Genetic diversity and striatal gene networks: focus on the heterogeneous stock-collaborative cross (HS-CC) mouse

Abstract

BackgroundThe current study focused on the extent genetic diversity within a species (Mus musculus) affects gene co-expression network structure. To examine this issue, we have created a new mouse resource, a heterogeneous stock (HS) formed from the same eight inbred strains that have been used to create the collaborative cross (CC). The eight inbred strains capture > 90% of the genetic diversity available within the species. For contrast with the HS-CC, a C57BL/6J (B6) × DBA/2J (D2) F2 intercross and the HS4, derived from crossing the B6, D2, BALB/cJ and LP/J strains, were used. Brain (striatum) gene expression data were obtained using the Illumina Mouse WG 6.1 array, and the data sets were interrogated using a weighted gene co-expression network analysis (WGCNA).ResultsGenes reliably detected as expressed were similar in all three data sets as was the variability of expression. As measured by the WGCNA, the modular structure of the transcriptome networks was also preserved both on the basis of module assignment and from the perspective of the topological overlap maps. Details of the HS-CC gene modules are provided; essentially identical results were obtained for the HS4 and F2 modules. Gene ontology annotation of the modules revealed a significant overrepresentation in some modules for neuronal processes, e.g., central nervous system development. Integration with known protein-protein interactions data indicated significant enrichment among co-expressed genes. We also noted significant overlap with markers of central nervous system cell types (neurons, oligodendrocytes and astrocytes). Using the Allen Brain Atlas, we found evidence of spatial co-localization within the striatum for several modules. Finally, for some modules it was possible to detect an enrichment of transcription binding sites. The binding site for Wt1, which is associated with neurodegeneration, was the most significantly overrepresented.ConclusionsDespite the marked differences in genetic diversity, the transcriptome structure was remarkably similar for the F2, HS4 and HS-CC. These data suggest that it should be possible to integrate network data from simple and complex crosses. A careful examination of the HS-CC transcriptome revealed the expected structure for striatal gene expression. Importantly, we demonstrate the integration of anatomical and network expression data.

Ten Years of the Collaborative Cross

“…An analysis of a commercial outbred stock, presented in a G3 article by W. Zhang et al, underscores the lack of genetic diversity in current mouse stocks that motivated the creation of the CC and DO populations (2012). Data presented in these articles confirm and extend the power of a previous heterogeneous stock also developed from the CC founders (Iancu et al 2010).…”

Association of novelty-related behaviors and intravenous cocaine self-administration in Diversity Outbred mice

“…While these resources have enabled substantial progress in the understanding of mechanisms underlying the effects of addictive drugs, each has some limitations in power, precision, genetic diversity, and genetic architecture. The Collaborative Cross inbred strains (CC), DO mouse population, and related populations (Ghazalpour et al 2012; Iancu et al 2010) complement these resources with a wealth of allelic variation, high mapping precision and a greater range of behavioral diversity (reviewed in Chesler 2014). Allelic variants can be identified using a QTL mapping approach in combination with functional genomic data resources (Recla et al 2014).…”

Neuropeptide Y response to alcohol is altered in nucleus accumbens of mice selectively bred for drinking to intoxication

“…Central administration of NPY or a selective NPY Y1 receptor agonist reduces intake and BEC in the DID test in B6 mice [15], and a similar effect has been seen with NPY Y1 receptor activation in the bed nucleus of the stria terminalis (BNST) [22]. In the HDID mice, gene network connectivity analysis of striatal tissue from naïve mice of both selection replicates and unselected heterogeneous stock (HS) mice found selection-dependent alteration of connectivity of the gene encoding the NPY Y2 receptor [20]. A microarray study measuring NPY mRNA in naïve HDID- 1 and HS mice showed greater Npy gene expression in the NAc, CeA, and BNST of HDID-1 mice than HS mice [23].…”

“…However, continuous access preference drinking may only result in limited experience of intoxicating BECs and might not always reflect consumption that is driven by the pharmacological effects of ethanol [19]. Continuous access preference drinking and limited access DID are also believed to be genetically distinct traits [20][21]. Therefore, investigating the neurobiological factors relevant to DID binge-like drinking is useful for fully understanding drinking to intoxication.…”