title: Genetic architecture of mouse skin inflammation and tumour susceptibility.
abstract: Germline polymorphisms in model organisms and humans influence susceptibility to complex trait diseases such as inflammation and cancer. 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. We have integrated germline polymorphisms with gene expression in normal skin from a M. musculus x 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.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94115, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Quigley
authors.forename: Minh D
authors.initials: MD
authors.lastname: To
authors.forename: Jesús
authors.initials: J
authors.lastname: Pérez-Losada
authors.forename: Facundo G
authors.initials: FG
authors.lastname: Pelorosso
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nagase
authors.forename: David G
authors.initials: DG
authors.lastname: Ginzinger
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D003433:Crosses, Genetic; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018859:Hair Follicle / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D040641:Quantitative Trait Loci; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: C493597:Lgr5 protein, mouse; D018167:Receptors, Calcitriol; D043562:Receptors, G-Protein-Coupled