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

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

Author information

1
1] Department of Psychiatry, University of California San Diego, La Jolla, California 92093, USA [2].
2
1] Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3].
3
1] Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
Donnelly Centre and Departments of Molecular Genetics & Computer Science, University of Toronto, and Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada M5S 3E1.
5
Department of Medical Protein Research, VIB, and Department of Biochemistry, Faculty of Medicine and Health Sciences, Ghent University, Ghent B-9000, Belgium.
6
Department of Computer Science and Informatics Institute, University of Missouri, Columbia, Missouri 65203, USA.
7
Beyster Center for Genomics of Psychiatric Diseases and Department of Psychiatry, University of California San Diego, La Jolla, California 92093, USA.
8
1] Beyster Center for Genomics of Psychiatric Diseases and Department of Psychiatry, University of California San Diego, La Jolla, California 92093, USA [2].
9
New York Genome Center, New York, New York 10013, USA.
10
1] Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Donnelly Centre and Departments of Molecular Genetics & Computer Science, University of Toronto, and Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada M5S 3E1.
11
Department of Human Genetics and Biostatistics, University of California, Los Angeles, California 90095, USA.
12
Department of Psychiatry, University of California San Diego, La Jolla, California 92093, USA.

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.

PMID:
24722188
PMCID:
PMC3996537
DOI:
10.1038/ncomms4650
[Indexed for MEDLINE]
Free PMC Article

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