Mycobacterium leprae diversity and population dynamics in medieval Europe from novel ancient genomes

Abstract

Background: Hansen's disease (leprosy), widespread in medieval Europe, is today mainly prevalent in tropical and subtropical regions with around 200,000 new cases reported annually. Despite its long history and appearance in historical records, its origins and past dissemination patterns are still widely unknown. Applying ancient DNA approaches to its major causative agent, Mycobacterium leprae, can significantly improve our understanding of the disease's complex history. Previous studies have identified a high genetic continuity of the pathogen over the last 1500 years and the existence of at least four M. leprae lineages in some parts of Europe since the Early Medieval period.

Results: Here, we reconstructed 19 ancient M. leprae genomes to further investigate M. leprae's genetic variation in Europe, with a dedicated focus on bacterial genomes from previously unstudied regions (Belarus, Iberia, Russia, Scotland), from multiple sites in a single region (Cambridgeshire, England), and from two Iberian leprosaria. Overall, our data confirm the existence of similar phylogeographic patterns across Europe, including high diversity in leprosaria. Further, we identified a new genotype in Belarus. By doubling the number of complete ancient M. leprae genomes, our results improve our knowledge of the past phylogeography of M. leprae and reveal a particularly high M. leprae diversity in European medieval leprosaria.

Conclusions: Our findings allow us to detect similar patterns of strain diversity across Europe with branch 3 as the most common branch and the leprosaria as centers for high diversity. The higher resolution of our phylogeny tree also refined our understanding of the interspecies transfer between red squirrels and humans pointing to a late antique/early medieval transmission. Furthermore, with our new estimates on the past population diversity of M. leprae, we gained first insights into the disease's global history in relation to major historic events such as the Roman expansion or the beginning of the regular transatlantic long distance trade. In summary, our findings highlight how studying ancient M. leprae genomes worldwide improves our understanding of leprosy's global history and can contribute to current models of M. leprae's worldwide dissemination, including interspecies transmissions.

Keywords: Ancient DNA; Ancient pathogen genomics; Leprosaria; Mycobacterium leprae; Paleomicrobiology; Paleopathology; Pathogen diversity; Pathogen population dynamics.

Fig. 1

Geographic location of previously published [44, 45, 49, 96, 97] and newly reconstructed ancient genomes. The rhombuses indicate the location of the sites covered by this study; circles and skulls with blue outlines show the sites of already published M. leprae strains. The color of the skulls corresponds to the branches in the M. leprae phylogeny

Fig. 2

Phylogenetic trees. A Maximum Parsimony tree of all published modern and ancient [, , , , , , , , –121], as well as newly sequenced leprosy strains. All ancient strains are bold, and all new ancient strains are bold and red. The bootstrap values are given as node labels (500 bs). Animal symbols and italicized labels indicate strains isolated from red squirrels (Brw15 strains), armadillos (W09), and non-human primates (CH4, SM1, and CM1). The main branches are color-coded with background boxes. B Bayesian Maximum Clade Credibility time-aware tree for the leprosy genomes including only genomes with at least 3-fold coverage and at least 60% of the genomic sites. Noteworthy nodes are labeled with the median estimated age (year CE/BCE) and 95% Highest Posterior Density for the age estimate (violet bars) as well as posterior probability estimate

Fig. 3

Bayesian skyline plot representing the effective population size of M. leprae over the period from ca. 1000 BCE to 2000 CE. Mean estimates are shown as solid line and 95% HPD limits as gray area