On the origin of Mycobacterium ulcerans, the causative agent of Buruli ulcer

BACKGROUND: Mycobacterium ulcerans is an unusual bacterial pathogen with elusive origins. While closelyrelated to the aquatic dwelling M. marinum, M. ulcerans has evolved the ability to producethe immunosuppressive polyketide toxin mycolactone and cause the neglected tropicaldisease Buruli ulcer. Other mycolactone-producing mycobacteria (MPM) have beenidentified in fish and frogs and given distinct species designations (M. pseudoshottsii, M.shinshuense, M. liflandii and M. marinum), however the evolution of M. ulcerans and itsrelationship to other MPM has not been defined. Here we report the comparative analysis ofwhole genome sequences from 30 MPM and five M. marinum. RESULTS: A high-resolution phylogeny based on genome-wide single nucleotide polymorphisms(SNPs) showed that M. ulcerans and all other MPM represent a single clonal group thatevolved from a common M. marinum progenitor. The emergence of the MPM was driven bythe acquisition of the pMUM plasmid encoding genes for the biosynthesis of mycolactones.This change was accompanied by the loss of at least 185 genes, with a significantoverrepresentation of genes associated with cell wall functions. Cell wall associated genesalso showed evidence of substantial adaptive selection, suggesting cell wall remodeling hasbeen critical for the survival of MPM. Fine-grain analysis of the MPM complex revealed atleast three distinct lineages, one of which comprised a highly clonal group, responsible forBuruli ulcer in Africa and Australia. This indicates relatively recent transfer of M. ulceransbetween these continents, which represent the vast majority of the global Buruli ulcer burden.Our data provide SNPs and gene sequences that can differentiate M. ulcerans lineages,suitable for use in the diagnosis and surveillance of Buruli ulcer. CONCLUSIONS: M. ulcerans and all mycolactone-producing mycobacteria are specialized variants of acommon Mycobacterium marinum progenitor that have adapted to live in restrictedenvironments. Examination of genes lost or retained and now under selective pressuresuggests these environments might be aerobic, and extracellular, where slow growth,production of an immune suppressor, cell wall remodeling, loss or modification of cell wallantigens, and biofilm-forming ability provide a survival advantage. These insights will guideour efforts to find the elusive reservoir(s) of M. ulcerans and to understand transmission ofBuruli ulcer