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Evolution Evolving Scientific American Sept 97

Does mutability carry a selective advantage under stress?

Nine years ago John Cairns and his colleagues at the Harvard School of Public Health reported in the influential journal Nature sensational experiments "suggesting that cells may have mechanisms for choosing which mutations will occur"-specifically, in ways that give those cells an advantage in stressful conditions. This radical proposal collided head-on with the sacrosanct principle of genetics that mutations occur at a rate that is completely unrelated to whatever consequences they might have. Cairns's suggestion thus conjured the ghost of jean-Baptiste Lamarck, who argued in tile 19th century that species evolve through the inheritance of "acquired" characteristics-ones that individuals develop in response to environmental challenges. Cairns postulated that bacterial cells, in effect, mysteriously know in advance which mutations are likely to benefit them. Then, when'-investigators stress the cells by starving them, the bacteria tip fate's scales so that rare beneficial mutations happen more often than chance would allow. This incendiary idea, known as directed mutation, ignited a firestorm of debate. Almost a decade later the dust has still not settled. Investigators around the world have immersed themselves in complex experiments to learn whether the apparent surplus of beneficial mutations in Cairns's studies - confirmed by other researchers-might have a less explosive alternative explanation. Potentially far-reaching discoveries are now emerging. Most biologists now believe-and Cairns has acknowledged-that the seeming excess of beneficial mutations found in many directed-mutation studies might arise because researchers are more likely to spot and so count beneficial events than they are harmful ones. Various theories have been advanced to explain why, although none has gained universal acceptance. Recent experiments, however, provide important evidence for one effect that could produce such a counting bias. The effect, hypermutation, thus might make true directed mutation unnecessary. But hypermutation itself opens the door to some intriguing possibilities.

Hypermutation was first proposed as an explanation for Cairns's results in 1990, by Barry G. Hall of the University of Rochester. Hall conjectured that when starving, a few bacterial cells might enter an unusual state in which they generate multiple mutations. Cells that by random chance produced favorable mutations in extreniis would survive to be counted, but others would probably die and leave no trace. So investigators would see niore beneficial mutations than harmful or neutral ones. For some years, technical obstacles made it hard to confirm or refute this explanation. Now Patricia L. Foster of Boston University and, separately, Susan Rosenberg of the University of Alberta have performed experiments that give it a boost. Like Cairns, the researchers studied bacteria that lack the ability to feed on the sugar lactose. When Foster and Rosenberg deprived the bacteria of all sugars except lactose, excess mutations arose not only iii a gene that allowed the bacteria to use the lactose but in other genes, too. The two sets of results "together show the generality of hypermutation under lactose selection," commented Bryn A. Bridges of the University of Sussex in Nature on Jun6 The results suggest, as Hall had proposed, that hypermutation occurs in some cells that are under physiological stress, possibly because DNA is more likely to break under such conditions. Bridges reserved judgment on whether bacteria evolved the capacity for hypermutation as an adaptation to overcome nutritional stress or whether the effect is merely a mechanical response to starvation. But studies reported in the same journal a week later suggest-to some, at least-a possible way that hypermutation may indeed have evolved as an adaptation. These latest findings show that in natural populations of bacteria, "mutator genes," which increase the mutation rate, can spread through a population by allowing the bacteria to evolve faster. Parado@ally, this happens even though mutations produced by the mutator genes, like others, are on average harmful. The seemingly impossible occurs because my4ators occasionally arise in individuals that also carry an ad,vantageous gene. In an asexual population, the mutator may then spread with the advantageous gene, a phenomenon called the hitchhiking effect. Franqois Taddei of the CNRS in Paris and an Anglo-French team showed in a theoretical study that in a changing environment, the faster evolution made possible by mutator genes often outweighs their disadvantage to the individual. And Pau.1 D. Sniegowski of the University of Pennsylvania and his colleagues showed that mutators can get ahead in real populations as well. In three out of 12 bacterial colonies evolving in a new environment, mutator genes swept through the population and became ubiquitous. Researchers have found evidence that mutator genes are especially common in tumors and pathogens. By allowing faster evolution, they might help the villains evade hosts' immune systems, Sniegowski suggests. And although he emphasizes that his finding has no immediate bearing on the notion of directed mutation, the new crop of results leads some biologists to suspect that mutation might play a more complicated role in evolution than they had believed. In a Nature conimentary on June 12, E. Richard Moxon of John Radcliffe Hospital in Oxford, England, and David S. Thaler of ttie Rockefeller University note that many pathogens have some collections of genes that are excessively prone to mutation. Mutation frequently varies the combinations of these hypermutable genes that are iii ictive service by making individual genes functional or not. Because the genes affect how the pathogen interacts with its liost, hypermutation within such special sets of genes allows tile microbe to confound immune defenses. Other hypermutable gene sets might assist in solving differ ent challenges, Moxoii atid Thaler conjecture. If, for example, the genes' rate of mutation is affected by a microbe's physiological state, like the mutation rates Rosenberg and Foster studied, hyper mutable genes could generate mutations when a cell was starv ing and so lielp mimic directed mutation. The mutations would still be random, but the most beneficial ones would remain long enough to be counted.

