. "Plenary Lecture." The Development of Science-based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop. Washington, DC: The National Academies Press, 2004.
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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop
inclined colleagues? Is the answer removing the experimenter from the experiment through automation? We tend to disagree with these gloomy thoughts. Rather, we think that the stability of genetic influences is often overlooked. Genotype was the strongest effect for all behaviors in the multisite trial. As Doug Wahlsten and I have continued our work exploring GXE interaction across strains in our two laboratories, we have been studying 21 strains drawn largely from the Mouse Phenome Project A and B list (Paigen and Eppig 2000). We recently explored the literature for evidence for or against stable strain differences in behavior through the years (Wahlsten and others 2003b). We sought tasks where several of the same substrains had been used and where very similar phenotypes were studied, even though apparatus and procedures could not be exactly the same over many years. Thus, we allowed a great deal more environmental variability than we allowed in the multisite trial. For each trait, data had also been collected identically in Portland in 2002. We then correlated the data for older studies with those gathered in Edmonton in 2002.
Another piece of untested laboratory lore is that morphology is less variable than behavior. One trait for which there are many historical data is mouse brain weight. Indeed, in addition to Edmonton and Portland data for 21 strains from 2002, we found eligible studies in 2000, 1973, and 1967. The correlations with Edmonton data for the Portland 2002, 2000, and 1973 studies were all between .84 and .97. These account for 71 to 95% of the variance. However, the oldest study correlated less well with the modern study (r2 = 0.23), though it was based on only four strains. For open field activity, we found studies from another laboratory in 2003, the Portland 2002 data, and studies from 1968 and 1953. All four correlations yielded r2 = 0.90! Clearly, activity in mice is at least as stable across laboratories (and decades) as brain weight, and appears to be more so. The findings were not all so stable however. Although Portland and Edmonton’s 2002 elevated plus maze outcomes correlated (r 2= 0.78), a study from 1993 showed only a very modest relationship (r2 = 0.37). because three of the seven strains in common behaved very differently in the two laboratories.
Understanding complex traits can be advanced through studies with mouse genetic models. However, modeling genetic effects cannot rely on simplistic assumptions about the environment. Although any careful experimenter standardizes conditions within his or her own laboratory to achieve reliable genetic results, it cannot be assumed that within-laboratory reliability translates directly into across-laboratory reliability. Some features of the laboratory environment are nearly impossible to duplicate.