灵长类大脑进化分子机制的转基因猕猴研究

The genetic mechanism of evolution of phenotypic and functional traits is one of the key biological questions, which serves as the basis for the synthetic theory combing genetics, development and evolution. The primate brain is a typical reflection of complex traits in animals. Dissecting the genetic mechanism of primate brain evolution is an important way of understanding the comprehensive cognitive skills of primates and the superior cognitive ability of humans. Based on previous study of cellular and transgenic mouse analyses, this project aims to construct a model of transgenic monkeys in order to reveal the functional consequences of the rapid evolution of the brain-size-control gene MCPH1 in primates using combined analyses of molecular, cellular, organ-level and cognitive tests. To dissect the influence of MCPH1 copies of different primate species on brain development, especially on the origin of the human brain, providing experimental evidence to primate brain evolution and origin of human intelligence. The novelty of this project lies in the application of evolutionary approaches in understanding primate brain development and the molecular mechanism of cognition. Furthermore, due to the close relationship between monkeys and humans as well as their brain structure, the transgenic monkey platform to be established in this project will provide highly useful tools and research paradigms of studying human brain function.

物种表型与功能进化的遗传机制是生物学的核心问题，也是建立遗传、发育和进化统一理论的基础。灵长类大脑是动物复杂性状的最典型体现，对其进化分子机制的阐明是了解灵长类复杂认知行为和人类智力起源的重要途径。本项目在前期细胞和转基因小鼠工作的基础上构建脑容量控制基因MCPH1的转基因猕猴模型，从分子、细胞、组织、器官和认知层面系统地研究MCPH1基因在灵长类中快速进化的功能后果；揭示不同灵长类物种MCPH1基因拷贝对大脑发育的影响，特别是人类特异的序列变异对人类大脑容量和结构起源的贡献及其作用的分子机制，为阐明灵长类大脑进化和人类智力起源的遗传基础提供实验进化生物学的证据。本项目的特色和创新之处在于将灵长类大脑发育和认知行为的分子机制问题放在进化的框架下进行研究。同时，由于猕猴同人类较近的亲缘关系和相似的大脑结构，本项目猕猴转基因模型的建立将为人类脑功能的研究提供一个非常有用的技术平台和研究范式。

灵长类在进化过程中形成了独特的大脑结构和发育模式。为了解析大脑发育关键基因MCPH1在灵长类进化过程中产生的序列变异对大脑发育和认知功能的影响，我们利用慢病毒系统成功建立了携带人类MCPH1基因拷贝的转基因猕猴模型。利用影像学、免疫组化以及分子技术手段的综合分析发现，转入人类MCPH1基因使得猕猴大脑发育表现出与人类相似的延迟现象。同时，我们构建了MCPH1基因敲除猕猴模型，通过和转基因猕猴进行比较分析，确定了MCPH1调控灵长类大脑发育和表型进化相关的基因和调控通路。另外，我们利用三代测序技术构建了高质量的中国猕猴参考基因组，并利用表观组学构建了猕猴大脑神经发育高峰期的三维基因组图谱。这两项基础工作的开展奠定为MCPH1转基因猕猴大脑发育分子机制的研究提供了重要的支撑。本项目通过对灵长类大脑进化关键基因MCPH1的研究，揭示了灵长类大脑容量和认知能力改变的遗传基础和分子机制。本项目中猕猴转基因模型的建立将有可能为人类脑功能和脑疾病的研究提供一个崭新的研究平台，为最终阐明人类智力的神经和遗传基础提供极具价值的数据。