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

Although new genes and regulatory events have been linked to the uniqueness of human brain development, it is unknown whether alternative polyadenylation (APA) also contributes to 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 affected by these events, we identified ZNF271P, which encodes a human-specific protein when using the distal polyadenylation site, a site that preferentially occurs during early brain development. The cortical organoids derived from ZNF271P-knockout human embryonic stem cells seemed to exhibit accelerated development and maturation, resulting in a significant decrease in organoid size, implicating that ZNF271P is involved in features unique to human brain development. We thus highlight APAs as new regulators in shaping the unique aspects of human brain development.