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Chunk #26 — Discussion

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Alcohol use disorder causes global changes in splicing in the human brain.
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Splicing takes a central place in cellular biology: constitutive splicing is responsible for the removal of introns, and alternative splicing generates proteomic diversity. We observed that while changes in gene expression were relatively modest across brain regions, mis-splicing events were observed on a much broader scale. In total, 3601 mis-splicing events have been detected, mostly skipping of exons and imbalance between mutually exclusive exons. To date, there were very few studies on the effect of alcohol on splicing, almost all of which focused on mis-splicing of specific genes. For example, alcohol was shown to be associated with a mis-splicing of AMPA receptors13 and GABA-B receptors14. Ethanol also affected alternative splicing of DRD2 (dopamine D2 receptor) in the pituitary30. Only one study highlighted relatively broad alcohol-induced changes in splicing. Kawasawa et al.15 found 382 alternative splicing events in the brain cortex of human fetuses exposed to alcohol. Qualitatively, eight mis-splicing events were detected: 5’ and 3’ alternative splice sites, mutually exclusive exons, intron retention, cassette exon, coordinate cassette exon, alternative first exon, and alternative last exon (exon skipping was likely not