 April 2002 |
A Mouse’s Tale
By Steven N. Austad
It’s a long and tortuous road from the steppes of Asia to a rustic New England farmhouse and thence to superstardom in the world of modern science, but that is exactly the journey made over thousands of generations by the humble house mouse. This small creature, known to science as Mus musculus, adopted humans about 10,000 years ago, when the development of agriculture led to the invention of grain storage bins, and permanent settlements grew up around the fertile swath formed by the Tigris and Euphrates Rivers in what is now Iraq. Every crack and crevice in the new civilization provided the tiny rodents—able to squeeze through spaces less than half an inch wide—access not only to a cornucopia of food but to relative safety as well. Such a life must certainly have been a pleasant change from searching out seeds on open, unpredictable, and hazardous Asian grasslands.
From that time on, the house mouse has earned its common name, splitting its time between living with us and seeking adventure in the wild. M. musculus spread across the steppes of Asia from Turkey to China and hitchhiked with humans to colonize much of the rest of the world. Today house mice are found from the equator to subpolar islands. They span the climatic range of modern civilization, too, having been discovered living, and even breeding, everywhere from heating ducts to refrigerated meat lockers.
Their zeal for cohabitation has not been generally reciprocated. Over the centuries, much human energy has been expended to keep mice out of homes and cupboards—to build a better mousetrap. Eventually, though, some humans began to think of house mice less as pests and more as pets. Our own species’ compulsion to selectively breed any animal that can be kept as a pet led to a trade in fancy mice, those with odd coat colors and forms (including tailless, Manx mice). Bred for centuries in China, fancy mice caught on in a big way in Victorian England. Clubs promoted, and continue to promote (see “Fancy That!”), officially recognized varieties. Fanciers hold regular competitions and shows in many countries, where ribbons, trophies, and prestige are awarded to the proud owners of the best-bred mice.
Breeding fancy mice became popular in the United States as well. Around the turn of the last century, Abbie Lathrop, a retired schoolteacher, turned her hobby into a business when she began to sell fancy mice from her farmhouse near Granby, Massachusetts. In 1902 Harvard geneticist William Castle purchased some of them to test new theories of mammalian inheritance. Thus was born the laboratory mouse. Today these descendants of house mice are indispensable to biomedical genetic research. It has become commonplace to turn individual mouse genes on and off or to soup up their normal activity in order to understand their function. As part of the research into the role of specific genes, researchers even insert human genes into the mouse genome. The mouse has indeed become an international superstar.
| Over the years, mice that bit their breeders
usually came to a bad end, leaving their gentler relations to form the next generation. |
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The two stages of our relationship with the house mouse have had very different biological consequences for the little creature. Stage one, the commensal stage, when mice lived furtively among us, probably did not change them very much. The warmer temperatures indoors and the steady supply of food did allow them to reproduce throughout the year, but as an opportunistic species, they had always been able to respond quickly to changes in their environment. Stage two, domestication, when we took control of their breeding to favor certain traits, was a different story. Selective breeding is the essence of evolutionary change. Usually nature provides the selection, but humans can as well. Animals evolve under domestication. They may grow larger or smaller than their wild ancestors. They may develop faster, become more fertile or docile, produce richer milk, a thicker coat, or more tender meat. This sort of evolution is obvious: these are the traits for which we breed.
The trait that breeders of fancy mice wanted first and foremost was docility. When handled, wild mice bite and attempt to escape. Anyone who has been the recipient of such a bite knows that the mice tend to hang on with the tenacity of bulldogs. And the escape jump of a wild house mouse is reminiscent of overheated popcorn. However, over the years, mice that bit ferociously usually came to a bad end at the hands of breeders, and escape artists soon found themselves back hiding among the cracks and crevices—leaving behind their less agile, gentler relations to form the next generation of pets.
