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Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation

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Abstract

Mandible shape in the mouse is a complex trait that is influenced by many genetic factors. However, little is known about the action of single genes on adult mandible shape so far, since most developmentally relevant genes are already required during embryogenesis, i.e., knockouts lead to embryonic death or severe deformations, before the mandible is fully formed. We employ here a geometric morphometric approach to identify subtle phenotypic differences caused by dosage effects of candidate genes. We use mouse strains with specific gene modifications (knockouts and knockins) to compare heterozygous animals with controls from the same stock, which is expected to be equivalent to a change of gene expression of the respective locus. Such differences in expression level are also likely to occur as part of the natural variation. We focus on Bmp pathway genes (Bmp4, its antagonist Noggin, and combinations of Bmp5-7 genotypes), but include also two other developmental control genes suspected to affect mandible development in some way (Egfr and Irf6). In addition, we study the effects of Hoxd13, as well as an extracellular matrix constituent (Col2a1). We find that subtle but significant shape differences are caused by differences in gene dosage of several of these genes. The changes seen for Bmp4 and Noggin are partially compatible with the action of these genes known from birds and fish. We find significant shape changes also for Hoxd13, although this gene has so far only been implicated in skeletal patterning processes of the limbs. Comparing the effect sizes of gene dosage changes to the variation found in natural populations of mice as well as quantitative trait loci (QTL) effects on mandible shape, we find that the effect sizes caused by gene dosage changes are at the lower end of the spectrum of natural variation, but larger than the average additive effects found in QTL studies. We conclude that studying gene dosage effects have the potential to provide new insights into aspects of craniofacial development, variation, and evolution.

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Acknowledgments

The authors are indebted to Christine Pfeifle and Heike Harre for their help with mouse breeding. The work was funded by institutional resources of the Max-Planck Society to DT. Financial support to BCS (#DE13513) and YAK (#1F31DE022696-01) came from the NIH National Institute of Dental and Craniofacial Research. Financial support to CB came from the Israel Science Foundation (grant no. 1391/11). LFP is a member of the International Max Planck Research School (IMPRS) for Evolutionary Biology.

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Authors and Affiliations

  1. Max-Planck-Institut für Evolutionsbiologie, August-Thienemann-str. 2, 24306, Plön, Germany

    Louis Boell, Luisa F. Pallares & Diethard Tautz

  2. Zlotowski Center for Neuroscience, Department of Physiology and Cell Biology, Faculty of Health Science, Laboratory for Developmental and Behavioural Neurogenetics, Ben-Gurion University of the Negev, Beersheba, Israel

    Claude Brodski & Orna Novikov

  3. Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA

    YiPing Chen

  4. Department of Neurobiology and Anatomy and Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, USA

    Jan L. Christian

  5. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA

    Youssef A. Kousa

  6. Max-Planck-Institut für molekulare Genetik, Ihnestraße 63-73, 14195, Berlin, Germany

    Pia Kuss

  7. Department of Integrative Biosciences, Oregon Health and Science University, Portland, OR, USA

    Sylvia Nelsen

  8. Departments of Microbiology and Molecular Genetics, and Pediatrics and Human Development, Michigan State University, East Lansing, MI, USA

    Brian C. Schutte

  9. Department of Operative Dentistry and Endodontics, College of Stomatology, The Fourth Military University, Xi’an, Shaanxi Province, China

    Ying Wang

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  1. Louis Boell
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  9. Orna Novikov
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  11. Ying Wang
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  12. Diethard Tautz
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Correspondence to Diethard Tautz.

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Communicated by A. Kispert

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Boell, L., Pallares, L.F., Brodski, C. et al. Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation. Dev Genes Evol 223, 279–287 (2013). https://doi.org/10.1007/s00427-013-0443-y

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