Transcriptional determinism and stochasticity contribute to the complexity of autism-associated SHANK family genes
Xiaona Lu,
Pengyu Ni,
Paola Suarez-Meade,
Yu Ma,
Emily Niemitz Forrest,
Guilin Wang,
Yi Wang,
Alfredo Quiñones-Hinojosa,
Mark Gerstein,
Yong-hui Jiang
Affiliations
Xiaona Lu
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
Pengyu Ni
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA
Paola Suarez-Meade
Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
Yu Ma
Department of Neurology, Children’s Hospital of Fudan University, Shanghai 201102, China
Emily Niemitz Forrest
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
Guilin Wang
Keck Microarray Shared Resource, Yale University School of Medicine, New Haven, CT 06520, USA
Yi Wang
Department of Neurology, Children’s Hospital of Fudan University, Shanghai 201102, China
Alfredo Quiñones-Hinojosa
Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
Mark Gerstein
Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06520, USA; Department of Statistics and Data Science, Yale University, New Haven, CT 06520, USA; Department of Biomedical Informatics & Data Science, Yale University, New Haven, CT 06520, USA
Yong-hui Jiang
Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA; Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA; Corresponding author
Summary: 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.
