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Journal ArticleDOI

Genomic Deletions Suggest a Phylogeny for the Mycobacterium tuberculosis Complex

01 Jul 2002-The Journal of Infectious Diseases (Oxford University Press)-Vol. 186, Iss: 1, pp 74-80
TL;DR: Genomic deletions present themselves as an attractive modality to study the evolution of the M. tuberculosis complex and provide compelling evidence that human tuberculosis did not originate from the present-day bovine form.
Abstract: To better understand the evolution of the Mycobacterium tuberculosis complex, subspecies were tested for large sequence polymorphisms. Samples with greater numbers of deletions, without exception, were missing all the same regions that were deleted from samples with lesser numbers of deletions. Principal genetic groups based on single-nucleotide polymorphisms were restricted to one of the deletion-based groups, and isolates that shared genotypes based on molecular epidemiological markers were assigned almost exclusively to the same deletion type. The data provide compelling evidence that human tuberculosis did not originate from the present-day bovine form. Genomic deletions present themselves as an attractive modality to study the evolution of the M. tuberculosis complex.

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Citations
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Journal ArticleDOI
TL;DR: Coalescent analyses indicate that MTBC emerged about 70,000 years ago, accompanied migrations of anatomically modern humans out of Africa and expanded as a consequence of increases in human population density during the Neolithic period, consistent with MTBC displaying characteristics indicative of adaptation to both low and high host densities.
Abstract: Tuberculosis caused 20% of all human deaths in the Western world between the seventeenth and nineteenth centuries and remains a cause of high mortality in developing countries. In analogy to other crowd diseases, the origin of human tuberculosis has been associated with the Neolithic Demographic Transition, but recent studies point to a much earlier origin. We analyzed the whole genomes of 259 M. tuberculosis complex (MTBC) strains and used this data set to characterize global diversity and to reconstruct the evolutionary history of this pathogen. Coalescent analyses indicate that MTBC emerged about 70,000 years ago, accompanied migrations of anatomically modern humans out of Africa and expanded as a consequence of increases in human population density during the Neolithic period. This long coevolutionary history is consistent with MTBC displaying characteristics indicative of adaptation to both low and high host densities.

894 citations

Journal ArticleDOI
29 Jun 2007-Cell
TL;DR: It is shown that lysosomes rapidly fuse with the virulent M. tuberculosis- and M. leprae-containing phagosomes of human monocyte-derived dendritic cells and macrophages, revealing a mechanism for MHC-based antigen presentation that is lacking in current vaccine strains.

870 citations


Cites background from "Genomic Deletions Suggest a Phyloge..."

  • ...From these 16 regions of difference (RD1-16) only RD1 is absent from all BCG strains thus far tested (Mostowy et al., 2002; Tekaia et al., 1999; Brosch et al., 2002)....

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Journal ArticleDOI
TL;DR: A strain selection framework is proposed, based on robust phylogenetic markers, which will allow for systematic and comprehensive evaluation of new tools for tuberculosis control and suggest strain-specific differences in virulence and immunogenicity.
Abstract: New tools for controlling tuberculosis are urgently needed. Despite our emerging understanding of the biogeography of Mycobacterium tuberculosis, the implications for development of new diagnostics, drugs, and vaccines is unknown. M tuberculosis has a clonal genetic population structure that is geographically constrained. Evidence suggests strain-specific differences in virulence and immunogenicity in light of this global phylogeography. We propose a strain selection framework, based on robust phylogenetic markers, which will allow for systematic and comprehensive evaluation of new tools for tuberculosis control.

693 citations

Journal ArticleDOI
TL;DR: This Review explores how Mycobacterium tuberculosis influences granuloma formation and maintenance, and ensures the spread of the disease.
Abstract: Tuberculosis (TB), an illness that mainly affects the respiratory system, is one of the world's most pernicious diseases. TB currently infects one-third of the world's population and kills approximately 1.7 million people each year. Most infected individuals fail to progress to full-blown disease because the TB bacilli are 'walled off' by the immune system inside a tissue nodule known as a granuloma. The granuloma's primary function is one of containment and it prevents the dissemination of the mycobacteria. But what is the role of the TB bacillus in the progression of the granuloma? This Review explores how Mycobacterium tuberculosis influences granuloma formation and maintenance, and ensures the spread of the disease.

