Genetic and developmental mechanisms that underlie craniofacial variation

颅面变异的遗传和发育机制

• 批准号: 9913618
• 负责人: Craig Albertson
• 金额: $ 9.17万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-12 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913618
• 关键词: 3-Dimensional; Address; Affect; African; Alleles; Animals; Area; Biological Models; Biology; CRISPR/Cas technology; Candidate Disease Gene; Cichlids; Cilia; Code; Complement; Complex; Data; Data Set; Development; Developmental Process; Disease; Embryology; Environment; Event; Evolution; Experimental Designs; Experimental Models; Face; Gender; Genes; Genetic; Genetic Epistasis; Genetic Models; Genetic Polymorphism; Genetic Recombination; Genomics; Geometry; Head; Health; Heritability; Human; Investigation; Jaw; Malawi; Maps; Measures; Mediating; Methods; Modeling; Modernization; Modification; Molecular Chaperones; Mutagenesis; Mutation; Pattern; Phenotype; Play; Population; Quantitative Trait Loci; Radiation; Resources; Role; Shapes; Signal Transduction; Skeleton; Specific qualifier value; Structure; System; Testing; Time; Transgenic Organisms; Variant; Vertebrates; Work; Zebrafish; bone; combinatorial; craniofacial; craniofacial development; cranium; design; experimental study; genetic pedigree; genome wide association study; insight; knock-down; mechanotransduction; novel; receptor; sex; sexual dimorphism; skeletal; smoothened signaling pathway; trait

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.

摘要/总结： 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， 有助于颅面形状的正常变化。模型系统中的突变筛选 提供了关于脊椎动物头部如何形成图案的广泛见解，但这些研究通常是有偏见的 对突变的影响，产生极端变化的形式，并限制在 了解形状上细微的数量变化另一方面，全基因组关联研究 一方面，提供了新的见解等位基因，有助于复杂性状的变化，但是， 这些方法只能解释大多数复杂性状中的一部分遗传变异。 因此，该领域的几个关键问题仍然没有答案：（1）哪些基因有助于 颅面形状(2)在何种程度上，它们与涉及早期颅面 发展？(3)这些基因座是如何与自身和环境相互作用，从而影响 面部形状？到目前为止，还没有一个实验系统来全面解决 这些问题。在这里，我提出了一个新的模式，非洲慈鲷鱼，与它的特点， 颅面变异的遗传/基因组基础，包括基因、基因对基因和基因对性别的影响。 此外，考虑到脊椎动物发育过程的保守性， 在慈鲷中鉴定的基因可以在实验模型如斑马鱼中得到验证。 慈鲷科在很短的时间内经历了头骨和颌骨的广泛进化修改。 段时间鉴于它们最近的起源，表型不同的慈鲷谱系继续分离 通过重组和杂交的祖先多态性，并以这种方式类似于 不同人群之间的比较。以广泛表型 在总体基因组均一性的背景下的变异对于遗传/基因组作图是理想的。这 该提案旨在利用这些优势以及我的实验室作为 在过去5年多的时间里积累了大量的经验，以提供对无数 影响脊椎动物面部形状变化的遗传机制。在此过程中，我们将测试三个 不同的假设：（1）颅面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模式的基因不同;（2）允许 遗传相互作用和环境影响（在这种情况下，性别）将解释一个显着更大的 表型变异比例高于单位点模型;（3）Skeleton几何形状受到影响 通过初级纤毛和Hedgehog信号通路的联合作用。初步数据 强烈支持这三个假设。