Crosses make lab mice even more useful

New strains of lab animals bred to better pinpoint the genetic roots of disease

Scientists have built a better mouse. But rest easy — these mice don’t require improved traps.

Mice bred for the Collaborative Cross project contain about 90 percent of the genetic diversity found in all laboratory mice. The animals are designed to help researchers better understand the genetic basis of disease. Univ. of North Carolina Dept. of Genetics

The new mice may give scientists an advantage in tracing genetic sources of common diseases and investigating interactions between genes and environmental factors. In a series of 15 papers published in the February issues of Genetics and G3: Genes, Genomes, Genetics, researchers describe the creation of the new-and-improved mice, known as the Collaborative Cross strains, and some of the ways scientists may use the mice in medical studies.

Biomedical researchers use inbred strains of mice to mimic human diseases and probe the genetics involved. Every mouse in an inbred strain is a genetic clone. That’s useful because the mice all generally respond in the same way to a drug or to infection with a virus. And altering the function of a single gene and seeing what happens in these mice can help scientists decipher the role of that gene in disease processes.

But because all the mice react so uniformly, they don’t reflect the range of responses humans may have. With conventional laboratory mice, it is also difficult to determine how multiple genes interact with each other or how disease-associated genes are influenced by the environment.

Mice that are more genetically diverse than typical laboratory strains could help solve those problems, David Threadgill, a geneticist at North Carolina State University, and some of his colleagues realized. The researchers set out to create mice that are as diverse as human populations, but also have the consistent and well-understood genetics of lab strains.

A consortium of researchers selected five strains of laboratory mice and three strains derived from mice caught in the wild to be the parents for an eventual 1,000 strains of mice. Together, the eight founder strains contain about 90 percent of the genetic diversity found in laboratory mice.

Breeding the founding strains and their offspring in carefully designed schemes has produced hundreds of lineages with different combinations of genetic variants. The strains look different from each other and have different responses to the environment.

Samir Kelada, a geneticist at the National Human Genome Research Institute in Bethesda, Md., wants to know why some people develop allergic asthma when they come in contact with certain substances. He plans to use the Collaborative Cross mice to help him map out genes that may contribute to asthma. But first, he and his colleagues needed to get an idea of how the mice’s immune systems function normally. Kelada and his colleagues counted different types of blood cells in 131 strains of the mice. The researchers report in the February G3 that the size of red blood cells differs among the strains and is controlled, in part, by variants in the hemoglobin beta gene and the annexin A7 gene.

Such a study would not be possible with conventional laboratory strains of mice, Kelada says. “I think this is the best experimental system I could ask for.”

Reporting in the same issue of G3, Shannon McWeeney of Oregon Health & Science University and her colleagues found that 44 of the new mouse strains differ widely in their response to influenza virus. Comparing the mice that get the sickest with those that shake the virus off easily, the team found more than 2,000 genes that behave differently. The researchers hope to pinpoint the genes responsible for the differences and determine whether the same genes play a role in how humans respond to the flu.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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