The Genetic Architecture of Human Facial Morphology

人类面部形态的遗传结构

• 批准号: 10560571
• 负责人: Peter Claes
• 金额: $ 63.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560571
• 关键词: 3-Dimensional; Address; Adolescence; Adolescent; African; Algorithms; Architecture; Automobile Driving; Biological; Biological Assay; Biology; Brain; Cephalic; Chromatin; Chromosome Mapping; Complex; Complex Genetic Trait; Congenital Abnormality; Data; Data Set; Development; Disease; Dysmorphology; Enhancers; Etiology; European; Experimental Designs; Face; Funding; Future; Gene Expression; Genes; Genetic; Genetic Enhancer Element; Genetic Markers; Genetic Models; Genetic Polymorphism; Genetic Variation; Genome; Genome Scan; Genomic Segment; Genomics; Genotype; Goals; Growth; Height; Heritability; Human; Image; Individual; Knowledge; Lead; Magnetic Resonance Imaging; Maps; Methods; Modeling; Molecular; Morphology; Nature; Neural Crest Cell; Normal Range; Nucleic Acid Regulatory Sequences; Operative Surgical Procedures; Orthodontics; Outcome; Outcome Study; Pathway interactions; Phase; Phenotype; Population; Reporter; Research Design; Sample Size; Sampling; Screening procedure; Series; Shapes; Signal Transduction; Sorting; Source; Surface; Syndrome; Techniques; Technology; Testing; Therapeutic Intervention; United States National Institutes of Health; Variant; Weight; candidate identification; cell type; chromatin immunoprecipitation; chromosome conformation capture; clinically relevant; cognitive development; cohort; craniofacial; craniofacial structure; data resource; design; embryo cell; experimental study; gene expression variation; genetic analysis; genetic architecture; genetic linkage; genetic variant; genome wide association study; genome-wide; human embryonic stem cell; image processing; improved; innovation; insight; knowledgebase; longitudinal dataset; multi-ethnic; novel; personalized medicine; personalized therapeutic; promoter; rate of change; reconstruction; shape analysis; success; targeted treatment; trait; treatment planning; variant detection

PROJECT SUMMARY/ABSTRACT Human facial morphology varies both within and among populations, and this variation is driven in large part by genetic factors. Over the past seven years, gene mapping studies have identified numerous chromosomal regions associated with normal-range facial variation. Using advanced methods of biological shape analysis, our group recently uncovered over 200 such regions. Despite our success, these signals collectively explain only a small fraction of the heritable variation in facial shape, suggesting that much of the genetic architecture underlying human facial shape is yet to be discovered. A more complete understanding of this genetic architecture may provide insights into the mechanisms that control how the human face forms, offer insights into the etiology of craniofacial syndromes and birth defects, and eventually lead the way toward genetically- informed personalized therapeutic interventions for craniofacial surgery and orthodontics. Critically, we also lack knowledge about which genetic variants are functionally active at the implicated chromosomal regions or which genes they even target, limiting our ability to design future studies to sort out the biological mechanisms involved in building faces. The current proposal has three aims designed to significantly advance our understanding of human facial genetics: (1) we will perform a series of high-throughput experiments designed to delineate functional variants from our gene-mapping studies that drive craniofacial gene expression; (2) we will leverage new sources of data to bolster the statistical power of our gene-mapping efforts, paving the way for the discovery of new genetic pathways and a deeper understanding of the complex genetic networks and interactions that underlie variation in facial features; and (3) by applying innovative image processing and morphometric modeling techniques, we will utilize a large longitudinal dataset of over 11,000 adolescents with genetic markers and craniofacial images available at multiple timepoints to scan the genome for variants that impact key aspects of facial growth, such as timing of maturation and rate of change. Understanding the genetic basis of these growth traits has potential clinical relevance for fields like craniofacial surgery and orthodontics, where an individual’s facial growth trajectory can be an important factor in personalized treatment planning. By connecting genotypes to facial phenotypes and subsequently delineating functional variants, this project promises to fill gaps in our knowledge about the genetic basis of human facial traits and offer novel insights into the molecular mechanisms underlying both normal and abnormal facial development.

项目摘要/摘要 人类面部形态在种群内和种群之间都有所不同，这种差异在很大程度上是由 遗传因素。在过去的七年里，基因图谱研究已经确定了大量的染色体 与正常范围的面部变异相关的区域。使用先进的生物形状分析方法， 我们的团队最近发现了200多个这样的区域。尽管我们取得了成功，但这些信号共同解释了 脸型的可遗传变异中只有一小部分，这表明大部分遗传结构 潜在的人类面部形状尚未被发现。对这一基因的更完整的理解 建筑可以提供对控制人脸如何形成的机制的洞察，提供洞察 研究颅面综合征和出生缺陷的病因学，并最终引领我们走向遗传学- 为颅面外科和正畸提供知情的个性化治疗干预。关键的是，我们还 缺乏关于哪些遗传变异在涉及的染色体区域功能活跃或 他们甚至以哪些基因为目标，限制了我们设计未来研究以理清生物机制的能力 参与建面。目前的提案有三个目标，旨在显著推进我们的 了解人类面部遗传学：(1)我们将进行一系列高通量设计的实验 从我们的基因图谱研究中描绘出驱动颅面基因表达的功能变异；(2)我们 将利用新的数据来源来支持我们基因图谱工作的统计能力，为 为了发现新的遗传途径，加深对复杂遗传网络和 面部特征变化的相互作用；以及(3)通过应用创新的图像处理和 形态测量建模技术，我们将利用超过11,000名青少年的大型纵向数据集， 可在多个时间点获得遗传标记和头面部图像来扫描基因组中 影响面部发育的关键方面，如成熟的时间和变化率。了解 这些生长性状的遗传基础在颅面外科和其他领域具有潜在的临床意义 正畸，其中个人的面部成长轨迹可能是个性化治疗的重要因素 计划。通过将基因类型与面部表型联系起来，并随后描绘出功能变异，这 该项目承诺填补我们关于人类面部特征遗传基础的知识空白，并提供新的 对面部发育正常和异常的分子机制的洞察。