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The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape.

G3 (Bethesda, Md.) | May 5, 2017

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, or Spry4) 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 that Spry4 loss is generally less severe than loss of Spry1 or Spry2 While 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.

Pubmed ID: 28280213 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Animals | Craniofacial Abnormalities | Epistasis, Genetic | Female | Gene Expression Regulation, Developmental | Genetic Background | Intracellular Signaling Peptides and Proteins | Male | Membrane Proteins | Mice | Mice, Inbred C57BL | Mutation | Phosphoproteins

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Voronoia

Voronoia is a program suite to analyse and visualize the atomic packing of protein structures. It is based on the Voronoi Cell method and can be used to estimate the quality of a protein structure, e.g. by comparing the packing density of buried atoms to a reference data set or by highlighting protein regions with large packing defects. Voronoia is also targeted to detect locations of putative internal water or binding sites for ligands. Accordingly, Voronoia is beneficial for a broad range of protein structure approaches. It is applicable as a standalone version coming with a user friendly GUI or, alternatively, as a Pymol Plugin. Finally, Voronoia is also available as an easy to use webtool to process user defined PDB-files or to asses precalculated packing files from DOPP, the regularly updated Dictionary of Packing in Proteins.

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FaceBase

A web portal that provides access to data, tools and materials that will aid in craniofacial research. Included is access to genomic and imaging based data sets from a variety of species, including zebrafish, human and mouse.

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National Institute of Dental and Craniofacial Research

The mission of the National Institute of Dental and Craniofacial Research (NIDCR) is to improve oral, dental and craniofacial health through research, research training, and the dissemination of health information. We accomplish our mission by: * Performing and supporting basic and clinical research; * Conducting and funding research training and career development programs to ensure an adequate number of talented, well-prepared and diverse investigators; * Coordinating and assisting relevant research and research-related activities among all sectors of the research community; * Promoting the timely transfer of knowledge gained from research and its implications for health to the public, health professionals, researchers, and policy-makers.

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Natural Sciences and Engineering Research Council of Canada

NSERC aims to make Canada a country of discoverers and innovators for the benefit of all Canadians. The agency supports university students in their advanced studies, promotes and supports discovery research, and fosters innovation by encouraging Canadian companies to participate and invest in postsecondary research projects. NSERC researchers are on the vanguard of science, building on Canada''s long tradition of scientific excellence.

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