Consomic mouse strain selection based on effect size measurement, statistical significance testing and integrated behavioral z-scoring: focus on anxiety-related behavior and locomotion.

BACKGROUND: Selecting chromosome substitution strains (CSSs, also called consomic strains/lines) used in the search for quantitative trait loci (QTLs) consistently requires the identification of the respective phenotypic trait of interest and is simply based on a significant difference between a consomic and host strain. However, statistical significance as represented by P values does not necessarily predicate practical importance. We therefore propose a method that pays attention to both the statistical significance and the actual size of the observed effect. The present paper extends on this approach and describes in more detail the use of effect size measures (Cohen's d, partial eta squared - η p (2) ) together with the P value as statistical selection parameters for the chromosomal assignment of QTLs influencing anxiety-related behavior and locomotion in laboratory mice. RESULTS: The effect size measures were based on integrated behavioral z-scoring and were calculated in three experiments: (A) a complete consomic male mouse panel with A/J as the donor strain and C57BL/6J as the host strain. This panel, including host and donor strains, was analyzed in the modified Hole Board (mHB). The consomic line with chromosome 19 from A/J (CSS-19A) was selected since it showed increased anxiety-related behavior, but similar locomotion compared to its host. (B) Following experiment A, female CSS-19A mice were compared with their C57BL/6J counterparts; however no significant differences and effect sizes close to zero were found. (C) A different consomic mouse strain (CSS-19PWD), with chromosome 19 from PWD/PhJ transferred on the genetic background of C57BL/6J, was compared with its host strain. Here, in contrast with CSS-19A, there was a decreased overall anxiety in CSS-19PWD compared to C57BL/6J males, but not locomotion. CONCLUSIONS: This new method shows an improved way to identify CSSs for QTL analysis for anxiety-related behavior using a combination of statistical significance testing and effect sizes. In addition, an intercross between CSS-19A and CSS-19PWD may be of interest for future studies on the genetic background of anxiety-related behavior.

An improved procedure for integrated behavioral z-scoring illustrated with modified Hole Board behavior of male inbred laboratory mice.

BACKGROUND: Guilloux et al. introduced: integrated behavioral z-scoring, a method for behavioral phenotyping of mice. Using this method multiple ethological variables can be combined to show an overall description of a certain behavioral dimension or motivational system. However, a problem may occur when the control group used for the calculation has a standard deviation of zero or when no control group is present to act as a reference group. NEW METHOD: In order to solve these problems, an improved procedure is suggested: taking the pooled data as reference. For this purpose a behavioral study with male mice from three inbred strains was carried out. The integrated behavioral z-scoring methodology was applied, thereby taking five different reference group options. The outcome regarding statistical significance and practical importance was compared. RESULTS: Significant effects and effect sizes were influenced by the choice of the reference group. In some cases it was impossible to use a certain population and condition, because one or more behavioral variables in question had a standard deviation of zero. Based on the improved method, male mice from the three inbred strains differed regarding activity and anxiety. COMPARISON WITH EXISTING METHOD: Taking the method described by Guilloux et al. as basis, the present procedure improved the generalizability to all types of experimental designs in animal behavioral research. CONCLUSIONS: To solve the aforementioned problems and to avoid getting the diagnosis of data manipulation, the pooled data (combining the data from all experimental groups in a study) as reference option is recommended.

Cross-species genetics converge to TLL2 for mouse avoidance behavior and human bipolar disorder.

Interspecies genetic analysis of neurobehavioral traits is critical for identifying neurobiological mechanisms underlying psychiatric disorders, and for developing models for translational research. Recently, after screening a chromosome substitution strain panel in an automated home cage environment, chromosomes 15 and 19 were identified in female mice for carrying genetic loci that contribute to increased avoidance behavior (sheltering preference). Furthermore, we showed that the quantitative trait locus (QTL) for baseline avoidance behavior on chromosome 15 is homologous with a human linkage region for bipolar disorder (8q24). Similarly, we now performed comparative analysis on the QTL for avoidance behavior found on chromosome 19 and correspondingly revealed an overlap of the mouse interval and human homologous region 10q23-24, which has been previously linked to bipolar disorders. By means of a comparative genetic strategy within the human homologous region, we describe an association for TLL2 with bipolar disorder using the genome-wide association study (GWAS) data set generated by the Wellcome Trust Case Control Consortium (WTCCC). On the basis of genetic homology and mood stabilizer sensitivity, our data indicate the intriguing possibility that mouse home cage avoidance behavior may translate to a common biochemical mechanisms underlying bipolar disorder susceptibility. These findings pave new roads for the identification of the molecular mechanisms and novel treatment possibilities for this psychiatric disorder, as well as for the validity of translational research of associated psychiatric endophenotypes.