Recently, it has been shown that genetic variation that perturbs the regulation of gene expression is widespread in eukaryotic genomes. Regulatory variation (RV) is expected to be an important driver of phenotypic differences, evolutionary change, and susceptibility to complex genetic diseases. Because trans-acting regulators of gene expression control mRNA levels of multiple genes simultaneously, we hypothesise that RV that affects these components will have a shared-influence upon the expression levels of multiple genes. Since genes are regulated in trans by combinations of basal and tissue specific factors, we further hypothesise that RV in these components may have different effects in each tissue. We used microarrays to identify 755 genes that were affected by RV in at least one of the brain, kidney and liver of two inbred mouse strains, C57BL/6J and DBA/2J. Just 2% were affected in all three tissues, suggesting that the influence of RV is predominantly tissue specific. To study shared-RV, we measured the expression levels of these 755 genes in the same 3 tissues from a panel of recombinant inbred mice, and identified groups of correlated genes that are putatively under the influence of shared trans-acting RV. Using methods that we developed for studying the effects of RV in multiple tissues, we identified 212 genes that are correlated in all three tissues, which include 10 groups of at least 3 genes. We developed a novel method called coherency analysis to show that RV consistently affected the expression levels of these groups of genes in different genetic backgrounds. Strikingly, the relative up- or down-regulation of genes in each group was markedly different in the three tissues of the same mouse, suggesting that the influence of RV itself is not tissue specific as previously expected, but that RV can influence genes with differing outcomes in each tissue. These observations are compatible with RV affecting combinations of basal and tissue specific regulatory factors. This is the first cross-tissue investigation into the influence of shared-RV in multiple tissues, which has important implications in humans, where access to the phenotypically relevant tissue may be necessarily limited.
| Identifer | oai:union.ndltd.org:ADTP/225855 |
| Date | January 2009 |
| Creators | Cowley, Mark, Biotechnology & Biomolecular Sciences, Faculty of Science, UNSW |
| Publisher | Awarded by:University of New South Wales. |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Cowley Mark., http://unsworks.unsw.edu.au/copyright |
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