title: Bayesian coestimation of phylogeny and sequence alignment.
abstract: BACKGROUND
  Two central problems in computational biology are the determination of the alignment and phylogeny of a set of biological sequences. The traditional approach to this problem is to first build a multiple alignment of these sequences, followed by a phylogenetic reconstruction step based on this multiple alignment. However, alignment and phylogenetic inference are fundamentally interdependent, and ignoring this fact leads to biased and overconfident estimations. Whether the main interest be in sequence alignment or phylogeny, a major goal of computational biology is the co-estimation of both.
  
  
  RESULTS
  We developed a fully Bayesian Markov chain Monte Carlo method for coestimating phylogeny and sequence alignment, under the Thorne-Kishino-Felsenstein model of substitution and single nucleotide insertion-deletion (indel) events. In our earlier work, we introduced a novel and efficient algorithm, termed the "indel peeling algorithm", which includes indels as phylogenetically informative evolutionary events, and resembles Felsenstein's peeling algorithm for substitutions on a phylogenetic tree. For a fixed alignment, our extension analytically integrates out both substitution and indel events within a proper statistical model, without the need for data augmentation at internal tree nodes, allowing for efficient sampling of tree topologies and edge lengths. To additionally sample multiple alignments, we here introduce an efficient partial Metropolized independence sampler for alignments, and combine these two algorithms into a fully Bayesian co-estimation procedure for the alignment and phylogeny problem. Our approach results in estimates for the posterior distribution of evolutionary rate parameters, for the maximum a-posteriori (MAP) phylogenetic tree, and for the posterior decoding alignment. Estimates for the evolutionary tree and multiple alignment are augmented with confidence estimates for each node height and alignment column. Our results indicate that the patterns in reliability broadly correspond to structural features of the proteins, and thus provides biologically meaningful information which is not existent in the usual point-estimate of the alignment. Our methods can handle input data of moderate size (10-20 protein sequences, each 100-200 bp), which we analyzed overnight on a standard 2 GHz personal computer.
  
  
  CONCLUSIONS
  Joint analysis of multiple sequence alignment, evolutionary trees and additional evolutionary parameters can be now done within a single coherent statistical framework.
authors.affiliation: Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK. lunter@stats.ox.ac.uk
authors.forename: Gerton
authors.initials: G
authors.lastname: Lunter
authors.forename: István
authors.initials: I
authors.lastname: Miklós
authors.forename: Alexei
authors.initials: A
authors.lastname: Drummond
authors.forename: Jens Ledet
authors.initials: JL
authors.lastname: Jensen
authors.forename: Jotun
authors.initials: J
authors.lastname: Hein
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001499:Bayes Theorem; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D019143:Evolution, Molecular; D017353:Gene Deletion; D006801:Humans; D016013:Likelihood Functions; D008390:Markov Chains; D008957:Models, Genetic; D015233:Models, Statistical; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D009154:Mutation; D009211:Myoglobin / Q000737:chemistry; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D012984:Software; D013045:Species Specificity
chemical_list: D009211:Myoglobin