Collaborative Research: Genetics of Craniofacial Variation and Human Origins

自从人类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。最重要的变化和化石记录中反映最好的变化包括头部的形状，与语言、饮食、防御、威胁、嗅觉、智力、视觉和姿势有关。这些包括缩短面部并将其塞进脑壳下，更小的牙齿（尤其是犬齿），更大的大脑，以及颅底的重新定位。在我们了解这些特征的潜在生物学基础，特别是遗传基础之前，我们对这些特征进化的了解仍然有限。这个试点项目的目的是确定在人类、猿和旧大陆猴的进化过程中，颅骨形状变化的性质和时间的遗传因素。综合策略将：(1)确定活的和化石的灵长类颅骨的自然颅面发育、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，可能负责物种内和物种间颅面形状的进化。从一组非洲papionin头骨化石中获得的一组计算机x射线断层扫描（CT）扫描的3D重建将进行定量分析，以确定颅面变异的单轴和多轴。这些结果将与文献中的观察结果相结合，以确定在这些动物的进化中重要的颅面变异特征。类似的CT扫描将从西南生物医学研究基金会（SFBR）一个已知的大型谱系中大约250只狒狒头骨中获得，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。连锁图谱将用于鉴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，将采用两种基因定位方法来实现这一目标。通过在小鼠和狒狒中绘制染色体图谱确定的染色体区域将通过检查基因表达和DNA序列变化的编码或调节区域进行实验测试，这些区域会影响从CT扫描中确定的颅面变化轴。这是一种综合的发育进化方法来理解颅面变异的遗传因素。目前的系统发育方法在缺乏其遗传基础知识的情况下使用颅面特征。结果之一是，我们无法区分由共同遗传决定的变化和适应性趋同，这导致了分子和基于形态的系统发生之间的不一致。发育遗传途径的鉴定将为这些性状的同源性提供检验。智力优势——复杂度量性状的发育遗传学的一般问题和方法引起了所有类型生物学家的广泛兴趣，因为类似的问题和过程在自然界中广泛存在。更广泛的影响——研究人员将创建一个主要的档案，包括狒狒头骨的3D CT图像、遗传物质和定量方法，并将其提供给其他研究人员。该项目涉及国内外多家机构，将招收本科生、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，少数民族学生将积极被招募。

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.