Abstract
BackgroundBased on large genomic sequence polymorphisms, several haplotypes belonging to two major lineages of the human pathogen Mycobacterium ulcerans could be distinguished among patient isolates from various geographic origins. However, the biological relevance of insertional/deletional diversity is not understood.MethodologyUsing comparative genomics, we have investigated the genes located in regions of difference recently identified by DNA microarray based hybridisation analysis. The analysed regions of difference comprise ∼7% of the entire M. ulcerans genome.Principal FindingsSeveral different mechanisms leading to loss of functional genes were identified, ranging from pseudogenization, caused by frame shift mutations or mobile genetic element interspersing, to large sequence polymorphisms. Four hot spot regions for genetic instability were unveiled. Altogether, 229 coding sequences were found to be differentially inactivated, constituting a repertoire of coding sequence variation in the rather monomorphic M. ulcerans.Conclusions/SignificanceThe differential gene inactivation patterns associated with the M. ulcerans haplotypes identified candidate genes that may confer enhanced adaptation upon ablation of expression. A number of gene conversions confined to the classical lineage may contribute to particular virulence of this group comprising isolates from Africa and Australia. Identification of this spectrum of anti-virulence gene candidates expands our understanding of the pathogenicity and ecology of the emerging infectious disease Buruli ulcer.
Highlights
Mycobacterium ulcerans is the etiologic agent of the emerging human disease Buruli ulcer, the third most common mycobacterial disease which occurs in more than 30 countries
We have identified six InDel haplotypes that can be grouped into two distinct lineages: the ancestral lineage comprising the haplotypes from Asia, South America, and Mexico, that is genetically closer to M. marinum in RD composition, and the classical lineage comprising the haplotypes originating from Africa, Australia, and South East Asia [9,13]
The continental distribution of severe disease focussing on West-Africa and Australia correlates with the presence of the M. ulcerans classical lineage, which is increasingly suspected to be more pathogenic than the ancestral lineage [9,15,16]
Summary
Mycobacterium ulcerans is the etiologic agent of the emerging human disease Buruli ulcer, the third most common mycobacterial disease which occurs in more than 30 countries. It is associated with necrosis of subcutaneous tissues, mainly in the extremities of children, and often leads to severe disability. We have identified regions of difference (RDs) between M. ulcerans patient isolates originating from different geographical areas [8] These genomic variations caused by deletions, combined insertions/deletions (InDels), insertions of mobile insertion sequence elements (ISEs), and genome rearrangements proved useful genetic markers for phylogenetic analyses [9]. The biological relevance of insertional/deletional diversity is not understood
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