Collaborative Research: Genetics of Craniofacial Variation and Human Origins

自从人类谱系与黑猩猩谱系分离以来，我们几乎所有的身体和行为特征都发生了变化。 在最重要的变化和化石记录中最好的反映涉及头部的形状，与语言，饮食，防御，威胁，嗅觉，智力，视觉和姿势有关。这些包括缩短脸和把它藏在脑壳下，更小的牙齿（特别是犬齿），增加大脑的大小，以及颅底的重新定位。 我们对这些特征进化的了解将仍然有限，直到我们了解它们的生物学基础，特别是遗传基础。 这个试点项目的目的是确定人类，猿和旧大陆猴进化过程中头骨形状变化的性质和时间的遗传因素。 综合战略将：（1）从活的和化石灵长类头骨中确定自然颅面发育、变异和进化的维度，（2）确定狒狒和小鼠中与这些维度变异相关的基因，（3）实验证实这些基因在颅面发育网络中适当表达，这些网络可能负责物种内和物种间颅面形状的进化。 从一组化石非洲papionin头骨采集的一组计算机X射线断层扫描（CT）的三维重建将进行定量分析，以确定颅面变化的单轴和多轴。 这些结果将与文献中的观察结果相结合，以确定这些动物进化中重要的颅面变化特征。 类似的CT扫描将从西南生物医学研究基金会（SFBR）的一个大型已知谱系中的大约250个狒狒头骨中获得，这些头骨已经在基因组中对大约350个微卫星标记进行了基因分型。 将进行连锁作图，以确定狒狒中影响这些变异轴的染色体区域。 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，并且将采用两种基因作图方法来实现这一点。将通过检查影响CT扫描确定的颅面变化轴的编码或调控区中的基因表达和DNA序列变化，对小鼠和狒狒中通过定位确定的染色体区域进行实验测试。 这是一个完整的发展进化的方法来了解颅面变异的遗传因素。目前的系统发育方法使用颅面特征的遗传基础知识的情况下。 一个后果是，我们不能区分由于共同的遗传决定和适应性收敛的变化，这导致了分子和形态学为基础的同源性之间的不一致。发育遗传途径的鉴定将提供这些性状同源性的测试。 智力优点-一般问题和复杂的度量性状的发育遗传学的方法是广泛的兴趣，所有类型的生物学家，因为类似的问题和过程是广泛的性质。 更广泛的影响-研究人员将创建一个狒狒头骨，遗传物质和定量方法的3D CT图像的主要档案，并将其提供给其他研究人员。该项目涉及国内外多个机构，将包括本科生，研究生和博士后学生。 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的培训。 妇女和少数民族学生定期在这些实验室接受培训，少数民族学生将被积极招募。

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.