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      Variation of BMP3 Contributes to Dog Breed Skull Diversity

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          Abstract

          Since the beginnings of domestication, the craniofacial architecture of the domestic dog has morphed and radiated to human whims. By beginning to define the genetic underpinnings of breed skull shapes, we can elucidate mechanisms of morphological diversification while presenting a framework for understanding human cephalic disorders. Using intrabreed association mapping with museum specimen measurements, we show that skull shape is regulated by at least five quantitative trait loci (QTLs). Our detailed analysis using whole-genome sequencing uncovers a missense mutation in BMP3. Validation studies in zebrafish show that Bmp3 function in cranial development is ancient. Our study reveals the causal variant for a canine QTL contributing to a major morphologic trait.

          Author Summary

          As a result of selective breeding practices, modern dogs display a multitude of head shapes. Breeds such as the Pug and Bulldog popularize one of these morphologies, termed “brachycephaly.” A short, upward-pointing snout, a massive and rounded head, and an underbite typify brachycephalic breeds. Here, we have coupled the phenotypes collected from museum skulls with the genotypes collected from dogs and identified five regions of the dog genome that are associated with canine brachycephaly. Fine mapping at one of these regions revealed a causal mutation in the gene BMP3. Bmp3's role in regulating cranial development is evolutionarily ancient, as zebrafish require its function to generate a normal craniofacial morphology. Our data begin to expose the genetic mechanisms unknowingly employed by breeders to create and diversify the cranial shape of dogs.

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          Most cited references35

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          A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase.

          We present a statistical model for patterns of genetic variation in samples of unrelated individuals from natural populations. This model is based on the idea that, over short regions, haplotypes in a population tend to cluster into groups of similar haplotypes. To capture the fact that, because of recombination, this clustering tends to be local in nature, our model allows cluster memberships to change continuously along the chromosome according to a hidden Markov model. This approach is flexible, allowing for both "block-like" patterns of linkage disequilibrium (LD) and gradual decline in LD with distance. The resulting model is also fast and, as a result, is practicable for large data sets (e.g., thousands of individuals typed at hundreds of thousands of markers). We illustrate the utility of the model by applying it to dense single-nucleotide-polymorphism genotype data for the tasks of imputing missing genotypes and estimating haplotypic phase. For imputing missing genotypes, methods based on this model are as accurate or more accurate than existing methods. For haplotype estimation, the point estimates are slightly less accurate than those from the best existing methods (e.g., for unrelated Centre d'Etude du Polymorphisme Humain individuals from the HapMap project, switch error was 0.055 for our method vs. 0.051 for PHASE) but require a small fraction of the computational cost. In addition, we demonstrate that the model accurately reflects uncertainty in its estimates, in that probabilities computed using the model are approximately well calibrated. The methods described in this article are implemented in a software package, fastPHASE, which is available from the Stephens Lab Web site.
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            The Tol2kit: a multisite gateway-based construction kit for Tol2 transposon transgenesis constructs.

            Transgenesis is an important tool for assessing gene function. In zebrafish, transgenesis has suffered from three problems: the labor of building complex expression constructs using conventional subcloning; low transgenesis efficiency, leading to mosaicism in transient transgenics and infrequent germline incorporation; and difficulty in identifying germline integrations unless using a fluorescent marker transgene. The Tol2kit system uses site-specific recombination-based cloning (multisite Gateway technology) to allow quick, modular assembly of [promoter]-[coding sequence]-[3' tag] constructs in a Tol2 transposon backbone. It includes a destination vector with a cmlc2:EGFP (enhanced green fluorescent protein) transgenesis marker and a variety of widely useful entry clones, including hsp70 and beta-actin promoters; cytoplasmic, nuclear, and membrane-localized fluorescent proteins; and internal ribosome entry sequence-driven EGFP cassettes for bicistronic expression. The Tol2kit greatly facilitates zebrafish transgenesis, simplifies the sharing of clones, and enables large-scale projects testing the functions of libraries of regulatory or coding sequences. Copyright 2007 Wiley-Liss, Inc.
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              A single IGF1 allele is a major determinant of small size in dogs.

              The domestic dog exhibits greater diversity in body size than any other terrestrial vertebrate. We used a strategy that exploits the breed structure of dogs to investigate the genetic basis of size. First, through a genome-wide scan, we identified a major quantitative trait locus (QTL) on chromosome 15 influencing size variation within a single breed. Second, we examined genetic variation in the 15-megabase interval surrounding the QTL in small and giant breeds and found marked evidence for a selective sweep spanning a single gene (IGF1), encoding insulin-like growth factor 1. A single IGF1 single-nucleotide polymorphism haplotype is common to all small breeds and nearly absent from giant breeds, suggesting that the same causal sequence variant is a major contributor to body size in all small dogs.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                August 2012
                August 2012
                2 August 2012
                : 8
                : 8
                : e1002849
                Affiliations
                [1 ]Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, United States of America
                [2 ]Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
                [3 ]Zebrafish Core, National Human Genome Research Institute, Bethesda, Maryland, United States of America
                [4 ]Department of Genetics, Stanford School of Medicine, Stanford, California, United States of America
                [5 ]Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, New York, United States of America
                [6 ]Department of Biology, University of Texas at Arlington, Arlington, Texas, United States of America
                [7 ]Department of Ecology and Evolutionary Biology, University of California Los Angeles, Los Angeles, California, United States of America
                [8 ]Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
                University of Bern, Switzerland
                Author notes

                Conceived and designed the experiments: JJ Schoenebeck, B Ciruna, HC Beale, B Decker, JW Fondon, RK Wayne, EA Ostrander. Performed the experiments: JJ Schoenebeck, SA Hutchinson, A Byers, B Carrington, DL Faden, M Rimbault. Analyzed the data: JJ Schoenebeck, SA Hutchinson, A Byers, M Rimbault, HC Beale, B Decker. Contributed reagents/materials/analysis tools: R Sood, JW Fondon, RK Wayne, AR Boyko, JM Kidd, CD Bustamante, B Ciruna, EA Ostrander. Wrote the paper: JJ Schoenebeck, HC Beale, EA Ostrander. Genome-wide sequence analysis: HC Beale, B Decker. Provided edits: SA Hutchinson, A Byers, DL Faden, AR Boyko, JW Fondon, RK Wayne, B Ciruna.

                Article
                PGENETICS-D-12-00531
                10.1371/journal.pgen.1002849
                3410846
                22876193
                dc501ed8-db4c-46d7-8244-6d9b29ba4a3c
                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
                History
                : 28 February 2012
                : 6 June 2012
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Developmental Biology
                Morphogenesis
                Skeletal Development
                Genetics
                Genetic Mutation
                Mutation Types
                Animal Genetics
                Gene Function
                Genome-Wide Association Studies
                Genomics
                Genome Sequencing
                Model Organisms
                Animal Models
                Zebrafish

                Genetics
                Genetics

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