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Lab mice breeder catalogs genetic surprises
Sunday, February 21, 1999 By Byron Spice, Science Editor, Post-Gazette
At the Jackson Laboratory, genetic curiosities are the stock in trade.
The Bar Harbor, Maine, genetics research center is a major producer of lab mice, boasting more than 1,700 strains, many of them bred to mimic human diseases such as cancer, heart disease and obesity. About 3 million mice are born in the earthy-smelling production facilities each year, and the Jackson Lab, or Jax, sells and ships about 2 million to researchers.
So when mice that look or behave unusually appear in any of the colonies, they and their parents are culled out and brought to a central facility for evaluation. That's what happened a couple years ago when researchers noticed mice with stubby feet and extra digits on each paw.
"We thought it was quite interesting," recalls Kenneth Johnson, a Jax research scientist. As he and his colleagues hoped, the mice proved to have a genetic mutation that also occurs in humans, causing a similar malformation of human feet and hands called synpolydactyly.
But the significance doesn't stop there, says the University of Pittsburgh's Jeffrey Schwartz, a physical anthropologist.
These mice with the strange paws, he maintains, demonstrate the sort of spontaneous genetic change that can lead to the creation of species.
As Johnson and his colleagues determined, the mutation occurred in a gene called Hoxd13, one of a number of homeobox genes that control how an embryo develops. Changing the activation or the timing of these genes can have dramatic effects on the shape an organism will take or the features it will have.
Schwartz, noting that these genes are shared by all animals, contends that changes in homeobox expression could result in the sudden appearance of new species.
These changes would first occur as a recessive trait, Schwartz says. That is, an animal would need to have a genetic code that included two copies of such a mutation before the trait would be expressed.
A single mutation could occur in one individual and be passed to offspring through many generations. Eventually, enough individuals in a population would have the recessive trait that carriers would begin mating with each other and producing offspring with the new trait.
That's pretty much what happened in the mouse population.
It would seem that the mutation occurred spontaneously within the colony of inbred mice, Johnson says, and spread silently through the population, generation after generation.
"They could have been carrying that [mutation] for some time," he says now.
The affected mice have extra digits on all four paws, sometimes fused to other digits, sometimes webbed to adjacent toes.
The digits are unusually short, Johnson said, but legs are of normal length.
When the mutation was mapped, Johnson wasn't surprised to find it occurred in Hoxd13.
Bjorn Olsen, a cell biologist at Harvard Medical School, reported three years ago that a Hoxd13 mutation was responsible for synpolydactyly in humans.
In humans, the Hoxd13 mutation results in an extra fused middle digit or webbed digits on the feet or on the hands, or sometimes on just one side of the body. It also can result in urogenital malformations in heavily affected individuals, as it also does in mice.
Homeobox genes differ little, if any, between species, and the type of mutation causing synpolydactyly in both humans and mice is the same: Extra copies of a DNA sequence that makes the amino acid called alanine.
This mutation doesn't result in a new species or even in any seeming advantage for either human or mouse; the affected male mice, in fact, are sterile. But Schwartz says it shows that "a gene is a gene," that homeobox gene expression can change and then be inherited and passed on just like any other genetic trait.
Johnson has never discussed the idea with Schwartz, but admits the notion that homeobox genes could cause the sudden occurrence of new species makes sense from the standpoint of molecular biology.
Olsen, the Hersey professor of cell biology at Harvard, goes further. "It's timely," he says of Schwartz's theory. "Given what we now know about these different genes ... somebody would have eventually had to have come to the same conclusion."
"It's becoming more and more clear that variations in these genes can lead to sudden changes in morphology."
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