表观遗传修饰的重要性越来越被人所认识，但是表观遗传的变化如何对表型的进化产生影响，特别是表观遗传调控在人类大脑进化中的作用仍然不是很清楚。美国乔治亚理工大学教授Soojin V.Yi 曾经对人和黑猩猩大脑进行了全基因组甲基化测序，发现了很多物种间甲基化差异区域，但这些甲基化差异区域是否属于人类特异的甲基化变化仍然不是很清楚。中国科学院昆明动物研究所宿兵实验室之前对小头症基因CENpJ甲基化模式的比较研究表明，该基因在人类大脑中存在人类特异的低甲基化变化，但缺少对全基因组水平人类特异性甲基化变化的认识。

有鉴于此，宿兵实验室助理研究员石磊以及硕士生虎恩志、张哲与Soojin V.Yi开展合作，对人类、黑猩猩和猕猴3个物种的大脑前额叶进行了大脑全基因组甲基化测序，发现了85个人类特异的甲基化变化区域（DMR）。同时，他们通过对多个灵长类代表物种（人类、黑猩猩、长臂猿、猕猴和食蟹猴）大脑样本的甲基化重测序对发现的人类特异的DMR进行了验证。研究结果显示，有相当一部分DMR集中在基因间区域，而这些区域基本上都是H3K4me3标识的转录活跃区域；进一步的基因表达分析发现，这些区域可能通过影响一些神经特异转录因子的结合参与神经发育调控过程。该研究提示在进化中表观遗传变化对人类大脑起源的重要作用。

研究结果发表在国际学术刊物《分子生物学与进化》（Molecular Biology and Evolution）上，石磊为共同第一作者，宿兵为共同通讯作者。

该项目得到了中科院先导B项目、科技部“973”项目、国家基金委重点项目、国家基金委青年基金项目和中科院青年促进会基金的支持。

昆明动物所等在人类大脑进化遗传机制研究中取得进展

原文摘要：

Comparative Methylome Analyses Identify Epigenetic Regulatory Loci of Human Brain Evolution

How do epigenetic modifications change across species and how do these modifications affect evolution? These are fundamental questions at the forefront of our evolutionary epigenomic understanding. Our previous work investigated human and chimpanzee brain methylomes, but it was limited by the lack of outgroup data which is critical for comparative (epi)genomic studies. Here we compared whole genome DNA methylation maps from brains of humans, chimpanzees and also rhesus macaques (outgroup) to elucidate DNA methylation changes during human brain evolution. Moreover, we validated that our approach is highly robust by further examining 38 human-specific DMRs using targeted deep genomic and bisulfite sequencing in an independent panel of 37 individuals from five primate species. Our unbiased genome-scan identified human brain differentially methylated regions (DMRs), irrespective of their associations with annotated genes. Remarkably, over half of the newly identified DMRs locate in intergenic regions or gene bodies. Nevertheless, their regulatory potential is on par with those of promoter DMRs. An intriguing observation is that DMRs are enriched in active chromatin loops, suggesting human-specific evolutionary remodeling at a higher-order chromatin structure. These findings indicate that there is substantial reprogramming of epigenomic landscapes during human brain evolution involving noncoding regions.