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

73 Pages Posted: 6 Apr 2018 Sneak Peek Status: Published

See all articles by Tatsiana Aneichyk

Tatsiana Aneichyk

Harvard University - Center for Genomic Medicine

William.T. Hendriks

Harvard University - Department of Neurology

Rachita Yadav

Harvard University - Center for Genomic Medicine

David Shin

Harvard University - Department of Neurology

Dadi Gao

Harvard University - Center for Genomic Medicine

Christine A. Vaine

Harvard University - Department of Neurology

Ryan L. Collins

Harvard University - Center for Genomic Medicine

Alexei Stortchevoi

Harvard University - Center for Genomic Medicine

Benjamin Currall

Harvard University - Center for Genomic Medicine

Harrison Brand

Harvard University - Center for Genomic Medicine

Carrie Hanscom

Harvard University - Center for Genomic Medicine

Caroline Antolik

Harvard University - Center for Genomic Medicine

Marisela Dy

Harvard University - Department of Neurology

Ashok Ragavendran

Harvard University - Center for Genomic Medicine

Patrick Acuña

Harvard University - Department of Neurology

Criscely Go

José R. Reyes Memorial Medical Center

Yechiam Sapir

Harvard University - Department of Neurology

Brian J. Wainger

Harvard University - Department of Neurology

Daniel Henderson

Harvard University - Department of Neurology

Jyotsna Dhakal

Harvard University - Department of Neurology

Naoto Ito

Harvard University - Department of Neurology

Neil Weisenfeld

Masssachusetts Institute of Technology and Harvard University - Genome Sequencing and Analysis Program

David Jaffe

Masssachusetts Institute of Technology and Harvard University - Genome Sequencing and Analysis Program

Nutan Sharma

Harvard University - Department of Neurology

Xandra O. Breakefield

Harvard University - Department of Neurology

Laurie J. Ozelius

Harvard University - Center for Genomic Medicine

D. Cristopher Bragg

Harvard University - Department of Neurology

Michael E. Talkowski

Harvard University - Center for Genomic Medicine

More...

Abstract

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.

Suggested Citation

Aneichyk, Tatsiana and Hendriks, William.T. and Yadav, Rachita and Shin, David and Gao, Dadi and Vaine, Christine A. and Collins, Ryan L. and Stortchevoi, Alexei and Currall, Benjamin and Brand, Harrison and Hanscom, Carrie and Antolik, Caroline and Dy, Marisela and Ragavendran, Ashok and Acuña, Patrick and Go, Criscely and Sapir, Yechiam and Wainger, Brian J. and Henderson, Daniel and Dhakal, Jyotsna and Ito, Naoto and Weisenfeld, Neil and Jaffe, David and Sharma, Nutan and Breakefield, Xandra O. and Ozelius, Laurie J. and Bragg, D. Cristopher and Talkowski, Michael E., Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly (2018). Available at SSRN: https://ssrn.com/abstract=3155907 or http://dx.doi.org/10.2139/ssrn.3155907
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Tatsiana Aneichyk

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

William.T. Hendriks

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Rachita Yadav

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

David Shin

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Dadi Gao

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

Christine A. Vaine

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Ryan L. Collins

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

Alexei Stortchevoi

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

Benjamin Currall

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

Harrison Brand

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

Carrie Hanscom

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

Caroline Antolik

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

Marisela Dy

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Ashok Ragavendran

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

Patrick Acuña

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Criscely Go

José R. Reyes Memorial Medical Center

San Lazaro Compound, Rizal Avenue
Manila, 1012
Philippines

Yechiam Sapir

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Brian J. Wainger

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Daniel Henderson

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Jyotsna Dhakal

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Naoto Ito

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Neil Weisenfeld

Masssachusetts Institute of Technology and Harvard University - Genome Sequencing and Analysis Program

Cambridge, MA 02141
United States

David Jaffe

Masssachusetts Institute of Technology and Harvard University - Genome Sequencing and Analysis Program

Cambridge, MA 02141
United States

Nutan Sharma

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Xandra O. Breakefield

Harvard University - Department of Neurology

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Laurie J. Ozelius

Harvard University - Center for Genomic Medicine

185 Cambridge Street
Boston, MA 02114
United States

D. Cristopher Bragg

Harvard University - Department of Neurology ( email )

15 Parkman Street
Wang Ambulatory Care Center, 8th Floor, Suite 835
Boston, MA 02114
United States

Michael E. Talkowski (Contact Author)

Harvard University - Center for Genomic Medicine ( email )

185 Cambridge Street
Boston, MA 02114
United States

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