Expansion of RNA sequence diversity and RNA editing rates throughout human cortical development

ABSTRACT Post-transcriptional modifications by RNA editing are essential for neurodevelopment, yet their developmental and regulatory features remain poorly resolved. We constructed a full temporal view of base-specific RNA editing in the developing human cortex, from early progenitors through fully mature cells found in the adult brain. Developmental regulation of RNA editing is characterized by an increase in editing rates for more than 10,000 selective editing sites, shifting between mid-fetal development and infancy, and a massive expansion of RNA hyper-editing sites that amass in the cortex through postnatal development into advanced age. These sites occur disproportionally in 3’UTRs of essential neurodevelopmental genes. These profiles are preserved in non-human primate and murine models, illustrating evolutionary conserved regulation of RNA editing in mammalian cortical development. RNA editing levels are commonly genetically regulated (editing quantitative trait loci, edQTLs) consistently across development or predominantly during prenatal or postnatal periods. Both consistent and temporal-predominant edQTLs co-localize with risk loci associated with neurological traits and disorders, including attention deficit hyperactivity disorder, schizophrenia, and sleep disorders. These findings expand the repertoire of highly regulated RNA editing sites in the brain and provide insights of how epitranscriptional sequence diversity by RNA editing contributes to neurodevelopment.