Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.
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.
Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA.
Roser
R
Corominas
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Xinping
X
Yang
Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA.
Guan Ning
GN
Lin
Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA.
Shuli
S
Kang
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Yun
Y
Shen
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.|Present address: Columbia University, New York, New York 10032, USA.
Lila
L
Ghamsari
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Martin
M
Broly
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Maria
M
Rodriguez
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Stanley
S
Tam
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.|Present address: Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Shelly A
SA
Wanamaker
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Changyu
C
Fan
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Song
S
Yi
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.
Murat
M
Tasan
Department of Medical Protein Research, and Department of Biochemistry, VIB, Faculty of Medicine and Health Sciences, Ghent University, Ghent, B-9000, Belgium.
Irma
I
Lemmens
Department of Computer Science and Informatics Institute, University of Missouri, Columbia, 65203, Missouri, USA.
Xingyan
X
Kuang
Department of Computer Science and Informatics Institute, University of Missouri, Columbia, 65203, Missouri, USA.
Nan
N
Zhao
Beyster Center for Genomics of Psychiatric Diseases and Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA.
Dheeraj
D
Malhotra
Beyster Center for Genomics of Psychiatric Diseases and Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA.|Present address: Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA.
Jacob J
JJ
Michaelson
New York Genome Center, New York, 10013, New York, USA.
Vladimir
V
Vacic
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
Michael A
MA
Calderwood
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.|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.
Frederick P
FP
Roth
Department of Medical Protein Research, and Department of Biochemistry, VIB, Faculty of Medicine and Health Sciences, Ghent University, Ghent, B-9000, Belgium.
Jan
J
Tavernier
Department of Human Genetics and Biostatistics, University of California, Los Angeles, 90095, California, USA.
Steve
S
Horvath
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.|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.
Kourosh
K
Salehi-Ashtiani
Department of Computer Science and Informatics Institute, University of Missouri, Columbia, 65203, Missouri, USA.
Dmitry
D
Korkin
Beyster Center for Genomics of Psychiatric Diseases and Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA.
Jonathan
J
Sebat
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA.
David E
DE
Hill
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA. tong_hao@dfci.harvard.edu.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA. tong_hao@dfci.harvard.edu.
Tong
T
Hao
Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA. marc_vidal@dfci.harvard.edu.|Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA. marc_vidal@dfci.harvard.edu.
Marc
M
Vidal
Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, USA. lilyak@ucsd.edu.
Lilia M
LM
Iakoucheva
D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D060066:Protein Interaction Maps / Q000235:genetics / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
D020033:Protein Isoforms