种内种间大脑发育差异的系统性进化机制研究

Human brain evolution represents on of the major phenotypic transitions that occurred during short time period in the recent past. Investigation of molecular changes that took place in the process of human brain evolution combined with study of intra-species variation among contemporary human populations that followed this speciation event gives us a unique opportunity to reconstruct micro-evolutionary mechanisms underlying this major phenotypic transition. In this project, we propose to approach this question by conducting a comprehensive genome-wide study of human brain development at various levels of molecular phenotype: transcriptome, proteome and metabolome. In parallel, we will determine its human-specific features by comparison to the developmental time-series data collected in brains of closely related non-human primates: chimpanzees and rhesus macaques. Finally, we will trace variation of human-specific features among three major contemporary human populations: Asians, Africans and Europeans at all levels of molecular phenotype. The resulting data will allow us to determine molecular mechanisms underlying human-specific changes and to identify causative evolutionary events through reconstruction of complex interplay of the genome sequence changes and changes in transcriptional and post-transcriptional regulatory networks, as well as structural changes to transcripts and proteins. Use of metabolome measurements collected in the same brain samples will allow us to assess functional consequences of observed regulatory and structural changes. Finally, evolutionary events predicted to result in human-specific changes would be tested in the cell line and animal models. Taken together, these results may allow us reconstruct evolutionary events leading to emergence of the human-specific cognitive phenotype and assess further evolutionary direction based on divergence among present-day human populations.

人脑的进化是极具有代表性的生物性状大演变。从灵长类动物大脑发育进化方面，结合现代人群体间的遗传差异性，对大脑功能进行深入、系统地研究有着重要的医学、临床、生物学乃至社会意义。本项目旨在使用高通量测序技术，蛋白质质谱测量技术，以及LC-MS/MS代谢物测量手段，对发育过程中不同年龄的人、黑猩猩和恒河猴的三个不同脑区进行转录组、蛋白组和代谢组全基因组范围的定量和分析比较，筛选出人类特异的分子标记。此外，结合这些人类特异的分子标记，在三个组学上研究现代人群的遗传差异性。通过研究基因相互作用，构建基因组序列差异、转录本和蛋白质的结构变化、转录和转录后差异的调控网络，揭示人脑特异的分子机制。代谢组的数据有助于了解转录调控和分子结构的变化导致的功能性后果。最后，本项目将用细胞系和动物模型验证进化过程中认知的差异。该项研究可有利于追溯那些涉及人类特异认知的进化事件，预见人类未来可能的进化方向。

人脑的进化是极具有代表性的生物性状大演变。从灵长类动物大脑发育进化方面,结合现代人群体间的遗传差异性,对大脑功能进行深入、系统地研究有着重要的医学、临床、生物学乃至社会意义。本项目使用高通量测序技术,LC-MS/ MS， GC-MS代谢物测量手段,对发育过程中不同年龄的人、黑猩猩和恒河猴的三个不同脑区进行转录组、代谢组全基因组范围的定量和分析比较，筛选出了人类特异的分子标记，构建了第一个人类及近缘物种大脑皮层层次结构的转录组图谱，发现了代谢物和脂类的组成在人类大脑特异功能形成过程中的作用，大规模研究了脂质在新皮质脑区进化发育过程中的作用，并且发现人脑发育过程中特殊的调控机制。此外,我们还研究了不同人群中的大脑发育的遗传多样性，我们发现脂类代谢酶以及脂类本身在欧洲人群体中发生了显著的进化差异。这一结果与尼安德特人对现代欧洲人大脑脂类组组成的贡献相一致。暗示尼安德特人遗传变异可能影响、塑造了现代欧洲人的某些脂类分解代谢过程。综合所有研究结果，我们可以重构人脑发育的进化事件。