The developmental genetic basis for evolutionary variation in the hominin shoulder

肩膀解剖结构（肩胛骨和上臂）的进化变化与现代人和我们的古人类祖先的一些最重要的行为变化有关，比如减少了在树上的时间，增加了工具的使用和操作，以及令人难以置信的准确投掷。考虑到许多进化是通过发育中的身体中基因的开启/关闭方式发生的变化，确定哪些基因和调节开关控制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事件序列至关重要。本项目通过比较类人猿和人类的肩部形状，进行实验，确定肩部发育过程中活跃的基因，并分析这些基因数据，重建人类肩部的独特进化，研究控制肩部形状的发育和遗传机制。更广泛的影响包括培训代表性不足的少数民族学生，通过讲习班和博物馆展览进行公共科学宣传，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研究结果。人类肩膀的独特特征，包括肩胛骨和肱骨近端，是从祖先的类人猿模式进化而来的，但最近的化石对其形态产生了怀疑。在人类谱系中，肩部形态的进化变化与古人类一些最重要的行为变化有关，如减少树栖，工具使用和增加操作，以及准确投掷。人类的肩膀受到强大的发育遗传程序的影响，其中关键的部件定位、方向和形状在子宫内就出现了。考虑到肩胛骨起源于多个细胞群，这些细胞群凝聚融合形成完整但形态不同的骨元素，每个骨元素对成年功能都至关重要，这种早期形状的形态发生是有趣的。考虑到这种复杂性，哪一种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变化发生的，确定哪些基因和调控开关（如增强子）控制肩部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部形态的突变事件序列至关重要。本研究旨在阐明人类肩带进化的发育机制：1)几何形态计量学，包括形状分析和肩部形态空间重建，以量化和模拟猿和人类形状变化的进化轨迹；2)对胚胎小鼠肩胛组织进行RNA-seq和ChIP-seq实验分析，分别鉴定肩胛组织中具有差异活性的基因和调控元件；3)对功能鉴定序列进行比较基因组学研究，以确定人类和黑猩猩之间导致肩部变异的碱基对差异；4) PAML似然比检验，确定功能编码序列和非编码序列自适应选择的系统发育时间，检验人类肩部进化的备选模型。

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.