A Human Accelerated Region participates in early human forebrain patterning and expansion

Abstract

The expansion of the mammalian brain is associated with specific developmental processes; however, not much is known about how evolutionary changes participated in the acquisition of human brain traits during early developmental stages. Here we investigated whether enhancers active during the phylotypic stage show human-specific genomic divergence which could contribute to the evolutionary expansion of the forebrain. Notably, we identified an active enhancer containing a human accelerated region (HAR) located in the Chromosome 14q12, a region enriched with neurodevelopmental genes, such as Foxg1, Nkx2.1 and Nova1. Reporter analysis revealed that the human variant is active in the forebrain in transgenic mice and that it has stronger enhancer activity than the mouse or chimpanzee versions. Humanization of the mouse enhancer variant in transgenic mice and in mouse organoids resulted in an expansion of Foxg1 expressing domains in the forebrain early neural progenitors with a bias towards dorsal identities. Overall, our results suggest that human-specific mutations in critical regulatory elements controlling early brain development impact the expansion and patterning of the forebrain.

Modeling uniquely human gene regulatory function in humanized mice

“…Many HARs act as transcriptional enhancers during embryonic development, particularly in structures showing human-specific morphological changes such as the brain and limb (7)(8)(9)(10)(11)(12). HARs have also been shown to exhibit human-specific changes in enhancer activity, both in transgenic assays and in massively parallel reporter assays in cultured cells (7,9,10,(13)(14)(15)(16)(17). These findings suggest a critical contribution for HARs in human evolution and support the long-standing hypothesis that changes in developmental gene regulatory programs contribute to evolutionary innovation (18,19).…”