M. Tuberculosis Genome Sequence

For this article, author Jennifer Fisher Wilson interviewed Julian Parkhill, Wellcome Trust Genome Campus, Sanger Centre, coauthor of this Nature paper. Data from the Web of Science (ISI, Philadelphia) show that this paper has been cited more frequently than others of the same type and vintage. S.T. Cole, R. Brosch, J. Parkhill, T. Garnier, C. Churcher, D. Harris, S.V. Gordon, K. Eiglemeier, S. Gas, C.E. Barry III, F. Tekaia, K. Badcock, D. Basham, D. Brown, T. Chillingworth, R. Coonor, R. Davies, K. Devlin, T. Feltwell, S. Gentles, N. Hamlin, S. Holroyd, T. Hornsby, K. Jagels, A. Krogh, J. McLean, S. Moule, L. Murphy, K. Oliver, J. Osborne, M.A. Quail, M.-A. Rajandream, J. Rogers, S. Rutter, K. Seeger, J. Skelton, R. Squares, J.E. Sulston, K. Taylor, S. Whitehead, and B.G. Barrell, "Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence," Nature, 393:537-44, June 11, 1998. (Cited in about 290 papers since publication) Most people who are infected with tuberculosis bacteria do not develop active tuberculosis--at least not at first. The immune system controls but does not kill the bacteria. Later, if the body becomes weakened and vulnerable, the tuberculosis bacteria can reactivate. When the disease is active, it can spread through the air with every breath. The complicated genesis of tuberculosis makes developing effective treatment for it a continued challenge for researchers--and an important one, since tuberculosis kills more people than any other single infectious agent. The recent link between tuberculosis and the human immunodeficiency virus further emphasizes the risk from Mycobacterium tuberculosis. Short-course chemotherapy and the Bacille Calmette-Guérin vaccine can act as treatments, but M. tuberculosis is naturally resistant to many antibiotics. So when researchers at the Wellcome Trust Genome Campus of the Sanger Centre, in collaboration with the Institut Pasteur in Paris, finished sequencing the 4,411,529 base pairs of the M. tuberculosis genome, their work was seen as an important step toward developing more effective treatment for tuberculosis. "We hope that our success in sequencing the tubercle bacillus will lead to better treatment for tuberculosis. Genome sequencing of pathogenic bacteria is basic research--it provides a data set that will underpin all future work on these organisms," says Julian Parkhill, a member of the pathogen sequencing group at the Sanger Centre. Parkhill, a coauthor of the Nature paper that published the genome sequence, said that it took two years to sequence M. tuberculosis using the cosmid and whole-genome shotgun approaches. Besides the possible public health implications, tuberculosis is an interesting organism from a purely biological point of view, Parkhill says, because M. tuberculosis is used widely by scientists in conducting research. It has proven particularly amenable to research because it has retained full virulence in animal models of tuberculosis, and it is susceptible to drugs and manipulated easily. "Many researchers work on M. tuberculosis, and almost all of these, we hope, will be using the genome sequence in their work," Parkhill says. The researchers at Sanger found that the tubercle bacillus differs significantly from other bacteria in that a large part of the coding capacity is devoted to the production of enzymes involved in lipogenesis and lipolysis. A large part of the coding--approximately 10 percent--is also devoted to two new families of glycine-rich proteins with a repetitive structure. "The most surprising elements were the repetitive gene families, called the PE and PPE families, and the presence of genes encoding anaerobic respiratory pathways," Parkhill says. These repetitive structures may represent a source of antigenic variation, he adds. Reprinted with permission from Nature Parkhill also notes that before the genome was sequenced, tuberculosis was described as an obligate aerobe. The genome sequencing revealed that, under aerobic growth conditions, oxidative phosphorylation generates ATP from electron transport chains involving a ubiquinone cytochrome b reductase complex and cytochrome c oxidase. But the sequencing also revealed several anaerobic electron transport chains, including genes for nitrate reductase, fumarate reductase, and a new reductase that results from rearrangement of a homologue of the nitrate reductase operon. These findings may have important ramifications for drug and vaccine design, according to Parkhill. The research group, led by Bart Barrell, is in the process of sequencing a number of other bacteria besides M. tuberculosis, including Corynebacterium diphtheriae, Salmonella typhi, Streptococcus pyogenes, and Yersinia pestis. "We are sequencing the genomes of a wide range of pathogenic bacteria. M. tuberculosis was just the first. It was chosen because of its enormous importance to human health." Jennifer Fisher Wilson is a freelance writer in Philadelphia.

M. Tuberculosis Genome Sequence

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Jennifer Fisher Wilson

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January 2000

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