Understanding what makes us uniquely human is a long-standing question permeating fields from genomics, neuroscience, and developmental biology to medicine. The discovery of human-specific genomic sequences has enabled a new understanding of the molecular features of human brain evolution. Advances in sequencing, computational, and in vitro screening approaches collectively reveal new roles of uniquely human sequences in regulating gene expression. Here, we review the landscape of human-specific loci and describe how emerging technologies are being used to understand their molecular functions and impact on brain development. We describe current challenges in the field and the potential of integrating new hypotheses and approaches to propel our understanding of the human brain.
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