Genetic Basis of Human Brain Evolution: Bioinformatics and Expression Analysis of Human Accelerated Regions in Transgenic Mice

GRETEL B. KAMM, RODRIGO LÓPEZ-LEAL, MARCELO RUBINSTEIN AND LUCÍA F. FRANCHINI

Tucumán, Argentina

Congreso; SAIB; 2009

SAIB

Exceptional cognitive capacities set humans apart among primates. Comparative genomics revealed that phenotypic divergence between humans and close related primates is mainly due to changes in gene regulation rather than in protein-coding sequences. To search for genetic evidences of human evolution we analyzed 202 genomic regions evolving very slowly in vertebrates but significantly faster in the human lineage (termed human accelerated regions [HARs]) that have been recently identified. The largest cluster of HARs is located within 648 kb of the neuronal PAS domain protein 3 (NPAS3) gene. NPAS3 encodes a bHLH-PAS transcription factor that is broadly expressed in the developing mouse nervous system, and its dysfunction has been associated with schizophrenia in humans. In order to explore the participation of NPAS3 HARs on this gene regulation we generated transgenic mice carrying HAR mouse ortholog sequences upstream of Hsp68 minimal promoter and the reporter gene lacZ.  Two Npas3 HARs were able to partially recapitulate the embryonic expression pattern of the endogenous gene suggesting their participation as Npas3 developmental enhancers. The identification of these HARs as functional NPAS3 enhancers will allow us to perform a comparative expression analysis of the human and mouse orthologs and to investigate their potential role in human brain evolution.