That researchers' staple, the laboratory mouse, has undergone the ultimate dissection: two competing teams have completed the most thorough maps yet of its genetic variation.

The catalogue of 8.27 million genetic differences provides a unique insight into the evolutionary origins of the mouse, and researchers also anticipate that it will speed up the discovery of disease-causing mutations in mice — and ultimately in humans.

It's a whole new era of mouse genetics.

Although the two groups disagree over the evolutionary history of the lab mouse (Mus musculus), they both assert that the maps will give researchers fast access to an unparallelled cache of genetic information on hundreds of lab strains. “It's a whole new era of mouse genetics,” says Gary Churchill, a mouse geneticist at Jackson Laboratory in Bar Harbor, Maine, and an author on one of the studies (H. Yang, T. A. Bell, G. A. Churchill & P.-M. de Villena Nature Genet. doi:10.1038/ng2087; 2007).

The researchers traced the lineage of small chunks of the mouse genome in 11 common lab strains back to four wild subspecies. Because of the genetic similarity between the 450-odd inbred classical lab strains, a relatively small number of single-nucleotide polymorphisms (SNPs), which are one-base-pair differences between two strains, can now be used to deduce the sequences of more than 8 million SNPs using the new map. If one segment of the genome can be attributed to a single ancestor, then all mouse strains that share that segment should have the same SNPs. As few as 50,000 SNPs spread across the genome per strain are needed to deduce the rest of the 8 million.

“You don't have to go and resequence [their genomes],” says Richard Mott, a bioinformatician at the Wellcome Trust Centre for Human Genetics in Oxford, UK, who was not involved in the studies. “That's tremendous.”

Signs of diversity: coat colour was the first way in which different mouse strains were recognized. Credit: Steven R. McCaw, Image Associates/NIEHS

Mus musculus is the most important model organism for human disease and the standard-bearer in cancer and immunology research, as 99% of mouse genes have a human counterpart. In the early 1900s, Abbie Lathrop, a former schoolteacher in Massachusetts, started breeding mice obtained from fanciers in Europe and Asia. These animals spawned the first lab, which were made genetically pure through dozens of generations of sibling mating. “It was really, truly just a handful of mice,” says Kelly Frazer, a geneticist who led the second mapping effort while at the biotechnology company Perlegen Sciences in Mountain View, California (K. A. Frazer et al. Nature, doi:10.1038/nature06067 ; 2007).

Subtle differences between strains — A/J mice are prone to cancer and BALB/cJ mice are susceptible to the bacterium Listeria, for example — can be traced to SNPs, of which fewer than 45 million are thought to exist in lab and wild strains together.

Difference matters

The first mouse genome to be sequenced was that of C57BL/6J, in 2002. The US National Institute of Environmental Health Sciences in Triangle Park, North Carolina, teamed up with Perlegen to roughly sequence 10 more strains, plus four subspecies of wild mice collected from all over the world. The sequences were completed in 2006 and made freely available.

To tease out more detail and to make the information applicable to other mouse strains, Frazer's team made a genomic map of each sequenced strain, and established the ancestral subspecies that gave rise to around 40,000 segments of the genome. Overall, says Frazer, a subspecies from Europe called domesticus contributes most (68%) of the lab mouse genome, but this varies from chromosome to chromosome and strain to strain.

Frazer's team didn't know that Churchill's team was doing the same thing. “It would have been nice if the two groups had talked with one another,” she says, “but they didn't let us know they were doing it.”

Using a slightly different method, Churchill and his colleagues at the University of North Carolina at Chapel Hill also conclude that domesticus provides the lion's share of diversity in lab mice, more than 90%. He says that the mouse genome is far more complex than he had thought. “This has been an unfolding story,” he says. “We saw patterns that were so confusing.” What has emerged is only a partial sketch, he says. Sequencing the entire genomes of more laboratory and wild strains will paint a fuller picture and settle the differences between the two maps. “It's going to be resolved,” Churchill says.

Although the teams present two evolutionary histories for the lab mouse, “the similarities are more important than the differences,” Mott says. And the ability to deduce polymorphisms in other strains doesn't depend on an unambiguous history.

Researchers will be eager to make use of the data, say both teams. Mark Daly at the Broad Institute in Cambridge, Massachusetts, and a co-author with Frazer, has already applied the map to 100 strains of mice that had been genotyped for 150,000 SNPs, and will soon be able to assign millions more SNPs to these mice.

The projects could also spur the use of less common lab strains by providing better genetic maps, says Elizabeth Fisher, a geneticist at University College London. “There's an enormous amount of diversity out there that we're not capitalizing on,” she says. A collaboration of hundreds of researchers called the Complex Trait Consortium plans to breed 1,000 new mouse strains (see 'Mice unlimited'). And now those strains will be easily genotyped. “It's going to allow us to make better mouse lines for the future, with levels of diversity that are more like human diversity,” Churchill says.