Studying ancient DNA allows us to retrace the evolutionary history of human pathogens, such as Mycobacterium leprae, the main causative agent of leprosy. Leprosy is one of the oldest recorded and most stigmatizing diseases in human history. The disease was prevalent in Europe until the 16th century and is still endemic in many countries with over 200,000 new cases reported annually. Previous worldwide studies on modern and European medieval M. leprae genomes revealed that they cluster into several distinct branches of which two were present in medieval Northwestern Europe. In this study, we analyzed 10 new medieval M. leprae genomes including the so far oldest M. leprae genome from one of the earliest known cases of leprosy in the United Kingdom-a skeleton from the Great Chesterford cemetery with a calibrated age of 415-545 C.E. This dataset provides a genetic time transect of M. leprae diversity in Europe over the past 1500 years. We find M. leprae strains from four distinct branches to be present in the Early Medieval Period, and strains from three different branches were detected within a single cemetery from the High Medieval Period. Altogether these findings suggest a higher genetic diversity of M. leprae strains in medieval Europe at various time points than previously assumed. The resulting more complex picture of the past phylogeography of leprosy in Europe impacts current phylogeographical models of M. leprae dissemination. It suggests alternative models for the past spread of leprosy such as a wide spread prevalence of strains from different branches in Eurasia already in Antiquity or maybe even an origin in Western Eurasia. Furthermore, these results highlight how studying ancient M. leprae strains improves understanding the history of leprosy worldwide.

ADES AMU CNRS EFS Anthropology and Health Aix Marseille Université Marseille France

Center for Bioinformatics University of Tübingen Tübingen Germany

Centre for Clinical Microbiology Division of Infection and Immunity University College London London United Kingdom

Department of Anthropology National Museum Prague Czech Republic

Department of Archaeogenetics Max Planck Institute for the Science of Human History Jena Germany

Department of Archaeology of Landscape and Archaeobiology Institute of Archaeology of the Czech Academy of Sciences Prague Czech Republic

Department of Archaeology University of Southampton Southampton United Kingdom

Department of Biological Anthropology University of Szeged Szeged Hungary

Department of Biological Geological and Environmental Sciences Bologna Italy

Department of Biology University of Florence Firenze Italy

Department of Microbial Sciences Faculty of Health and Medical Sciences University of Surrey Guildford United Kingdom

Department of Microbiology and Biotechnology Centre The Maharaja Sayajirao University of Baroda Vadodara India

Global Health Institute Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland

Historic England Portsmouth United Kingdom

Institut Pasteur Paris France

Institute for Archaeological Sciences University of Tübingen Tübingen Germany

Institute of Clinical Molecular Biology Kiel University Kiel Germany

Institute of Evolutionary Medicine University of Zurich Zurich Switzerland

McDonald Institute for Archaeological Research University of Cambridge Cambridge United Kingdom

Senckenberg Centre for Human Evolution and Palaeoenvironment University of Tübingen Tübingen Germany

Unit of Anthropology Department of Forensic Medicine University of Southern Denmark Odense S Denmark

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Stone Age Yersinia pestis genomes shed light on the early evolution, diversity, and ecology of plague