Cognitive Neuroscience - Dear Colleague Letter: Genomic Changes that During Human Origins Increased the Brain's Cognitive Capacities

大脑功能蛋白表达和结构的适应性变化可能是人类无与伦比的认知能力和复杂心理行为的关键过程。对潜在的正选择基因组变化的搜索将通过功能基因组学和分子系统遗传学的方法进行。这项研究将集中在前扣带皮层（ACC）上，这是一个新的皮质区域，涉及监控和修改任务特定行为（执行功能），这些行为需要新的反应或克服干扰反应，这可能将人类与其他灵长类动物区分开来。在人类的前扣带皮层中存在着一种独特的梭形投射神经元群，在普通黑猩猩和倭黑猩猩（人类的姐妹群）、大猩猩（近亲）和猩猩中也有少量的细胞，但在任何其他灵长类动物或其他哺乳动物中都没有。此外，在5种猿类中，猩猩的纺锤体神经元最少，倭黑猩猩的纺锤体神经元最多。因此，有理由假设达尔文的积极选择在人类进化史的最近阶段对编码ACC细胞结构和功能相关蛋白质的基因起了作用。DNA阵列将用于分析数千个基因的基因表达水平，这些基因编码ACC中起作用的蛋白质。比较人类和黑猩猩ACC中数千个基因的表达水平，将确定候选基因，即在表达水平上显示显着物种差异的基因子集。原位杂交将用于定位表达候选基因的细胞群，从而测试候选基因将在纺锤形投射神经元中共定位的预测。由于候选基因可能参与功能性相互作用的生化途径，ACC中的基因表达数据应有助于认知神经科学家阐明ACC在人类认知中的作用。这些和其他候选基因将在一系列类人猿和原猿灵长类动物中进行分析，以寻找控制基因表达的顺式调控元件的变化，并确定在人类祖先中编码的蛋白质是否经历了快速氨基酸替换的爆发。这种方法建立在先前的研究基础上，该研究表明，作为线粒体氧化能量代谢途径一部分的许多蛋白质经历了这种正选择氨基酸替代的爆发。这个为期一年的项目将证明这种方法的有效性，并将为未来更广泛、更全面的研究奠定基础，以确定一些重要的基因变化的特征，这些基因变化导致了大脑较大的灵长类动物的出现。

Adaptive changes in the expression and structures of brain functioning proteins may have been the crucial process responsible for humankind's unrivaled cognitive abilities and complex mental behavior. A search for the underlying positively selected genomic changes will be conducted by the methods of functional genomics and molecular phylogenetics. This search will focus on the anterior cingulate cortex (ACC), a neocortical region involved in monitoring and modifying task-specific behaviors (executive function) that require novel responses or overriding interfering responses and that may separate humans from other primates. A unique population of spindle shaped projection neurons is present in the ACC in humans and with lesser numbers of cells in common and bonobo chimpanzees (the sister-group of humans), gorillas (next closest relative), and orangutans but not in any other primates or other mammals. Moreover, among the five ape species, the orangutan ACC has the least spindle neurons and the bonobo ACC has the most. Thus, there is reason to hypothesize that Darwinian positive selection acted during the more recent stages of humankind's evolutionary history on the genes encoding proteins involved in the ACC's cellular architecture and function. DNA arrays will be used to analyze gene expression levels of thousands of genes that encode proteins that function in the ACC. Comparing the expression levels of these thousands of genes in the human vs. chimpanzee ACC will identify candidate genes, the subset of genes that show marked species differences in expression levels. In situ hybridization will be used to locate the cell populations that express the candidate genes, thereby testing the prediction that the candidate genes will co-localize in the spindle shaped projection neurons. As the candidate genes are likely to be involved in functionally interacting biochemical pathways, this gene expression data in the ACC should assist cognitive neuroscientists in elucidating the role of the ACC in human cognition. These and other candidate genes will be analyzed in a series of anthropoid and prosimian primates to look for changes in the cis-regulatory elements that control expression of the genes and to determine whether the encoded proteins underwent bursts of rapid amino acid replacements during humankind's ancestry. This approach builds upon previous work showing a number of proteins that are part of the mitochondrial oxidative energy metabolism pathway have undergone such bursts of positively selected amino acid replacements. This one-year project will show the validity of this approach and will set the stage for a more widespread and comprehensive attack in the future to characterize some of the important genetic changes that allowed the emergence of the large-brained primates.