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Evolution and diversity of clonal bacteria: the paradigm of Mycobacterium tuberculosis.

Dos Vultos T, Mestre O, Rauzier J, Golec M, Rastogi N, Rasolofo V, Tonjum T, Sola C, Matic I, Gicquel B - PLoS ONE (2008)

Bottom Line: We found that single-nucleotide polymorphism (SNP) analysis of DNA repair, recombination and replication (3R) genes in a comprehensive selection of M. tuberculosis complex strains from across the world, yielded surprisingly high levels of polymorphisms as compared to house-keeping genes, making it possible to distinguish between 80% of clinical isolates analyzed in this study.Bioinformatics analysis suggests that a large number of these polymorphisms are potentially deleterious.This situation, and the consequent lack of fidelity in genome maintenance, may serve as a starting point for the evolution of antibiotic resistance, fitness for survival and pathogenicity, possibly conferring a selective advantage in certain stressful situations.

View Article: PubMed Central - PubMed

Affiliation: Unité de Génétique mycobactérienne, Institut Pasteur, Paris, France.

ABSTRACT

Background: Mycobacterium tuberculosis complex species display relatively static genomes and 99.9% nucleotide sequence identity. Studying the evolutionary history of such monomorphic bacteria is a difficult and challenging task.

Principal findings: We found that single-nucleotide polymorphism (SNP) analysis of DNA repair, recombination and replication (3R) genes in a comprehensive selection of M. tuberculosis complex strains from across the world, yielded surprisingly high levels of polymorphisms as compared to house-keeping genes, making it possible to distinguish between 80% of clinical isolates analyzed in this study. Bioinformatics analysis suggests that a large number of these polymorphisms are potentially deleterious. Site frequency spectrum comparison of synonymous and non-synonymous variants and Ka/Ks ratio analysis suggest a general negative/purifying selection acting on these sets of genes that may lead to suboptimal 3R system activity. In turn, the relaxed fidelity of 3R genes may allow the occurrence of adaptive variants, some of which will survive. Furthermore, 3R-based phylogenetic trees are a new tool for distinguishing between M. tuberculosis complex strains.

Conclusions/significance: This situation, and the consequent lack of fidelity in genome maintenance, may serve as a starting point for the evolution of antibiotic resistance, fitness for survival and pathogenicity, possibly conferring a selective advantage in certain stressful situations. These findings suggest that 3R genes may play an important role in the evolution of highly clonal bacteria, such as M. tuberculosis. They also facilitate further epidemiological studies of these bacteria, through the development of high-resolution tools. With many more microbial genomes being sequenced, our results open the door to 3R gene-based studies of adaptation and evolution of other, highly clonal bacteria.

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Related in: MedlinePlus

Site frequency spectrum of sSNPs and nsSNPs.This spectrum summarizes the allele frequencies of the various mutations in the sample.
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pone-0001538-g005: Site frequency spectrum of sSNPs and nsSNPs.This spectrum summarizes the allele frequencies of the various mutations in the sample.

Mentions: We investigated whether some form of natural selection could account for the patterns of diversity observed, by comparing the site frequency spectrum (SFS) of synonymous and non synonymous variants (Figure 5). The frequency spectrum is a count of the number of mutations that exist at a frequency of xi = i/n for i = 1, 2,…, n−1, in a sample of size n. In other words, it represents a summary of the allele frequencies of the various mutations in the sample. In a standard neutral model (i.e., a model with random mating, constant population size, no population subdivision, etc.), the expected value of xi is proportional to 1/i. Selection against deleterious mutations will increase the fraction of mutations segregating at low frequencies in the sample. A selective sweep has roughly the same effect on the frequency spectrum. Conversely, positive selection will tend to increase the frequency in a sample of mutations segregating at high frequencies. Under a strictly neutral model, these two classes of genetic variants should present a similar SFS [21]. The higher values observed for the singleton ns SNPs than for s SNPs are suggestive of negative/purifying selection. However, caution is required in interpretation, because different selective/demographic scenarios may mimic similar patterns of diversity. Negative selection alone and/or population growth might be equally likely to account for the patterns observed [21]. We compared the non synonymous and synonymous substitution rates for each gene, by calculating the ratio of non synonymous mutations per non synonymous site (Ka) to synonymous mutations per synonymous site (Ks) (Tables 3, 4 and 5). Under a strictly neutral model of evolution, this ratio should be equal to one. For this particular analysis, we used the oldest strain from the panel analyzed (as determined by the number of spoligotype spacers) as the outgroup. Nine of the 52 genes presented KA/KS values higher than 1. Six of these nine genes had considerably higher KA/KS ratios, suggesting that the evolution of these genes might have been driven by positive natural selection. The remaining genes had KA/KS ratios below one, consistent with negative/purifying selection, as suggested by the SFS spectrum. Further detailed evolutionary studies will be required to elucidate the evolutionary forces that may account for the patterns observed, and to determine which of these genes have contributed significantly to the evolution of M. tuberculosis.


