INGEBI   02650
INSTITUTO DE INVESTIGACIONES EN INGENIERIA GENETICA Y BIOLOGIA MOLECULAR "DR. HECTOR N TORRES"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
The Developmental Brain Gene NPAS3 Contains the Largest Number of Accelerated Non-Coding Elements in the Human Genome
Autor/es:
GRETEL B. KAMM; LÓPEZ-LEAL RODRIGO; PISCIOTTANO FRANCISCO; KLIGER RAFI; RUBINSTEIN MARCELO; FRANCHINI LF
Lugar:
Montevideo
Reunión:
Congreso; VI International Meeting of the Latin American Society for Developmental Biology; 2012
Resumen:
Using available datasets of human accelerated elements (HAEs) in otherwise highly conserved non-protein coding sequences we found that the neuronal PAS domain-containing protein 3 (NPAS3) gene contains 14 HAEs, the largest number of HAEs for a single gene in the entire human genome. Although NPAS3 is the human gene with the largest cluster of HAEs, its encoded protein is highly conserved among mammals showing an average of ~95 % of identity that increases to 98.7% among primates. Moreover, NPAS3 identity between human and chimpanzee is 99.8 %, with only 2 aminoacid substitutions over 940 residues (A559P and A787G). Together, these data reveal that while the coding region of NPAS3 has been evolving under strong purifying selection, a significant portion of conserved intronic sequences (3.9%) underwent a recent human-specific accelerated evolutionary process. 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. The finding that this gene shows a set of highly conserved putative regulatory regions that evolved faster in the human lineage suggests that it might have acquired a new expression pattern in the human brain and probably a novel function. Using a transposon-based transgenic assay in zebrafish we tested the ability of NPAS3 HAEs to function as developmental enhancers. Our results indicated that 9 HAEs behave as developmental enhancers. Additionally, we performed a comparative expression analysis over selected NPAS3 elements in transgenic mice. So far our results show that ortholog human and mouse sequences of two HAEs display differences in expression patterns in transgenic mouse.