1. Transcriptional determinism and stochasticity contribute to the complexity of autism-associated SHANK family genes.
- Author
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Lu, Xiaona, Ni, Pengyu, Suarez-Meade, Paola, Ma, Yu, Forrest, Emily Niemitz, Wang, Guilin, Wang, Yi, Quiñones-Hinojosa, Alfredo, Gerstein, Mark, and Jiang, Yong-hui
- Abstract
Precision 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. SHANK3 is one of the most common autism causative genes. Twenty-four Shank3 -mutant animal lines have been developed for autism modeling. However, their preclinical validity has been questioned due to incomplete Shank3 transcript structure. We apply an integrative approach combining cDNA-capture and long-read sequencing to profile the SHANK3 transcriptome in humans and mice. We unexpectedly discover an extremely complex SHANK3 transcriptome. Specific SHANK3 transcripts are altered in Shank3 -mutant mice and postmortem brain tissues from individuals with autism spectrum disorder. The enhanced SHANK3 transcriptome significantly improves the detection rate for potential deleterious variants from genomics studies of neuropsychiatric disorders. Our findings suggest that both deterministic and stochastic transcription of the genome is associated with SHANK family genes. [Display omitted] • Revealed the transcriptional complexity of SHANK family genes in human and mouse brains • Improved detection rate for potential deleterious variants of neuropsychiatric disorders • Evidence for the debate over transcriptional determinism and stochasticity Lu et al. revealed the sophisticated transcriptional landscape of SHANK family genes with an integrative approach combining targeted capture and long-read sequencing. The findings elucidated a full spectrum of transcriptome, illustrated the deterministic and potentially stochastic nature of transcription, and sharpened the profiling of autism-related genetic variations. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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