These base-specific changes exponentially amplify RNA sequence diversity and expand the functionality of many brain expressed genes, by allowing the same coding sequence to produce different mRNA and products. A-to-I editing occurs at single isolated adenosines (selective editing) as well in extended regions with multiple neighboring adenosines (RNA hyper-editing) 5– 7, and is catalyzed by adenosine acting on RNA (ADAR) enzymes. Adenosine to inosine (A-to-I) RNA editing is abundant in the human brain and predicted to occur at millions of locations across the genome 3, 4. The complexity of the central nervous system (CNS) is largely coordinated through multiple layers of transcriptional regulation, generating functionally distinct RNA molecules with specialized post-transcriptional modifications 1, 2. These data reveal an expansive repertoire of highly regulated RNA editing sites across human brain cell types and provide a resolved atlas linking cell types to editing variation and genetic regulatory effects. Finally, we discovered 661,791 cis-editing quantitative trait loci across thirteen brain regions, including hundreds with cell type-associated features. Importantly, cell type-associated sites were enriched in GTEx RNA-sequencing data, edited ∼twentyfold higher than all other sites, and variation in RNA editing was predominantly explained by neuronal proportions in bulk brain tissue. The cellular specificity for thousands of sites was confirmed by single nucleus RNA-sequencing. The pattern of RNA editing was highly cell type-specific, with 189,229 cell type-associated sites. We found more selective editing and RNA hyper-editing in neurons relative to oligodendrocytes.
We quantified base-specific RNA editing across three major cell populations from the human prefrontal cortex: glutamatergic neurons, medial ganglionic eminence GABAergic neurons, and oligodendrocytes. Posttranscriptional adenosine-to-inosine modifications amplify the functionality of RNA molecules in the brain, yet the cellular and genetic regulation of RNA editing is poorly described.
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