Tuesday, August 28, 2007

The Mutant Mouse Factory

The Jackson Laboratory, in Maine, USA, has been breeding mice for genetic research for almost 75 years.

Mutant mice. Mice with tweaked genes, or severely inbred, so they have the tendency to develop cancer, or diabetes, or hypertension, Alzheimers, osteoporosis. The list is long, and sometimes horrifying. Today, this weird but fascinating story explains, the lab offers researchers some 3000 strains of 'altered' mice.

The history of humankind's discovery of its own building blocks, its DNA, would have been impossible without these mice. But the future of this kind of research, the future of these sometimes miracle mice, holds the key to the evolution of humanity, where the humans, not nature, are responsible for the dramatic changes in the historical span of our own species.

And it also means the development of a 'new' and supposedly 'better' mouse. In fact, an entire new species of the fabulous little rodent :

In most cases, these traits (and hundreds more) arose through chance mutations in single animals. They caught the eye of a scientist, who in turn "captured" the trait by mating the animal with its siblings, and then those offspring with one another. After 25 generations, such animals are all identical and -- if things go as planned -- all carry the gene or genes responsible for the trait of interest.

The usefulness of these animals is hard to overstate. They help biologists understand basic physiology. They help identify genetic defects that lead to disease. The benefits or risks of experimental drugs are often easier to detect when tried on animals that are the same.

Mice became workhorses of medical research in the decades after World War I. They were cheap and easy to raise, prolific, reached maturity quickly and were all around more practical than larger animals such as dogs.

At the time, the mouse's genetic malleability was well known and the source of popular entertainment.

Clubs of "mouse fanciers" in the early years of the 20th century bred animals to have exotic coat colors and strange behaviors. (A type of "waltzing mice" from that period turned out to have an inner ear defect.) This briefly fueled even a fashion fad. Full-length mouse coats, made of 400 skins, sold for about $350 in the 1930s.

Through much of the 20th century, scientists collected mice from around the world (including places as remote as the Faroe Islands in the North Atlantic) for breeding stock. The idea was to ensure genetic diversity in the mix of animals used to create inbred strains.

How successful this effort was -- or was not -- became clear only this summer.

A paper published in July in the journal Nature Genetics analyzed the DNA sequences of 15 strains of mice. Eleven were "classical" inbred strains used in laboratories for years. Four were strains derived from animals caught in the wild more recently, including one from the sewers of Prague.

To the researchers' surprise, the older strains had much less genetic diversity than anyone assumed.

About 92 percent of all those strains' genomes derive from the Mus musculus domesticus subspecies native to Western Europe. There was relatively little contribution from subspecies of Central Asia or Southeast Asia, or from a hybrid of the two found in Japan.

This told mouse geneticists there were many more variations of DNA in the mouse universe that could potentially go into making new strains of the animals.

"Only one-quarter of the total diversity in the 15 strains is present in the classical laboratory strains," said Churchill, a biostatistician at the Jackson Lab.

This diversity takes the form of single-letter variations that individuals or inbred strains have by chance in their DNA chains. The chains, comprising an ordered sequence of four chemical letters (called nucleotides and designated A, T, C and G) otherwise differ very little from one strain to the next.

Most of the single-letter variations are in stretches of the 3-billion-letter chain where there is no decipherable message. (Most of the mouse's genome -- and people's, too -- is this non-coding DNA, whose function is just starting to be discovered). But a few are in message-carrying stretches: the genes. There, a substitution of one letter -- say, an A where a C normally is -- can affect an animal's appearance, behavior or functioning.

Regardless of where they occur, these variations, called single nucleotide polymorphisms, or SNPs, are extremely important in genetic research.

They function as mile markers on the nearly endless DNA highway, although sprinkled along the road with less regularity. They allow scientists to know where they're working when they create, through selective breeding or genetic engineering, strains of mice with particular characteristics.

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