Abstracts

Rationale: Little is known about the chromosomal organization of genes involved in human epilepsy. Here, we have taken a functional genomic approach to map and characterize the evolutionary, cellular, and functional patterns of differentially expressed human neocortical genes. Methods: In order to understand the genomic organization of human epileptic gene transcription, we compared protein coding and non-coding gene transcription between human neocortical brain regions with low versus high interictal activity recorded in vivo from 20 epileptic patients. Using microarrays, differential gene expression of both protein coding and long non-coding RNAs (lncRNAs) were measured. We mapped the spatial organization of transcription, compared coding to non-coding transcription, examined the evolutionary significance, examined promoter usage, and identified clusters of genes involved in specific cell types and functional pathway. Results: We found the presence of 33 non-random gene clusters or ""hotspots"" of increased or decreased transcription throughout the genome. In these genomic clusters, 19 were found to be recently evolved, and 12 of these contained one or more modern human specific genomic regions. Further analysis found that seven of these gene clusters contain specific promoter modules that could explain part of the mechanism behind the differential expression of these genes. We identified at least of these 4 gene clusters that contain known association to genetic disorders associated with seizures. As non protein-coding genes may have important regulatory functions, we detected a significant over-representation of non-coding gene transcription occurring within 150kb of the transcription of protein coding genes, suggesting novel transcriptional control mechanisms associated with epileptic brain activity. Finally, differential expression of many of these gene clusters implicate changes in specific cell types previously found to be implicated in the electrical activity of the epileptic brain. Conclusions: Functional genomic analysis of the human neocortex resected from epilepsy patients provides new insights into the genomics and genetics of human brain activity and begins to decode what makes the human brain unique from other species.