A fast-evolving human NPAS3 enhancer gained reporter expression in the developing forebrain of transgenic mice

Abstract

The developmental brain gene NPAS3 stands out as a hot spot in human evolution since it contains the largest number of human-specific fast-evolving conserved non-coding elements. In this paper we studied 2xHAR142, one of these elements that is located in the 5th intron of NPAS3. Using transgenic mice we show that the mouse and chimp 2xHAR142 orthologs behave as transcriptional enhancers driving expression of the reporter gene lacZ to a similar NPAS3 expression subdomain in the mouse central nervous system. Interestingly, the human 2xHAR142 ortholog drives lacZ expression to an extended expression pattern in the nervous system. Thus, molecular evolution of 2xHAR142 provides a first documented example of human-specific heterotopy in the forebrain promoted by a transcriptional enhancer and suggests that it may have contributed to assemble the unique properties of the human brain.