Abstract
Rat is a major model organism in toxicogenomics and pharmacogenomics. Hepatic mRNA profiles after treatment with xenobiotic chemicals are used to predict and understand drug toxicity and mechanisms. Surprisingly, neither inter- and intra-strain variability of mRNA abundances in control rats nor the heritability of rat mRNA abundances yet been established. We address these issues by studying five populations: the popular Sprague-Dawley strain, sub-strains of Long-Evans and Wistar rats, and two lines derived from crosses between the Long-Evans and Wistar sub-strains. Using three independent techniques – variance analysis, linear modelling, and unsupervised pattern recognition – we characterize extensive intra- and inter-strain variability in mRNA levels. We find that both sources of variability are non-random and are enriched for specific functional groups. Specific transcription-factor binding-sites are enriched in their promoter regions and these genes occur in “islands” scattered throughout the rat genome. Using the two lines generated by crossbreeding we tested heritability of hepatic mRNA levels: the majority of rat genes appear to exhibit directional genetics, with only a few interacting loci. Finally, a comparison of inter-strain heterogeneity between mouse and rat orthologs shows more heterogeneity in rats than mice; thus rat and mouse heterogeneity are uncorrelated. Our results establish that control hepatic mRNA levels are relatively homogeneous within rat strains but highly variable between strains. This variability may be related to increased activity of specific transcription-factors and has clear functional consequences. Future studies may take advantage of this phenomenon by surveying panels of rat strains.
Highlights
The brown Norway rat, Rattus norvegicus, is a major model organism for pharmacogenomic and toxicogenomic research and is widely used to assess the potential human toxicities of drugs [1,2,3]
We looked at genes stimulated by TCDD in mouse liver [32] to see if there was any cross-species conservation and, again, found no correlation (Figure 4E)
In mouse, we found that genes whose mRNA levels are influenced by aryl hydrocarbon receptor (Ahr) status alone as well as genes that respond to AHR activation by dioxin are widely dispersed across the genome with only modest clustering into ‘‘hotspots’’ [33]
Summary
The brown Norway rat, Rattus norvegicus, is a major model organism for pharmacogenomic and toxicogenomic research and is widely used to assess the potential human toxicities of drugs [1,2,3]. The recent sequencing of the rat genome has increased the amount of mechanistic work done in this model [5], and has underpinned additional pharmacogenomic and toxicogenomic studies [6,7]. When dealing with a model organism, it is necessary to consider the variability between members of the population as well as among different subpopulations of the same species. These features are captured in analyses of intra- and inter-strain variability amongst presumed genetically identical members of the population
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