Custom-Made Mice Have Served Men for Decades

A pair of mice from the Granby farm produced a lineage that became known as "Black 6" or B6. It is the most popular research mammal in the world. It was a B6 mouse whose genome was sequenced in 2002 as part of the ongoing effort to get full DNA transcripts of many life forms, from yeast and mustard plants to microscopic worms, cats and human beings.

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.

Take, for example, a mouse with a defective gene in a part of the brain called the cerebellum that causes it to stagger when it walks. Among the many things researchers want to know is where that gene is.

If they know that mice with the staggering trait always have a handful of SNPs known to reside on a particular chromosome, then they can deduce that the gene and those SNPs are "linked" -- physically near each other on that stretch of the DNA highway.

Diversity in the form of more SNPs will provide more mile markers in the genome and possibly allow the production of mice with new, unrecognized traits. To that end, the Jackson Laboratory and the federal government's Oak Ridge National Laboratory, in Tennessee, are creating about 1,000 new strains of inbred mice.

The scientists are starting with a more diverse group of "founders" than went into current lab strains. They are creating the inbred lines through the classic technique of brother-sister mating.

The work will take about seven years. The result may not be better mice, but it will be more varied ones.