The Evolution of Lineage-Specific Regulatory Activities in the Human Embryonic Limb

The evolution of human anatomical features likely involved changes in gene regulation during development. However, the nature and extent of human specific developmental regulatory functions remain unknown. We obtained a genome-wide view of cis regulatory evolution in human embryonic tissues by comparing the histone modification H3K27ac, which provides a quantitative readout of promoter and enhancer activity, during human, rhesus, and mouse limb development. Based on increased H3K27ac, we find that 13% of promoters and 11% of enhancers have gained activity on the human lineage since the human-rhesus divergence. These gains largely arose by modification of ancestral regulatory activities in the limb or potential co-option from other tissues and are likely to have heterogeneous genetic causes. Most enhancers that exhibit gain of activity in humans originated in mammals. Gains at promoters and enhancers in the human limb are associated with increased gene expression, suggesting they include molecular drivers of human morphological evolution. ChIP-Seq and RNA-Seq of autopod tissue of developing limb buds of Human (E33-E47), rhesus (E31-E36), and mouse (E10.5-E13.5). No raw data are provided for human samples. Human alignments were anonymized by removing sequence information and converting to bed format.人类解剖学特征的演化过程大概率涉及发育阶段的基因调控改变。然而，人类特异性发育调控功能的本质与覆盖范围仍未明确。我们通过比对人类、恒河猴与小鼠肢体发育过程中的组蛋白修饰H3K27ac（histone H3 lysine 27 acetylation，可定量反映启动子与增强子的活性），获得了人类胚胎组织中顺式调控演化（cis-regulatory evolution）的全基因组视图。基于H3K27ac信号增强的情况，我们发现自人类与恒河猴分化以来，人类谱系中已有13%的启动子与11%的增强子获得了调控活性。这些活性的获得主要通过修饰肢体中的祖先调控活性，或是从其他组织中潜在的共选择而来，且其遗传成因具有异质性。大多数在人类中出现活性增强的增强子起源于哺乳动物类群。人类肢体中启动子与增强子的活性增强与基因表达上调相关，这表明其中包含了推动人类形态演化的分子驱动因素。本数据集涵盖人类（E33-E47）、恒河猴（E31-E36）与小鼠（E10.5-E13.5）发育肢芽的肢端组织的染色质免疫共沉淀测序（ChIP-Seq）与RNA测序（RNA-Seq）数据。未提供人类样本的原始数据。人类比对序列已通过移除序列信息并转换为BED格式进行匿名化处理。