Another trait selected for by the pet trade was an ability to thrive in comfortable confinement—a shoe-box-sized cage, for example. We humans have bred for gentleness, tolerance of confinement, and bizarre appearance in a number of other species, such as chickens, guinea pigs, and dogs. (How else does one explain the existence of the pug?) Observations of this sort of selective change under domestication were pivotal to Charles Darwin’s work on his theory of evolution by natural selection.
Once fancy mice became popular in the laboratory, their commercial success was directly proportional to the rate at which the animals could produce offspring. Those that reached sexual maturity fastest, reproduced most frequently, and had the largest litters were favored by standard husbandry practices.
What are the results of all this tinkering? Are there other, less obvious traits that we may have inadvertently selected for as well? Richard Miller and Robert Dysko, of the University of Michigan, and I have been looking at differences between lab mice and their wild relatives. When we began, in 1996, we were particularly interested to see whether life in the laboratory accelerated the aging rate. This appears to be the case; recently we lost what may have been the world’s oldest mouse—a codger from Idaho who, when he expired a few days short of his fourth birthday, was more than seven months older than the oldest lab mouse in a comparative longevity experiment. In the course of our studies, however, we began to notice lots of other differences as well. Most laboratory mice are highly inbred, the product of so many generations of brother-sister mating that each individual in a so-called strain is virtually identical to all the others. In order to produce a generic laboratory mouse for our own studies, Miller, Dysko, and I interbred four commonly used strains. Then we compared our lab mice with the laboratory-raised offspring of animals caught in the wild. (To control for differences in early life conditions—life in a field or barn versus life in the lab—the wild mice in our experiments are actually the offspring or grand-offspring of the original captives. For all intents and purposes, though, they are still wild.)
We found, as have others, that laboratory mice grow faster than wild mice and are much bigger as adults. In nature, mice generally weigh between ten and twenty grams, depending on where they live. Laboratory mice can weigh more than fifty grams (not quite two ounces). Even the immediate descendants of our wild mice—which had been born in the laboratory and had unlimited access to food their entire lives—weighed only about half as much as lab mice. Wild mice also take twice as long to reach sexual maturity (two months versus one month) and produce litters of about half the size (five versus ten pups).
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Compared with their wild relatives, laboratory house mice are
real wimps—slower, weaker, and less active. |
Other traits of laboratory mice have changed in ways that might be characterized as “use it or lose it.” Physical fitness has deteriorated over the generations. With a steady supply of food and no predators, lab mice had no need for qualities such as strength, speed, and endurance; genetic mutations that compromised physical fitness were thus not weeded out by selection. Consequently, compared with wild mice, lab mice are wimps—slower, weaker, and less active—even if both have lived their entire lives in cages the size of a shoe box. Given an exercise wheel, wild mice voluntarily run faster and longer than lab mice. Experimenters in the laboratory of physiologist Ted Garland, of the University of Wisconsin, discovered that if forced to exercise, wild mice can sprint about 50 percent faster, but they consume only about 20 percent more oxygen at maximum exercise intensity than do laboratory mice. Even heart ventricles are about 12 percent larger in wild mice.
The greater strength of wild mice makes it impossible to subject them to some behavioral tests designed for the comparatively feeble lab mice. For instance, a standard test of muscle endurance is called the cord drop. The test is quite simple: a mouse is dangled from a taut cord by its front feet—your basic pull-up position—and scored according to how many seconds it can hang on before dropping to the ground. A robust young laboratory mouse is doing well to hang on for thirty or forty seconds. When we tried this test with our wild mice, they simply pulled themselves up onto the top of the cord and walked off. We didn’t actually see them sneer with contempt, but they may have.
There are other use-it-or-lose-it stories among domesticated animals. Wolves, for instance, have greater visual acuity and larger teeth with broader, deeper roots than dogs do. Broiler chickens have smaller leg bones than their ancestor the red jungle fowl. We’ve noted that laboratory mice have smaller eyes than wild mice. And just about every domesticated mammal you can think of has a smaller brain than its wild ancestor.
