The developmental genetic basis for evolutionary variation in the hominin shoulder

古人类肩部进化变异的发育遗传基础

• 批准号: 1518596
• 负责人: Terence Capellini
• 金额: $ 21.69万
• 依托单位: Harvard University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1518596&HistoricalAwards=false
• 关键词: developmental; genetic; basis; evolutionary; variation

Evolutionary changes in the anatomy of the shoulder (shoulder blade and upper arm) are associated with some of the most important behavioral changes in modern humans and our hominin ancestors, such as reduced time spent in trees, increased tool use and manipulation, and incredibly accurate throwing. Considering much of evolution occurs via changes in how genes are turned on/off in the developing body, determining which genes and regulatory switches control shoulder development is of critical importance for understanding the genetic basis of skeletal shape and the sequence of events that has produced our unique shoulders. This project investigates the developmental and genetic mechanisms that control shoulder shape, by comparing shoulder shape in apes and humans, conducting experiments that will identify genes that are active during shoulder development, and analyzing these genetic data to reconstruct the unique evolution of the human shoulder. Broader impacts include training of underrepresented minority students, public science outreach through workshops and museum exhibits, and findings that may be informative for biomedical studies of shoulder dysfunction or disease.The unique features of the human shoulder, consisting of the scapula and proximal humerus, evolved from an ancestral hominoid pattern, but recent fossils cast doubt as to the morphotype. In the human lineage, evolutionary shifts in shoulder morphology are associated with some of the most important behavioral changes in hominins, such as reduced arboreality, tool use and increased manipulation, and accurate throwing. The human shoulder is under strong developmental genetic programming in which key aspects of component positioning, orientation, and shape emerge in utero. This early shape morphogenesis is intriguing considering that the scapula arises from multiple cell populations, which condense and fuse to form integrated, yet morphologically distinct, bony elements, each of which is critical to adult function. Given this complexity, which developmental and genetic mechanisms control shoulder shape? Considering that much of phenotypic evolution occurs via changes in the non-coding regulatory genome, determining which genes and regulatory switches (e.g., enhancers) control shoulder morphogenesis is of critical importance for understanding the genetic basis of skeletal shape and for reconstructing the sequence of mutational events that has produced the unique human shoulder morphology. This proposal aims to illuminate developmental mechanisms contributing to the evolution of the human shoulder girdle using: 1) Geometric morphometrics including shape analyses and reconstructions of shoulder morphospaces in order to quantify and model evolutionary trajectories in shape variation in apes and humans; 2) RNA-seq and ChIP-seq experimental assays on embryonic mouse shoulder tissues to identify both genes and regulatory elements, respectively, that are differentially active in shoulder components; 3) comparative genomics on functionally identified sequences to identify base-pair differences between humans and chimps that contribute to shoulder variation; and 4) PAML likelihood ratio testing to identify phylogenetic timing of adaptive selection on functional coding and non-coding sequences and test alternative models of human shoulder evolution.

肩部(肩胛骨和上臂)解剖结构的进化变化与现代人和我们的原始人的一些最重要的行为变化有关，例如减少了在树上花费的时间，增加了工具的使用和操作，以及令人难以置信的准确投掷。考虑到大部分进化是通过基因在发育中的开启/关闭方式的变化而发生的，确定哪些基因和调控开关控制着肩膀的发育，对于理解骨骼形状的遗传基础和产生我们独特肩膀的一系列事件至关重要。该项目通过比较类人猿和人类的肩部形状，进行实验以确定在肩部发育过程中活跃的基因，并分析这些遗传数据来重建人类肩部的独特进化，从而研究控制肩部形状的发育和遗传机制。更广泛的影响包括对未被充分代表的少数族裔学生进行培训，通过研讨会和博物馆展品进行公共科学宣传，以及可能为肩部功能障碍或疾病的生物医学研究提供信息的发现。人类肩膀的独特特征，包括肩胛骨和近端肱骨，是从祖先的类人型进化而来的，但最近的化石让人对形态类型产生了怀疑。在人类谱系中，肩部形态的进化变化与古人类中一些最重要的行为变化有关，例如减少了树丛现实、工具的使用和更多的操纵以及准确的投掷。人类的肩膀处于强烈的发育遗传编程下，在子宫中出现了部件位置、方向和形状的关键方面。考虑到肩胛骨是由多个细胞群形成的，这些细胞群浓缩并融合形成完整的、但在形态上不同的骨元素，每个骨元素对成人的功能至关重要，所以这种早期的形状形态发生很有趣。考虑到这种复杂性，哪些发育和遗传机制控制着肩膀的形状？考虑到许多表型进化是通过非编码调控基因组的改变而发生的，确定哪些基因和调控开关(如增强子)控制着肩的形态发生，对于理解骨骼形状的遗传基础和重建产生独特人类肩形态的突变事件序列至关重要。这项建议旨在通过以下方法阐明人类肩带进化的发育机制：1)几何形态计量学，包括肩部形态空间的形状分析和重建，以量化和模拟类人猿和人类的形状变异的进化轨迹；2)对小鼠胚胎肩部组织进行RNA-SEQ和CHIP-SEQ实验，分别鉴定在肩部组成部分中差异活跃的基因和调控元件；3)对功能鉴定的序列进行比较基因组学研究，以确定导致肩部变异的人类和黑猩猩之间的碱基对差异；以及4)PAML似然比检验，以确定功能编码和非编码序列上的适应性选择的系统发育时机，并测试人类肩膀进化的替代模型。