中国科学院昆明动物研究所机构知识库

人类和非人灵长类之间最显著的区别是人类具有高度发达的认知能力。人类大脑进化的遗传机制包括蛋白质序列变化，基因的复制和缺失，以及基因组中非编码区进化导致的一些顺式调控元件的改变等。MCPH1蛋白序列的改变对于大脑进化具有重大的影响，我们将MCPH1在物种间最保守的第96位和第101位两个氨基酸位点在B6小鼠品系中进行人源化替换，即建立一个MCPH1人源化（hMCPH1）小鼠模型，观察人源化MCPH1是否对小鼠的神经发生有影响，是否在小鼠的大脑发育中起着关键的作用。RNA-seq分析表明，人源化MCPH1小鼠与野生型小鼠在胚胎期的基因表达没有显著差异，出生后的两个时期——P0与P60存在基因表达差异，这提示我们hMCPH1行使功能可能是在出生后。另外，通过P0和P8时期的组织免疫荧光染色发现，hMCPH1小鼠具有更多较晚产生的皮层上层神经元，与野生型对照相比可能存在神经发育的延迟，这与我们之前建立的过表达hMCPH1猕猴的表型一致。该研究可以帮助我们更好地理解MCPH1在人类大脑进化中的作用机制。

The most striking difference between human and non-human primates is the highly developed cognitive ability of humans. The genetic mechanisms of human brain evolution involve the change of protein sequence, gene duplication and gene loss, and the change of cis-regulatory elements caused by the evolution of the non-coding region in the genome. The change of the MCPH1 protein sequence has a significant effect on the evolution of the human brain. In this study, we generated a gene-replacement mouse model (B6 mouse) by introducing two human-specific amino acid changes at the 96th and the 101th sites of the MCPH1 protein that are highly conserved during mammalian evolution. We tested whether the humanized MCPH1 has an effect on neurogenesis, and whether it plays a key role in brain development of the hMCPH1 mouse. The RNA-seq analysis showed that no significant gene expression difference exist between the hMCPH1 mouse and the wild-type mouse during the embryonic period. The gene expression difference was observed between P0 and P60 after birth, suggesting that hMCPH1 functions during the post-natal period. Importantly, the hMCPH1 mice have more late-born cortical upper neurons compared to the wild-type controls, implying a delayed neural development, consistent with the phenotype of the previously established hMCPH1 rhesus monkeys. This study can help us better understand the role of MCPH1 in human brain evolution.