title: 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 oncis- andtrans-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 incisThe remainder localized outside the blocks, and therefore must be regulated intransMosttrans-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% predominantlycis-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.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kaisaki
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom.
authors.forename: Georg W
authors.initials: GW
authors.lastname: Otto
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom.
authors.forename: Karène
authors.initials: K
authors.lastname: Argoud
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Collins
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wallis
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilder
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom.
authors.forename: Anthony C Y
authors.initials: ACY
authors.lastname: Yau
authors.affiliation: Cordeliers Research Centre, Institut National de la Santé et de la Recherche Médicale Unités Mixtes de Recherche Scientifique 1138, Sorbonne Universities, University Pierre & Marie Curie, University Paris Descartes, Sorbonne Paris Cité, 75006, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hue
authors.affiliation: Cordeliers Research Centre, Institut National de la Santé et de la Recherche Médicale Unités Mixtes de Recherche Scientifique 1138, Sorbonne Universities, University Pierre & Marie Curie, University Paris Descartes, Sorbonne Paris Cité, 75006, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Calderari
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom.
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Bihoreau
authors.affiliation: Centre for Computational Biology, University of Birmingham, Edgbaston B15 2TT, United Kingdom.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.affiliation: University College London Genetics Institute, WC1E 6BT, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Mott
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN, United Kingdom dominique.gauguier@crc.jussieu.fr.|Cordeliers Research Centre, Institut National de la Santé et de la Recherche Médicale Unités Mixtes de Recherche Scientifique 1138, Sorbonne Universities, University Pierre & Marie Curie, University Paris Descartes, Sorbonne Paris Cité, 75006, France.
authors.forename: Dominique
authors.identifier: http://orcid.org/0000-0001-6156-9530
authors.initials: D
authors.lastname: Gauguier
keywords: Goto–Kakizaki; diabetes mellitus; eQTL; epistasis; quantitative trait locus