Phenotypic instability between the near isogenic substrains BALB/cJ and BALB/cByJ

Abstract

Closely related substrains of inbred mice often show phenotypic difzferences that are presumed to be caused by recent mutations. The substrains BALB/cJ and BALB/cByJ, which were separated in 1935, have been reported to show numerous highly significant behavioral and morphological differences. In an effort to identify some of the causal mutations, we phenotyped BALB/cJ and BALB/cByJ mice as well as their F1, F2, and N2 progeny for behavioral and morphological phenotypes. We also generated whole genome sequence data for both inbred strains (∼3.5× coverage) with the intention of identifying polymorphic markers to be used for linkage analysis. We observed significant differences in body weight, the weight of the heart, liver, spleen and brain, and corpus callosum length between the two substrains. We also observed that BALB/cJ animals showed greater anxiety-like behavior in the open field test, less depression-like behavior in the tail suspension test, and reduced aggression compared to BALB/cByJ mice. Some but not all of these physiological and behavioral results were inconsistent with prior publications. These inconsistencies led us to suspect that the differences were due to, or modified by, non-genetic factors. Thus, we did not perform linkage analysis. We provide a comprehensive summary of the prior literature about phenotypic differences between these substrains as well as our current findings. We conclude that many differences between these strains are unstable and therefore ill-suited to linkage analysis; the source of this instability is unclear. We discuss the broader implications of these observations for the design of future studies.

Experiments done in Black-6 mice: what does it mean?

“…The phenotypic differences between the genetically close sub-strains of the C57BL/6 mice, coupled with the effect of vendor highlight the possible problems associated with choosing the background for genetically modified mice, interpretation of the results and reproducibility of the findings. Obviously, these cautions are not limited only to the C57BL/6 mice [91][92][93] . Moreover, further confounds can be caused by the local breeding schemes at the research institutions 94 .…”

Antidepressant-like effects of buprenorphine in rats are strain dependent

“…Such shifts in behavioral phenotype in rodents are not ideal but neither is it uncommon. Indeed a recent study conducted in the near isogeneic substrains of BALB/cJ and BALB/cByJ mice reported greater levels of aggression, depressive-like behavior in the tail suspension test and reduced anxiety-like behavior in the open field of BALB/cByJ mice [48]. Other potential causal factors that have been attributed to such shifts in behavioral phenotype include, 1) incomplete fixation of a genetic factor at specific loci, 2) impact of environmental stressors/enrichment and epigenetic variance of genetic factors, 3) inter-laboratory and inter-experimental differences.…”

De novo germline mutation in the Dual Specificity Phosphatase 10 gene accelerates autoimmune diabetes in Non-Obese Diabetic (NOD) mice

“…Genetic drift is one major factor explaining phenotypic differences within inbred strains; data has been reported in C57BL/6, C3H/HeJ, BALB/c and 129/sV mice (9)(10)(11)(12)(13). At generation 7 we sequenced the whole genome of four individuals of each subline to search for specific and apparently fixed genetic variation that might contribute to the phenotypic differences in T1D incidence between the NOD/Nck H and NOD/Nck L sublines.…”