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NIH Team Links Single-Nucleotide Mutations to Higher Brain Functioning in Humans

Many small mutations may be responsible for driving the features of the human brain that enable advanced cognition, according to a study appearing this week in Science Advances. The neocortex is a mammalian brain innovation that handles higher functioning, and its size and complexity in humans underlies our unique brain capabilities. Yet the evolutionary and regulatory mechanisms behind the expansion and functional elaboration of the neocortex in humans are unclear. To investigate, a group from the National Institutes of Health developed a deep learning model that they combined with human and macaque embryonic neocortical H3K27ac chromatin immunoprecipitation sequencing data to quantify the functional effect of single-nucleotide mutations on enhancer activity. They identify around 4,000 enhancer gains in humans that can often be attributed to single-nucleotide essential mutations. Further analysis suggests that "functional gains in embryonic brain development are associated with de novo enhancers whose putative target genes exhibit increased expression in progenitor cells and interneurons and partake in critical neural developmental processes," the researchers write. Overall, the work points to essential mutations leading to gain of embryonic neocortex enhancers, which control the expression of genes involved in critical developmental processes associated with human cognition, they add.