Abstract
Germline polymorphisms in model organisms and humans influence susceptibility to complex trait diseases such as inflammation and cancer1,2,3,4. Mice of the Mus spretus species are resistant to tumour development, and crosses between M. spretus and susceptible Mus musculus strains have been used to map locations of genetic variants that contribute to skin cancer susceptibility4,5,6. We have integrated germline polymorphisms with gene expression in normal skin from a M. musculus × M. spretus backcross to generate a network view of the gene expression architecture of mouse skin. Here we demonstrate how this approach identifies expression motifs that contribute to tissue organization and biological functions related to inflammation, haematopoiesis, cell cycle control and tumour susceptibility. Motifs associated with inflammation, epidermal barrier function and proliferation are differentially regulated in backcross mice susceptible or resistant to tumour development. The intestinal stem cell marker Lgr5 is identified as a candidate master regulator of the hair follicle, and the vitamin D receptor (Vdr) is linked to coordinated control of epidermal barrier function, inflammation and tumour susceptibility.
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Acknowledgements
We are grateful to R. Del Rosario for technical assistance with mouse breeding. We thank G. Hirst, R. Akhurst and H. Quigley for their comments. This work was supported by the National Cancer Institute. A.B. acknowledges support from the Barbara Bass Bakar Chair of Cancer Genetics. M.D.T. was supported in part by a Sandler Foundation postdoctoral research fellowship. J.P.-L. is an investigator of the ‘Programa Ramón y Cajal’ from the Spanish ‘Ministerio de Educación y Ciencia’ partially supported by the European Community; his research is partially funded by the ‘Fondo de Investigaciones Sanitarias’ and Junta de Castilla y León.
Author Contributions The study was conceived and supervised by A.B. The software was written and the bioinformatics analysis was carried out by D.A.Q. H.N. carried out the primary tumour induction experiments, and M.D.T. isolated the DNA and RNA and carried out the gene expression microarray analysis. D.G.G. provided the genotyping data, J.-H.M. provided statistical support, and F.G.P. performed Taqman validation and DNA sequencing. J.P.-L. carried out the separate backcross for analysis of blood parameters, and measured all blood phenotypes. The paper was written by D.A.Q. and A.B., with important contributions from the other authors.
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Quigley, D., To, M., Pérez-Losada, J. et al. Genetic architecture of mouse skin inflammation and tumour susceptibility. Nature 458, 505–508 (2009). https://doi.org/10.1038/nature07683
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DOI: https://doi.org/10.1038/nature07683
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