Biomedical subjects

Dirk Metzler

Publications and source records attributed to Dirk Metzler.

4 recordsLinked to original sources

PubMed2006

Robust E-values for gapped local alignments.

We examine a Poisson heuristic for judging the significance of local sequence alignments with gaps. Model parameters are estimated directly from the sequences to be aligned, so that laborious prior simulation studies or database comparisons for the estimation of parameters describing the connection between score and E-value are unnecessary. Simulation studies give evidence that this method gives reasonable results even when the usual assumptions like the independence of sequence positions are violated.

Amino Acid Sequence↗

PubMed2005

Simultaneous statistical multiple alignment and phylogeny reconstruction.

Although the reconstruction of phylogenetic trees and the computation of multiple sequence alignments are highly interdependent, these two areas of research lead quite separate lives, the former often making use of stochastic modeling, whereas the latter normally does not. Despite the fact that reasonable insertion and deletion models for sequence pairs were already introduced more than 10 years ago, they have only recently been applied to multiple alignment and only in their simplest version. In this paper we present and discuss a strategy based on simulated annealing, which makes use of these models to infer a phylogenetic tree for a set of DNA or protein sequences together with the sequences'indel history, i.e., their multiple alignment augmented with information about the positioning of insertion and deletion events in the tree. Our method is also the first application of the TKF2 model in the context of multiple sequence alignment. We validate the method via simulations and illustrate it using a data set of primate mtDNA.

Algorithms↗

PubMed2003

Statistical alignment based on fragment insertion and deletion models.

MOTIVATION: The topic of this paper is the estimation of alignments and mutation rates based on stochastic sequence-evolution models that allow insertions and deletions of subsequences ('fragments') and not just single bases. The model we propose is a variant of a model introduced by Thorne et al., (J. Mol. Evol., 34, 3-16, 1992). The computational tractability of the model depends on certain restrictions in the insertion/deletion process; possible effects we discuss. RESULTS: The process of fragment insertion and deletion in the sequence-evolution model induces a hidden Markov structure at the level of alignments and thus makes possible efficient statistical alignment algorithms. As an example we apply a sampling procedure to assess the variability in alignment and mutation parameter estimates for HVR1 sequences of human and orangutan, improving results of previous work. Simulation studies give evidence that estimation methods based on the proposed model also give satisfactory results when applied to data for which the restrictions in the insertion/deletion process do not hold. AVAILABILITY: The source code of the software for sampling alignments and mutation rates for a pair of DNA sequences according to the fragment insertion and deletion model is freely available from http://www.math.uni-frankfurt.de/~stoch/software/mcmcsalut under the terms of the GNU public license (GPL, 2000).

Algorithms↗

PubMed2002

Genomewide comparison of DNA sequences between humans and chimpanzees.

A total of 8,859 DNA sequences encompassing approximately 1.9 million base pairs of the chimpanzee genome were sequenced and compared to corresponding human DNA sequences. Although the average sequence difference is low (1.24%), the extent of changes is markedly different among sites and types of substitutions. Whereas approximately 15% of all CpG sites have experienced changes between humans and chimpanzees, owing to a 23-fold excess of transitions and a 7-fold excess of transversions, substitutions at other sites vary in frequency, between 0.1% and 0.5%. If the nucleotide diversity in the common ancestral species of humans and chimpanzees is assumed to have been about fourfold higher than in contemporary humans, all possible comparisons between autosomes and X and Y chromosomes result in estimates of the ratio between male and female mutation rates of approximately 3. Thus, the relative time spent in the male and female germlines may be a major determinant of the overall accumulation of nucleotide substitutions. However, since the extent of divergence differs significantly among autosomes, additional unknown factors must also influence the accumulation of substitutions in the human genome.

Animals↗