Bioinformatics Methods for the Comparative Analysis of Metazoan Mitochondrial Genome Sequences Matthias Bernt a,* , Anke Braband b , Martin Middendorf a , Bernhard Misof c , Omar Rota-Stabelli d , Peter F. Stadler e,f,g,h,i a Parallel Computing and Complex Systems Group, Department of Computer Science, University of Leipzig, Johannisgasse 26, D-04103 Leipzig, Germany b LGC Genomics GmbH, Ostendstr. 25, 12459 Berlin c Molekulare Biodiversit¨ atsforschung, Zoologisches Forschungsmuseum Alexander Koenig, Adenauerallee 160, D-53113 Bonn, Germany d Department of Sustainable Agro-Ecosystems and Bioresources, Istituto Agrario di San Michele all’Adige, Via E. Mach 1, I-38010 San Michele all’Adige (TN), Italy e Bioinformatics Group, Department of Computer Science, and Interdisciplinary Center for Bioinformatics, Universit¨ at Leipzig, H¨ artelstraße 16-18, D-04107 Leipzig, Germany f Max-Planck-Institute for Mathematics in the Sciences, Inselstraße 22, D-04103 Leipzig, Germany g Fraunhofer Institut f¨ ur Zelltherapie und Immunologie Perlickstraße 1, D-04103 Leipzig, Germany h Department of Theoretical Chemistry University of Vienna, W¨ ahringerstraße 17, A-1090 Wien, Austria i Santa Fe Institute, 1399 Hyde Park Rd., Santa Fe, NM 87501, USA Abstract In this review we provide an overview of various bioinformatics methods and tools for the analysis of metazoan mitochondrial genomes. We compare available dedicated databases and present current tools for accurate genome annotation, identification of protein coding genes, and determination of tRNA and rRNA models.We also evaluate various tools and models for phylogenetic tree inference using gene order or sequence based data. As for gene order based methods, we compare rearrangement based and gene cluster based methods for gene order rearrangement analysis. As for sequence based methods, we give special emphasis to substitution models or data treatment that reduces certain systematic biases that are typical for metazoan mitogenomes such as within genome and/or among lineage compositional heterogeneity. Keywords: Bioinformatics, Mitochondria, Genome Rearrangements, Substitution * Corresponding author at: Parallel Computing and Complex Systems Group, Department of Computer Science, University of Leipzig, Johannisgasse 26, D-04103 Leipzig, Germany. Fax: +49 341 97 32252 Email addresses: bernt@informatik.uni-leipzig.de (Matthias Bernt), phylogenetics@arcor.de (Anke Braband), middendorf@informatik.uni-leipzig.de (Martin Middendorf), b.misof.zfmk@uni-bonn.de (Bernhard Misof), omar.rota@iasma.it (Omar Rota-Stabelli), studla@bioinf.uni-leipzig.de (Peter F. Stadler) Preprint submitted to Preprint October 3, 2012