A Human-specific Protein Regulated by Alternative Polyadenylation Shapes Uniqueness of Human Brain Development

Abstract Although new genes and regulatory events have been linked to the uniqueness of human brain development, it is unknown whether alternative polyadenylation (APA) could also be involved in shaping this key feature that differentiates humans from other species. Here, we present an atlas of APAs of the human brain and identified 161 development-related, open-reading-frame-disrupting APAs associated with the dynamic translation of protein products. Among the genes impacted by these events we identified ZNF271P, encoding a human-specific protein when using the distal polyadenylation site, which preferentially occurs during early brain development. The cortical organoids grown from ZNF271P-knockout human embryonic stem cells seemed to exhibit accelerated development and maturation, resulting in a significant decrease in organoid size, implicating ZNF271P in features unique to human brain development. We thus highlight APAs as new regulators in shaping the unique aspects of human brain development.