Transcriptome organization in human and chimpanzee brains.

다국어 초록 (Multilingual Abstract)

Humans possess a unique and powerful brand of cognition that is seemingly discontinuous from the rest of the animal kingdom. Yet at a molecular level, our genome is remarkably similar to that of our closest living relative, the chimpanzee. At the heart of this apparent paradox is the finite set of molecular instructions that distinguish human and chimpanzee brain development and function. These instructions can be directly studied by comparing the organization of human and chimpanzee brain transcriptomes through systematic analysis of gene coexpression relationships. In this dissertation, two studies are presented that provide a new perspective on the molecular evolution of the brain. In the first, gene coexpression networks in human and chimpanzee brains were compared across matched cortical and sub-cortical brain regions. This study found that large modules of coexpressed genes corresponded to functionally relevant brain anatomy and introduced an approach for comparing module conservation between the species. Module conservation was significantly weaker in cortex than in sub-cortical brain regions. This study also provided evidence that interspecies differences in a gene's network position could be related to differences in expression levels and protein sequence, suggesting that differential connectivity in gene coexpression networks might serve as a unifying principle for disparate types of evolutionary change. In the second study, region-specific gene coexpression networks were generated from human cerebral cortex, caudate nucleus, and cerebellum. This study identified modules of coexpressed genes that corresponded to neurons, oligodendrocytes, astrocytes, and microglia, invalidating the commonly held assumption that cellular heterogeneity precludes the recovery of cell type-specific information in microarray data generated from whole brain tissue and providing an initial description of the transcriptional programs that distinguish the major cell classes of the human brain. Other modules distinguished additional cell types, organelles, synaptic function, response to hypoxia, gender differences, and the subventricular neurogenic niche. The characterization of gene coexpression network architecture in specific human brain regions provides a new foundation for exploring molecular changes that have occurred in specific cell types or functional processes during recent human and chimpanzee brain evolution.