ArticleHGG advances2026
Positive selection on brain cis-regulatory elements in the human lineage drives changes in gene expression and susceptibility to neuropsychiatric disorders.
Article in HGG advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Human brain evolution is hypothesized to be driven primarily by regulatory rather than protein-coding changes. Identifying evolutionary changes in regulatory elements, however, has been constrained by numbers and relationships of taxa and by methodology targeting conserved sequences. These approaches are independent of any experimental assessment of function and overlook potential neofunctionalization in less constrained regions. Here, we leveraged 243 primate genomes to apply a human branch-specific positive selection test to over 350,000 experimentally confirmed human brain-active cis-regulatory elements, identifying 8,522 elements under positive selection on the human lineage. Genes regulated by human positively selected elements showed differential expression between humans and macaques during fetal and adult stages compared to non-selected elements. Elements under positive selection that remained active across fetal and adult stages showed the strongest enrichment for genetic variants associated with neuropsychiatric conditions, including schizophrenia and bipolar disorder.
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