1Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 2Department of Anthropology, University of Oregon, 3Department of Anthropology, The George Washington Univeristy, 4Department of Anthropology, Northwestern University, 5Departments of Pediatrics and Neurology, Wayne State University School of Medicine
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Using genomic data to identify developmental changes in gene expression is of fundamental importance in understanding human brain evolution. Human brain development follows a unique pattern characterized by a prolonged period of postnatal growth and reorganization, in addition to a postnatal peak of glucose utilization. The molecular processes underlying these developmental changes are poorly characterized. We used microarrays (48,803 probes) to determine age-related patterns of mRNA expression in human cerebral cortical samples ranging from infancy to adulthood. In contrast to previous developmental gene expression studies of human neocortex using postmortem tissue, we measured mRNA expression derived from surgically resected samples. We used regression models designed to identify transcripts that followed significant linear or curvilinear functions of age and used population genetics techniques to examine the evolution of these genes. We identified 40 transcripts that demonstrated gene expression trajectories that were significantly associated with age. Sixteen transcripts show similar patterns of expression change with age, characterized by high expression in infancy and childhood and decreasing expression postadolescence. In addition, we downloaded sequences of noncoding regions of these genes in 21 recently sequenced human genomes available from 1000 Genomes Project. We used an extension of the McDonald-Kreitman test that compares neighboring coding and non-coding sequences to examine adaptive evolution in putative regulatory regions. Comparative genomic analyses revealed that three of these genes (BCAN, GRIN3A, STAT4) show evidence of adaptive evolution. These findings provide evidence that a subset of genes expressed in the human cerebral cortex mirror developmental patterns of cortical glucose consumption.
This research is funded by the National Science Foundation grants (BCS0827546 and BCS0827531).