Evolution and diversity of clonal bacteria: the paradigm of Mycobacterium tuberculosis.

Dos Vultos T, Mestre O, Rauzier J, Golec M, Rastogi N, Rasolofo V, Tonjum T, Sola C, Matic I, Gicquel B - PLoS ONE (2008)

Site frequency spectrum of sSNPs and nsSNPs.This spectrum summarizes the allele frequencies of the various mutations in the sample.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211405&req=5

pone-0001538-g005: Site frequency spectrum of sSNPs and nsSNPs.This spectrum summarizes the allele frequencies of the various mutations in the sample.
Mentions: We investigated whether some form of natural selection could account for the patterns of diversity observed, by comparing the site frequency spectrum (SFS) of synonymous and non synonymous variants (Figure 5). The frequency spectrum is a count of the number of mutations that exist at a frequency of xi = i/n for i = 1, 2,…, n−1, in a sample of size n. In other words, it represents a summary of the allele frequencies of the various mutations in the sample. In a standard neutral model (i.e., a model with random mating, constant population size, no population subdivision, etc.), the expected value of xi is proportional to 1/i. Selection against deleterious mutations will increase the fraction of mutations segregating at low frequencies in the sample. A selective sweep has roughly the same effect on the frequency spectrum. Conversely, positive selection will tend to increase the frequency in a sample of mutations segregating at high frequencies. Under a strictly neutral model, these two classes of genetic variants should present a similar SFS [21]. The higher values observed for the singleton ns SNPs than for s SNPs are suggestive of negative/purifying selection. However, caution is required in interpretation, because different selective/demographic scenarios may mimic similar patterns of diversity. Negative selection alone and/or population growth might be equally likely to account for the patterns observed [21]. We compared the non synonymous and synonymous substitution rates for each gene, by calculating the ratio of non synonymous mutations per non synonymous site (Ka) to synonymous mutations per synonymous site (Ks) (Tables 3, 4 and 5). Under a strictly neutral model of evolution, this ratio should be equal to one. For this particular analysis, we used the oldest strain from the panel analyzed (as determined by the number of spoligotype spacers) as the outgroup. Nine of the 52 genes presented KA/KS values higher than 1. Six of these nine genes had considerably higher KA/KS ratios, suggesting that the evolution of these genes might have been driven by positive natural selection. The remaining genes had KA/KS ratios below one, consistent with negative/purifying selection, as suggested by the SFS spectrum. Further detailed evolutionary studies will be required to elucidate the evolutionary forces that may account for the patterns observed, and to determine which of these genes have contributed significantly to the evolution of M. tuberculosis.

Bottom Line: We found that single-nucleotide polymorphism (SNP) analysis of DNA repair, recombination and replication (3R) genes in a comprehensive selection of M. tuberculosis complex strains from across the world, yielded surprisingly high levels of polymorphisms as compared to house-keeping genes, making it possible to distinguish between 80% of clinical isolates analyzed in this study.Bioinformatics analysis suggests that a large number of these polymorphisms are potentially deleterious.This situation, and the consequent lack of fidelity in genome maintenance, may serve as a starting point for the evolution of antibiotic resistance, fitness for survival and pathogenicity, possibly conferring a selective advantage in certain stressful situations.

View Article: PubMed Central - PubMed

Affiliation: Unité de Génétique mycobactérienne, Institut Pasteur, Paris, France.

ABSTRACT

Background: Mycobacterium tuberculosis complex species display relatively static genomes and 99.9% nucleotide sequence identity. Studying the evolutionary history of such monomorphic bacteria is a difficult and challenging task.

Principal findings: We found that single-nucleotide polymorphism (SNP) analysis of DNA repair, recombination and replication (3R) genes in a comprehensive selection of M. tuberculosis complex strains from across the world, yielded surprisingly high levels of polymorphisms as compared to house-keeping genes, making it possible to distinguish between 80% of clinical isolates analyzed in this study. Bioinformatics analysis suggests that a large number of these polymorphisms are potentially deleterious. Site frequency spectrum comparison of synonymous and non-synonymous variants and Ka/Ks ratio analysis suggest a general negative/purifying selection acting on these sets of genes that may lead to suboptimal 3R system activity. In turn, the relaxed fidelity of 3R genes may allow the occurrence of adaptive variants, some of which will survive. Furthermore, 3R-based phylogenetic trees are a new tool for distinguishing between M. tuberculosis complex strains.

Conclusions/significance: This situation, and the consequent lack of fidelity in genome maintenance, may serve as a starting point for the evolution of antibiotic resistance, fitness for survival and pathogenicity, possibly conferring a selective advantage in certain stressful situations. These findings suggest that 3R genes may play an important role in the evolution of highly clonal bacteria, such as M. tuberculosis. They also facilitate further epidemiological studies of these bacteria, through the development of high-resolution tools. With many more microbial genomes being sequenced, our results open the door to 3R gene-based studies of adaptation and evolution of other, highly clonal bacteria.

Show MeSH
Related in: MedlinePlus