Transcriptional Determinism and Stochasticity Contribute to the Complexity of Autism AssociatedSHANKFamily Genes

Abstract

AbstractPrecision of transcription is critical because transcriptional dysregulation is disease causing. Traditional methods of transcriptional profiling are inadequate to elucidate the full spectrum of the transcriptome, particularly for longer and less abundant mRNAs.SHANK3is one of the most common autism causative genes. Twenty-fourShank3mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incompleteShank3transcript structure. We applied an integrative approach combining cDNA-capture and long-read sequencing to profile theSHANK3transcriptome in human and mice. We unexpectedly discovered an extremely complexSHANK3transcriptome. SpecificSHANK3transcripts were altered inShank3mutant mice and postmortem brains tissues from individuals with ASD. The enhancedSHANK3transcriptome significantly improved the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest the stochastic transcription of genome associated withSHANKfamily genes.