Researchers have found that a single nucleotide polymorphism (SNP) causes a disparity in drug responses between two substrains of the C57BL/6 inbred laboratory mouse. The finding points to the care that must be taken when comparing behavioral data from mice of difference substrains.

The research mouse strain C57BL/6J has been maintained at the Jackson Laboratory since 1948. In 1951, a colony of these mice was sent to the National Institutes of Health, and C57BL/6N became a second major source of C57BL/6 mice. Because of genetic drift over nearly a century, populations of C57BL/6 mice have developed into at least 20 substrains. Although behavioral differences have been noted in C57BL/6 substrains, their genetic basis has not been elucidated.

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A team led by Joseph Takahashi (University of Texas Southwestern Medical Center and Howard Hughes Medical Institute, Dallas, TX) compared the locomotor response to cocaine and methamphetamine in C57BL/6J mice and C57BL/6N mice. C57BL/6N mice had a 45% lower acute response to both drugs at multiple doses and sensitized to cocaine much less efficiently than the C57BL/6J strain (Science 342, 1508–1512; 2013). “They are clearly not interchangeable,” says Gary Churchill, one of the study's authors.

They further demonstrated that C57BL/6N mice have a lower number of total dendritic spines on the medium spiny neurons in the nucleus accumbens; these cells play an important role in drug addiction.

To find out if SNPs accumulated through genetic drift could account for the phenotypic difference, the scientists carry out quantitative trait locus analysis. They were able to map the genetic difference between the strains that was associated with the drug response to a single locus on a 22-Mb interval between 35 Mb and 57 Mb of chromosome 11. Whole-genome sequencing further uncovered a SNP within that interval producing a missense mutation in Cyfip2. This gene encodes a highly conserved protein that is widely expressed throughout the brain. The SNP destabilizes the structure of CYFIP2, though the scientists could not pinpoint an alteration in the protein's function. Still, they confirmed the importance of the protein in regulating the response to drugs by generating mice with the Cyfip2 mutation; these mice showed acute and sensitized responses to drug administration similar to the C57BL/6N mice.

They further estimated that the Cyfip2 polymorphism was fixed in the C57BL/6N genome sometime between 1961 and 1974 and is present in the most commercially available sources of the strain, including those from Charles River Laboratories and Taconic.