Genetic and developmental mechanisms that underlie craniofacial variation

摘要/摘要： 生物学家面临的一个持续挑战是揭示基因和遗传相互作用的全谱 导致颅面形状的正常变化。模型系统中的诱变筛选具有 提供了关于脊椎动物头部是如何形成图案的广泛见解，但此类研究通常是有偏见的 在形式上产生极端变异的突变的影响，并且仅限于 了解形状上微妙的数量变化。另一方面，全基因组关联研究 然而，这为导致复杂性状变异的等位基因提供了新的见解 这些方法只能解释大多数复杂性状中可遗传变异的一小部分。 因此，该领域的几个关键问题仍然没有得到回答：(1)哪些基因对 头面部形状？(2)它们与早期头面部相关基因有多大不同？ 发展？(3)这些基因座如何与自身和环境相互作用，从而影响 脸型？到目前为止，还没有一个试验性的系统来全面解决 这些问题。在这里，我提出了一个新的模型，非洲慈鱼，用它来描述 颅面变异的遗传/基因组基础，包括基因、逐个基因和逐个性别的影响。 此外，考虑到脊椎动物发育过程的保守性，候选基因 可以在斑马鱼等实验模型中验证在慈鱼中发现的这种基因。 慈鱼在很短的时间内对其头骨和颌骨进行了广泛的进化修改 一段时间。考虑到它们最近的起源，表型上截然不同的慈鱼血统继续分离。 祖先通过重组和杂交获得的多态，在这种方式上类似于 不同人类群体之间的比较。具有广泛表型特征的系统 在总体基因组一致性的背景下，变异是遗传/基因组图谱的理想选择。这 提案旨在利用这些优势以及我的实验室所拥有的遗传/基因组资源 在过去5年多的时间里积累起来，提供了对无数 影响脊椎动物面部形态变异的遗传机制。在此过程中，我们将测试三个 不同的假设：(1)头面部骨骼的形状是由一组独特的基因决定的 与那些在发育早期形成头部图案的模型不同；(2)允许 遗传交互作用和环境影响(在这种情况下是性别)将解释显著更大的 表型变异比例大于单基因座模型；(3)骨骼几何构型受影响 通过初级纤毛和Hedgehog信号通路的共同作用。初步数据 强烈支持所有这三个假设。

Abstract/Summary: An ongoing challenge for biologists is to reveal the full spectrum of genes and genetic interactions that contribute to normal variation in craniofacial shape. Mutagenesis screens in model systems have provided broad insights into how the vertebrate head is patterned, but such studies are generally biased toward the effects of mutations that produce extreme variation in form, and limited with respect to understanding subtle, quantitative variation in shape. Genome-wide association studies, on the other hand, have provided new insights into the alleles that contribute to variation in complex traits, however these methods have only been able to explain a faction of the heritable variation in most complex traits. Thus, several key questions remain unanswered in the field: (1) What are the genes that contribute to craniofacial shape? (2) To what extent do they differ from genes implicated in early craniofacial development? (3) How do these loci interact with themselves and the environment to effect variation in facial form? To date, there hasn't been an experimental system with which to comprehensively address these questions. Here I propose a new model, African cichlid fishes, with which to characterize the genetic/genomic basis of craniofacial variation, including gene, gene-by-gene, and gene-by-sex effects. In addition, given the conservation of developmental processes across vertebrates, gene candidate identified in cichlids can be validated in experimental models such as the zebrafish. Cichlids have undergone extensive evolutionary modifications of their skulls and jaws in a very brief period of time. Given their recent origins, phenotypically distinct cichlid lineages continue to segregate ancestral polymorphisms through recombination and hybridization, and in this way are similar to comparisons between diverse human populations. Systems characterized by extensive phenotypic variation in the context of overall genomic uniformity are ideal for genetic/genomic mapping. This proposal aims to leverage these advantages as well as the genetic/genomic resources that my lab as accumulated over the past 5+ years to provide a more comprehensive understanding of the myriad genetic mechanisms that influence variation in vertebrate facial form. In doing so we will test three different hypotheses: (1) The shape of the craniofacial skeleton is determined by a unique set of genes that are distinct from those that pattern the head early in development; (2) Genetic models that allow for genetic interactions and environmental effects (in this case sex) will explain a significantly greater proportion of the phenotypic variation than will single locus models; (3) Skeletal geometry is influenced through the combined effects of the primary cilia and Hedgehog signaling pathway. Preliminary data strongly support all three hypotheses.