CHAPEL HILL — Scientists in the exploding world of genetic research needed not just one better kind of mouse, but hundreds.
Now they have a whole living library of mice that offers 10 times the genetic diversity of typical lab mice and forms the heart of a powerful new research tool that can be used for free anywhere in the world.
Researchers at UNC-Chapel Hill and N.C. State University are leading the international project, which has developed hundreds of new strains of mice and is meticulously mapping and indexing digital information about their DNA.
The Collaborative Cross project - which included breeding operations here and in Australia and Israel - was formally unveiled today in a series of papers in journals of the Genetics Society of America.
The idea is to offer researchers more diverse alternatives to common lab mice, which are so closely related to each other that they have only a fraction of the genetic diversity that researchers now need for most projects, said Fernando Pardo-Manuel de Villena, a professor in the genetics department at UNC-CH and a member of UNC Lineberger Comprehensive Cancer Center.Pardo-Manuel de Villena, NCSU geneticist David Threadgill, and Gary Churchill of the Jackson Laboratory in Maine led the project, but it involved more than 125 researchers and technicians all over the world.
The project is centered in Chapel Hill, but the sheer number of mice - about 16,000 cages of them - dictated that the breeding be done elsewhere, too.
"No facility in the world could handle it alone," Pardo-Manuel de Villena said.
Mice with the right stuff
The library of mice and data is expected to form a crucial part of the underpinning of an entire new discipline, called systems genetics.
The project and its potential are so large that it took 15 papers today with more than 100 authors in two journals - Genetics and G3: Genes|Genomes|Genetics - to explain them.
The Collaborative Cross is expected to eventually comprise between 300 and 500 new strains of mice that will offer two things that today's inbred lab mice can't: a vastly more diverse base of genes and an online index detailing those genes.
That database will allow researchers to use the Internet to select the genetic qualities they need for a specific kind of research, then order the mice they need. The database can also help them understand their research results.
Its breadth and power is expected to vastly speed some kinds of research, make other types possible for the first time and make some of the results more pertinent to human health and human biology.
Mouse studies are often a crucial step in research, in part because mice and humans share a surprising amount of genetic material: about 95 percent.
Mice have other good attributes for research into human disease and biology, including that they breed and mature quickly.
But typical lab mice have such limited diversity that it reduces their usefulness for some research looking at DNA.
Dr. Norman E. Sharpless, UNC Lineberger's associate director for translational research, said he used to wonder why it was worth the trouble for researchers interested in human disease to study large collections of mouse DNA, when they could go straight to humans.
But for some diseases, potential genetic causes can only be tracked to a broad region in humans. Mice, meanwhile, can be genetically manipulated to make it possible to identify the exact gene associated with a disease.
"This Collaborative Cross is so useful for mapping genetic traits. ... I expect labs all over the world to begin working with these strains, and I can envision a need to expand the number of mice strains," Sharpless said. "There's really no other way to do some of these experiments."
All told, about 1,600 strains of mice were bred via an elaborate plan that among other things brought in genes from wild mice. Some weren't suitable for various reasons, and the team is still working to make the maximum number of strains available to researchers, said Pardo-Manuel de Villena.
About 450 strains are now housed at a UNC facility, with 10 cages per strain and typically at least two mice per cage.
Some of these strains will become extinct, others added. A handful of strains still haven't arrived from overseas. All the DNA indexing is being done here, and the scientists want to have representatives of all the different lines.
'Curating' genetic traits
The researchers working with the project refer to the work of overseeing the mice as "curating" because it's such responsibility to care for and accurately track the various strains. Even a small mistake could have disastrous results for researchers using the mice.
The diversity of the new mice is often expressed in ways that are hidden, but some characteristics, such as being unusually lean or chubby, are obvious, Pardo-Manuel de Villena said.
Research technicians who work with mice daily will have to be aware of another trait: Collaborative Cross mice are not typically docile, like traditional lab mice. When someone opens a cage door, they may leap out, and often they are not happy about being handled.
"Our mice are much more like real mice than pets," he said.
The plan is to create distribution facilities around the world, Pardo-Manuel de Villena said. For now, the North American one will be at Chapel Hill. Whether it stays there or has to be relocated could depend on how popular the mice become among researchers.
"At this point, we don't know exactly how it will go," Pardo-Manuel de Villena said. "If we are very successful, they could fire me because the mice would take over the whole university."