Dynamics of DNA Methylation in Recent Human and Great Ape Evolution

DNA methylation is an epigenetic modification involved in regulatory processes such as cell differentiation during development, X-chromosome inactivation, genomic imprinting and susceptibility to complex disease. However, the dynamics of DNA methylation changes between humans and their closest relatives are still poorly understood. We performed a comparative analysis of CpG methylation patterns between 9 humans and 23 primate samples including all species of great apes (chimpanzee, bonobo, gorilla and orangutan) using Illumina Methylation450 bead arrays. Our analysis identified ∼800 genes with significantly altered methylation patterns among the great apes, including ∼170 genes with a methylation pattern unique to human. Some of these are known to be involved in developmental and neurological features, suggesting that epigenetic changes have been frequent during recent human and primate evolution. We identified a significant positive relationship between the rate of coding variation and alterations of methylation at the promoter level, indicative of co-occurrence between evolution of protein sequence and gene regulation. In contrast, and supporting the idea that many phenotypic differences between humans and great apes are not due to amino acid differences, our analysis also identified 184 genes that are perfectly conserved at protein level between human and chimpanzee, yet show significant epigenetic differences between these two species. We conclude that epigenetic alterations are an important force during primate evolution and have been under-explored in evolutionary comparative genomics.

DNA甲基化（DNA methylation）是一类参与多种核心调控过程的表观遗传修饰，涉及发育阶段的细胞分化、X染色体失活、基因组印记以及复杂疾病易感性等生物学环节。然而，当前学界对人类与其近缘灵长类之间DNA甲基化变化的动态特征仍了解有限。本研究采用Illumina Methylation450微珠芯片（Illumina Methylation450 bead arrays），对9个人类样本与23个涵盖所有类人猿物种（黑猩猩、倭黑猩猩、大猩猩及红毛猩猩）的灵长类样本的CpG甲基化模式开展比较分析。研究鉴定出约800个在类人猿类群间甲基化模式发生显著改变的基因，其中包含约170个仅在人类中呈现特异性甲基化模式的基因。其中部分基因已被证实与发育及神经生物学特征相关，这表明在近期人类与灵长类的进化历程中，表观遗传改变事件较为频繁。本研究发现编码序列变异速率与启动子区域甲基化改变速率之间存在显著正相关关系，提示蛋白质序列进化与基因调控进化之间存在协同发生现象。与之相对，本研究还鉴定出184个在人类与黑猩猩的蛋白质水平上完全保守，但二者间却存在显著表观遗传差异的基因，这一结果支持了“人类与类人猿的诸多表型差异并非由氨基酸序列差异所导致”的观点。综上，本研究认为表观遗传改变是灵长类进化过程中的重要驱动力，且在进化比较基因组学领域尚未得到充分探索。