TY - JOUR T1 - Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly JF - bioRxiv DO - 10.1101/149872 SP - 149872 AU - Tatsiana Aneichyk AU - William.T. Hendriks AU - Rachita Yadav AU - David Shin AU - Dadi Gao AU - Christine A. Vaine AU - Ryan L. Collins AU - Alexei Stortchevoi AU - Benjamin Currall AU - Harrison Brand AU - Carrie Hanscom AU - Caroline Antolik AU - Marisela Dy AU - Ashok Ragavendran AU - Patrick Acuña AU - Criscely Go AU - Yechiam Sapir AU - Brian J. Wainger AU - Daniel Henderson AU - Jyotsna Dhakal AU - Naoto Ito AU - Neil Weisenfeld AU - David Jaffe AU - Nutan Sharma AU - Xandra O. Breakefield AU - Laurie J. Ozelius AU - D. Cristopher Bragg AU - Michael E. Talkowski Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/14/149872.abstract N2 - X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease endemic to the Philippines. We integrated genome and transcriptome assembly with induced pluripotent stem cell-based modeling to identify the XDP causal locus and potential pathogenic mechanism. Genome sequencing identified novel variation that was shared by all probands and three recombination events that narrowed the causal locus to a genomic segment including TAF1. Transcriptome assembly in neural derivative cells discovered novel TAF1 transcripts, including a truncated transcript exclusively observed in probands that involved aberrant splicing and intron retention (IR) associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion. This IR correlated with decreased expression of the predominant TAF1 transcript and altered expression of neurodevelopmental genes; both the IR and aberrant TAF1 expression patterns were rescued by CRISPR/Cas9 excision of the SVA. These data suggest a unique genomic cause of XDP and may provide a roadmap for integrative genomic studies in other unsolved Mendelian disorders.Highlights Genome assembly narrows the XDP causal locus to a segment including TAF1XDP-specific SVA insertion induces intron retention and down-regulation of TAF1CRISPR/Cas9 excision of SVA rescues aberrant splicing and cTAF1 expression in XDPGene networks perturbed in proband cells associate to synapse and neurodevelopment ER -