The Genetic Architecture of Human Facial Morphology

项目总结/摘要 人类面部形态在人群内和人群之间都有差异，这种差异在很大程度上是由以下因素驱动的： 遗传因素在过去的七年里，基因图谱研究已经确定了许多染色体 与正常范围面部变化相关的区域。利用先进的生物形状分析方法， 我们小组最近发现了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 只有一小部分的遗传变异的面部形状，这表明大部分的遗传结构， 人类面部的基本形状还有待发现。更全面地了解这种基因 建筑可以提供对控制人脸如何形成的机制的见解， 研究颅面综合征和出生缺陷的病因学，并最终导致遗传学- 为颅面手术和整形外科提供个性化的治疗干预。关键是，我们也 缺乏关于哪些遗传变异在所涉及的染色体区域具有功能活性的知识，或 它们甚至针对哪些基因，限制了我们设计未来研究以理清生物机制的能力 参与了面部的塑造。目前的建议有三个目标，旨在大大推进我们的 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体;（2）我们 将利用新的数据来源来加强我们基因图谱工作的统计能力， 发现新的遗传途径和更深入地了解复杂的遗传网络， 面部特征变化背后的相互作用;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， 在多个时间点可用的遗传标记和颅面图像，以扫描基因组的变体， 影响面部生长的关键方面，如成熟的时间和变化率。了解 这些生长性状的遗传基础对颅面外科等领域具有潜在的临床相关性， 面部发育，其中个人的面部生长轨迹可以是个性化治疗的重要因素 规划通过将基因型与面部表型联系起来，并随后描绘出功能变异， 该项目有望填补我们对人类面部特征遗传基础知识的空白，并提供新的 深入了解正常和异常面部发育的分子机制。

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.