INGEBI   02650
INSTITUTO DE INVESTIGACIONES EN INGENIERIA GENETICA Y BIOLOGIA MOLECULAR "DR. HECTOR N TORRES"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Searching the genetic basis underlying the evolution of the human brain.
Autor/es:
FRANCHINI LF
Lugar:
Dublin
Reunión:
Congreso; Society for Molecular Biology and Evolution; 2012
Resumen:
It has been hypothesized that the evolution of the unique human cognitive capacities is due to the acquisition of new temporal and spatial expression patterns of preexisting genes rather than changes in the protein-coding sequences. Using a combination of bioinformatics and functional studies including the generation of transgenic zebrafish and mice we are investigating differences in gene regulation which may have contributed to the evolution of the human brain. I will present here our results involving the functional characterization of the largest cluster of the most rapidly evolving human elements yet identified [termed human accelerated elements (HAEs)] located within 648 kb of the neuronal PAS domain-containing protein 3 (NPAS3) gene. We tested the ability of the 14 NPAS3-HAEs to function as developmental enhancers using a transposon-based transgenic assay in zebrafish. Our results indicated that 9 HAEs behave as developmental enhancers. The finding that the NPAS3 gene shows a set of highly conserved regulatory regions that evolved faster in the human lineage suggests it might have acquired a new expression pattern and probably a novel function. In order to test this hypothesis, we performed a comparative expression analysis over selected NPAS3 elements in transgenic mice. We found that one of the selected HAEs acts as a neurodevelopmental enhancer driving the expression of the reporter gene lacZ between E9.5 and E14.5 in a subdomain of the NPAS3 expression pattern in mice. We also observed that the human ortholog of this HAE shows a new expression territory in the developing cortex. The NPAS3 gene is a transcription factor of the bHLH-PAS family that is broadly expressed in the developing mouse nervous system playing an important role in normal brain development and neurosignaling pathways. In addition, its dysfunction has been associated with schizophrenia in humans. Our results indicated that the regulation of NPAS3 has been shaped during human evolution. In addition, our data suggest that changes in the expression pattern acquired by at least one of the NPAS3 regulatory regions could have contributed to changes in the spatio-temporal expression of NPAS3 in the human lineage and, therefore, to play unique roles during human brain development and mental illness.