Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly

Tatsiana Aneichyk; William T Hendriks; Rachita Yadav; David Shin; Dadi Gao; Christine A Vaine; Ryan L Collins; Aloysius Domingo; Benjamin Currall; Alexei Stortchevoi; Trisha Multhaupt-Buell; Ellen B Penney; Lilian Cruz; Jyotsna Dhakal; Harrison Brand; Carrie Hanscom; Caroline Antolik; Marisela Dy; Ashok Ragavendran; Jason Underwood; Stuart Cantsilieris; Katherine M Munson; Evan E Eichler; Patrick Acuña; Criscely Go; R Dominic G Jamora; Raymond L Rosales; Deanna M Church; Stephen R Williams; Sarah Garcia; Christine Klein; Ulrich Müller; Kirk C Wilhelmsen; H T Marc Timmers; Yechiam Sapir; Brian J Wainger; Daniel Henderson; Naoto Ito; Neil Weisenfeld; David Jaffe; Nutan Sharma; Xandra O Breakefield; Laurie J Ozelius; D Cristopher Bragg; Michael E Talkowski

doi:10.1016/j.cell.2018.02.011

Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly

Cell. 2018 Feb 22;172(5):897-909.e21. doi: 10.1016/j.cell.2018.02.011.

Authors

Tatsiana Aneichyk¹, William T Hendriks², Rachita Yadav¹, David Shin², Dadi Gao¹, Christine A Vaine², Ryan L Collins³, Aloysius Domingo⁴, Benjamin Currall⁵, Alexei Stortchevoi⁵, Trisha Multhaupt-Buell², Ellen B Penney², Lilian Cruz², Jyotsna Dhakal², Harrison Brand⁵, Carrie Hanscom⁵, Caroline Antolik⁵, Marisela Dy², Ashok Ragavendran⁵, Jason Underwood⁶, Stuart Cantsilieris⁷, Katherine M Munson⁷, Evan E Eichler⁸, Patrick Acuña², Criscely Go⁹, R Dominic G Jamora¹⁰, Raymond L Rosales¹¹, Deanna M Church¹², Stephen R Williams¹², Sarah Garcia¹², Christine Klein¹³, Ulrich Müller¹⁴, Kirk C Wilhelmsen¹⁵, H T Marc Timmers¹⁶, Yechiam Sapir¹⁷, Brian J Wainger¹⁷, Daniel Henderson², Naoto Ito², Neil Weisenfeld¹⁸, David Jaffe¹⁸, Nutan Sharma², Xandra O Breakefield², Laurie J Ozelius², D Cristopher Bragg¹⁹, Michael E Talkowski²⁰

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA.
² Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
³ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA.
⁴ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA.
⁵ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁶ Pacific Biosciences, Menlo Park, CA 94025, USA; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
⁷ Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
⁸ Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
⁹ Jose Reyes Memorial Medical Center, Manila, Philippines.
¹⁰ Philippine General Hospital, Manila, Philippines.
¹¹ University of Santo Tomas Hospital, Manila, Philippines.
¹² 10X Genomics, Pleasanton, CA 94566, USA.
¹³ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
¹⁴ Institut für Humangenetik, Justus-Liebig-Universität, Giessen, Germany.
¹⁵ University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁶ German Cancer Consortium (DKTK) partner site Freiburg and Department of Urology, University Medical Center, Freiburg, Germany.
¹⁷ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹⁸ 10X Genomics, Pleasanton, CA 94566, USA; Genome Sequencing and Analysis Program, Broad Institute, Cambridge, MA 02142, USA.
¹⁹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA. Electronic address: bragg@helix.mgh.harvard.edu.
²⁰ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Program in Medical and Population Genetics and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02142, USA; The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA 02129, USA; Departments of Psychiatry and Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: mtalkowski@mgh.harvard.edu.

Abstract

X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of the gene. Transcriptome analyses identified decreased expression of the canonical cTAF1 transcript among XDP probands, and de novo assembly across multiple pluripotent stem-cell-derived neuronal lineages discovered aberrant TAF1 transcription that involved alternative splicing and intron retention (IR) in proximity to the SVA that was anti-correlated with overall TAF1 expression. CRISPR/Cas9 excision of the SVA rescued this XDP-specific transcriptional signature and normalized TAF1 expression in probands. These data suggest an SVA-mediated aberrant transcriptional mechanism associated with XDP and may provide a roadmap for layered technologies and integrated assembly-based analyses for other unsolved Mendelian disorders.

Keywords: DYT3; Parkinson’s disease; SVA; TAF1; XDP; dystonia; genome assembly; intron retention; retrotransposon; transcriptome assembly.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing / genetics
Alu Elements / genetics
Base Sequence
CRISPR-Cas Systems / genetics
Cohort Studies
Dystonic Disorders / genetics*
Family
Female
Genetic Diseases, X-Linked / genetics*
Genetic Loci
Genome, Human*
Haplotypes / genetics
High-Throughput Nucleotide Sequencing
Histone Acetyltransferases / genetics
Histone Acetyltransferases / metabolism
Humans
Induced Pluripotent Stem Cells / metabolism
Introns / genetics
Male
Minisatellite Repeats / genetics
Models, Genetic
Nerve Degeneration / genetics
Nerve Degeneration / pathology
Neural Stem Cells / metabolism
Neurons / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Short Interspersed Nucleotide Elements
TATA-Binding Protein Associated Factors / genetics
TATA-Binding Protein Associated Factors / metabolism
Transcription Factor TFIID / genetics
Transcription Factor TFIID / metabolism
Transcriptome / genetics*

Substances

RNA, Messenger
TATA-Binding Protein Associated Factors
Transcription Factor TFIID
Histone Acetyltransferases
TATA-binding protein associated factor 250 kDa

Supplementary concepts

Dystonia 3, Torsion, X-Linked

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding