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.

Leprosy, a chronic infectious disease caused by Mycobacterium leprae (M. leprae), was very common in Europe till the 16th century. Here, we perform an ancient DNA study on medieval skeletons from Denmark that show lesions specific for lepromatous leprosy (LL). First, we test the remains for M. leprae DNA to confirm the infection status of the individuals and to assess the bacterial diversity. We assemble 10 complete M. leprae genomes that all differ from each other. Second, we evaluate whether the human leukocyte antigen allele DRB1*15:01, a strong LL susceptibility factor in modern populations, also predisposed medieval Europeans to the disease. The comparison of genotype data from 69 M. leprae DNA-positive LL cases with those from contemporary and medieval controls reveals a statistically significant association in both instances. In addition, we observe that DRB1*15:01 co-occurs with DQB1*06:02 on a haplotype that is a strong risk factor for inflammatory diseases today.

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Sensitivity and specificity estimates for 18 skeletal lesions were generated from modern skeletal samples for future paleoepidemiological analyses of tuberculosis (TB) prevalence in archaeological samples. A case-control study was conducted using 480 skeletons from two 20 th century American skeletal collections. One-half of the skeletons were documented TB cases (Terry Collection), and the remaining age and sex-matched skeletons were controls (Bass Collection). The association between 18 candidate skeletal lesions and TB was established by comparing lesion distributions in case and control groups. Skeletal lesion indicators at six locationsthe visceral surface of ribs, ventral part of thoracic and lumbar vertebral bodies, lateral part of ilium, acetabular fossa, iliac auricular surface, and ulna olecranon process -occurred significantly more often among cases than in controls, and were associated with one another. The most useful TB indicator proved to be a bony reaction on ventral thoracic and lumbar vertebral bodies. Its presence means a 53.3% probability of a true TB diagnosis. Because of the nature of the reference sample -20th century American casesthe sensitivity and specificity estimates will better estimate disease prevalence in archaeological samples from cultural settings where pulmonary TB predominated. The general approach of this proof-of-concept study is applicable to other diseases that occur commonly and affect bone.

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