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

Abstract

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 (1–183 Mb) of genetic polymorphisms, and in 123 genetically heterogeneous rats of an (GK × BN)F2 offspring. Within each congenic we identified 73–1351 differentially expressed genes (DEGs), only 7.7% of which mapped within the congenic blocks, and which may be regulated in cis. The remainder localized outside the blocks, and therefore must be regulated in trans. Most trans-regulated genes exhibited approximately twofold expression changes, consistent with monoallelic expression. Altered biological pathways were replicated between congenic strains sharing blocks of genetic polymorphisms, but polymorphisms at different loci also had redundant effects on transcription of common distant genes and pathways. We mapped 2735 expression quantitative trait loci (eQTL) in the F2 cross, including 26% predominantly cis-regulated genes, which validated DEGs in congenic strains. A hotspot of >300 eQTL in a 10 cM region of chromosome 1 was enriched in DEGs in a congenic strain. However, many DEGs among GK, BN and congenic strains did not replicate as eQTL 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 monoallelic expression on gene transcription.

Genetics of trans-regulatory variation in gene expression

“…In our cross between two yeast strains, we identified over one hundred hotspot regions, and found evidence for additional, weaker hotspots. Studies in many multicellular organisms, including plants ( Cubillos et al, 2012 ; Fu et al, 2009 ; West et al, 2007 ; Zhang et al, 2011 ), nematodes (Li et al, 2006; Rockman et al, 2010 ), mice ( Hasin-Brumshtein et al, 2016 ; Kelly et al, 2012 ; Orozco et al, 2012 ) and rats ( Heinig et al, 2010 ; Hubner et al, 2005 ; Kaisaki et al, 2016 ) have also observed trans -eQTL hotspots, showing that this phenomenon is not restricted to yeast. Compared to our yeast cross, human populations harbor orders of magnitudes more variants, and the human genome has many more genes and more extensive and complex regulatory regions that offer a large target space for regulatory variation.…”

Genetic associations of the vitamin D and antiviral pathways with natural resistance to HIV-1 infection are influenced by interpopulation variability

“…Allelic heterogeneity, in which different mutations originated as a result of natural selection processes, genetic drift, or genetic migration at the same locus cause a similar phenotype, could be the phenomenon behind our results, as previously reported for other diseases (Chavez-Saldana et al, 2010). Moreover, the gene expression signature of specific phenotypes is influenced not only by the genotype but also by the architecture of the genome, epistasis and genome-ambient interactions (Kaisaki et al, 2016).…”

Rat Models of Metabolic Syndrome

“…Glucose intolerance and Type 2 diabetes in the GK rat have been extensively studied, and further studies revealed the GK strain also shows increased basal blood pressure compared to Wistar controls and salt sensitivity [63]. Several genetic loci have been identified that regulate not only the GK phenotypes but also its transcriptome and metabolome [64,65]. Furthermore, the specific genetic contributions evolve over the lifetime of the animal and the disease progression [66,67].…”