Transcriptome Profiling in Rat Inbred Strains and Experimental Cross RevealsDiscrepant Genetic Architecture of Genome-Wide Gene Expression

To test the impact of genetic heterogeneity on cis- and trans-mediated mechanisms of gene expression regulation, we profiled the transcriptome of adipose tissue in 20 inbred congenic strains derived from diabetic Goto-Kakizaki (GK) rats and Brown-Norway (BN) controls, which contain well-defined blocks (1Mb-183Mb) of genetic polymorphisms, and in 123 genetically heterogeneous rats of an (GKxBN)F2 offspring. Within each congenic we identified 73 to 1,351 differentially expressed genes (DEG), only 7.7% of which mapped within the congenic blocks, and which may be regulated in cis. The remainder localised outside the blocks, and therefore must be regulated in trans. Most trans-regulated genes exhibited approximately two-fold expression changes, consistent with mono-allelic expression. Altered biological pathways were replicated between congenics sharing blocks of genetic polymorphisms, but polymorphisms at different loci also had redundant effects on transcription of common distant genes and pathways. We mapped 2,735 eQTLs in the F2 cross, including 26% predominantly cis-regulated genes which validated DEG in congenics. A hotspot of over 300 eQTLs in a 10cM region of chromosome 1 was enriched in DEG in a congenic strain. However, many DEG among congenics, GK and BN did not replicate as eQTLs in F2 hybrids, demonstrating distinct mechanisms of gene expression when alleles segregate in an outbred population or are fixed homozygous across the entire genome or in short genomic regions. Our analysis provides conceptual advances in our understanding of the complex architecture of genome expression and pathway regulation and suggests a prominent impact of epistasis and mono-allelic expression on gene transcription.

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