Do domesticated animals lose these traits passively—that is, simply because the advantage of maintaining them has disappeared—or actively, because something in the domesticated environment favors such a reduction? The latter scenario requires that there be some kind of cost, however subtle, associated with maintaining a trait. For instance, reduction in eye size has occurred again and again in mammals that have evolved to live largely underground. Blind mole rats have eyes about one-hundredth the size of their aboveground relatives’ eyes. They have lost the pupil, as well as the muscles associated with focusing the lens, and even the lens no longer has a functional shape. Eviatar Nevo, of Israel’s University of Haifa, has calculated that blind mole rats use 1 to 2 percent fewer calories as a consequence of not having to maintain large functional eyes and the considerable brain structures that go along with them. And as the mole rat’s visual cortex has been reduced, some of its other brain structures, associated with touch and smell, have expanded. Selection has favored a reallocation of brain space.
It’s difficult to imagine how laboratory conditions could favor active selection for smaller eyes in mice. Neither energy savings nor the expansion of other sensory capabilities would lead to an obvious reproductive advantage in animals occupying a small cage that is regularly replenished with food. Mouse eyes, thus, have probably shrunk passively in the laboratory. The loss of melatonin production in laboratory mice, however, may be the result of active selection. Melatonin is a hormone produced by the pineal gland, a small organ deep in the mammalian brain that conveys information to the rest of the brain and body about the length of light-dark cycles. The pineal gland is thought to be involved in the maintenance of daily and seasonal biorhythms as well as in the timing of reproduction. (Some researchers also think melatonin is an immune-system stimulant that plays a role in cancer resistance, although the evidence for such a function is not strong.)
Because of mutations affecting two brain enzymes, most laboratory mouse strains are unable to manufacture any melatonin whatsoever. These mutations could have been favored by chance alone, but they might also have conferred an advantage. Animals lacking melatonin are less likely to be strictly nocturnal or diurnal. Instead of feeding and being active primarily in the dark, as are most mice, melatonin-deficient mice might feed during both dark and light hours and might thus grow faster and reproduce sooner and more often. Since rapid reproduction is favored by breeders of lab mice, standard laboratory husbandry may favor the loss of melatonin production.
But some trends in laboratory evolution defy even the most imaginative explanations. Wimpy muscles are easy to understand. Wimpy chromosomes are not.
Chromosomes, the long stretches of DNA composing our genome, routinely break and re-fuse, particularly when eggs or sperm are formed by the division of their precursor cells. During this process, pairs of chromosomes (one inherited from the mother, the other from the father) align themselves side by side and are then pulled apart, with one going to each new descendant cell. (This way, sperm and egg end up with only half the number of chromosomes in the original cell. Later, when an egg is fertilized by sperm from another individual, the number of chromosomes doubles, yielding the original chromosome number again in the new generation.) Before being pulled apart, however, each chromosome breaks in one or more places and then joins up, not with pieces of its former self but with pieces of its counterpart, creating a new chromosome that contains a mixture of genes from both parents.
During the routine process of egg and sperm formation, chromosomes from laboratory mice break and re-fuse more frequently than do those of wild mice. Exposure to radiation and certain chemicals can increase the rate of chromosome breakage—again, more frequently in lab than in wild mice. And this pattern isn’t confined to domesticated mice. Domesticated dogs, cats, pigs, cows, sheep, and goats all have more routine chromosome breakage than their wild ancestors do. Why domestication should have such a uniform effect remains a mystery.
Just as mysterious are data that we, and also researchers in several other laboratories, have recently collected about another chromosome trait that differs between laboratory and wild mice: the length of telomeres. Telomeres are long stretches of DNA that protect the ends of chromosomes, much as the plastic tips on shoelaces keep their ends from fraying. Each time cells divide, telomeres shorten a bit; eventually the telomeres become too short to provide protection. At that point, a cellular emergency-response program kicks in and either shuts down the cell division or forces the cell to commit suicide. In either case, telomere shortening seems to operate as a mechanism to prevent out-of-control cell division—cancer, in other words.
