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.
Highlights
The current study focused on the extent genetic diversity within a species (Mus musculus) affects gene co-expression network structure
The current study focuses on the conservation of brain gene co-expression networks from the perspective of how marked differences in genetic diversity within a species affect network structure
Detectable and variable genes are preserved across populations The initial comparison of gene expression in the three mouse populations (F2, HS4 and heterogeneous stock (HS)-collaborative cross (CC)) focused on what transcripts had a detectable expression
Summary
The 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 current study focuses on the conservation of brain gene co-expression networks from the perspective of how marked differences in genetic diversity within a species (here Mus musculus) affect 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) [8]; hereafter this resource is referred to as the HS-CC. From the SNP perspective, the HS-CC is ~6 times more diverse than the F2 intercross and ~4 times more diverse than the HS4; the actual differences in genetic diversity will be somewhat less because of genetic drift associated with breeding the HS populations for multiple generations
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