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 morphometrics approach to identify subtle phenotypic differences caused by dosage effects of candidate genes. We use mouse strains with specific gene modifications (knock-outs and knock-ins) 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 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 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.

Haploinsufficiency of interferon regulatory factor 6 alters brain morphology in the mouse

“…Additional work is needed to connect the observed phenotypic changes to altered gene expression and to pinpoint the timing and sequencing of events leading to abnormal brain morphogenesis. A recent paper found no significant change in mandibular morphometry in Irf6 adult het mice using micro-CT [Boell et al, 2013], although mandibular hypoplasia was observed in knockout embryos [Ingraham et al, 2006]. This suggests that development of the brain is more sensitive to Irf6 dosage than development of the mandible.…”

Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect

“…On the other hand, single-nucleotide polymorphism of NOGGIN has been linked to mandibular hypoplasia (Gutiérrez et al, 2010). In mice, gene dosage of BMP signaling pathway components has been shown to correlate with the size and shape of mandible (Boell et al, 2013). Tissue specific deletion of Bmp4 by Nestin-Cre in craniofacial epithelium and mesenchyme causes cleft lip and inactivation of BmprIa using either Nestin-Cre or Wnt1Cre results in the formation of both cleft lip and cleft palate (Li et al, 2011; Liu et al, 2005).…”

Parallel Universes for Models of X Chromosome Dosage Compensation in <b><i>Drosophila</i></b>: A Review

“…Collectively, this result parallels the realization that most haploinsufficient clinical conditions in human are lesions in transcription factors or other proteins involved with oligomeric complexes [Seidman and Seidman, 2002;Veitia, 2002;Kondrashov and Koonin, 2004]. Gene dosage has an effect on murine phenotypes when mutations in developmental transcriptional regulators are present in a heterozygous state [Boell et al, 2013].…”