Use of repeated measures to interpret genetic and environmental correlations in animal research.

A method for partitioning environmental correlations into two distinct sources of covariation--lifetime rearing effects and idiosyncratic stimulus events occurring during testing ("noise")--is presented. The method, which is based on structural equation modeling of repeated tests, is demonstrated using correlations obtained from pairs of sessions in an Open Field Test and in a Light-Dark Test. Heritabilities of most behaviors are low, but genetic correlations between- and within-test sessions are high and thus substantively influence phenotypic correlations, including test-retest reliability. Testing "noise" is usually the primary source of environmental covariance among pairs of measures, although some instances of rearing environment being the sole source of E correlations were observed. Effects of Session 1 testing and/or the additional experience between S1 and S2 test sessions produce some significant differences between S1 and S2 within-session correlations, but these are usually not large. Although varying in size, the genetic, the rearing environment and the test environment correlations between a pair of variables were always consistent in sign. The analysis demonstrates the value of incorporating some of the contemporary research and analytic strategies used in the human individual differences field into animal studies.

Multivariate analysis of quantitative trait loci influencing variation in anxiety-related behavior in laboratory mice.

The number and mode of action of quantitative trait loci (QTL) that contribute to behavioral variation in rodents is still largely unknown. On theoretical grounds, multivariate techniques are expected to yield new insights into this problem, but there are only a few examples of its application in practice. Here we explore the power of multivariate approaches to uncover the genetic architecture of 23 anxiety-related phenotypes in 1636 F2 laboratory mice. We detected QTL with a genome-wide significance threshold of P < 0.05 on 14 chromosomes, of which 10 correspond to those identified by univariate analysis. Novel QTL were found on Chromosomes 3, 9, 13, and 17. Thus, multivariate analyses increased the yield of QTL exceeding a genome-wide significance threshold by 40%. On the basis of these results and by the application of a QTL estimator, we show that the mean number of QTL influencing anxiety-related behavior in mice is 6, with a 95% upper limit of 14.

Little epistasis for anxiety-related measures in the DeFries strains of laboratory mice.

Recent advances in methodologies for testing epistatic interactions, combined with several successes in demonstrating genetic interaction effects in animal and human genetics, have rekindled interest in the role of epistatic influences on complex traits. It has even been suggested that the unacknowledged presence of epistasis vitiates the genetic dissection of human and animal behavior. Here we report a genome-wide interaction analysis of 1636 F2 mice to show that epistasis is of minimal importance in an animal model of anxiety. By using a sufficiently large sample of F2 animals, we provide evidence that interaction effects between any two loci contribute less than 5% to the total phenotypic variance in multiple tests of anxiety. We conclude that interactions between loci do not necessarily vitiate the genetic analysis of behavior in at least one animal model of anxiety.

QTL analysis of multiple behavioral measures of anxiety in mice.

In a test battery consisting of an open-field arena, a light-dark box, a mirror-chamber box, an elevated plus maze, and an elevated square maze, 1,671 mice were tested, generating over 100 putative measures of anxiety in rodents. Quantitative trait loci (QTL) analysis was carried out on all measures, plus composite measures and phenotypic factor scores. Significant LOD scores were found for QTL on 17 chromosomes, with large and consistent QTL behavioral effects on chromosomes 1, 4, 7, 8, 14, 15, l8, and X. QTL on chromosomes 4 and 8 largely influence locomotor activity in both home cages and novel environments, whereas QTL on chromosomes 1, 15, and 18 influence anxiety-related behaviors. Five genetically separable, cross-test dimensions of anxiety could be identified: (i) the suppression of locomotor activity in low to moderately anxiogenic regions of the tests; (ii) a shift toward proportionally less time and activity spent in high-anxiogenic test areas; (iii) the suppression of rearing behavior; (iv) increased latency to enter novel areas; (v) increased autonomic responses, as assessed by defecation and urination. Patterns of QTL influence on cross-test composite scores were distinctive. For example, the QTL on chromosome 1 strongly influenced safe-area locomotor activity (LOD = 35) and autonomic responses (LOD = 16), whereas the QTL on chromosome 15 influenced the proportion of activity in high-anxiogenic areas (LOD = 16), latency to enter novel areas (LOD = 36) and rearing behavior (LOD = 57). Phenotypic factor analysis identified factors heavily loaded on single tests, rather than cross-test factors. The use of factor analysis or within-test principal components for data reduction before genetic analysis was less satisfactory than using genetic dissection methods on the original measures and logically derived composites.