Collaborative Research: Genetics of Craniofacial Variation and Human Origins

自从人类的血统与黑猩猩的血统分离以来，我们几乎所有的身体和行为特征都发生了变化。最重要的变化，也是化石记录中最能反映的变化包括头部的形状，与语言、饮食、防御、威胁、嗅觉、智力、视力和姿势有关。这些措施包括缩短面部并将其藏在脑壳下，缩小牙齿(尤其是犬齿)，增加大脑大小，以及重新定位颅底。我们对这些特征的进化的了解将仍然有限，直到我们了解它们潜在的生物学基础，特别是遗传基础。这个试点项目的目的是确定在人类、猿类和东半球猴子进化过程中头骨形状变化的性质和时间的潜在遗传因素。一种综合的策略将：(1)从活的和化石的灵长类头骨中识别自然颅面发育、变异和进化的维度，(2)识别与这些维度的变异相关的基因，以及(3)通过实验证实这些基因在颅面发育网络中得到适当表达，这可能是物种内和物种之间颅面形状进化的原因。从一组非洲罂粟头骨化石中获得的一组计算机X射线断层扫描(CT)的3D重建将被定量分析，以识别头面部变异的单变量和多变量轴。这些结果将与文献中的观察相结合，以确定在这些动物的进化中重要的头面部变异特征。类似的CT扫描将从西南生物医学研究基金会(SFBR)已知的大型系谱中的大约250个狒狒头骨中获得，这些系谱已经对整个基因组中的约350个微卫星标记进行了基因分型。将进行连锁作图，以确定影响这些变异轴的狒狒的染色体区域。小鼠和灵长类动物共享骨骼发育的基本过程，因此小鼠是识别这些过程的表型和遗传模型，将采取两种基因作图方法来实现这一点。通过作图在小鼠和狒狒身上识别出的染色体区域将通过检查编码或调控区域的基因表达和DNA序列变化来进行实验测试，这些区域影响从CT扫描中识别出的头面部变化的轴。这是一种完整的发育进化方法来了解颅面变异的遗传因素。目前的系统发育方法在缺乏遗传基础的情况下使用头面部特征。一个后果是，我们不能区分共同的基因决定和适应性趋同造成的变化，这导致了基于分子和形态的系统发育之间的不一致。对发育遗传途径的鉴定将提供对这些特征的同源性的测试。智力价值--复杂度量性状的发展遗传学的一般问题和方法引起了所有类型的生物学家的广泛兴趣，因为类似的问题和过程在自然界中普遍存在。更广泛的影响--研究人员将创建一个大型档案，其中包括狒狒头骨、遗传物质和定量方法的3D CT图像，并将它们提供给其他研究人员。这个项目涉及国内外的几个机构，将包括本科生、研究生和博士后。在各个实验室工作的博士后将前往西南基金会接受分析方法培训。妇女和少数族裔学生在这些实验室定期接受培训，并将积极招募少数族裔学生。

Almost all of our physical and behavioral traits have changed since the human lineage separated from that of the chimpanzees. Among the most important changes and those best reflected in the fossil record involved the shape of the head, related to language, diet, defense, threat, olfaction, intelligence, vision, and posture. These include shortening the face and tucking it under the braincase, smaller teeth (especially canines), increased brain size, and reorientation of the cranial base. Our knowledge of the evolution of these traits will remain limited until we understand their underlying biological, and in particular, genetic bases. The purpose of this pilot project is to identify genetic factors underlying the nature and timing of changes in skull shape during the evolution of humans, apes, and Old World monkeys. A combined strategy will: (1) identify the dimensions of natural craniofacial development, variation and evolution from living and fossil primate skulls, (2) identify genes that in baboons and mice are associated with variation in those dimensions, and (3) experimentally confirm that these genes are appropriately expressed during craniofacial developmental networks that may be responsible for evolution of craniofacial shape within and between species. 3D reconstructions of a set of computed X-ray tomography (CT) scans acquired from a set of fossil African papionin skulls will be analyzed quantitatively to identify single and multivariate axes of craniofacial variation. These results will be coupled with observations from the literature to identify features of craniofacial variation that were important in the evolution of these animals. Similar CT scans will be obtained from approximately 250 baboon skulls in a large, known genealogy at the Southwest Foundation for Biomedical Research (SFBR), that have been genotyped for about 350 microsatellite markers across the genome. Linkage mapping will be done to identify chromosomal regions in the baboons that affect these axes of variation. Mice and primates share the basic processes of skeletal development, so the mouse is a phenotypic and genetic model for identifying these processes, and two gene mapping approaches will be taken to do that. Chromosomal regions identified by mapping in the mouse and baboon will be tested experimentally by examining gene expression and DNA sequence changes in coding or regulatory regions that affect the axes of craniofacial change that were identified from the CT scans. This is an integrated developmental evolutionary approach to understand the genetic elements of craniofacial variation. Current phylogenetic approaches use craniofacial features in the absence of knowledge of their genetic basis. One consequence is that we cannot discriminate between change due to common genetic determination and adaptive convergence and this has led to inconsistencies between molecular and morphologically based phylogenies. The identification of developmental genetic pathways will provide tests of the homology of such traits. Intellectual Merit -- The general problems and approaches to the developmental genetics of complex metric traits are of widespread interest to biologists of all types because similar problems and processes are widespread in nature. Broader Impact -- The researchers will create a major archive of 3D CT images of baboon skulls, genetic materials, and quantitative methods, and make them available to other investigators. This project involves several institutions here and abroad, and will include undergraduate, graduate, and post-doctoral students. Post docs working in the various laboratories will travel to the Southwest Foundation to train in methods of analysis. Women and minority students are regularly trained in these labs and minority students will be actively recruited.