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

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 UnderwoodStuart 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

^*Corresponding author for this work

Institute of Neurogenetics

179 Citations (Scopus)

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. A Mendelian form of dystonia arises from altered splicing and intron retention within a general transcription factor.

Original language	English
Journal	Cell
Volume	172
Issue number	5
Pages (from-to)	897-909
Number of pages	13
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2018.02.011
Publication status	Published - 22.02.2018

Funding

Flow cytometry services were supported by grants 1S10OD012027-01A1 , 1S10OD016372-01 , 1S10RR020936-01 , and 1S10RR023440-01A1 at the MGH Department of Pathology Flow and Image Cytometry Research Core . We thank Daniel MacArthur for review of mutation patterns in ExAC and Nikka Keivanfar for DNA extractions for the 10X Genomics library preparation. Funding for this study was provided by the MGH Collaborative Center for X-Linked Dystonia-Parkinsonism (D.C.B., M.E.T., N.S.) and by National Institutes of Health grants R01NS102423 (M.E.T. and D.C.B.), 5P01NS087997 (D.C.B., N.S., L.J.O., X.O.B.), and UM1HG008900 (M.E.T.). E.E.E. is an investigator of the Howard Hughes Medical Institute. M.E.T. was also supported as the Desmond and Ann Heathwood MGH Research Scholar.

Research Areas and Centers

Research Area: Medical Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2018.02.011

Cite this

Aneichyk, T., Hendriks, W. T., Yadav, R., Shin, D., Gao, D., Vaine, C. A., Collins, R. L., Domingo, A., Currall, B., Stortchevoi, A., Multhaupt-Buell, T., Penney, E. B., Cruz, L., Dhakal, J., Brand, H., Hanscom, C., Antolik, C., Dy, M., Ragavendran, A., ... Talkowski, M. E. (2018). Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly. Cell, 172(5), 897-909. https://doi.org/10.1016/j.cell.2018.02.011

@article{2b1ea712220e47f2b448d1bb7b55357b,

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

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. A Mendelian form of dystonia arises from altered splicing and intron retention within a general transcription factor.",

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

year = "2018",

month = feb,

day = "22",

doi = "10.1016/j.cell.2018.02.011",

language = "English",

volume = "172",

pages = "897--909",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "5",

}

Aneichyk, T, Hendriks, WT, Yadav, R, Shin, D, Gao, D, Vaine, CA, Collins, RL, Domingo, A, Currall, B, Stortchevoi, A, Multhaupt-Buell, T, Penney, EB, Cruz, L, Dhakal, J, Brand, H, Hanscom, C, Antolik, C, Dy, M, Ragavendran, A, Underwood, J, Cantsilieris, S, Munson, KM, Eichler, EE, Acuña, P, Go, C, Jamora, RDG, Rosales, RL, Church, DM, Williams, SR, Garcia, S, Klein, C, Müller, U, Wilhelmsen, KC, Timmers, HTM, Sapir, Y, Wainger, BJ, Henderson, D, Ito, N, Weisenfeld, N, Jaffe, D, Sharma, N, Breakefield, XO, Ozelius, LJ, Bragg, DC & Talkowski, ME 2018, 'Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly', Cell, vol. 172, no. 5, pp. 897-909. https://doi.org/10.1016/j.cell.2018.02.011

TY - JOUR

T1 - Dissecting the Causal Mechanism of X-Linked Dystonia-Parkinsonism by Integrating Genome and Transcriptome Assembly

AU - Aneichyk, Tatsiana

AU - Hendriks, William T.

AU - Yadav, Rachita

AU - Shin, David

AU - Gao, Dadi

AU - Vaine, Christine A.

AU - Collins, Ryan L.

AU - Domingo, Aloysius

AU - Currall, Benjamin

AU - Stortchevoi, Alexei

AU - Multhaupt-Buell, Trisha

AU - Penney, Ellen B.

AU - Cruz, Lilian

AU - Dhakal, Jyotsna

AU - Brand, Harrison

AU - Hanscom, Carrie

AU - Antolik, Caroline

AU - Dy, Marisela

AU - Ragavendran, Ashok

AU - Underwood, Jason

AU - Cantsilieris, Stuart

AU - Munson, Katherine M.

AU - Eichler, Evan E.

AU - Acuña, Patrick

AU - Go, Criscely

AU - Jamora, R. Dominic G.

AU - Rosales, Raymond L.

AU - Church, Deanna M.

AU - Williams, Stephen R.

AU - Garcia, Sarah

AU - Klein, Christine

AU - Müller, Ulrich

AU - Wilhelmsen, Kirk C.

AU - Timmers, H. T.Marc

AU - Sapir, Yechiam

AU - Wainger, Brian J.

AU - Henderson, Daniel

AU - Ito, Naoto

AU - Weisenfeld, Neil

AU - Jaffe, David

AU - Sharma, Nutan

AU - Breakefield, Xandra O.

AU - Ozelius, Laurie J.

AU - Bragg, D. Cristopher

AU - Talkowski, Michael E.

PY - 2018/2/22

Y1 - 2018/2/22

N2 - 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. A Mendelian form of dystonia arises from altered splicing and intron retention within a general transcription factor.

AB - 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. A Mendelian form of dystonia arises from altered splicing and intron retention within a general transcription factor.

UR - https://www.scopus.com/pages/publications/85042368049

U2 - 10.1016/j.cell.2018.02.011

DO - 10.1016/j.cell.2018.02.011

M3 - Journal articles

C2 - 29474918

AN - SCOPUS:85042368049

SN - 0092-8674

VL - 172

SP - 897

EP - 909

JO - Cell

JF - Cell

IS - 5

ER -

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

Abstract

Funding

Research Areas and Centers

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this