PT  - JOURNAL ARTICLE
AU  - Ryn Cuddleston
AU  - Junhao Li
AU  - Xuanjia Fan
AU  - Alexey Kozenkov
AU  - Matthew Lalli
AU  - Shahrukh Khalique
AU  - Stella Dracheva
AU  - Eran A. Mukamel
AU  - Michael S. Breen
TI  - Cellular and genetic drivers of RNA editing variation in the human brain
AID  - 10.1101/2021.07.16.452690
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.16.452690
4099  - http://biorxiv.org/content/early/2021/07/16/2021.07.16.452690.short
4100  - http://biorxiv.org/content/early/2021/07/16/2021.07.16.452690.full
AB  - 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. 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. We found more selective editing and RNA hyper-editing in neurons relative to oligodendrocytes. The pattern of RNA editing was highly cell type-specific, with 189,229 cell type-associated sites. The cellular specificity for thousands of sites was confirmed by single nucleus RNA-sequencing. 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. Finally, we discovered 661,791 cis-editing quantitative trait loci across thirteen brain regions, including hundreds with cell type-associated features. 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.Competing Interest StatementThe authors have declared no competing interest.