| David Haussler?s laboratory has recently identified a number of genomic elements that display a high level of DNA-sequence conservation outside the human lineage but have rapidly evolved since we diverged from our common ancestor with chimpanzees. Clearly, comparative genomics has proven its value in identifying functional non-coding genomic elements that may have contributed to human-specific features. However, the increasing availability of genome-wide epigenomic data, indicating the biochemical activity of genomic DNA, has revealed a considerable discrepancy between evolutionary DNA-sequence constraint and actual annotated functionality of DNA elements. Therefore, one may expect that a large number of yet unidentified functional elements (such as enhancers) exists in the non-coding part of the genome showing more moderate evolutionary constraint. Through a functional approach, complementing comparative genomics strategies, I will aim to identify functional elements on the genome, disregarding evolutionary constraint as primary selection criteria. With the goal of defining a molecular basis for human-specific brain features, I will perform genome-wide profiling of histone-methylation marks and transcription factor (TF)-binding sites in human and mouse ES-cell derived neurons to identify genomic elements that display an epigenomic signature unique to the human lineage. These elements may act as human-specific transcriptional enhancers with regards to spatial, temporal or quantitative regulatory properties, which will be validated in transgenic ES-cell lines. Finally, high-confidence human-specific enhancers will be analyzed in transgenic mouse lines to determine their gene-regulatory roles in the brain and assess whether and how they may have contributed to human-specific brain features. |
