areces. Work at Centro de Astrobiología was supported by INTA, MEC, CAM and UE. CIBERehd is funded by Instituto de Salud Carlos III. S.O. was supported by a predoctoral fellowship from the Ministerio de Educacion y Ciencia.Peer reviewe

From genotypes to organisms: State-of-the-art and perspectives of a cornerstone in evolutionary dynamics

Understanding how genotypes map onto phenotypes, fitness, and eventually organisms is arguably the next major missing piece in a fully predictive theory of evolution. We refer to this generally as the problem of the genotype-phenotype map. Though we are still far from achieving a complete picture of these relationships, our current understanding of simpler questions, such as the structure induced in the space of genotypes by sequences mapped to molecular structures, has revealed important facts that deeply affect the dynamical description of evolutionary processes. Empirical evidence supporting the fundamental relevance of features such as phenotypic bias is mounting as well, while the synthesis of conceptual and experimental progress leads to questioning current assumptions on the nature of evolutionary dynamics-cancer progression models or synthetic biology approaches being notable examples. This work delves into a critical and constructive attitude in our current knowledge of how genotypes map onto molecular phenotypes and organismal functions, and discusses theoretical and empirical avenues to broaden and improve this comprehension. As a final goal, this community should aim at deriving an updated picture of evolutionary processes soundly relying on the structural properties of genotype spaces, as revealed by modern techniques of molecular and functional analysis.Comment: 111 pages, 11 figures uses elsarticle latex clas

Bayesian Model-building in Phylogenetics

DNA sequencing costs have decreased dramatically over recent decades, resulting in a flood of phylogenetic information available to researchers. While it is often assumed that additional data will lead to more accurate conclusions, it also raises a number of problems for phylogeneticists, including mundane computational issues such as data management and complex statistical problems such as obtaining a single species tree from multiple conflicting gene trees. Developing new methods to make better use of existing data and probe the causes of conflicting signal will be necessary to confidently resolve phylogenies in the genomic era. Here, we examine two current problems in statistical phylogenetics and attempt to address them in a Bayesian framework. The first problem involves inflated tree lengths in Bayesian phylogenies, which can be an order of magnitude longer than maximum likelihood estimates. We developed EmpPrior, a program which queries TreeBASE for datasets similar to the focal data, then estimates parameters from each dataset to inform priors on the focal data. This approach greatly improves the tree length credible intervals in four exemplar datasets and, when combined with other approaches such as the use of a compound Dirichlet prior on tree length, can nearly eliminate the problem of inflated trees. The second problem involves incongruence between morphological and molecular phylogenies in squamates. Here, we use posterior prediction with inferential test statistics to investigate whether systematic error may be biasing inference in the molecular data. While we detected some model violation in most of the 44 genes, the genes with the most model violation were more distant from the molecular phylogeny. This suggests that model violation is not a major source of error in the molecular data. Hence, the source of incongruence between the molecular and morphological squamate topologies remains unknown. In both problems, we found that incorporating tools such as informed priors and posterior prediction from Bayesian statistical literature into phylogenetic analyses can improve results and help uncover why different datasets lead to conflicting topologies. As phylogenetic datasets continue to grow, using methodological best practices will only become more important if we want to have confidence in our conclusions