Genetic and developmental mechanisms that underlie craniofacial (co)variation

摘要/总结： 脊椎动物颅面骨骼是一个动态器官，它是通过一个 基因和环境输入的复杂平衡。对任何一方的干扰都可能导致有害的 健康成果。虽然在理解遗传和基因方面取得了重大进展， 早期颅面模式的细胞机制，对颅面模式的基础知之甚少。 颅面的变化，表现在长期的发展，并取决于 它发生的环境背景。无论是细胞之间的物理相互作用， 发育中的胚胎内的组织，或施加在系统上的机械力，这些背景 将决定基因编码系统如何随着时间的推移展开，以确定颅面几何形状。 这些想法隐含着系统中的反馈。反馈是指不同的发展单位 聚集在一起形成集成的功能系统-例如，相邻但相互之间的信令 发育不同的组织。它也是必要的正常生长和动态平衡 系统-例如，祖细胞必须感知环境输入，包括机械负荷， 相应的发展过程。从广义上讲，这一建议旨在了解两者如何 反馈的类型在基因水平上受到调节。为此，将提出三个具体问题， 问题：（1）影响颅面形状的基因有哪些？(2)它们发挥了它们的作用吗 通过多效性或作为同一信号通路的一部分，在一个以上的组织？(3)怎么 这些位点与环境相互作用，通过机械感应，影响面部形状的变化？ 慈鲷鱼将被用作实验模型，因为它们经历了广泛的 他们的头骨和颌骨在很短的时间内进化修改，使他们成为理想的 遗传/基因组作图。慈鲷科也是众所周知的，他们的能力，改造他们的下巴下， 不同的觅食环境，但不是所有的慈鲷都有这种能力，因此可塑性本身是 基因决定的，在这个系统中产生了分歧。因此，慈鲷是一种理想的模式， 识别和解析颅面变异性背后的遗传、环境和GxE效应。这 该提案利用了这些实验属性，并整合了先进的表型，基因型和 功能性工具，以提供对颅面机制的更全面的理解 形状

Abstract/Summary: The vertebrate craniofacial skeleton is a dynamic organ that arises and is maintained through an intricate balance of genetic and environmental inputs. Disruptions to either can lead to deleterious health outcomes. While significant progress has been made toward understanding the genetic and cellular mechanisms that underlie early craniofacial patterning, much less is known about the basis for craniofacial variation that manifests over extended periods of development, and depends upon the environmental context in which it occurs. Whether it's the physical interactions between cells and tissues within the developing embryo, or the mechanic forces imposed on the system, these contexts will determine how genetically-encoded systems unfold over time to determine craniofacial geometry. Implicit to these ideas is feedback in the system. Feedback is how disparate developmental units come together to form integrated functional systems - e.g., reciprocal signaling between adjacent but developmentally distinct tissues. It is also necessary for normal growth and homeostasis in kinetic systems - e.g., progenitor cells must sense environmental inputs, including mechanical load, and adjust developmental processes accordingly. Broadly speaking this proposal seeks to understand how both types of feedback are regulated at the genetic level. In doing so, three specific questions will be addressed: (1) What are the genes that contribute to craniofacial shape? (2) Do they exert their effects on more than one tissue, either via pleiotropy or as part of the same signaling pathway? (3) How do these loci interact with the environment, via mechanosensing, to affect variation in facial form? Cichlid fishes will be used as the experimental model, as they have undergone extensive evolutionary modifications of their skulls and jaws in a very brief period of time, making them ideal for genetic/genomic mapping. Cichlids are also well known for their capacity to remodel their jaws under different foraging environment, but not all cichlids share this ability, and thus plasticity itself is genetically determined and has diverged in this system. Cichlids therefore represent an ideal model to identify and parse the genetic, environmental, and GxE effects that underlie craniofacial variability. This proposal leverages these experimental attributes, and integrates advanced phenotypic, genotypic and functional tools to provide a more holistic understanding of the mechanisms that underlie craniofacial shape.