An Integrative Study of the Genetic and Molecular Basis of Human Brain Evolution

人类进化的一个标志是我们大脑的特殊大小和复杂性。先前的遗传学研究表明，人类大脑特有的基因在DNA序列和基因表达水平上都表现出特定的进化特征。然而，这种分子变化的原因尚不清楚。拟议的研究将采用遗传、表观遗传和基因表达分析的综合方法来研究人脑进化的分子基础。这项研究的一个中心假设是，表观遗传变化，特别是DNA甲基化的变化，促进了人类大脑的进化。DNA甲基化是基因组DNA的关键表观遗传修饰，介导基因型和表型之间的信息传递。 本研究的目的是首先生成多个人类、黑猩猩、猕猴和绒猴的DNA甲基化图谱。这些新的数据将与相同样本的基因表达图谱相结合。通过这样做，我们可以回答1）DNA甲基化水平是否在所研究的灵长类动物大脑中表现出特定的进化趋势，2）DNA甲基化变化是否以物种特异性的方式与基因表达变化相关，以及3）这种变化是否对与大脑大小和复杂性相关的基因更为明显。因此，拟议的研究将阐明人类大脑中DNA甲基化的进化变化和功能后果。 拟议的研究是综合性的，将有助于培养不同学科的本科生和研究生，包括灵长类动物进化，遗传学，分子人类学和比较基因组学。拟议的研究是与机构的推广计划，格鲁吉亚工业奖学金教师，在亚特兰大大都会地区的高中学生和教师提供培训相结合。作为拟议研究的中心活动，将开发一个开放获取网站，包含有关研究物种的基因组，表观基因组和表达差异的全面信息。最后，拟议的研究将增加我们对人类大脑进化的遗传和分子基础的理解，这是人类进化最迷人的方面之一。

A hallmark of human evolution is the exceptional size and complexity of our brains. Previous genetic studies have revealed that genes that are specific to human brains show particular evolutionary characteristics both at the DNA sequence and at the level of gene expression. However, the causes of such molecular changes are not known. The proposed research will investigate the molecular basis of human brain evolution using an integrative approach of genetic, epigenetic, and gene expression analyses. A central hypothesis of the proposed research is that epigenetic changes, in particular changes of DNA methylation, have facilitated the evolution of human brains. DNA methylation is a key epigenetic modification of genomic DNA that mediates information transfer between the genotype and phenotypes. The objectives of this study are first to generate DNA methylation maps of multiple humans, chimpanzees, macaques and marmosets. This novel data will be then integrated with gene expression maps of the same samples. By doing so, we can answer 1) whether DNA methylation levels exhibit a particular evolutionary trend among the primate brains examined, 2) if DNA methylation changes are correlated with gene expression changes in a species-specific manner, and 3) whether such changes are more pronounced for genes that are pertinent for the brain size and complexity. Consequently, the proposed research will elucidate the evolutionary changes and the functional consequences of DNA methylation in human brains. The proposed research is integrative in nature and will contribute to training undergraduate and graduate students in diverse disciplines including primate evolution, phylogenetics, molecular anthropology, and comparative genomics. The proposed research is integrated with an institutional outreach program, Georgia Industrial Fellowship for Teachers, to provide training for high school students and teachers in the metro Atlanta area. As a central activity of the proposed research, an open access website harboring comprehensive information on genomic, epigenomic and expression differences of the study species will be developed. Finally, the proposed research will increase our understanding of the genetic and molecular basis of the evolution of human brains, which is one of the most fascinating aspects of human evolution.