647 citations

Journal ArticleDOI
TL;DR: It is suggested that the current increases in human population, urbanization, and global travel, combined with the population genetic characteristics of M. tuberculosis described here, could contribute to the emergence and spread of drug-resistant tuberculosis.
Abstract: Mycobacterium tuberculosis infects one third of the human world population and kills someone every 15 seconds. For more than a century, scientists and clinicians have been distinguishing between the human- and animal-adapted members of the M. tuberculosis complex (MTBC). However, all human-adapted strains of MTBC have traditionally been considered to be essentially identical. We surveyed sequence diversity within a global collection of strains belonging to MTBC using seven megabase pairs of DNA sequence data. We show that the members of MTBC affecting humans are more genetically diverse than generally assumed, and that this diversity can be linked to human demographic and migratory events. We further demonstrate that these organisms are under extremely reduced purifying selection and that, as a result of increased genetic drift, much of this genetic diversity is likely to have functional consequences. Our findings suggest that the current increases in human population, urbanization, and global travel, combined with the population genetic characteristics of M. tuberculosis described here, could contribute to the emergence and spread of drug-resistant tuberculosis.

585 citations

References
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Journal ArticleDOI
11 Jun 1998-Nature
TL;DR: The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve the understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions.
Abstract: Countless millions of people have died from tuberculosis, a chronic infectious disease caused by the tubercle bacillus. The complete genome sequence of the best-characterized strain of Mycobacterium tuberculosis, H37Rv, has been determined and analysed in order to improve our understanding of the biology of this slow-growing pathogen and to help the conception of new prophylactic and therapeutic interventions. The genome comprises 4,411,529 base pairs, contains around 4,000 genes, and has a very high guanine + cytosine content that is reflected in the biased amino-acid content of the proteins. M. tuberculosis differs radically from other bacteria in that a very large portion of its coding capacity is devoted to the production of enzymes involved in lipogenesis and lipolysis, and to two new families of glycine-rich proteins with a repetitive structure that may represent a source of antigenic variation.

7,779 citations

Journal ArticleDOI
TL;DR: A novel method based on strain-dependent hybridization patterns of in vitro-amplified DNA with multiple spacer oligonucleotides was found to differentiate M. bovis from M. tuberculosis, a distinction which is often difficult to make by traditional methods.
Abstract: Widespread use of DNA restriction fragment length polymorphism (RFLP) to differentiate strains of Mycobacterium tuberculosis to monitor the transmission of tuberculosis has been hampered by the need to culture this slow-growing organism and by the level of technical sophistication needed for RFLP typing. We have developed a simple method which allows simultaneous detection and typing of M. tuberculosis in clinical specimens and reduces the time between suspicion of the disease and typing from 1 or several months to 1 or 3 days. The method is based on polymorphism of the chromosomal DR locus, which contains a variable number of short direct repeats interspersed with nonrepetitive spacers. The method is referred to as spacer oligotyping or "spoligotyping" because it is based on strain-dependent hybridization patterns of in vitro-amplified DNA with multiple spacer oligonucleotides. Most of the clinical isolates tested showed unique hybridization patterns, whereas outbreak strains shared the same spoligotype. The types obtained from direct examination of clinical samples were identical to those obtained by using DNA from cultured M. tuberculosis. This novel preliminary study shows that the novel method may be a useful tool for rapid disclosure of linked outbreak cases in a community, in hospitals, or in other institutions and for monitoring of transmission of multidrug-resistant M. tuberculosis. Unexpectedly, spoligotyping was found to differentiate M. bovis from M. tuberculosis, a distinction which is often difficult to make by traditional methods.

2,845 citations


Additional excerpts

  • ...Nearly all these samples had been genotyped previously by restriction fragment–length polymorphism (RFLP) [14, 15], using the molecular epidemiologic markers IS6110 [16] (63 of 66 isolates), polymorphic GC-rich sequence (PGRS) [17] (58 of 66 isolates), and direct repeat (DR) [18] (54 of 66 isolates), and by spoligotyping [19, 20] (64 of 66 isolates)....

