Genetic and developmental mechanisms that underlie craniofacial (co)variation

颅面（共同）变异背后的遗传和发育机制

• 批准号: 10578143
• 负责人: Craig Albertson
• 金额: $ 35.85万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578143
• 关键词: 3-Dimensional; ATAC-seq; Address; Adult; Affect; Animals; Area; Award; Biological; Biological Models; Biology; Bone Tissue; Brain; CRISPR/Cas technology; Candidate Disease Gene; Cells; Chromosome Mapping; Cichlids; Complex; Data; Data Set; Development; Developmental Process; Disease; Disparate; Ecology; Embryo; Environment; Environmental Risk Factor; Equilibrium; Evolution; Experimental Models; Eye; Face; Feedback; Gene Expression; Genes; Genetic; Genome; Genomics; Genotype; Geometry; Goals; Growth; Hand; Head; Health; Heart; Homeostasis; Human; Investigation; Iodine; Jaw; Kinetics; Malawi; Maps; Mechanics; Modeling; Modernization; Modification; Morphology; Muscle; Nature; Organ; Outcome; Pattern; Phenotype; Procedures; Process; Quantitative Trait Loci; Regulation; Research; Scanning; Series; Shapes; Signal Pathway; Signal Transduction; Skeleton; Specific qualifier value; Stains; System; Time; Tissues; Variant; Work; bone; candidate identification; comparative genomics; craniofacial; craniofacial bone; craniofacial complex; craniofacial development; cranium; genetic pedigree; genome wide association study; genomic data; insight; kinematics; mechanical force; mechanical load; mechanotransduction; multiple datasets; pleiotropism; shape analysis; skeletal; soft tissue; stem cells; three-dimensional modeling; tool; trait; transcriptome sequencing

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.

摘要/摘要： 脊椎动物的头面部骨骼是一种动态器官，通过 基因和环境投入之间错综复杂的平衡。其中任何一个的中断都可能导致有害的 健康结果。虽然在理解基因和基因方面已经取得了重大进展 早期颅面图案背后的细胞机制，对其基础知之甚少 在较长的发育期内表现出来的头面部变异，取决于 它发生的环境背景。无论是细胞和细胞之间的物理相互作用 发育中胚胎内的组织，或施加在系统上的机械力，这些上下文 将决定基因编码系统如何随着时间的推移而展开，以确定头面部的几何形状。 这些想法隐含的是系统中的反馈。反馈是不同的发展单位 聚集在一起形成集成的功能系统-例如，相邻但 发育不同的组织。它也是正常生长和动态平衡所必需的。 系统-例如，祖细胞必须感知环境输入，包括机械负荷，并调整 相应的发育过程。概括地说，这项提案试图理解如何将 反馈的类型在基因水平上受到调节。在这样做的过程中，将有三个具体问题 解决：(1)哪些基因影响头面部的形状？(2)它们发挥作用了吗？ 在多个组织上，通过多效性或作为同一信号通路的一部分？(3)如何 这些基因座通过机械感应与环境相互作用，从而影响脸型的变化？ 实验模型将以慈鱼作为实验模型，因为它们经历了广泛的实验。 在非常短的时间内对它们的头骨和颌骨进行进化改造，使它们成为 基因/基因组图谱。慈鱼也是众所周知的能力，他们的能力，重塑他们的颌骨在 不同的觅食环境，但并不是所有的慈鱼都有这种能力，因此可塑性本身是 基因决定的，并在这个系统中发生了分化。因此，慈鱼代表了一个理想的模型 确定和分析遗传、环境和GxE的影响，这是颅面变异的基础。这 Proposal利用了这些实验属性，并将高级表型、遗传型和 为更全面地了解颅面部的机制提供功能工具 形状。