Ancient genomes reveal a high diversity of Mycobacterium leprae in medieval Europe

Abstract

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.

Ancient pathogen genomics as an emerging tool for infectious disease research

“…Direct sampling from skeletal lesions, where present, has proved a rich source of aDNA for some chronic disease causing bacteria, such as Mycobacterium tuberculosis, which was isolated from vertebrae 26 ; Mycobacterium leprae, which could be isolated from portions of the maxilla and various long bones 27,28 ; and Treponema pallidum subsp. pallidum and T. pallidum subsp.…”

“…Consequently, tooth sampling has proved successful in the retrieval of whole genomes or genome wide data (that is, low coverage genomes that have provided limited analytical resolution) from ancient bacteria such as Y. pestis 20,[30][31][32][33][34][35][36][37][38][39] , Borrelia recurrentis 40 and Salmonella enterica 41 ; ancient eukaryotic pathogens such as Plasmodium falciparum 42 ; and ancient viruses such as hepatitis B virus (HBV) 43,44 and human parvovirus B19 (B19V) 45 . Even M. leprae, which commonly manifests in the chronic form, has been retrieved from ancient teeth 27,28 .…”

“…The evaluation of genetic relationships between ancient and modern pathogens is often conducted by direct whole genome or genome wide SNP compari sons of bacteria 20,27,29,36,48 , viruses 43,44,50,53 or mito chondrial genomes and nuclear genome data from eukaryotic microorganisms 56,59,60 . Hence, accurate variant calling is critical for drawing reliable evolutionary inferences, although this process is often a challenge when handling data sets derived from samples with high rates of DNA fragmentation (resulting in ultrashort read data), low endogenous DNA content and high levels of DNA dam age.…”

“…Among the most commonly used tools in ancient microbial genomics are MEGA 99 , which comprises several phylogenetic methods; PhyML 100 , RAxML 101 and IQ TREE 102 , which implement maximum likelihood approaches; MrBayes 103 , which uses a Bayesian approach; and programs used for phylo genetic network inference, such as SplitsTree 104 . Two notable studies that examined phylogenetic relationships among ancient M. leprae genomes revealed a high strain diversity in Europe between the 5th and 14th centuries ce 27,105 . Considered alongside the oldest palaeopatholog ical cases of leprosy dating to as early as the Copper and Bronze Age in Eurasia 106,107 and the high frequency of protective immune variants against the disease identi fied in modern day Europeans 108 , these results may sug gest a long history of M. leprae presence in this region.…”

HOPS: Automated detection and authentication of pathogen DNA in archaeological remains

“…Genomic-level investigations of ancient pathogens have provided valuable information about the evolution of Yersinia pestis (11–18), Mycobacterium leprae (19, 20), Mycobacterium tuberculosis (21, 22), pathogenic Brucella species (23, 24), Salmonella enterica (25, 26) and Helicobacter pylori (27), with others surely on the horizon. Notably, most studies to date have leveraged paleopathological evidence or historical context to pinpoint a priori involvement of a specific bacterial pathogen.…”