1. Helen Diller Family Comprehensive Cancer Center,
2. Department of Surgery, University of California San Francisco, San Francisco, California 94115, USA
3. Departamento de Medicina, Facultad de Medicina, Universidad de Salamanca, Campus Miguel de Unamuno s/n, 37007 Salamanca, Spain
4. Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA
5. Advanced Research Institute for the Sciences and Humanities, Nihon University, Tokyo, Japan
6. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA

Correspondence to: Allan Balmain¹ Correspondence and requests for materials should be addressed to A.B. (Email: abalmain@cc.ucsf.edu).

Abstract

Germline polymorphisms in model organisms and humans influence susceptibility to complex trait diseases such as inflammation and cancer^{1, 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 susceptibility^{4, 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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