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

Wayne State University, Detroit MI

Investigators

Abstract

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.