Lineage is an epigenetic modifier of QTL influencing behavioral coping with stress

Abstract

A genome-wide scan was carried out on a segregating F2 population of rats derived from reciprocal intercrosses between two inbred strains of rats, Fisher 344 (F344) and Wistar Kyoto (WKY) that differ significantly in their behavioral coping responses to stress measured by the defensive burying (DB) test. The DB test measures differences in coping strategies by assaying an animal's behavioral response to an immediate threat. We have previously identified three X-linked loci contributing to the phenotypic variance in behavioral coping. Here we report on six significant autosomal quantitative trait loci (QTL) related to different behaviors in the DB test:one for the number of shocks received, three for number of prod approaches, one for latency to bury, and one pleiotropic locus affecting both approach and latency. These QTL contributing to different aspects of coping behaviors show that the effect of genotype on phenotype is highly dependent on lineage. The WKY lineage was particularly influential, with five out of the six QTL affecting coping behavior only in rats of the WKY lineage, and one locus affecting only those in the F344 lineage. Thus, epigenetic factors, primarily of WKY origin, may significantly modulate the genetic contribution to variance in behavioral responses to stress in the DB test.

Figure 1

Genome scans of DB-specific traits showing locations where shocks (Fig. 1), approach (Fig. 2), latency (Fig. 3), and duration (Fig. 4) loci lie, each determined by analyzing (a) sex and grandmaternal lineage as additive covariates, (b) sex as an interactive covariate, (c) grandmaternal lineage as an interactive covariate, and (d) sex and grandmaternal lineage simultaneously interacting. X-axis contains representative chromosomal locations, Y-axis displays LOD score. Genome-wide permutation-derived thresholds of significance are shown by red line (significant: p < 0.05), blue line (suggestive: p < 0.63), with green line and green plots representing the interaction only portion of variance in the interaction models.

Figure 2

Please refer the figure caption of Figure1.

Figure 3

Please refer the figure caption of Figure1

Figure 4

Please refer the figure caption of Figure1

Figure 5

Allele-effect plots of F2 generation offspring stratified by sex and lineage showing the phenotypic effect of genotypes at (the marker most tightly linked to) each locus found to be significant in the initial genome scans and represented in Table II. (a) shocks, (b) approach, (c) latency. Genotypes are shown on the X-axis, log transformed phenotypes on the Y-axis, with means ± SEM displayed. One-Way ANOVA was used to detect phenotypic differences between F344 homozygotes (FF), heterozygotes (FW), and WKY homozygotes (WW), with the probability of finding a difference by chance reflected in the p-values. “F-females” denotes F2 females derived from the F344 grandmaternal lineage, “W-females” are F2 females derived from the WKY grandmaternal lineage, “F-males” are F2 males derived from F344 grandmaternal lineage, “W-males” are F2 males derived from WKY grandmaternal lineage. WKY lineage-specific effects are highlighted in pink, while F344 lineage-specific effects are highlighted in yellow.