通过转基因小鼠模型在转录组和代谢组水平上解析GLUD2基因在人类认知功能进化过程中的调控机制

The brain is the most complex organ in the human body with the big brain volume and the high cognitive ability, but the molecular mechanism that led to such a high level of cognitive ability is unclear. The results show that GLUD2 originated by retroposition from GLUD1 in the hominoid ancestor less than 23 million years ago. It was suggested that the appearance of this new gene was probably beneficial to the evolution of the glutamate or energy metabolism of the hominoid brain and the cognitive ability. Although considerable progress has been made in the past two decade, for example, localization, structure and function of encoded isoenzyme, many issues related to this interesting protein remain unanswered. We still do not know to what extent GLUD2 is involved in nervous system and cognitive ability. In this project we propose to approach this question by conducting a comprehensive genome-wide study at transcriptome and metabolome level on GLUD2 transgenic mice brain. In parallel, we will determine the differentially expressed gene by comparing to the developmental time-series data collected in brains of transgenic and wild-type mice. The resulting data will allow us to identify causative evolutionary events through comparative analysis on human-rhesus brain data which was published previously. Finally, use of metabolome measurements collected in the same samples will allow us to assess functional consequences of observed regulatory network. Taken together, these results may lead us to understand the important biological function of GLUD2 and to understand evolutionary events leading to emergence of human-specific cognitive phenotype.

人类脑容量的增加和认知能力的提高是进化过程中最突出的生物特征，但是导致人类具有这种能力的遗传学机制尚不清楚。GLUD2是谷氨酸脱氢酶的两种同工酶之一，在人和猿类的脑中特异表达。约在两千多万年前，GLUD1通过随机突变和定向选择产生GLUD2。GLUD2的出现有可能加速了大脑认知能力的巨大飞跃。尽管对GLUD2从分子生物学和进化生物学上已有一定的研究，但一直缺乏系统全面的分子机理研究。本项目利用野生型和GLUD2转基因小鼠为材料，通过RNA-Seq测序技术和GC-MS/CE-MS质谱技术，对整个发育阶段的小鼠大脑进行转录组和代谢组全面测量。进而利用比较生物学方法，结合已有的人和恒河猴大脑基因表达数据，系统分析GLUD2在两种不同基因型小鼠大脑中的功能差异，找到关键调控机制以及代谢通路，以探索GLUD2在人脑中的重要生物学功能，并为最终阐明人类大脑功能演化与高级认知能力的调控机制提供依据。

人类脑容量的增加和认知能力的提高是进化过程中最突出的生物特征,但是导致人类具有这种能力的遗传学机制尚不清楚。GLUD2是谷氨酸脱氢酶的两种同工酶之一,在人和猿类的脑中特异表达。约在两千多万年前,GLUD1通过随机突变和定向选择产生GLUD2。GLUD2 的出现有可能加速了大脑认知能力的巨大飞跃。尽管对GLUD2从分子生物学和进化生物学上已有一定的研究,但一直缺乏系统全面的分子机理研究。本项目利用野生型和GLUD2转 基因小鼠为材料,通过RNA-Seq测序技术和GC-MS/CE-MS质谱技术,对整个发育阶段的小鼠大脑进行转录组和代谢组全面测量。进而利用比较生物学方法,结合已有的人和恒河猴大脑基因表达数据,系统分析GLUD2在两种不同基因型小鼠大脑中的功能差异,发现GLUD2的代谢效应集中在三羧酸循环上，表明了在大脑早期发育中GLUD2具有调节能量和碳代谢的特殊作用，并且GLUD2在基因表达和代谢物浓度上的效应在早期发育阶段中是最明显的，揭示了GLUD2在分子水平特别是脂质合成中对人脑功能的影响，以及其在人脑功能演化以及认知能力进化中所扮演的角色。