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

Louis Boell, Luisa F. Pallares, Claude Brodski, Yiping Chen, Jan L. Christian, Youssef A. Kousa, Pia Kuss, Sylvia Nelsen, Orna Novikov, Brian C. Schutte, Ying Wang, Diethard Tautz

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)279-287
Number of pages9
JournalDevelopment Genes and Evolution
Volume223
Issue number5
DOIs
StatePublished - Sep 2013

Fingerprint

Gene Dosage
Genetic Models
Mandible
Genes
Quantitative Trait Loci
Developmental Genes
Gene Knockout Techniques
Birds
Embryonic Development
Extracellular Matrix
Fishes
Extremities
Genotype
Gene Expression
Population

Keywords

  • Dosage effects
  • Mandible development
  • Morphometry
  • Mus musculus
  • Shape analysis

ASJC Scopus subject areas

  • Developmental Biology
  • Genetics

Cite this

Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation. / Boell, Louis; Pallares, Luisa F.; Brodski, Claude; Chen, Yiping; Christian, Jan L.; Kousa, Youssef A.; Kuss, Pia; Nelsen, Sylvia; Novikov, Orna; Schutte, Brian C.; Wang, Ying; Tautz, Diethard.

In: Development Genes and Evolution, Vol. 223, No. 5, 09.2013, p. 279-287.

Research output: Contribution to journalArticle

Boell, L, Pallares, LF, Brodski, C, Chen, Y, Christian, JL, Kousa, YA, Kuss, P, Nelsen, S, Novikov, O, Schutte, BC, Wang, Y & Tautz, D 2013, 'Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation', Development Genes and Evolution, vol. 223, no. 5, pp. 279-287. https://doi.org/10.1007/s00427-013-0443-y
Boell, Louis ; Pallares, Luisa F. ; Brodski, Claude ; Chen, Yiping ; Christian, Jan L. ; Kousa, Youssef A. ; Kuss, Pia ; Nelsen, Sylvia ; Novikov, Orna ; Schutte, Brian C. ; Wang, Ying ; Tautz, Diethard. / Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation. In: Development Genes and Evolution. 2013 ; Vol. 223, No. 5. pp. 279-287.
@article{e577fab96edf4e63afb8548f8d3113b3,
title = "Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation",
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.",
keywords = "Dosage effects, Mandible development, Morphometry, Mus musculus, Shape analysis",
author = "Louis Boell and Pallares, {Luisa F.} and Claude Brodski and Yiping Chen and Christian, {Jan L.} and Kousa, {Youssef A.} and Pia Kuss and Sylvia Nelsen and Orna Novikov and Schutte, {Brian C.} and Ying Wang and Diethard Tautz",
year = "2013",
month = "9",
doi = "10.1007/s00427-013-0443-y",
language = "English (US)",
volume = "223",
pages = "279--287",
journal = "Development Genes and Evolution",
issn = "0949-944X",
publisher = "Springer Verlag",
number = "5",

}

TY - JOUR

T1 - Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation

AU - Boell, Louis

AU - Pallares, Luisa F.

AU - Brodski, Claude

AU - Chen, Yiping

AU - Christian, Jan L.

AU - Kousa, Youssef A.

AU - Kuss, Pia

AU - Nelsen, Sylvia

AU - Novikov, Orna

AU - Schutte, Brian C.

AU - Wang, Ying

AU - Tautz, Diethard

PY - 2013/9

Y1 - 2013/9

N2 - 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.

AB - 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.

KW - Dosage effects

KW - Mandible development

KW - Morphometry

KW - Mus musculus

KW - Shape analysis

UR - http://www.scopus.com/inward/record.url?scp=84882830825&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84882830825&partnerID=8YFLogxK

U2 - 10.1007/s00427-013-0443-y

DO - 10.1007/s00427-013-0443-y

M3 - Article

VL - 223

SP - 279

EP - 287

JO - Development Genes and Evolution

JF - Development Genes and Evolution

SN - 0949-944X

IS - 5

ER -