人类大脑进化关键基因MCPH1的调控功能研究

MCPH1 is one of the key genes that regulate human brain size. During primate evolution, MCPH1 has undergone strong Darwinian positive selection, especially in the lineage leading to humans, resulting in a significant protein sequence divergence between humans and nonhuman primates and possible functional changes. In this study, we aim to test this hypothesis, and we will utilize co-immunoprecipitation and reporter gene assays to examine the activating and repressing effects of MCPH1 on a set of its down-stream genes among representative primate species including human, chimpanzee, gibbon and rhesus monkey, and compare the functional outcomes of a series of mutant MCPH1 proteins which carry mutations at the human-specific sites. This study focuses on understanding the functional divergence of MCPH1 between humans and non-human primates in view of its transcriptional regulation of the down-stream genes, which may have led to a greatly enlarged neuro-progenitor pool during brain development, thus providing a potential molecular mechanism of how lineage-specific mutations of MCPH1 contributed to the enlargement of brain size during human evolution. It will provide experimental and theoretical foundations to the construction MCPH1 transgenic monkey model, and offer a new insight to a better understanding of human brain evolution and origin of human intelligence.

小头症基因（MCPH1）是调控人类大脑容量的关键基因之一。在灵长类进化过程中，MCPH1受到强烈的正选择，特别是在人类进化分支中发生了快速的进化，从而可能导致MCPH1的功能分化。为了阐明MCPH1的生物学功能演化的分子机制，我们拟在MCPH1的分子进化分析的前期研究基础上，本项目重点利用细胞水平的功能验证实验，检测人与非人灵长类的MCPH1是否存在功能分化，以及人类、黑猩猩、长臂猿和猕猴等灵长类代表物种的MCPH1蛋白对下游基因调控效应的差异，检验携带人类特异突变的MCPH1基因的调控效应。旨在揭示人类大脑进化过程中，MCPH1基因的调控功能的分化，特别是在脑发育过程中，是如何通过MCPH1调控功能来达到调控神经细胞数目的。研究结果将为我们后期建立MCPH1转基因猕猴模型提供理论依据。

本项目研究严格按照计划进行，超额完成目标，于项目执行期间先后在国际SCI杂志《BMC Biology》,《BMC Evolutionary Biology》, 《Scientific Reports》, 《Human Genetics》发表研究论文各1篇，并在《Molecular Biology and Evolution》发表研究论文2篇，累计影响因子超过40，目前总计被引用35次。. 大脑容量的扩增和高度的认知能力是人类区别于其他非人灵长类重要的特征之一。尽管人与非人灵长类差异很明显，但揭示这一差异的遗传学机制还不清楚，本项目主要通过比较现代人类与非人灵长类甚至与古人类脑容量大小调控基因在各个层面上的差异包括功能分化，甲基化，雌激素调控，来揭示人类大脑进化的遗传学机制。本研究理论上能够让我们更加全面的认识到人类智慧的由来，并进一步为中枢神经系统疾病例如老年痴呆等的治疗提供指导。