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

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

Huerta Grande

Congreso; II Reunion Conjunta de Neurociencias; 2010

Sociedad Argentina de Investigación en Neurociencias

It has been hypothesized that the unparalleled explosion in human cognitive capacities and behavioral repertoire is due the acquisition of new temporal and spatial expression patterns of preexisting genes rather than changes in the protein-coding sequences. In order to study differences in gene regulation which may have contributed to the evolution of human brain we are functionally characterizing some of the most rapidly evolving human elements yet identified (termed human accelerated regions [HARs]). We focused on the largest cluster of HARs located within 648 kb of the neuronal PAS domain protein 3 (NPAS3) gene. Using a transposon-based transgenic assay in zebrafish we tested the ability of NPAS3-HARs to function as developmental enhancers. Additionally, we performed a comparative expression analysis in transgenic mice. Two human and mouse NPAS3-HARs ortholog sequences were able to drive reproducible patterns of reporter expression across three mouse developmental stages partially recapitulating the endogenous Npas3 expression pattern. These findings suggest the participation of tested sequences in NPAS3 developmental expression. This approach is allowing us to analyze the role of human NPAS3-HARs in gene regulation and their potential role in human brain evolution.