TY - JOUR
T1 - Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism
AU - Corominas, Roser
AU - Yang, Xinping
AU - Lin, Guan Ning
AU - Kang, Shuli
AU - Shen, Yun
AU - Ghamsari, Lila
AU - Broly, Martin
AU - Rodriguez, Maria
AU - Tam, Stanley
AU - Trigg, Shelly A.
AU - Fan, Changyu
AU - Yi, Song
AU - Tasan, Murat
AU - Lemmens, Irma
AU - Kuang, Xingyan
AU - Zhao, Nan
AU - Malhotra, Dheeraj
AU - Michaelson, Jacob J.
AU - Vacic, Vladimir
AU - Calderwood, Michael A.
AU - Roth, Frederick P.
AU - Tavernier, Jan
AU - Horvath, Steve
AU - Salehi-Ashtiani, Kourosh
AU - Korkin, Dmitry
AU - Sebat, Jonathan
AU - Hill, David E.
AU - Hao, Tong
AU - Vidal, Marc
AU - Iakoucheva, Lilia M.
N1 - Funding Information:
We thank all members of the DFCI Center for Cancer Systems Biology (CCSB) for helpful discussions throughout the course of this project. We also thank Dr Joseph Gleeson for valuable comments on the manuscript, the members of Dr Sebat laboratory for helpful discussions and Abhishek Bhandari, Ashleigh Schaffer and Naiara Akizu for technical assistance. This work was supported by NIH grants ARRA R01HD065288 from NICHD to L.M.I and K.S.-A. and by R01MH091350 from NIMH to L.M.I. and T.H., R01HG001715 from NHGRI to M.V., D.E.H., F.P.R. and J.T.; by The Ellison Foundation, Boston, MA to M.V.; by Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative to M.V.; by NIH (MH076431) and the Simons Foundation Autism Research Initiative (275724) to J.S.; by a Canadian Institute for Advanced Research Fellowship and the Canada Excellence Research Chairs Program to F.P.R. and by National Science Foundation grants DBI-0845196 and IOS-1126992 to D.K. I.L. is a postdoctoral fellow with the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO). M.V. is a ‘‘Chercheur Qualifié Honoraire’’ from the Fonds de la Recherche Scientifique (FRS-FNRS, Wallonia-Brussels Federation, Belgium).
PY - 2014/4/11
Y1 - 2014/4/11
N2 - 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.
AB - 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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U2 - 10.1038/ncomms4650
DO - 10.1038/ncomms4650
M3 - Article
C2 - 24722188
AN - SCOPUS:84898612068
SN - 2041-1723
VL - 5
JO - Nature communications
JF - Nature communications
M1 - 3650
ER -