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Journal of Clinical Microbiology, June 2000, p. 2081-2086, Vol. 38, No. 6
Department of Medical Microbiology, Royal
Free and University College Medical School, University College London,
Royal Free Campus, London NW3 2PF, United Kingdom
Received 8 November 1999/Returned for modification 1 February
2000/Accepted 4 March 2000
We sought to determine whether nonrandom association of
IS6110 with Mycobacterium tuberculosis could
result in false-positive clustering in unselected collections of
isolates. We typed 196 strains of M. tuberculosis from an
unselected community-based study in northern Tanzania by
IS6110 and polymorphic GC-rich repetitive-sequence (PGRS)
methodologies. The strains were analyzed by Gelcompar computer software. Analysis of 13 out of 25 groups showed that isolates with
identical IS6110 and PGRS patterns were likely to be the same strain. Some IS6110 groups containing strains with
identical PGRS patterns had similar IS6110 patterns that
differed only by movement of the element. Isolates assigned to a single
group (i.e., group 11) on the basis of sharing an identical
IS6110 fingerprint pattern did not share identical PGRS
fingerprint patterns. Six out of the nine bands in these isolates were
in hot-spot locations, as previously defined. This indicates that
nonrandom association may result in false-positive clustering in
unselected community-based studies. Only strains with identical PGRS
and IS6110 patterns are likely to be recently transmitted.
The incidence of tuberculosis is
rising throughout the world, prompting detailed investigation of the
epidemiology of this disease. Typing techniques based on the
polymorphism of insertion sequence position in the genome
(IS6110) and repetitive sequences (e.g., polymorphic GC-rich
repetitive sequence [PGRS]) have provided molecular methods to
distinguish strains. There have been many reports of their application
in routine clinical practice (3, 8, 15).
Mycobacterial typing has moved beyond the investigation of point source
outbreaks into wider community-based studies. IS6110 typing
has proved valuable in this context when a focused question is being
posed. Thus, it has been possible to follow the spread of particular
isolates from intravenous drug abuser and alcoholic groups into the
general population (6, 10). It has also been useful to
follow the spread of drug-resistant clones, such as strain W, in New
York and throughout the United States (19). Similarly, it
has been possible to follow the spread of the susceptible strain C in
the same population (9). These studies were successful, as
they sought to identify one or more identical isolates within a larger
unselected group of isolates.
Several large genotyping studies have been initiated in major cities,
such as London (P. D. Butcher, H. C. Maguire, A. Pearson, S. H. Gillespie, J. W. Dale, and D. K. Banerjee, Proc. 17th Annu. Meet.
Eur. Soc. Mycobacteriol., abstr. P163, 1996), Paris (12), New York (19), and San Francisco (2). Networks
have been established to pool the results of smaller studies into
databases covering the United States and the European Union. The
databases have allowed the transmission of some strains to be followed
across state and national borders as described above to answer focused epidemiological questions (1, 16). It has been hoped that retrospective interrogation of these databases would provide insight into the epidemiology of tuberculosis on a wider scale. This approach raises questions about the definition and significance of molecular clustering. Typing of Mycobacterium tuberculosis using only
IS6110 is dependent on the assumption that integration of
the insertion sequence into the genome is random and that the
discrimination of the technique increases in proportion to copy number.
We have shown previously that there are hot spots for integration
(17) and therefore insertion is, in fact, a nonrandom event.
It is possible that nonrandom insertion might confound the algorithms for cluster analysis. These observations make no assumptions with regard to evolutionary associations between IS6110 and the
PGRS region.
This study was designed to define a practical approach for the
interpretation of IS6110 and PGRS cluster analyses. To do
this, we investigated an unselected collection of sequential routine isolates from Northern Tanzania, among which there were no known epidemiological clusters, by both IS6110 and PGRS typing.
The terms "strain" and "isolate" are often used without
precision. In this study, isolate refers to a mycobacterial culture
derived from a single patient on a single occasion. Strain defines one or more isolates that are thought to be isogenic. A practical aim of
this study is to offer a paradigm for the classification of strains
using established molecular techniques, thus providing a rationale for
further epidemiological investigation.
Bacterial isolates.
Single M. tuberculosis
isolates were prospectively collected from all culture-positive
patients diagnosed by the National Tuberculosis and Leprosy Control
Programme Reference Laboratory at Kibongoto Hospital over the 6-month
period from April to September 1995. Speciation was confirmed by
standard microbiological techniques. The isolates were maintained on
Löwenstein-Jenson slopes at 37°C for a minimum of 4 weeks and
subsequently transported to the Department of Medical Microbiology,
Royal Free & University College Medical School, London, United Kingdom.