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Journal ArticleDOI
TL;DR: In this article, the authors proposed a standardized technique which exploits variability in both the number and genomic position of IS6110 to generate strain-specific patterns for DNA fingerprinting of Mycobacterium tuberculosis.
Abstract: DNA fingerprinting of Mycobacterium tuberculosis has been shown to be a powerful epidemiologic tool. We propose a standardized technique which exploits variability in both the number and genomic position of IS6110 to generate strain-specific patterns. General use of this technique will permit comparison of results between different laboratories. Such comparisons will facilitate investigations into the international transmission of tuberculosis and may identify specific strains with unique properties such as high infectivity, virulence, or drug resistance.

2,386 citations

Journal ArticleDOI
28 May 1999-Science
TL;DR: In this article, the differences between M. tuberculosis, M. bovis, and Bacille Calmette-Guerin (BCG) vaccines were studied by performing comparative hybridization experiments on a DNA microarray.
Abstract: Bacille Calmette-Guerin (BCG) vaccines are live attenuated strains of Mycobacterium bovis administered to prevent tuberculosis. To better understand the differences between M. tuberculosis, M. bovis, and the various BCG daughter strains, their genomic compositions were studied by performing comparative hybridization experiments on a DNA microarray. Regions deleted from BCG vaccines relative to the virulent M. tuberculosis H37Rv reference strain were confirmed by sequencing across the missing segment of the H37Rv genome. Eleven regions (encompassing 91 open reading frames) of H37Rv were found that were absent from one or more virulent strains of M. bovis. Five additional regions representing 38 open reading frames were present in M. bovis but absent from some or all BCG strains; this is evidence for the ongoing evolution of BCG strains since their original derivation. A precise understanding of the genetic differences between closely related Mycobacteria suggests rational approaches to the design of improved diagnostics and vaccines.

1,532 citations


"Genomic Deletions Suggest a Phyloge..." refers background in this paper

  • ...are expected to represent unidirectional genetic events [7, 12],...

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  • ...[7] documented that BCG-specific deletions superimpose perfectly on D ow naded rom http/academ ic....

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Journal ArticleDOI
TL;DR: The live attenuated bacillus Calmette-Guerin (BCG) vaccine for the prevention of disease associated with mycobacterium tuberculosis was derived from the closely related virulent tubercle bacilli, Mycobacteriaium bovis, and the precise junctions and DNA sequence of each deletion were determined as discussed by the authors.
Abstract: The live attenuated bacillus Calmette-Guerin (BCG) vaccine for the prevention of disease associated with Mycobacterium tuberculosis was derived from the closely related virulent tubercle bacillus, Mycobacterium bovis. Although the BCG vaccine has been one of the most widely used vaccines in the world for over 40 years, the genetic basis of BCG's attenuation has never been elucidated. We employed subtractive genomic hybridization to identify genetic differences between virulent M. bovis and M. tuberculosis and avirulent BCG. Three distinct genomic regions of difference (designated RD1 to RD3) were found to be deleted from BCG, and the precise junctions and DNA sequence of each deletion were determined. RD3, a 9.3-kb genomic segment present in virulent laboratory strains of M. bovis and M. tuberculosis, was absent from BCG and 84% of virulent clinical isolates. RD2, a 10.7-kb DNA segment containing a novel repetitive element and the previously identified mpt-64 gene, was conserved in all virulent laboratory and clinical tubercle bacilli tested and was deleted only from substrains derived from the original BCG Pasteur strain after 1925. Thus, the RD2 deletion occurred after the original derivation of BCG. RD1, a 9.5-kb DNA segment found to be deleted from all BCG substrains, was conserved in all virulent laboratory and clinical isolates of M. bovis and M. tuberculosis tested. The reintroduction of RD1 into BCG repressed the expression of at least 10 proteins and resulted in a protein expression profile almost identical to that of virulent M. bovis and M. tuberculosis, as determined by two-dimensional gel electrophoresis. These data indicate a role for RD1 in the regulation of multiple genetic loci, suggesting that the loss of virulence by BCG is due to a regulatory mutation. These findings may be applicable to the rational design of a new attenuated tuberculosis vaccine and the development of new diagnostic tests to distinguish BCG vaccination from tuberculosis infection.

1,129 citations

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The data provide compelling evidence that human tuberculosis did not originate from the present-day bovine form.