|Bacteria use quick-switch genes to dodge host defenses|
By Bijal P. Trivedi
March 24, 2000
Bacteria have the reputation of being primitive, unsophisticated types. But this microscopic menagerie of organisms has the uncanny ability to rapidly adapt to vastly different environments and evade host immune systems. While random mutation has been thought to explain this ability, Richard Moxon, of Oxford University, believes bacteria have a slicker, quicker system.
In the March 10 issue of Science, a group of American, British and Italian scientists present the deciphered genetic sequence of Neisseria meningitidisthe bacterium responsible for life-threatening infections like meningitis and septicemia. Within the approximately 2.2 million building blocks of DNA code the researchers predict 2,158 genes. They hope knowing the genes will eventually help them find good targets for drugs.
Searching through these genes, Moxon has identified a set of "contingency genes," which contain a region with a higher rate of mutation than other areas of the genome. Mutations in these regions garble the whole gene sequence, effectively switching the gene off. Moxon calls these stretches of DNA "switch regions."
When bacteria invade a new host, they face a hostile battlefield. If this were a bacterial video game, it would be called "Adapt or Die." Swarms of immune cells attempt to wipe out the invaders, some with toxic chemicals and others with molecular harpoons. Still other immune cells just eat the invaders whole. The invaders must brave not only this shower of cellular ammunition but also varying temperature, acidity and humidity.
"Contingency genes are the bacterium’s answer to the rapidly changing landscape," says Moxon.
Each gene can be flicked on or off, and the switching mechanism is random mutation within the switch region. Each time a bacterium divides, one mutation within the switch region might turn the gene sequence to rubbish, effectively turning the gene off. A mutation in a switched-off gene’s switch region might restore that gene’s activity.
Contingency genes function like a "library of thousands to millions of potential variants," says Moxon. With one of these genes, the bacterium has two variations on hand. Two genes provide four alternatives. With 20 contingency genes, a bacterium would have a repertoire of more than a million possible variations. When Moxon’s team analyzed the genome of the bacterium N. meningitidis, they found 65 possible contingency genesenough to put billions and billions of variations in the bank.
Moxon believes that mutations occur frequently in the switch regions because they are filled with short repetitive sequences of DNA’s four building blocksA, C, G, and T. Replication in such repetitive sequences is prone to "slipping and mis-pairing," says Moxon. When repair machinery surveys the DNA before the replication step, it sees the mis-pairing and either adds or subtracts a base. This causes the DNA sequence to be shifted either one place to the left or right. Such mistakes can eventually prevent the gene from being read, effectively switching it off. In the next generation of bacteria, another slip and mis-pairing in the same region could turn the gene back on.
Contingency genes provide an intriguing potential explanation of how a population of bacteria can rapidly adapt. According to his hypothesis, randomly flipping genes on and off creates unique genetic combinations in the rapidly reproducing population. With so many genetic variants, some are likely to survive even the most concerted onslaughts of the immune system.
The finding has implications for drug development, Moxon points out, because a drug targeted at a gene’s product will not be of much use if the gene is frequently switched on and off. In any population of bacteria, some cells will succumb to the drug, while others survive to reproduce.
With the complete sequence of the N. meningitidis genome in hand, researchers can now choose to target genes that lack switch regions. Furthermore, the research offers clues about which genes to avoid and which to target in other disease-causing bacteria.
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