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

Nat Commun. 2014 Apr 11:5:3650. doi: 10.1038/ncomms4650.

Roser Corominas ^# ¹, Xinping Yang ^# ² ³, Guan Ning Lin ^# ¹, Shuli Kang ^# ¹, Yun Shen ² ³, Lila Ghamsari ² ³ ⁴, Martin Broly ² ³, Maria Rodriguez ² ³, Stanley Tam ² ³, Shelly A Wanamaker ² ³ ⁵, Changyu Fan ² ³, Song Yi ² ³, Murat Tasan ⁶, Irma Lemmens ⁷, Xingyan Kuang ⁸, Nan Zhao ⁸, Dheeraj Malhotra ⁹, Jacob J Michaelson ⁹ ¹⁰, Vladimir Vacic ¹¹, Michael A Calderwood ² ³, Frederick P Roth ² ³ ⁶, Jan Tavernier ⁷, Steve Horvath ¹², Kourosh Salehi-Ashtiani ² ³ ¹³, Dmitry Korkin ⁸, Jonathan Sebat ⁹, David E Hill ² ³, Tong Hao ¹⁴ ¹⁵, Marc Vidal ¹⁶ ¹⁷, Lilia M Iakoucheva ¹⁸

Affiliations

1 Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA.
2 Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.
3 Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
4 Present address: Columbia University, New York, New York 10032, USA.
5 Present address: Salk Institute for Biological Studies, La Jolla, California 92037, USA.
6 Donnelly Centre and Departments of Molecular Genetics & Computer Science, University of Toronto, and Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, M5S 3E1, Ontario, Canada.
7 Department of Medical Protein Research, and Department of Biochemistry, VIB, Faculty of Medicine and Health Sciences, Ghent University, Ghent, B-9000, Belgium.
8 Department of Computer Science and Informatics Institute, University of Missouri, Columbia, 65203, Missouri, USA.
9 Beyster Center for Genomics of Psychiatric Diseases and Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA.
10 Present address: Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA.
11 New York Genome Center, New York, 10013, New York, USA.
12 Department of Human Genetics and Biostatistics, University of California, Los Angeles, 90095, California, USA.
13 Present address: Division of Science and Math, and Center for Genomics and Systems Biology, New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates.
14 Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA. tong_hao@dfci.harvard.edu.
15 Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA. tong_hao@dfci.harvard.edu.
16 Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA. marc_vidal@dfci.harvard.edu.
17 Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA. marc_vidal@dfci.harvard.edu.
18 Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA. lilyak@ucsd.edu.
# Contributed equally.

PMID: 24722188 DOI: 10.1038/ncomms4650

Abstract

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.

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