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Lipidomics and genomics of Mycobacterium tuberculosis reveal lineage-specific trends in mycolic acid biosynthesis.

Portevin D, Sukumar S, Coscolla M, Shui G, Li B, Guan XL, Bendt AK, Young D, Gagneux S, Wenk MR - Microbiologyopen (2014)

Bottom Line: We found significant variations in the MA patterns between different MTBC strains and lineages.By interrogating the whole genome sequences of these MTBC strains, we identified relevant single-nucleotide polymorphisms that may sustain the lineage-specific MA patterns.Our results show that the strain genetic background influences MA metabolism and suggests that strain diversity should be considered in the development of new anti-tuberculosis drugs that target MA synthesis.

View Article: PubMed Central - PubMed

Affiliation: Mycobacterial Division Research, NIMR, MRC, NW71AA, London, United Kingdom; Department of Medical Parasitology and Infection Biology, Swiss TPH, 4002, Basel, Switzerland; University of Basel, 4002, Basel, Switzerland.

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Lineage-specific nonsynonymous single-nucleotide polymorphisms (nsSNPs) from “ancient” lineages are predicted deleterious. nsSNPs specific to each Mycobacterium tuberculosis complex (MTBC) lineage were extracted and the related genes listed and grouped according to their involvement in the different step of the metabolic pathway of mycolic acid biosynthesis (white color code was used for SNPs shared by the two “modern” lineages). The amino acid substitutions were subjected to SIFT algorithm to predict loss of function based on the degree of conservation of amino acid residues in sequence alignments derived from closely related sequences (Sim et al. 2012). Genes highlighted in boxes presented substitutions with a statistically significant probability to affect protein function (P < 0.05) whereas others were predicted to be tolerated. Gene names, amino acid substitution, SIFT score as well as the predicted domain affected by the mutation are presented for deleterious substitutions.
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fig06: Lineage-specific nonsynonymous single-nucleotide polymorphisms (nsSNPs) from “ancient” lineages are predicted deleterious. nsSNPs specific to each Mycobacterium tuberculosis complex (MTBC) lineage were extracted and the related genes listed and grouped according to their involvement in the different step of the metabolic pathway of mycolic acid biosynthesis (white color code was used for SNPs shared by the two “modern” lineages). The amino acid substitutions were subjected to SIFT algorithm to predict loss of function based on the degree of conservation of amino acid residues in sequence alignments derived from closely related sequences (Sim et al. 2012). Genes highlighted in boxes presented substitutions with a statistically significant probability to affect protein function (P < 0.05) whereas others were predicted to be tolerated. Gene names, amino acid substitution, SIFT score as well as the predicted domain affected by the mutation are presented for deleterious substitutions.

Mentions: Nonsynonymous SNPs among the MA pathway were extracted from full genome sequences and listed in Table S2. We identified 97 SNPs across all four lineages, and almost 50% of them were singletons; that is, only detected in one strain. About 30% of these polymorphisms were shared by two strains or more within the same lineage. We identified 17 nsSNPs present exclusively in one of the four MTB lineages, and three nsSNPs shared by the two “modern” lineages. Only one lineage-specific nsSNP was found in each of Lineage 2 and 4, whereas five and 11 nsSNPs were detected in Lineage 1 and 6, respectively. The genes were grouped according to their involvement in the MA metabolism pathway and depicted in Figure 6. We then investigated the predicted functional effect that individual nsSNPs, and therefore amino acid substitution, could bring to the related protein using SIFT prediction algorithm (Sim et al. 2012). When the amino acid substitution was predicted to have a significant effect on protein function (P < 0.05), the respective gene was highlighted (Fig. 6). Interestingly, nine of the 20 nsSNPs that were predicted to affect protein function belonged to “ancient” strains but none to the “modern” lineages.


Lipidomics and genomics of Mycobacterium tuberculosis reveal lineage-specific trends in mycolic acid biosynthesis.

Portevin D, Sukumar S, Coscolla M, Shui G, Li B, Guan XL, Bendt AK, Young D, Gagneux S, Wenk MR - Microbiologyopen (2014)

Lineage-specific nonsynonymous single-nucleotide polymorphisms (nsSNPs) from “ancient” lineages are predicted deleterious. nsSNPs specific to each Mycobacterium tuberculosis complex (MTBC) lineage were extracted and the related genes listed and grouped according to their involvement in the different step of the metabolic pathway of mycolic acid biosynthesis (white color code was used for SNPs shared by the two “modern” lineages). The amino acid substitutions were subjected to SIFT algorithm to predict loss of function based on the degree of conservation of amino acid residues in sequence alignments derived from closely related sequences (Sim et al. 2012). Genes highlighted in boxes presented substitutions with a statistically significant probability to affect protein function (P < 0.05) whereas others were predicted to be tolerated. Gene names, amino acid substitution, SIFT score as well as the predicted domain affected by the mutation are presented for deleterious substitutions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263507&req=5

fig06: Lineage-specific nonsynonymous single-nucleotide polymorphisms (nsSNPs) from “ancient” lineages are predicted deleterious. nsSNPs specific to each Mycobacterium tuberculosis complex (MTBC) lineage were extracted and the related genes listed and grouped according to their involvement in the different step of the metabolic pathway of mycolic acid biosynthesis (white color code was used for SNPs shared by the two “modern” lineages). The amino acid substitutions were subjected to SIFT algorithm to predict loss of function based on the degree of conservation of amino acid residues in sequence alignments derived from closely related sequences (Sim et al. 2012). Genes highlighted in boxes presented substitutions with a statistically significant probability to affect protein function (P < 0.05) whereas others were predicted to be tolerated. Gene names, amino acid substitution, SIFT score as well as the predicted domain affected by the mutation are presented for deleterious substitutions.
Mentions: Nonsynonymous SNPs among the MA pathway were extracted from full genome sequences and listed in Table S2. We identified 97 SNPs across all four lineages, and almost 50% of them were singletons; that is, only detected in one strain. About 30% of these polymorphisms were shared by two strains or more within the same lineage. We identified 17 nsSNPs present exclusively in one of the four MTB lineages, and three nsSNPs shared by the two “modern” lineages. Only one lineage-specific nsSNP was found in each of Lineage 2 and 4, whereas five and 11 nsSNPs were detected in Lineage 1 and 6, respectively. The genes were grouped according to their involvement in the MA metabolism pathway and depicted in Figure 6. We then investigated the predicted functional effect that individual nsSNPs, and therefore amino acid substitution, could bring to the related protein using SIFT prediction algorithm (Sim et al. 2012). When the amino acid substitution was predicted to have a significant effect on protein function (P < 0.05), the respective gene was highlighted (Fig. 6). Interestingly, nine of the 20 nsSNPs that were predicted to affect protein function belonged to “ancient” strains but none to the “modern” lineages.

Bottom Line: We found significant variations in the MA patterns between different MTBC strains and lineages.By interrogating the whole genome sequences of these MTBC strains, we identified relevant single-nucleotide polymorphisms that may sustain the lineage-specific MA patterns.Our results show that the strain genetic background influences MA metabolism and suggests that strain diversity should be considered in the development of new anti-tuberculosis drugs that target MA synthesis.

View Article: PubMed Central - PubMed

Affiliation: Mycobacterial Division Research, NIMR, MRC, NW71AA, London, United Kingdom; Department of Medical Parasitology and Infection Biology, Swiss TPH, 4002, Basel, Switzerland; University of Basel, 4002, Basel, Switzerland.

Show MeSH
Related in: MedlinePlus