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Differential gene repertoire in Mycobacterium ulcerans identifies candidate genes for patho-adaptation.

Käser M, Pluschke G - PLoS Negl Trop Dis (2008)

Bottom Line: Altogether, 229 coding sequences were found to be differentially inactivated, constituting a repertoire of coding sequence variation in the rather monomorphic M. ulcerans.The differential gene inactivation patterns associated with the M. ulcerans haplotypes identified candidate genes that may confer enhanced adaptation upon ablation of expression.Identification of this spectrum of anti-virulence gene candidates expands our understanding of the pathogenicity and ecology of the emerging infectious disease Buruli ulcer.

View Article: PubMed Central - PubMed

Affiliation: Swiss Tropical Institute, Basel, Switzerland. m.kaeser@unibas.ch

ABSTRACT

Background: Based 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.

Methodology: Using 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 approximately 7% of the entire M. ulcerans genome.

Principal findings: Several 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/significance: The 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.

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Related in: MedlinePlus

Numbers of CDSs deleted in M. ulcerans lineages.CDSs were subdivided in being deleted only in the ancestral lineage (light gray), only in the classical lineage (dark gray), or in both lineages (white). The percentage of silenced CDSs per functional category when set in relation to the respective number of genes in the whole genome is indicated above the bars.
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pntd-0000353-g004: Numbers of CDSs deleted in M. ulcerans lineages.CDSs were subdivided in being deleted only in the ancestral lineage (light gray), only in the classical lineage (dark gray), or in both lineages (white). The percentage of silenced CDSs per functional category when set in relation to the respective number of genes in the whole genome is indicated above the bars.

Mentions: The investigated RDs comprise in their ∼400 kbp DNA sequence 338 genes with respect to the M. marinum M sequence. Altogether 229 genes were found to be affected by differential inactivation. While a number of these genes was lost or inactivated only in one of the haplotypes (32 in the classical lineage), a large fraction (156) of the genes were silenced by independent events in two or more haplotypes (Fig. 4; for a comprehensive list see Fig. 2 and Table S1). This gene repertoire constitutes a broad spectrum of genomic variation on CDS level in the otherwise genetically monomorphic M. ulcerans. Subdivision of the lost or pseudogenized CDSs into functional protein categories (Fig. 4) showed that i) proteins lost only in the ancestral lineage belong predominantly to the functional categories cell wall/cell processes, lipid metabolism, intermediary metabolism/respiration and regulatory proteins; and ii) for the proteins lost in both lineages the categories virulence/detoxification/adaptation and PE/PPE proteins are overrepresented. When set in relation to the number of genes allocated to the functional categories in the whole genome, over 10% of all virulence/detoxification/adaptation and PE/PPE protein genes have been inactivated in one or both lineages alone in the analysed 7% of the genome (Fig. 4). We identified four regions of preferential genome instability (RDs9, 12, 13, 14) with twelve CDSs that were inactivated by three different events in the haplotypes analysed (Table 1). Seven of these CDSs are coding for proteins likely to interact with the environment/host of the bacterial cells (secreted or membrane proteins and PE/PPE proteins). Three of the CDSs are involved in the mycobacterial ESX-1 secretion apparatus, and embR_1 which is involved in cell wall biosynthesis.


Differential gene repertoire in Mycobacterium ulcerans identifies candidate genes for patho-adaptation.

Käser M, Pluschke G - PLoS Negl Trop Dis (2008)

Numbers of CDSs deleted in M. ulcerans lineages.CDSs were subdivided in being deleted only in the ancestral lineage (light gray), only in the classical lineage (dark gray), or in both lineages (white). The percentage of silenced CDSs per functional category when set in relation to the respective number of genes in the whole genome is indicated above the bars.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2600814&req=5

pntd-0000353-g004: Numbers of CDSs deleted in M. ulcerans lineages.CDSs were subdivided in being deleted only in the ancestral lineage (light gray), only in the classical lineage (dark gray), or in both lineages (white). The percentage of silenced CDSs per functional category when set in relation to the respective number of genes in the whole genome is indicated above the bars.
Mentions: The investigated RDs comprise in their ∼400 kbp DNA sequence 338 genes with respect to the M. marinum M sequence. Altogether 229 genes were found to be affected by differential inactivation. While a number of these genes was lost or inactivated only in one of the haplotypes (32 in the classical lineage), a large fraction (156) of the genes were silenced by independent events in two or more haplotypes (Fig. 4; for a comprehensive list see Fig. 2 and Table S1). This gene repertoire constitutes a broad spectrum of genomic variation on CDS level in the otherwise genetically monomorphic M. ulcerans. Subdivision of the lost or pseudogenized CDSs into functional protein categories (Fig. 4) showed that i) proteins lost only in the ancestral lineage belong predominantly to the functional categories cell wall/cell processes, lipid metabolism, intermediary metabolism/respiration and regulatory proteins; and ii) for the proteins lost in both lineages the categories virulence/detoxification/adaptation and PE/PPE proteins are overrepresented. When set in relation to the number of genes allocated to the functional categories in the whole genome, over 10% of all virulence/detoxification/adaptation and PE/PPE protein genes have been inactivated in one or both lineages alone in the analysed 7% of the genome (Fig. 4). We identified four regions of preferential genome instability (RDs9, 12, 13, 14) with twelve CDSs that were inactivated by three different events in the haplotypes analysed (Table 1). Seven of these CDSs are coding for proteins likely to interact with the environment/host of the bacterial cells (secreted or membrane proteins and PE/PPE proteins). Three of the CDSs are involved in the mycobacterial ESX-1 secretion apparatus, and embR_1 which is involved in cell wall biosynthesis.

Bottom Line: Altogether, 229 coding sequences were found to be differentially inactivated, constituting a repertoire of coding sequence variation in the rather monomorphic M. ulcerans.The differential gene inactivation patterns associated with the M. ulcerans haplotypes identified candidate genes that may confer enhanced adaptation upon ablation of expression.Identification of this spectrum of anti-virulence gene candidates expands our understanding of the pathogenicity and ecology of the emerging infectious disease Buruli ulcer.

View Article: PubMed Central - PubMed

Affiliation: Swiss Tropical Institute, Basel, Switzerland. m.kaeser@unibas.ch

ABSTRACT

Background: Based 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.

Methodology: Using 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 approximately 7% of the entire M. ulcerans genome.

Principal findings: Several 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/significance: The 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.

Show MeSH
Related in: MedlinePlus