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Mutations are not always entirely random and monotonous, according to several researchers who spoke during the symposium, ``Genome Strategies in Evolution and Disease,'' held as part of the annual meeting of the American Association for the Advancement of Science in Washington, D.C., in February. From immune system-baffling antigenic variation in certain pathogens to mutator-like behavior in human tumors, some cell-based systems are equipped to change in ways that seem to suit their needs. Of course, pathogens and other more benign microorganisms ``don't have brains'' and what they do to adapt to their hosts does not involve ``cognition,'' says symposium participant Richard Moxon of the University of Oxford in the United Kingdom.

In biology, suggests symposium organizer Lynn Caporale, perhaps certain genetically determined accidents are waiting to happen more than others. ``Genetic mutations can be focused in space, and regulated in time and circumstance,'' she says. For instance, pathogens often are adapted to their hosts, sometimes in ways that depend on the microbe modulating its own capacities for generating genetic variants. Meanwhile, many of the more complex organisms, such as corn, fruit flies, and humans, are capable of generating a great deal of genetic variability within their own respective genomes, says symposium participant Margaret Kidwell of the University of Arizona in Tucson. Those genomes often encode numerous transposable elements (TEs) that can serve as ``potent endogenous mutagens,'' she adds. Sometimes parasitic and perhaps also beneficial at times, the enigmatic TEs have figuratively left their fingerprints all over the genetic maps of many complex organisms--serving what purposes is not always so easy to say.

With an estimated 3.2 billion years of earth-bound adaptation under the collective genetic belt of prokaryotes, they have managed to accumulate an impressive degree of ``dynamic versatility,'' says Moxon. Such versatility may help to explain how the meningococcus, which ordinarily resides in the upper respiratory tract of humans where it seldom causes harm, abruptly may breach nearby barriers, intrude on the central nervous system or the blood, and, once there, inflict major damage on the host. Such dramatic changes, which involve genetically determined switching of cell surface components of these microorganisms, trace to special ``repetitive elements'' within the genome that are characterized by tetranucleotide repeats, he says. These ``contingency loci,'' although relatively rare among bacteria, seem to provide meningococci with a ready-made ``mutational mechanism for [generating] variation,'' one that confers on such cells a very powerful way of interacting with their environments.

The meningococcus contains at least 66 ``binary switches'' within its genome, and they can ``generate billions of phenotypic variations,'' Moxon says. Similar sites consisting of tetranucleotide repeats also are found in the genomes of other pathogens, including Haemophilus influenzae and Neisseria meningitidis. The products encoded by these highly variable genes probably are not ``good candidates for vaccine targets'' because they can be so readily switched, he points out. But others ``look to be invariant, and would be good targets.''

A similar type of genetically determined state of high variability appears to be a prominent component of many tumor cells, according to symposium participant Lawrence Loeb of the University of Washington in Seattle. Mutations in ordinary human somatic cells are a relative rarity, but not among tumor cells. Thus, he hypothesizes that tumor cells, which are ``highly polymorphic,'' have a ``mutator phenotype''--something like what occurs in certain mutants of Escherichia coli that undergo successive selections for variation.

Early damage to cells that are destined to become tumors arises from natural processes and other insults, leading to unrepaired DNA segments, Loeb says. Eventually, a wider set of genes changes, and the overall mutation rate in such cells increases, as the mutator phenotype takes over. Only later, he says, do these events impinge on what many cancer researchers commonly call oncogenes, assortments of genes with crucial control over the truly dangerous (to the host) growth and invasive characteristics of cells that can be considered fully malignant. And, by the time there is a clinically detectable tumor, the mutator phenotype is ``selected out'' or shut down, he says.

One way to prevent many types of cancer would be to delay unleashing the mutator phenotype, he suggests. If that could be done, it might change lung cancer from being ``a disease that kills people at age 55, into a disease that kills at 75,'' Loeb says. Similarly, the mean ages of onset and death for other types of cancer might be pushed back if we could better ``understand how to manipulate mutation rates'' of those cells that depart from ordinary function to enter pathways that prove so destructive to their hosts.

Jeffrey L. Fox
Jeffrey L. Fox is the ASM News Current Topics and Features editor.