Science Selection January 2018 | Volume 126 | Issue 1
Capturing Genetic Diversity: The Power of the CC and DO Mouse Models
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Published: 26 January 2018
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Related EHP Article
New Rodent Population Models May Inform Human Health Risk Assessment and Identification of Genetic Susceptibility to Environmental Exposures
Extrapolating data from lab experiments in mice to humans will always be a big leap, but by purposefully breeding mice to better mimic human genetic variation, that leap is now smaller than it was before. A new review in Environmental Health Perspectives describes why.1
Two recently developed rodent population models—the Collaborative Cross (CC)2 and the Diversity Outbred (DO)3—have already gained a solid footing in the genetics community. With their review, authors Alison Harrill and Kimberly McAllister, researchers at the National Institute of Environmental Health Sciences (NIEHS), aim to increase awareness of these resources and to encourage their broader adoption in toxicologic and environmental research.
For decades, toxicologists primarily used single inbred (genetically identical) strains of mice to determine the dose at which chemicals may cause adverse effects in animals. Then they used that information to estimate exposures that could be hazardous for humans.4 With genetically identical strains, the response of one mouse is expected to be the same as that of another mouse to the same dose of chemical. However, we now recognize that human responses to similar environmental exposures are highly variable, presumably because of genetic differences between people. To better mimic human genetic heterogeneity for the purpose of toxicity testing, toxicologists began to explore the use of more genetically diverse mouse reference populations, taking advantage of resources that had already been developed for genetic mapping studies.
Researchers created CC mice by intercrossing eight inbred “founder” strains that were chosen to maximize genetic diversity. The resulting inbred strains are distinct, but within each strain, CC mice are genetically identical. As a complementary resource, researchers also created DO mice by randomly mating pairs from the same eight founder strains, with each mouse being genetically unique (what is known as randomized outbred stock). The CC and DO mice allow toxicologists to observe a range of environmental responses in genetically diverse animals.
“These new models offer unique advantages to environmental health scientists,” says Steven Munger, an assistant professor at Maine’s Jackson Laboratory, who was not involved in the review. “Although genetic variation differs in mice and humans, many of the [metabolic] pathways are the same, which means the detection of an extremely sensitive subgroup of mice has implications for humans.”
The power of these new resources is illustrated by two landmark studies discussed in the review. In the first study, researchers exposed 47 lines of CC mice to the mouse-adapted strain of Ebola virus.5 Until that study, the virus was primarily studied in nonhuman primates because traditional inbred mice did not produce the hallmark of human Ebola infection: hemorrhagic fever with excessive bleeding. The authors observed extensive phenotypic variation in the responses of CC mice to the virus, ranging from complete resistance to severe pathology similar to that observed in the human disease. This observation changed Ebola research by producing its first powerful mouse model.
The second study used DO mice to evaluate benzene toxicity and compared the results with those obtained using inbred mice.6 The results of such studies are relevant to regulations designed to protect genetically susceptible workers in industries where they may be exposed to benzene, such as petrochemical and rubber manufacturing. The authors found that DO mice varied greatly in their susceptibility to benzene-induced chromosomal damage. The estimated threshold for adverse effects was an order of magnitude lower in DO mice than in inbred mice and was more consistent with susceptibility estimates in human studies. Illustrating the greater statistical power of DO mice to map genetic susceptibility, the researchers also identified specific genes that modify the animals’ capacity to detoxify benzene.
“This was one of the clearest examples of establishing a dose–response relationship and then identifying the mode of action; that is, the genes that mediate this response in the most sensitive group of DO mice,” Munger notes.
David Aylor, an assistant professor in the Center for Human Health and the Environment at North Carolina State University, considers these new resources a powerful bridge between what is possible in human studies versus those using single inbred strains of mice. “I think it is very important for these models to gain some traction among environmental health scientists now that they have proven their worth in the mouse genetics community,” says Aylor, who was not involved in the review.
Harrill and McAllister emphasize that the new models do not replace existing tools in the toxicologist’s toolbox. “They complement, rather than replace, the traditional models,” McAllister says. “The study design and overall research goals determine what combination of tools will work best.”
Silke Schmidt, PhD, is a Madison, Wisconsin–based journalist who writes about science, engineering, and the environment.
1. Harrill AH, McAllister KA. 2017. New rodent population models may inform human health risk assessment and identification of genetic susceptibility to environmental exposures. Environ Health Perspect 125(8):086002, PMID: 28886592, 10.1289/EHP1274.
2. Threadgill DW, Miller DR, Churchill GA, de Villena FP. 2011. The Collaborative Cross: a recombinant inbred mouse population for the systems genetic era. ILAR J 52(1):24–31, PMID: 21411855, 10.1093/ilar.52.1.24.
3. Svenson KL, Gatti DM, Valdar W, Welsh CE, Cheng R, Chesler EJ, et al. 2012. High-resolution genetic mapping using the mouse Diversity Outbred population. Genetics 190(2):437–447, PMID: 22345611, 10.1534/genetics.111.132597.
4. King-Herbert A, Thayer K. 2006. NTP workshop: Animal models for the NTP rodent cancer bioassay: Stocks and strains—should we switch?. Toxicol Pathol 34(6):802–805, PMID: 17162538, 10.1080/01926230600935938.
5. Rasmussen AL, Okumura A, Ferris MT, Green R, Feldmann F, Kelly SM, et al. 2014. Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance. Science 346(6212):987–991, PMID: 25359852, 10.1126/science.1259595.
6. French JE, Gatti DM, Morgan DL, Kissling GE, Shockley KR, Knudsen GA, et al. 2015. Diversity Outbred mice identify population-based exposure thresholds and genetic factors that influence benzene-induced genotoxicity. Environ Health Perspect 123(3):237–245, PMID: 25376053, 10.1289/ehp.1408202.