Comparative Sequencing

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Abstract
We would like to respond to the letter by Julian E. Davies ([30 Aug., p. 1155][1]) expressing concern about the National Institutes of Health (NIH)-funded effort to sequence the genome of Mycobacterium tuberculosis . The NIH funding was a result of an investigator-initiated R01 application from The Institute for Genomic Research (TIGR) that scored exceptionally well in peer review this past February. The TIGR investigators became aware of a pending announcement by the Wellcome Trust of their intention to fund a similar effort at the Sanger Centre to sequence the H37Rv laboratory strain of M. tuberculosis (the same strain proposed in the TIGR application), and immediately notified the National Institute of Allergy and Infectious Diseases (NIAID). It was agreed to convene an External Advisory Panel (composed of the signatories of this letter), from a variety of M. tuberculosis research disciplines, to review the situation and to make a recommendation as to how and if to proceed. In early May we met to discuss alternatives to sequencing the H37Rv strain, including sequencing such genomes as M. smegmatis , virulent M. bovis , M. bovis bacille Calmette-Guérin (BCG), M. avium , M. microti , and a recent virulent clinical isolate of M. tuberculosis . Forceful arguments were made for and against sequencing each of these species. It was unanimously agreed that, while all the above organisms had their merits, the sequencing of a recent, drug-sensitive, genetically tractable, virulent, clinical isolate of M. tuberculosis would be of most value in light of the comparative data it would provide with the H37Rv laboratory strain. The panel decided that seed lots should be prepared from four recent clinical isolates—strains A, C, W, and Oshkosh—that these strains would be evaluated for their virulence in mice and transformability, and that sample sequencing would proceed from libraries prepared from each strain. This decision was subsequently reviewed and accepted by NIAID. This evaluation process is currently under way, and a final strain selection is pending these results. The decision to sequence a clinical isolate of M. tuberculosis in this particular initative should not be looked on as a lack of recognition of the importance of other organisms, including M. smegmatis , in pathogenesis and research. Significant differences have been demonstrated between genomes of laboratory strains with long histories of passage and recent clinical isolates. H37Rv was first isolated in 1905 and has been passaged for many decades. Of greater importance is that H37Rv is of unknown virulence in humans. The selection of a clinical isolate that has been involved in a recent cluster of tuberculosis cases (that is, known to be transmissible and virulent in humans) ensures that the sequence of the genome of a fully virulent M. tuberculosis strain will be available in a timely fashion. Moreover, the availability of sequences from both genomes will provide the first opportunity for a complete comparison between two closely related organisms of the same bacterial species. The comparisons afforded by this opportunity provide the potential to recognize the genetic basis for successful human colonization, infectivity, and fully fledged transmission of a pathogen. These comparisons, along with the likely completion of the M. leprae genome, will take genome sequence comparison to an unprecedented level. At a recent meeting at the World Health Organization in Geneva, there was unanimous enthusiasm from researchers in the areas of detection, prevention, and therapy about the impact that the availability of these M. tuberculosis genome sequences would have on future research efforts to combat this ancient and reemerging killer. [1]: /lookup/doi/10.1126/science.274.5290.1155

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