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      Interfrontal Bone Among Inbred Strains of Mice and QTL Mapping

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          Abstract

          The interfrontal bone (IF) is a minor skeletal trait residing between the frontal bones. IF is considered a quasi-continuous trait. Genetic and environmental factors appear to play roles in its development. The mechanism(s) underlying IF bone development are poorly understood. We sought to survey inbred strains of mice for the prevalence of IF and to perform QTL mapping studies. Archived mouse skulls from a mouse phenome project (MPP) were available for this study. 27 inbred strains were investigated with 6–20 mice examined for each strain. Skulls were viewed dorsally and the IF measured using a zoom stereomicroscope equipped with a calibrated reticle. A two generation cross between C3H/HeJ and C57BL/6J mice was performed to generate a panel of 468 F2 mice. F2 mice were phenotyped for presence or absence of IF bone and among mice with the IF bone maximum widths and lengths were measured. F2 mice were genotyped for 573 SNP markers informative between the two strains and subjected to linkage map construction and interval QTL mapping. Results: Strain dependent differences in the prevalence of IF bones were observed. Overall, 77.8% or 21/27, of the inbred strains examined had IF bones. Six strains (C3H/HeJ, MOLF/EiJ, NZW/LacJ, SPRET/EiJ, SWR/J, and WSB/EiJ) lack IF bones. Among the strains with IF bones, the prevalence ranged from 100% for C57BL/6J, C57/LJ, CBA/J, and NZB/B1NJ and down to 5% for strains such as CAST/Ei. QTL mapping for IF bone length and widths identifies for each trait one strong QTL detected on chromosome 14 along with several other significant QTLs on chromosomes 3, 4, 7, and 11. Strain dependent differences in IF will facilitate investigation of genetic factors contributing to IF development. IF bone formation may be a model to understand intrasutural bone formation.

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          Most cited references32

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          Cleidocranial dysplasia: clinical and molecular genetics.

          S Mundlos (1999)
          Cleidocranial dysplasia (CCD) (MIM 119600) is an autosomal dominant skeletal dysplasia characterised by abnormal clavicles, patent sutures and fontanelles, supernumerary teeth, short stature, and a variety of other skeletal changes. The disease gene has been mapped to chromosome 6p21 within a region containing CBFA1, a member of the runt family of transcription factors. Mutations in the CBFA1 gene that presumably lead to synthesis of an inactive gene product were identified in patients with CCD. The function of CBFA1 during skeletal development was further elucidated by the generation of mutated mice in which the Cbfa1 gene locus was targeted. Loss of one Cbfa1 allele (+/-) leads to a phenotype very similar to human CCD, featuring hypoplasia of the clavicles and patent fontanelles. Loss of both alleles (-/-) leads to a complete absence of bone owing to a lack of osteoblast differentiation. These studies show that haploinsufficiency of CBFA1 causes the CCD phenotype. CBFA1 controls differentiation of precursor cells into osteoblasts and is thus essential for membranous as well as endochondral bone formation.
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            Mouse Phenome Database

            The Mouse Phenome Database (MPD; phenome.jax.org) was launched in 2001 as the data coordination center for the international Mouse Phenome Project. MPD integrates quantitative phenotype, gene expression and genotype data into a common annotated framework to facilitate query and analysis. MPD contains >3500 phenotype measurements or traits relevant to human health, including cancer, aging, cardiovascular disorders, obesity, infectious disease susceptibility, blood disorders, neurosensory disorders, drug addiction and toxicity. Since our 2012 NAR report, we have added >70 new data sets, including data from Collaborative Cross lines and Diversity Outbred mice. During this time we have completely revamped our homepage, improved search and navigational aspects of the MPD application, developed several web-enabled data analysis and visualization tools, annotated phenotype data to public ontologies, developed an ontology browser and released new single nucleotide polymorphism query functionality with much higher density coverage than before. Here, we summarize recent data acquisitions and describe our latest improvements.
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              A mouse phenome project.

              A community-wide effort to establish baseline phenotypic data on commonly used and genetically diverse inbred mouse strains and to provide the information through a publicly accessible database.
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                Author and article information

                Contributors
                Journal
                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                1664-8021
                02 April 2019
                2019
                : 10
                : 291
                Affiliations
                [1] 1Dental Research, School of Dentistry, The University of North Carolina at Chapel Hill , Chapel Hill, NC, United States
                [2] 2Department of Biostatistics, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, NC, United States
                [3] 3Department of Pediatric Dentistry, School of Dentistry, The University of North Carolina at Chapel Hill , Chapel Hill, NC, United States
                Author notes

                Edited by: Daniel Shriner, National Human Genome Research Institute (NHGRI), United States

                Reviewed by: Qing Lu, Michigan State University, United States; Joan Therese Richtsmeier, Pennsylvania State University, United States

                *Correspondence: Eric T. Everett, eric_everett@ 123456unc.edu

                This article was submitted to Applied Genetic Epidemiology, a section of the journal Frontiers in Genetics

                Article
                10.3389/fgene.2019.00291
                6454051
                31001328
                fae83e56-6309-403a-8a2e-b0e0e41acdab
                Copyright © 2019 Zimmerman, Yin, Zou and Everett.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 August 2018
                : 18 March 2019
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 36, Pages: 6, Words: 0
                Funding
                Funded by: National Institute of Dental and Craniofacial Research 10.13039/100000072
                Categories
                Genetics
                Original Research

                Genetics
                inbred mouse strains,interfrontal bone,wormian bone,qtl,quantitative trait,skeletal variant
                Genetics
                inbred mouse strains, interfrontal bone, wormian bone, qtl, quantitative trait, skeletal variant

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