ausblenden:
Schlagwörter:
shape analysis; morphometry; dosage effects; mandible development; Mus musculus
Zusammenfassung:
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.
