Dead Genes Puzzling

Reprinted with permission from Nature LEPROSY REDUCED: Circular genome map showing the position and orientation of known genes, pseudogenes and repetitive sequences. The scale in Mb is indicated by the numbers on the outside ring. Leprosy remains an epidemiological mystery, even 130 years after the leprosy bacillus was discovered.1 Despite the many helpful antibiotics now available to treat this mutilating disease, leprosy's transmission and mechanism of cell and tissue destruction remain poorly understood: Some 650,000 new cases are diagnosed worldwide each year, with about half in India and Brazil alone. But researchers are gaining a better understanding of the leprosy bacillus with the help of genomic data and insights provided by another infamous bacterial killer. As part of a collaborative effort between L'Institut Pasteur in Paris and the Wellcome Trust Sanger Institute in Cambridge, UK, investigators highlighted intriguing genomic features of Mycobacterium leprae, the topic of this Hot Paper.2 The researchers compared M. leprae, the rod-shaped bacillus that causes leprosy, to its close relative, Mycobacterium tuberculosis, the bacillus that causes tuberculosis (TB). "Having two genome sequences is an extremely powerful way of understanding what happens during the evolution of pathogens," says lead author Stewart Cole, a professor of microbiology at the Pasteur. Data derived from the Science Watch/Hot Papers database and the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. S. Cole et al., "Massive gene decay in the leprosy bacillus," Nature, 409:1007-11, 2001. (Cited in 155 papers) The most striking genomic feature: The 3,268,203 base pairs of M. leprae contain an extraordinary number of pseudogenes--the "dead," nonfunctional gene look-alikes that become inactive as the result of mutations. "The breadth and wealth of these pseudogenes was quite shocking," says leprosy expert Thomas Gillis, chief of the National Hansen's Disease Programs, Baton Rouge, La. Of the approximately 2,720 genes in the leprosy bacillus, only about 1,604 are active, protein-coding genes. The TB bacillus genome, with its 4,411,532 base pairs and nearly 4,000 protein-coding genes, has a mere six pseudogenes. "Prior to this publication, nobody had seen pseudogenes on such a huge scale in a bacterium before," says Cole. These results indicate a major case of so-called reductive evolution. Since its divergence from the last microbial ancestor in common with M. tuberculosis, M. leprae has lost about 2,000 protein-coding genes. In most organisms that undergo reductive evolution--that is, they lose genes and become very restricted in their physiological capabilities--the dead genes have been lost completely. In M. leprae, however, many are still there. "That was quite a puzzle," says Cole. This paucity of active genes could explain the bacterium's ex-ceedingly long generation time compared with M. tuberculosis. M. leprae has lost many genes that are important for metabolism and energy-generating capabilities. In the lab, metabolic limitations and the bacterium's resulting long generation time have made it impossible to cultivate, thus impeding microbiological studies. Researchers are limited to surrogate animal hosts such as the nine-banded armadillo, which naturally acquires a leprosy bacillus indistinguishable from the human pathogen, and the nude mouse, in which researchers can grow M. leprae. According to Cole, the study of the M. leprae genome already has had public-health ramifications. He and his group, for example, are working on developing better diagnostics for a hard-to-identify form of leprosy called tuberculoid leprosy. More accurate and rapid diagnosis means less irreversible nerve damage and a lower chance of mutilation or handicap. Yet, leprosy continues to perplex investigators. Since the early 1980s, there has been a large-scale effort underway to identify and treat as many patients as possible. Investigators had expected that the incidence of the new cases would decline. "But in fact," says Cole, "it's stayed relatively constant." Possible explanations include undis-covered disease reservoirs, and unexpectedly high levels of transmission. Gillis hopes to break the transmission cycle by developing a vaccine, something re-searchers have tried and failed to do for 20 years. But with the genome in hand, investigators are hoping to circumvent the bacillus' cultivation problems by selecting and studying genes whose protein products may make good vaccine candidates. Gillis says he envisions vaccines that may even cross-protect against both TB and leprosy, though the research is still in its infancy. Eugene Russo (erusso@the-scientist.com) is a freelance writer in Takoma Park, Md. References 1. G.H.A. Hansen et al., "Undersogelser angaende spedalskhedens aasager," Norsk Magazin for Laegervidens-kaben, 4(Suppl), 1-88, 1874. 2. S. Cole et al., "Massive gene decay in the leprosy bacillus," Nature, 409:1007-11, 2001. 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Dead Genes Puzzling

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