Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism

被引：108

作者：

Corominas, Roser ^{[1
]}

Yang, Xinping ^{[2
,3
,4
]}

Lin, Guan Ning ^{[1
]}

Kang, Shuli ^{[1
]}

Shen, Yun ^{[2
,3
,4
]}

Ghamsari, Lila ^{[2
,3
,4
]}

Broly, Martin ^{[2
,3
,4
]}

Rodriguez, Maria ^{[2
,3
,4
]}

Tam, Stanley ^{[2
,3
,4
]}

Trigg, Shelly A. ^{[2
,3
,4
]}

Fan, Changyu ^{[2
,3
,4
]}

Yi, Song ^{[2
,3
,4
]}

Tasan, Murat ^{[5
,6
,7
,8
]}

Lemmens, Irma ^{[9
,10
]}

Kuang, Xingyan ^{[11
,12
]}

Zhao, Nan ^{[11
,12
]}

Malhotra, Dheeraj ^{[13
,14
]}

Michaelson, Jacob J. ^{[13
,14
]}

Vacic, Vladimir ^{[15
]}

Calderwood, Michael A. ^{[2
,3
,4
]}

Roth, Frederick P. ^{[2
,3
,4
,5
,6
,7
,8
]}

Tavernier, Jan ^{[9
,10
]}

Horvath, Steve ^{[16
]}

Salehi-Ashtiani, Kourosh ^{[2
,3
,4
]}

Korkin, Dmitry ^{[11
,12
]}

Sebat, Jonathan ^{[13
,14
]}

Hill, David E. ^{[2
,3
,4
]}

Hao, Tong ^{[2
,3
,4
]}

Vidal, Marc ^{[2
,3
,4
]}

Iakoucheva, Lilia M. ^{[1
]}

机构：

[1] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[2] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[5] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada

[6] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada

[7] Univ Toronto, Dept Comp Sci, Toronto, ON M5S 3E1, Canada

[8] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5S 3E1, Canada

[9] Univ Ghent VIB, Dept Med Prot Res, B-9000 Ghent, Belgium

[10] Univ Ghent, Fac Med & Hlth Sci, Dept Biochem, B-9000 Ghent, Belgium

[11] Univ Missouri, Dept Comp Sci, Columbia, MO 65203 USA

[12] Univ Missouri, Inst Informat, Columbia, MO 65203 USA

[13] Univ Calif San Diego, Beyster Ctr Genom Psychiat Dis, La Jolla, CA 92093 USA

[14] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA

[15] New York Genome Ctr, New York, NY 10013 USA

[16] Univ Calif Los Angeles, Dept Human Genet & Biostat, Los Angeles, CA 90095 USA

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

基金：

美国国家科学基金会;

关键词：

COPY-NUMBER VARIATION; DE-NOVO MUTATIONS; STRUCTURAL VARIATION; COMMON VARIANTS; CONFERRING RISK; DUPLICATIONS; REVEALS; LOCI; DISORDERS; FRAMEWORK;

D O I：

10.1038/ncomms4650

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of genetic loci. The convergence of ASD variants have been investigated using various approaches, including protein interactions extracted from the published literature. However, these datasets are frequently incomplete, carry biases and are limited to interactions of a single splicing isoform, which may not be expressed in the disease-relevant tissue. Here we introduce a new interactome mapping approach by experimentally identifying interactions between brain-expressed alternatively spliced variants of ASD risk factors. The Autism Spliceform Interaction Network reveals that almost half of the detected interactions and about 30% of the newly identified interacting partners represent contribution from splicing variants, emphasizing the importance of isoform networks. Isoform interactions greatly contribute to establishing direct physical connections between proteins from the de novo autism CNVs. Our findings demonstrate the critical role of spliceform networks for translating genetic knowledge into a better understanding of human diseases.

引用

页数：12

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