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Leprosy, a chronic human disease with potentially debilitating neurological consequences, results from infection with Mycobacterium leprae. This unculturable pathogen has undergone extensive reductive evolution, with half of its genome now occupied by pseudogenes. Using comparative genomics, we demonstrated that all extant cases of leprosy are attributable to a single clone whose dissemination worldwide can be retraced from analysis of very rare single-nucleotide polymorphisms. The disease seems to have originated in Eastern Africa or the Near East and spread with successive human migrations. Europeans or North Africans introduced leprosy into West Africa and the Americas within the past 500 years.
Comparative genomics enables us to establish solid genealogical relationships with greater precision than ever before. Leprosy (1) has plagued human populations for thousands of years and puzzled scientists since the identification of its etiological agent, Mycobacterium leprae, by Hansen in 1873 (2). The main difficulties of working with M. leprae are that it cannot be grown in axenic culture and that its doubling time in tissue is slow, nearly 13 days (3). It was only when it was discovered that the nine-banded armadillo, Dasypus novemcinctus, could be infected (4) that sufficient quantities of M. leprae were obtained for biological and immunological analysis. Comparison of the genome sequence of the armadillo-passaged strain of M. leprae from Tamil Nadu, India (TN strain) with that of the close relative Mycobacterium tuberculosis (5), led to a major breakthrough (6). M. leprae was shown to have embarked upon a path of reductive evolution in which the genome underwent downsizing and accumulated more than 1130 pseudogenes. The concomitant loss of catabolic and respiratory functions appears to have resulted in severe metabolic constraints (6, 7).
To establish whether all strains of M. leprae had undergone similar events and to determine their level of relatedness, we used technological approaches that have successfully detected polymorphic regions in the M. tuberculosis complex (8-10). First, genomic DNA, prepared from seven different strains of leprosy bacilli (Table 1), was hybridized to microarrays corresponding to the complete genome of the TN strain, but no evidence for further gene loss was uncovered in these isolates (fig. S1). Second, to establish whether differences existed in the copy number of insertion-sequence-like, dispersed repetitive sequences, quantitative polymerase chain reaction was performed to...