title: Using regulatory and epistatic networks to extend the findings of a genome scan: identifying the gene drivers of pigmentation in merino sheep.
abstract: Extending genome wide association analysis by the inclusion of gene expression data may assist in the dissection of complex traits. We examined piebald, a pigmentation phenotype in both human and Merino sheep, by analysing multiple data types using a systems approach. First, a case control analysis of 49,034 ovine SNP was performed which confirmed a multigenic basis for the condition. We combined these results with gene expression data from five tissue types analysed with a skin-specific microarray. Promoter sequence analysis of differentially expressed genes allowed us to reverse-engineer a regulatory network. Likewise, by testing two-loci models derived from all pair-wise comparisons across piebald-associated SNP, we generated an epistatic network. At the intersection of both networks, we identified thirteen genes with insulin-like growth factor binding protein 7 (IGFBP7), platelet-derived growth factor alpha (PDGFRA) and the tetraspanin platelet activator CD9 at the kernel of the intersection. Further, we report a number of differentially expressed genes in regions containing highly associated SNP including ATRN, DOCK7, FGFR1OP, GLI3, SILV and TBX15. The application of network theory facilitated co-analysis of genetic variation with gene expression, recapitulated aspects of the known molecular biology of skin pigmentation and provided insights into the transcription regulation and epistatic interactions involved in piebald Merino sheep.
authors.affiliation: Livestock Industries, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Brisbane, Queensland, Australia.
authors.forename: Elsa
authors.initials: E
authors.lastname: García-Gámez
authors.forename: Antonio
authors.initials: A
authors.lastname: Reverter
authors.forename: Vicki
authors.initials: V
authors.lastname: Whan
authors.forename: Sean M
authors.initials: SM
authors.lastname: McWilliam
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Arranz
authors.forename: James
authors.initials: J
authors.lastname: Kijas
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics; D016678:Genome / Q000235:genetics*; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D010858:Pigmentation / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics; D012756:Sheep; D020825:T-Box Domain Proteins / Q000235:genetics; D060245:Tetraspanin 29
chemical_list: D015703:Antigens, CD; C554869:CD9 protein, human; D020690:GTPase-Activating Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D017468:Receptors, Fibroblast Growth Factor; D020825:T-Box Domain Proteins; D060245:Tetraspanin 29; C102529:insulin-like growth factor binding protein-related protein 1; C075278:platelet-derived growth factor A