Abstract
Speciation is associated with substantial rewiring of the regulatory circuitry underlying the expression of genes. Determining which changes are relevant and underlie the emergence of the human brain or its unique susceptibility to neural disease has been challenging. Here we annotate changes to gene regulatory elements (GREs) at cell type resolution in the brains of multiple primate species spanning most of primate evolution. We identify a unique set of regulatory elements that emerged in hominins prior to the separation of humans and chimpanzees. We demonstrate that these hominin gains perferentially affect oligodendrocyte function postnatally and are preferentially affected in the brains of autism patients. This preference is also observed for human-specific GREs suggesting this system is under continued selective pressure. Our data provide a roadmap of regulatory rewiring across primate evolution providing insight into the genomic changes that underlie the emergence of the brain and its susceptibility to neural disease.
Highlights
Speciation is associated with substantial rewiring of the regulatory circuitry underlying the expression of genes
To assess regulatory changes across primate evolution, we focused on H3K27ac enrichment and compared our data to active gene regulatory elements (GREs) identified in rhesus macaque, chimpanzee and human in prefrontal cortex (PFC) and CB (Supplementary Fig. 2a, b)[14]
In agreement with previous analysis we found a correlation between regions that were deregulated in autism spectrum disorder (ASD) patients and genome-wide association (GWAS) variants linked to schizophrenia (Supplementary Fig. 8a)
Summary
Speciation is associated with substantial rewiring of the regulatory circuitry underlying the expression of genes. We identify a unique set of regulatory elements that emerged in hominins prior to the separation of humans and chimpanzees We demonstrate that these hominin gains perferentially affect oligodendrocyte function postnatally and are preferentially affected in the brains of autism patients. As the human brain is the result of a process that spans the entirety of primate evolution, giving rise to primate brains of variable sizes and cognitive complexities[1,6], its understanding may require a broader evolutionary context This is especially relevant given the absence of pervasive data on neural disorders in great apes[7] and the challenges in assessing their cognitive abilities[8]. We identify a set of regulatory changes that emerged after the separation from old world monkeys but prior to the separation between chimpanzee and human These elements are referred to as hominin-specific and are preferentially enriched in oligodendrocytes in adults and deregulated in the brains of autism spectrum disorder (ASD) patients. We propose that evolution of regulatory DNA in hominins may have helped set the stage for the emergence of the human brain and its susceptibility to disease
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