Mutant Mice and Neuroscience: Recommendations Concerning Genetic Background

Abstract

Banbury Conference on Genetic Background in Mice*identity of the genetic elements governing these other factors (modifiers) is usually unknown, it is important to keep them constant when evaluating the impact of a Mouse mutants derived by targeted mutagenesis in emmutation. Only if the same genetic background is used bryonic stem (ES) cells offer many advantages to the across experiments can differences between the phenostudy of the molecular and cellular mechanisms underlytypes obtained be ascribed to the mutations rather than ing behaviors such as learning and memory, circadian to different genetic backgrounds. Adoption of a comrhythms, motor coordination, and aggression, as well mon genetic background does not preclude comparison as other neuroscience research areas such as brain of the effects of a given mutation in different backdevelopment. The beginning of any new field, however, grounds. is often marked by a period in which key issues are Genetic background can be used as a tool in the debated, and as a consequence the approach is sharpanalysis of a mutation (e.g., quantitative trait loci analyened and focused. Theoretical and practical issues resis and enhancer/suppressor screens; Takahashi et al., lated to the impact of genetic background on the analy-1994). By placing the same mutation in different genetic sis of mutant mice have been a central topic of backgrounds, it is possible to study facets of gene funcdiscussion in this new field (Crawley, 1996(Crawley, , 1997 Crusio, tion that would elude studies in any single background. 1996;Gerlai, 1996;Lathe, 1996;Wehner and Silva, 1996).Additionally, powerful new mapping and cloning strate-Analysis of the literature reveals that there is no consengies may allow the identification of modifiers from differsus on the nature of appropriate controls for genetic ent backgrounds (Dietrich et al., 1993; Gould et al., background. This report summarizes a recent Banbury 1996). Genetic interactions between a mutation and the workshop held in Cold Spring Harbor, New York, on genetic background may account for the variable pene-December 8-11, 1996, to discuss these issues in an trance of human genetic diseases, and it is important effort to come to a consensus within the field. The recto study and understand the nature of these interactions. ommendations that follow reflect the need for rigorously Most targeting experiments to date have relied on controlling the genetic background of experimental anithe use of ES cells derived from substrain 129 mice. mals, and the practical issues surrounding the imple-However, the 129 substrains are a complex collection mentation of the appropriate controls.

Fierce: a new mouse deletion of Nr2e1; violent behaviour and ocular abnormalities are background-dependent

“…F2 animals, produced from F1 × F1 crosses, have mixed, segregating backgrounds, and thus, were not studied. Hence, we generated three genetic backgrounds for study from two congenic strains [33].…”

“…To interpret the effects of a genetic lesion accurately, genetic background must be considered [6,13,33]. This may be particularly relevant for variable phenotypes such as behaviour studied in highly inbred strains recognized as having identifiable characteristics [6,24].…”

Hippocampal LTP and memory in mouse strains: Is there evidence for a causal relationship?

“…Conversely, natural variation observable in inbred strains represents less robust and perhaps physiologically more relevant alterations. Indeed, although gene targeting and transgenic techniques have provided invaluable insights into the mechanisms of memory, these approaches have been criticized on technical grounds (Gerlai, 1996a;Lathe, 1996;Crusio, 1996;Silva et al, 1997), and their utility questioned, because of the problem of compensation (Crawley, 1996;Crusio, 1996;Gerlai, 1996b;Lathe, 1996, Routtenberg, 1995. Similarly, pharmacological approaches have been deemed inappropriate: the specificity and selectivity of small molecule tools have been questioned and problems associated with significant side effects have been pointed out (Grant and Silva, 1994;Tonegawa et al, 1995).…”

Two genetic loci control syllable sequences of ultrasonic courtship vocalizations in inbred mice

“…The F1 hybrid of B6 and 129 is suggested as an ideal genetic background for the study of gene knockout mice, because the effects of homozygous recessive mutations accumulate in the two inbred mice strains [19]. However, the current study suggests that F1 mice should be used carefully in USV analysis, because dominant mutations in B6 mice can produce a short-rich USV phenotype in the F1 genetic background (Figure 1).…”