Exploring the effects of gene dosage on mandible shape in mice as a model for studying the genetic basis of natural variation
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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DOI：
10.1007/s00427-013-0443-y
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发表时间：
2013-09-01
影响因子：
2.4
通讯作者：
Tautz, Diethard
中科院分区：
文献类型：
--
作者：
Boell, Louis;Pallares, Luisa F.;Tautz, Diethard
小鼠的下颌骨形状是一个复杂的性状，受到许多遗传因素的影响。然而，到目前为止，关于单个基因对成年下颌骨形状的作用知之甚少，因为大多数发育相关基因在胚胎发生期间已经需要，即，在下颌骨完全形成之前，敲除导致胚胎死亡或严重变形。我们在这里采用几何形态计量学的方法来确定候选基因的剂量效应引起的微妙的表型差异。我们使用具有特定基因修饰（敲除和敲入）的小鼠品系来比较杂合动物与来自相同原种的对照，这预期相当于相应基因座的基因表达的变化。这种表达水平的差异也可能作为自然变异的一部分而发生。我们专注于Bmp通路基因（Bmp 4，其拮抗剂Noggin和Bmp 5 -7基因型的组合），但也包括其他两个发育控制基因，怀疑以某种方式影响下颌骨发育（Egfr和Irf 6）。此外，我们研究了Hoxd 13以及细胞外基质成分（Col 2a 1）的影响。我们发现，微妙但显着的形状差异是由这些基因中的几个基因剂量的差异。Bmp 4和Noggin的变化与鸟类和鱼类已知的这些基因的作用部分兼容。我们发现Hoxd 13也有显著的形状变化，尽管到目前为止，该基因只涉及四肢的骨骼图案化过程。将基因剂量变化的效应大小与自然种群中发现的小鼠变异以及数量性状基因座（QTL）对下颌骨形状的影响进行比较，我们发现基因剂量变化引起的效应大小处于自然变异谱的低端，但大于QTL研究中发现的平均加性效应。我们的结论是，研究基因剂量效应有可能提供新的见解方面的颅面发育，变异和进化。
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.