Tackling pathogens

"Genome analysis gives you an insight into what makes microbes adaptable, infectious and dangerous," says Dr Bart Barrell, Head of the Pathogen Sequencing Unit (PSU) at the Sanger Institute. "It accelerates fundamental research, and can bring people into working on a subject."

The genomes of a bevy of microbes have been sequenced by the Pathogen Sequencing Unit over the last few months. Some of humankind’s most dangerous enemies have been tackled, and the high-profile publications of three of the genome sequences is testament to their importance to human health (see box below). "With the genome available, you can be rational about your choice of antibacterial drugs," says Dr Barrell’s colleague, Dr Julian Parkhill. "The genome contains all the potential vaccine and drug targets, so you can screen all of your candidate targets systematically."

Comparative sequencing

While researchers at the Pathogen Sequencing Unit are continuing to sequence new species of pathogens, they are also turning their attention to different strains of the same species. Such comparative sequencing can help identify genes, and provide valuable information about genome organisation, evolution and why some strains are harmless and others deadly. "The genomes of two strains of the same species of bacteria can vary by 10–15 per cent," says Dr Parkhill. "To put this into perspective, this is more variability than in the whole primate order. Bacteria appear to be exchanging DNA continually, so by sequencing several strains we can identify the ‘gene pool’ of a species."

The Wellcome Trust has therefore funded the PSU to do comparative sequencing of Escherichia coli and Shigella, which cause gastrointestinal disease and are the leading causes of death in children in developing countries, and of salmonellas, which also cause food poisoning.

Joining the comparative sequencing projects is a new initiative to compare the genomes of six Plasmodium species to that of Plasmodium falciparum – almost completed – which causes the severe form of malaria, and many deaths, particularly in Africa and the Far East. "Plasmodium falciparum is a dreadful organism to sequence," says Dr Barrell. "In places, the genome DNA is 80–90 per cent As and Ts. This makes it extremely difficult to isolate, clone and sequence the DNA, and when you have some sequence it’s very difficult to assemble the sequence in the right order. It’s taken a lot of effort to get the sequence together."

The comparative sequencing project will help the team identify where the genes are in the P. falciparum genome. "It’s relatively easy to find genes in a bacterial genome," says Dr Barrell. "Malaria genes have introns and exons, and it’s often less clear which sequences are genes and which aren’t. But the genes and exons are conserved between species, so we can use comparative genomics to line the sequences up and find the coding sequences."

The project will also be sequencing a field isolate of P. falciparum. "It’s possible that the cultured parasite that is used in the laboratory has lost some of its virulence," says Dr Arnab Pain, a malariologist who joined the PSU recently. "We’ll be comparing all these sequences of Plasmodium, and we should get an excellent understanding of the parasite’s genome and find things that can be tested in the laboratory."

The Pathogen Sequencing Unit is also pushing at the boundaries of sequencing technologies. "One of the projects we’ve just been funded to do is the bacterium Trophyrema whippelii, which causes Whipple’s disease," says Dr Parkhill. (Whipple’s disease is a slowly progressive, chronic, but fatal disorder of the intestinal tract and other tissues.) "Nothing is known about this organism at all, as it’s almost impossible to grow in culture – which also makes it very difficult to obtain enough DNA for sequencing. So we’re working on sequencing it from a very small number of bacteria isolated from the cerebrospinal fluid of a patient."

See also

• The Human Genome Project: Information on the project and the key issues
• Know thy enemy: Article on pathogen genome sequencing

External links

• Microbial Genome Sequencing at the Sanger Institute
• Massive gene decay in the leprosy bacillus, Nature 409:1007-1011 (22 February 2001)
• Genome sequence of Yersinia pestis, the causative agent of plague, Nature 413: 523-527 (4 October 2001)
• Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18, Nature 413: 848-852 (25 October 2001)
• Complete genome sequence of Salmonella enterica serovar Typhimurium LT2, Nature 413, 852-856 (25 October 2001)