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Molecular features driving cellular and regulatory complexity of human brain evolution [ATAC-seq]

ABSTRACT: Genomic changes acquired in human evolution contribute to the unique abilities of human brain. However, characterizing the molecular underpinnings of human-specific traits is a multifaceted challenge due to the cellular heterogeneity of human brain and complex regulation of gene expression. Here, we performed single-nuclei RNA-sequencing (snRNA-seq) and single-nuclei ATAC-seq (snATAC-seq) in human, chimpanzee, and rhesus macaque brain tissue (brodmann area 23, posterior cingulate cortex). Human-specific changes were distinct among neuronal subtypes indicating that human brain evolution was accompanied by molecular alterations in finer cellular resolution. We also observed more human-specific alterations in epigenome compared to transcriptome. Interestingly, human-specific accessibility changes in neurons were not as concordant with gene expression changes in comparison to other species, partially explaining this discrepancy. These cis-regulatory elements were enriched for immediate early gene motifs, identifying accelerated evolution of activity regulated genes in humans. We also uncovered associations between human evolution and brain disease genes at the cell type level. Together, these results reveal multiple mechanisms for human brain evolution at cell type resolution and establish the first direct evidence for accelerated human-specificity of activity-dependent molecular changes.

ORGANISM(S): Pan troglodytes Homo sapiens Macaca mulatta

PROVIDER: GSE192772 | GEO | 2023/04/26

REPOSITORIES: GEO

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Project description:Human Accelerated Regions (HARs) are highly conserved across species but exhibit a significant excess of human-specific sequence changes, suggesting they may have gained novel functions in human evolution. HARs include gene regulatory elements with human-specific activity and have been implicated in the evolution of the human brain. However, our understanding of how HARs contributed to uniquely human features of the brain is hindered by a lack of insight into the genes and pathways that HARs regulate. It is unknown whether HARs acted by altering the expression of gene targets conserved between HARs and their chimpanzee orthologs or by gaining new gene targets in human, a mechanism termed enhancer hijacking. We generated a high-resolution map of chromatin interactions for 1,590 HARs and their orthologs in human and chimpanzee neural stem cells (NSCs) to comprehensively identify gene targets in both species. HARs and their chimpanzee orthologs targeted a conserved set of 2,963 genes enriched for neurodevelopmental processes including neurogenesis and synaptic transmission. Changes in HAR enhancer activity were correlated with changes in conserved gene target expression. Conserved targets were enriched among genes differentially expressed between human and chimpanzee NSCs or between human and non-human primate developing and adult brain. Species-specific HAR gene targets did not converge on known biological functions and were not significantly enriched among differentially expressed genes, suggesting that most HARs did not alter gene expression via enhancer hijacking. HAR gene targets, including differentially expressed targets, also showed cell type-specific expression patterns in the developing human brain, notably in outer radial glia, which are hypothesized to contribute to human cortical expansion. Our findings support that HARs influenced human brain evolution by altering the expression of a conserved set of gene targets and provide the means to functionally link HARs with novel human brain features.

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Molecular features driving cellular and regulatory complexity of human brain evolution [ATAC-seq]

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