The appearance of directed mutation might thus arise "with no requirement for new molecular mechanisms," Moxon and Thaler surmise. The scientists suggest further that if physiological factors can influence hypermutable genes, perhaps separate mutator genes can also switch on and off hypermutable genes. Mutation rates would then be subject to fine-grained genetic control. Thaler says that "the mechanisms for the generation of variants are themselves subject to evo!ution." It might take another decade to learn whether evolution routinely plays such a sophisticated game with mutation rates. But one piece of unpublished work lends support to the notion tliat mutator genes might liave a part iii how hypermutation simulates directed mutation. Hall has recently isolated five bacterial genes that niake excess favorable mutations seem to appear elsewhere in the bacterial DNA. Hall thinks his newly isolated genes soii-icliow stimulate liypermutatioii and so generate the illusion of overabuiidaiit advantageous mutations. "In my gut I feel it's an evolved phenomenon," lie says. Pure directed ii-iutation, with its spooky foreknowledge, may be dead. But real mechanisms that produce the ghost of directed mutation could yet shake up biology. "In evolutionary theory there has been ali overemphasis on the power of selection as opposed to the generation of diversity," Thaler goes on to reflect. "Maybe this will take it to an other level." -Tim Beardsley in Washington, D.C.

Aug 21 98 Jumping genes formed the immune system

WASHINGTON - A little piece of genetic material that jumped into animals, perhaps from a microbe, may expwn our complex and sophisticated immune system, say American researchers. They said yesterday that they had found evidence of how this so- called 'jumping gene" made it into humans, explaining how our umune systems can fight off a huge array of viruses, bacteria and parasites. Writing in the science journal Nature, David Schatz and colleagues at Yale University said they thought the gene, known as a transposon, might have acted like a virus, insinuating itself into the genetic material of whatever animal it infected 450 million years ago. "I would have thought that there some sort of microbe that harboured that transposon, and that transposon somehow jumped out of that ndcrobe's genome and into our ancestor's genome," said Dr Schatz, an immunologist. "This helps explain why the jawed vertebrates are the only species that have a second, adaptive immune system, in addition to the innate immune system that all other species have." Our immune system has two elements. The innate immune system consists of macrophages that engulf invaders, and natural killer cells that kill in a relatively nonspecific manner. The second line of attack, the adaptive immune system, uses antigens - proteins on the surface of the invader that flag it as a foreign body - to help white blood lymphocytes to recognise the bad cells. Lymphocytes use a kind of lock- and-key system to attack invaders. Each memory cell rearranges its surface molecules to match an invader -, and can "remember this combination for the next attack. It is this ability to cut and paste DNA so rearrangement can. take place that jumped into animals from th ancient microbe. Dr Schatz's teajn found that two genes, Ragl and Rag2 work together as a transposase, an enzyme that cuts and pastes pieces of the gene from place to place. 'What jumped was a piece:, of DNA,' said Dr Schatz, "and that piece of DNA contained the genes Ragl and Rag2.' REUTERS