Abstract
Modern genetic studies indicate that human brain evolution is driven primarily by changes in gene regulation, which requires understanding the biological function of largely non-coding gene regulatory elements, many of which act in tissue specific manner. We leverage chromatin interaction profiles in human fetal and adult cortex to assign three classes of human-evolved elements to putative target genes. We find that human-evolved elements involving DNA sequence changes and those involving epigenetic changes are associated with human-specific gene regulation via effects on different classes of genes representing distinct biological pathways. However, both types of human-evolved elements converge on specific cell types and laminae involved in cerebral cortical expansion. Moreover, human evolved elements interact with neurodevelopmental disease risk genes, and genes with a high level of evolutionary constraint, highlighting a relationship between brain evolution and vulnerability to disorders affecting cognition and behavior. These results provide novel insights into gene regulatory mechanisms driving the evolution of human cognition and mechanisms of vulnerability to neuropsychiatric conditions.
Highlights
Modern genetic studies indicate that human brain evolution is driven primarily by changes in gene regulation, which requires understanding the biological function of largely non-coding gene regulatory elements, many of which act in tissue specific manner
Consistent with previous results, human accelerated regions (HARs) were significantly enriched in putative regulatory elements active prenatally[4], the strongest enrichment being observed in fetal brain (Fig. 1a, Supplementary Fig. 1a)
HARs were enriched in regulatory elements that were significantly more likely to be accessible in the germinal zones of the developing cortex[13], highlighting their potential role in cortical neurogenesis (Supplementary Fig. 1d)
Summary
Modern genetic studies indicate that human brain evolution is driven primarily by changes in gene regulation, which requires understanding the biological function of largely non-coding gene regulatory elements, many of which act in tissue specific manner. We find that HARs and HGEs target different genes and molecular pathways and exhibit different developmental trajectories, they converge in terms of their cell-type enrichment patterns These patterns highlight that these elements regulate specific genes involved in primate cortical expansion enriched in neural progenitors of the outer subventricular zone (oSVZ), and their progeny, supragranular neurons, providing a regulatory map for understanding the molecular mechanisms underlying human cortical expansion. Both forms of regulatory elements converge on genes that are highly conserved at the protein level, consistent with the model that noncoding regulatory elements drive evolutionary divergence by regulation of essential, highly constrained transcripts. We use CRISPR activation in primary human neural progenitors to validate the functional impact of HARs predicted to regulate three highly conserved genes involved in brain patterning, GLI2, GLI3, and TBR1
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