In the proposed project we aim at delineating the factors that have transformed A. baumannii from an environmental bacterium into a potent human pathogen. We will begin with setting up the bioinformatics infrastructure facilitating an automated establishment of function-aware phylogenetic profiles for proteins. In parallel we will use comparative genomics between successful epidemic clonal lineages and non-epidemic lineages complemented with data from non-pathogenic close relatives of A. baumannii to investigate the general evolution of gene repertoires in this genus. This will obtain for each gene in the pan-genome of Acinetobacter information about its phylogenetic distribution in the genus, of when it has been introduced into the genus and of its propensity for gene loss. Integrating the results with functional annotations of Acinetobacter genes and their involvement in functional networks will form the foundation of linking phenotypic characteristics of the various Acinetobacter species and strains to their genotype. We expect that this novel catalogue will form an unprecedented basis for delineating the genetic network of A. baumannii virulence. We will then proceed with integrating the pan-genome of Acinetobacter into a proteinfunction-aware phylogenomic network connecting this genus to an exhaustive collection of bacteria, archaea and eukaryotes. In this network we will identify edges connecting proteins that most likely share the same biochemical activity. This will allow, in particular, the tracing of virulence related factors, e.g. efflux pumps, motility functions, and functional protein networks, such as the A. baylyi natural transformation system or metabolic pathways across species. We will then investigate the evolutionary origins of A. baumannii virulence factors and the routes these factors have taken to enter the A. baumannii genome. More precisely, we will address the question how A. baumannii mines environmental genetic diversity for adaptive genes. We will concentrate on investigating the role of natural competence as the most versatile source of genetic information for bacterial evolution. To this end, we will establish phylogenetic profiles of the known natural competence systems to investigate their evolutionary history and to assess their prevalence in contemporary bacteria. In a complementary approach we will investigate the footprint of natural competence in the genomes of competent bacteria. We will assess prevalence, distribution and origin of laterally acquired genes in bacteria competent under a broad variety of conditions, relative to that in bacteria with inducible competence and non-competent bacteria. Both results in combination will contribute to the understanding to what extent A. baumannii makes use of its facultative natural competence for acquiring novel genes. These analyses will form the basis for an initial model of genetic innovation flux into and within the system A. baumannii.