Heritability, correlations and in silico mapping of locomotor behavior and neurochemistry in inbred strains of mice

Abstract

The midbrain dopamine system mediates normal and pathologic behaviors related to motor activity, attention, motivation/reward and cognition. These are complex, quantitative traits whose variation among individuals is modulated by genetic, epigenetic and environmental factors. Conventional genetic methods have identified several genes important to this system, but the majority of factors contributing to the variation remain unknown. To understand these genetic and environmental factors, we initiated a study measuring 21 behavioral and neurochemical traits in 15 common inbred mouse strains. We report trait data, heritabilities and genetic and non-genetic correlations between phenotypes. In general, the behavioral traits were more heritable than neurochemical traits, and both genetic and non-genetic correlations within these trait sets were high. Surprisingly, there were few significant correlations between the behavioral and the individual neurochemical traits. However, striatal serotonin and one measure of dopamine turnover (DOPAC/DA) were highly correlated with most behavioral measures. The variable accounting for the most variation in behavior was mouse strain and not a specific neurochemical measure, suggesting that additional genetic factors remain to be determined to account for these behavioral differences. We also report the prospective use of the in silico method of quantitative trait loci (QTL) analysis and demonstrate difficulties in the use of this method, which failed to detect significant QTLs for the majority of these traits. These data serve as a framework for further studies of correlations between different midbrain dopamine traits and as a guide for experimental cross designs to identify QTLs and genes that contribute to these traits.

The influence of visual ability on learning and memory performance in 13 strains of mice

“…Quantitative trait loci (QTL) methods have been employed in an attempt to map genes underlying polygenic traits such as locomotor behavior (Mhyre et al 2005), anxiety (Henderson et al 2004), contextual fear conditioning (Radcliffe et al 2000), and spatial learning in the Morris water maze (Owen et al 1997;Leil et al 2002;Steinberger et al 2003). QTL analysis involves studying phenotypic traits in multiple strains of mice to determine the locus of the genes regulating these traits (Henderson et al 2004;Mhyre et al 2005).…”

“…Strain differences have been observed in brain weight and size (Wahlsten et al 2006); hippocampal morphology (Guillot et al 1994;Abusaad et al 1999;Peirce et al 2003); corpus callosum anatomy (Wahlsten et al 2003); cerebellar foliation patterns (Wahlsten and Andison 1991); monoamine neurochemistry (Mhyre et al 2005); noradrenaline, choline, and GABA uptake (Schoemaker et al 1982); hippocampal (Nguyen et al 2000) and amygdalar long-term potentiation (LTP) (Schimanski and Nguyen 2005); and gene expression patterns in multiple brain regions (Fernandes et al 2004;Nadler et al 2006).…”

Prospects for Association Mapping in Classical Inbred Mouse Strains

“…Additionally, the classical strains have a complex history that includes several forms of nonrandom mating: admixture between divergent natural populations, inbreeding, and other biases (Silver 1995;Beck et al 2000;Wade and Daly 2005). This history has led to unequal relatedness among the strains, a phenomenon with the potential to produce correlations between genotype and phenotype in the absence of QTL (Lander and Schork 1994;Ewens and Spielman 1995;Pritchard and Rosenberg 1999;Risch 2000;Cervino et al 2005;Mhyre et al 2005). The history of the strains also affects allele frequency spectra, patterns of linkage disequilibrium, and the distribution of haplotypes across the genome.…”

“…Although the strain sets examined in empirical studies might vary on the basis of the phenotype of interest, we reasoned that the availability of genotypic and phenotypic information for this strain collection makes it a likely focus for association mapping studies. We did not consider wildderived strains because their divergent evolutionary histories have strong potential to generate spurious associations between genotype and phenotype (Mhyre et al 2005).Power simulations: Phenotypes for individual strains were created from SNP genotypes. To simulate an additive QTL mapping to a particular genomic region, one SNP was designated as the causal locus.…”

Systems genetics of hepatocellular damage in vivo and in vitro: identification of a critical network on chromosome 11 in mouse

“…Within-strain and between-strain variances were calculated with anal- ysis of variance (36). Heritability (h 2 ) was estimated with the intraclass correlation coefficient (27).…”