The use of whole-genome phylogenetic analysis has revolutionized our understanding of the evolution and spread of many important bacterial pathogens due to the high resolution view it provides. However, the majority of such analyses do not consider the potential role of accessory genes when inferring evolutionary trajectories. Moreover, the recently discovered importance of the switching of gene regulatory elements suggests that an exhaustive analysis, combining information from core and accessory genes with regulatory elements could provide unparalleled detail of the evolution of a bacterial population. Here we demonstrate this principle by applying it to a worldwide multi-host sample of the important pathogenic E. coli lineage ST131. Our approach reveals the existence of multiple circulating subtypes of the major drug-resistant clade of ST131 and provides the first ever population level evidence of core genome substitutions in gene regulatory regions associated with the acquisition and maintenance of different accessory genome elements.

Centre for Infection Medicine Institute of Microbiology and Epizootics Freie Universitat Berlin Germany

Centre for Infectious Diseases West China Hospital of Sichuan University Chengdu China

College of Medicine University of Swansea Swansea United Kingdom

Department of Biology and Wildlife Diseases Faculty of Veterinary Hygiene and Ecology and CEITEC VFU University of Veterinary and Pharmaceutical Sciences Brno Czech Republic

Department of Biology National University Ireland Maynooth Ireland

Department of Biostatistics University of Oslo Oslo Norway

Department of Cell Research and Immunology George S Wise Faculty of Life Sciences Tel Aviv University Tel Aviv Israel

Department of Mathematics and Statistics University of Helsinki Helsinki Finland

Departments of Pathology and Microbiology University College Cork Cork Ireland

Faculty of Life Sciences The University of Manchester Manchester United Kingdom

Institute of Hygiene Universitat Muenster Muenster Germany

Institute of Microbiology and Infection University of Birmingham Birmingham United Kingdom

Pathogen Research Group Nottingham Trent University Nottingham United Kingdom

Robert Koch Institute Berlin Germany

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