DNA extraction.
Bacteria were harvested from the
Löwenstein-Jensen slopes, heat killed, and incubated with
lysozyme (1 h; 37°C) followed by digestion with 50 µg of proteinase
K (Sigma, Poole, United Kingdom) in 10% sodium dodecyl sulfate for 10 min at 65°C. A further incubation with 1% (wt/vol)
cetyltrimethylammonium bromide in IS6110 typing.
Genomic DNA was digested with
PvuII restriction endonuclease and separated by agarose gel
electrophoresis and Southern hybridization according to the
International Standard Typing method for M. tuberculosis (21). The probe used was a PCR amplimer derived from
reactions using M. tuberculosis strain H37Rv DNA as a
template and the following primer set: INS1, 5' CGT GAG GGC ATC GAG GTG
GC 3', and INS2, 5' GCG TAG GCG TCG GTG ACA AA 3' (18).
Hybridization was performed at 50°C, and the final wash was 0.5× SSC
(1× SSC is 0.15 M NaCl plus 0.015 M sodium citrate) at 50°C.
PGRS typing.
All available isolates were submitted to PGRS
analysis. Genomic DNA was digested with AluI restriction
endonuclease and separated by agarose gel electrophoresis followed by
Southern hybridization. The probe used was an oligonucleotide
consisting of two copies of the PGRS consensus repeat (5)
sequence, 3' GGC GGC AAC GGC GGC AAC GGC GGC GGC GGC AAC GGC GGC AAC
GGC GGC 5'. Hybridization was performed at 40°C, and the final wash
was 2× SSC at room temperature.
Detection.
The probes were labeled and detected by
chemiluminescent procedures as recommended by the manufacturers
(Gene-Star and Amersham Pharmacia Biotech).
Cluster analysis.
Comparison of DNA fingerprints was done
with the GelCompar version 4.0 package (Applied Maths, Kourtrai,
Belgium). Cluster analysis was performed by calculation of the Dice
coefficient. Similarity, defined by the Dice coefficient, was
calculated using the parameter settings at 0.8% band position
tolerance for IS6110 typing and 1.2% band position
tolerance for PGRS typing. A cluster was defined as a series of
isolates with 100% identity, and a group was defined as a series of
isolates with less than 100% but greater than 90% similarity by
either technique.
IS6110 analysis of 141 isolates of M. tuberculosis with six or more bands revealed 25 groups (66 isolates) at 90% identity, of which 4 were robust at 100% identity
(Fig. 1).
Cultures were available for further
analysis of 13 of these groups (35 isolates) by PGRS (Table
1). For the remaining groups, one or more
cultures were no longer viable and so were not available for DNA
extraction.
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False Molecular Clusters due to Nonrandom
Association of IS6110 with Mycobacterium
tuberculosis
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
0.5 M NaCl for 10 min at 65°C was
followed by partition using chloroform-isoamyl alcohol (24:1
[vol/vol]).
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
View larger version (2928K):
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FIG. 1.
Master dendrogram of relationships between
IS6110 profiles of 141 isolates of Mycobacterium
tuberculosis as calculated by the Dice coefficient.
TABLE 1.
Comparison of isolates by IS6110 and
PGRS typing
Isolates in 7 of the 13 different IS6110 groups shared the same PGRS pattern and thus maintained the close relationships defined by IS6110 typing (Table 1).
Group 11 contained three isolates clustered at 100% by
IS6110 analysis, but the PGRS analysis showed only 84%
identity. Isolates A180 and A157 were 88% similar; A180 had one more
band than A157, and there were marked band position differences. A180
had the same number of bands as A123 (13 bands) but had different
positional changes (Fig. 2).
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In groups 6 and 10, both the IS6110 pattern and the PGRS pattern showed marked variation. Group 6 contained two isolates with 92% similarity by IS6110 analysis; isolate A113 had one more band than A120, and there were further band position differences between these isolates. By PGRS analysis, these isolates were 96% similar, with isolate A113 containing one extra band. Group 10 showed 94% similarity between two isolates by IS6110 analysis. Isolate A281 contained one extra band. PGRS analysis revealed a similarity of 92%; the isolates had the same number of bands but had two positional changes.
Group 4 contained six isolates with 92% similarity by
IS6110 analysis and 96% similarity by PGRS analysis (Fig.
3).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In this unselected community-based study, we were seeking to identify molecular relationships between strains that had not been detected in clinical practice. IS6110 typing of 141 isolates with six or more bands yielded 25 groups, of which 13 were available for further analysis. Current practice would lead to detailed epidemiological investigation of patients in these groups and the attribution of epidemiological significance to these results.
