title: The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape.
abstract: Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice (Mus musculus) with loss of function in three members of the Sprouty family of growth factor negative regulators (Spry1,Spry2, orSpry4) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and thatSpry4loss is generally less severe than loss ofSpry1orSpry2While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice.
authors.affiliation: Alberta Children's Hospital Institute for Child and Maternal Health, University of Calgary, Alberta T2N 4N1, Canada.|The McCaig Bone and Joint Institute, University of Calgary, Alberta T2N 4Z6, Canada.|Department of Cell Biology and Anatomy, University of Calgary, Alberta T2N 4N1, Canada.
authors.forename: Christopher J
authors.identifier: 0000-0002-8883-9737
authors.initials: CJ
authors.lastname: Percival
authors.affiliation: Department of Orofacial Sciences, University of California, San Francisco, California 94143.|Program in Craniofacial Biology, University of California, San Francisco, California 94143.
authors.forename: Pauline
authors.identifier: 0000-0002-4355-7322
authors.initials: P
authors.lastname: Marangoni
authors.affiliation: Department of Orofacial Sciences, University of California, San Francisco, California 94143.|Program in Craniofacial Biology, University of California, San Francisco, California 94143.|Department of Preventive and Restorative Dental Sciences, University of California, San Francisco, California 94143.
authors.forename: Vagan
authors.initials: V
authors.lastname: Tapaltsyan
authors.affiliation: Department of Orofacial Sciences, University of California, San Francisco, California 94143 ophir.klein@ucsf.edu bhallgri@ucalgary.ca.|Program in Craniofacial Biology, University of California, San Francisco, California 94143.|Department of Pediatrics, University of California, San Francisco, California 94143.|Institute for Human Genetics, University of California, San Francisco, California 94143.
authors.forename: Ophir
authors.identifier: 0000-0002-6254-7082
authors.initials: O
authors.lastname: Klein
authors.affiliation: Alberta Children's Hospital Institute for Child and Maternal Health, University of Calgary, Alberta T2N 4N1, Canada ophir.klein@ucsf.edu bhallgri@ucalgary.ca.|The McCaig Bone and Joint Institute, University of Calgary, Alberta T2N 4Z6, Canada.|Department of Cell Biology and Anatomy, University of Calgary, Alberta T2N 4N1, Canada.
authors.forename: Benedikt
authors.identifier: 0000-0002-7192-9103
authors.initials: B
authors.lastname: Hallgrímsson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D000068617:Genetic Background; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C425468:Spry1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse
keywords: Sprouty; background effect; epistasis; inbred background; morphometrics; skull