Laboratory mice have proved of little use in studying telomere dynamics, because their telomeres are so long—two to ten times as long as human telomeres—that they never shorten appreciably during the life of an animal. When we began looking at telomeres from wild mice, however, we were surprised to find that their telomeres were much shorter, just a bit longer than human ones. So far, no one has come up with a convincing explanation for why telomere length has increased under laboratory conditions. One might speculate that early on in their laboratory existence, mice—which are prone to developing a wide variety of cancers—attracted the attention of cancer biologists. Perhaps commercial demand from cancer biologists led to greater production of cancer-prone mice and, perhaps as an unintended consequence, to longer telomeres (the shortening of which, you’ll remember, is associated with cancer prevention).
A second speculation is that telomere lengthening may have something to do with guaranteeing male fertility. Like other mammals, female mice manufacture prenatally all the eggs they will ever have. Sperm production, however, requires continuing cell division throughout a male’s life. If telomeres shorten too much in the precursors of sperm cells, the emergency response kicks in, cell division ceases, and sperm production stops.
| To understand Mus musculus in its full glory, we need to decipher the genomes of both wild and lab house mice. |
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Carrie Bickle, a graduate student of mine, has found some tantalizing evidence that telomere lengthening in the lab might have some benefit—though what that might be is anybody’s guess at this point. She discovered that mice brought into the laboratory only a couple of decades ago have telomeres intermediate in length between those of wild mice and those of long-established strains of lab mice (whose forebears were bred as fancy mice for who knows how many generations and then bred in the laboratory for about 200 generations more). Telomere length thus seems to increase with each generation that animals have lived in the laboratory. To see if this was a general trend of laboratory domestication or was something specific to the house mouse, she investigated a second species, the deer mouse (Peromyscus maniculatus). During the late 1940s, just after World War II, deer mice were domesticated in the laboratory for use as an alternative to house mice in genetic and physiological research. For reasons no one understands, deer mice have exceptionally short telomeres—shorter than those of almost any animal we know, even humans. Bickle studied tissues from two groups of laboratory-bred deer mice: in one, telomeres had indeed lengthened, but in the second, telomere length was the same as in wild deer mice. Perhaps significantly, the second group had developed breeding problems and died out (working with this group involved using tissues that had been frozen years before). Were the breeding problems somehow associated with an inability to evolve longer telomeres in the lab? And if so, what is the nature of the connection? More questions to be answered, we hope, in the future.
It is more than a simple oddity that laboratory mice have smaller eyes and brains, faster development, larger bodies and litters, weaker muscles and chromosomes, and longer telomeres than their wild relatives. In an unintended genetic experiment, laboratory researchers have created genetic blueprints of the transformation from strong muscles and chromosomes to weak ones, rapid reflexes to slow ones, good eyes to poor ones. If we could read these blueprints properly, they should reveal the steps necessary to reverse these trends. Given the rapid progress being made in mapping and sequencing the genome of the laboratory mouse, that day may not be far off. But, of course, if we want to understand Mus musculus in its full glory, we will also need to decipher the genome of the lab mouse’s wild brethren, the free-living descendants of the little mouse that slipped through a tiny crack thousands of years ago in search of a bite to eat and thus joined its fate with ours.
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Steven N. Austad dates his interest in laboratory mice back to the first time he saw a lab technician pick one up without gloves. When the placid mouse didn't try to bite or escape, Austad asked himself, “What kind of self-respecting animal would allow itself to be handled like that?” As interested as he is in the history of the house mouse, however, he is even more intrigued by his own species. As he says, “Any species that would turn a wolf into a pug bears close watching.” A professor in the Department of Biological Sciences at the University of Idaho in Moscow, Austad conducts research on aging and the physiology of stress as well as on the biology of domestication. On the lighter side, he is the co-author, with his wife, veterinarian Veronika Kiklevich, of Real People Don't Own Monkeys: And Other Stories of Pets, Their People, and the Vets Who See It All, to be published this spring by Sourcebooks.
Copyright © 2002 American Museum of Natural History