For isolates in group 11, the IS6110 patterns are identical but the PGRS patterns show considerable variation, indicating that these are likely to be different strains. Of the nine IS6110 band positions in the group 11 pattern, six are located in hot spots for integration that we have defined previously (17). We therefore conclude that this IS6110 similarity has arisen through a chance association. In a large genotype study of an unselected population, the bias resulting from hot spots for integration represents a risk that may serve to compromise the epidemiological investigation. Such a bias is already recognized by many groups, as low-copy-number isolates are routinely excluded from analysis. The majority of low-copy-number band positions are at hot spots for integration (4, 7, 14, 17). Where the PGRS genotypes are different but the IS6110 genotypes are similar, this represents a false cluster caused by nonrandom association which should not be investigated further.
Introduction of a second sensitive typing technique enabled the validation of each of the groups. Three IS6110 groups were robust when tested by PGRS analysis. Clusters 7, 9, and 13 were identical by both methods and must be considered to be composed of one strain each. Further investigation is required in such cases to plot the epidemiological links between them. Clusters 1, 2, 3, and 5 were identical by PGRS typing, but the IS6110 patterns showed slight variation. This variation was due to the addition or deletion of bands and suggested that the PGRS clustering was valid and the difference in IS6110 was due to recent movement of the element. Evidence presented by Yeh et al. indicates that the rate of change of PGRS is significantly lower than that of IS6110 (22). These authors also note that PGRS and IS6110 instability are independent of each other. Our data support the view that IS6110 typing provides the more stringent test for recent epidemiological links between cases. Groups 6 and 10 had a calculated similarity by both methods. By previously published criteria for IS6110 typing, the members of these groups would have been classified as related (11). In group 6 there are four changes in IS6110 band position, indicating that if these isolates were related, a considerable time had elapsed since they had diverged, and this is confirmed by the difference in PGRS pattern. In group 10 there are differences in the position and number of bands, also suggesting that any relationship is distant. This conclusion is confirmed by the differences in the PGRS types. Although these isolates may be related, they have diverged a considerable time previously and are therefore unlikely to be linked epidemiologically, and thus they are not worthy of an investment of epidemiological resources to identify links.
We propose that only isolates with identical PGRS and IS6110 patterns can be considered a strain and can indicate recent transmission. Subsequent epidemiological investigation is essential to demonstrate the nature of any relationship. Where the PGRS genotypes are identical and the IS6110 patterns differ, these are likely to be related isolates in which movement of the element has occurred. The relationship of such isolates in an unselected population would be uncertain, as they have had the opportunity to diverge from a common origin. These more distant relationships may be of significance in a community-based study and could reveal important epidemiological associations, as seen in our previous study (11). Thus, such isolates might merit further detailed investigation to identify epidemiological relationships in a community-based or unselected population study but could probably be excluded from an outbreak investigation. A large community-based study is under way in London which will address this issue (Butcher et al., Proc. 17th Annu. Meet. Eur. Soc. Mycobacteriol.). An exception to the exclusion of such isolates from an outbreak investigation may be if the outbreak occurs in an enclosed community and takes place over a number years with multiple infection events. An example of such a community is provided by the outbreak described in Portugal (13), in which a single strain of M. tuberculosis circulated in the human immunodeficiency virus-positive community over a number of years. Minor differences in the IS6110 patterns were observed, and these were interpreted as transpositional events within a single strain. Epidemiological data corroborated this conclusion.
The data presented here are in accordance with the observation of Salamon et al. (20) that dendrogram clustering methods are at risk of failing to reconstruct the true relationships between isolates. Thus, molecular clustering cannot be accepted uncritically; nonidentical isolates may have their associations obscured as a result of the movement of elements, and conversely, identical clusters may be false due to nonrandom association of insertion elements.
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ACKNOWLEDGMENTS |
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We gratefully acknowledge the help of N. Sam, A. Ramsey, A. O. S. Saruni, and G. M. Kisyombe for their assistance in collecting isolates.
This study was funded by grants from Special Trustees of the Royal Free Hospital held by S. H. Gillespie.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Medical Microbiology, Royal Free & University College Medical School, University College London, Royal Free Campus, Rowland Hill St., London NW3 2PF, United Kingdom. Phone: (44)-171-794-0500. Fax: (44)-171-794-0433. E-mail: stepheng{at}rfhsm.ac.uk.
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Journal of Clinical Microbiology, June 2000, p. 2081-2086, Vol. 38, No. 6
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