Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage.

Abstract

One fundamental, but understudied mechanism of gene regulation in disease is allele specific expression (ASE), the preferential expression of one allele. We leveraged RNA-seq from human brain to assess ASE in autism spectrum disorder (ASD). When ASE is observed in ASD, the allele with lower population frequency (minor allele) is preferentially more highly expressed than the major allele, opposite than the canonical pattern. Importantly, genes showing monoallelic expression (MAE) in ASD are enriched in those down-regulated in ASD postmortem brain and in genes harboring de novo mutations in ASD. Two regions, 14q32 and 15q11, containing all known orphan C/D box snoRNAs, are particularly enriched in shifts to higher minor allele expression. We demonstrate that this allele shifting enhances snoRNA targeted splicing changes in ASD-related target genes in idiopathic ASD and 15q11-q13 duplication syndrome. Together, these results implicate allelic imbalance and dysregulation of orphan C/D box snoRNAs in ASD pathogenesis.