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Splice Variants Reveal Connections Among Autism Genes

A team of researchers from the University of California, San Diego School of Medicine and the Center for Cancer Systems Biology (CCSB) at the Dana-Farber Cancer Institute has uncovered a new aspect of autism, revealing that proteins involved in autism interact with many more partners than previously known. These interactions had not been detected earlier because they involve alternatively spliced forms of autism genes found in the brain.

In their study, published in the April 11, 2014 online issue of Nature Communications, the scientists isolated hundreds of new variants of autism genes from the human brain, and then screened their protein products against thousands of other proteins to identify interacting partners. Proteins produced by alternatively-spliced autism genes and their many partners formed a biological network that produced an unprecedented view of how autism genes are connected.

“When the newly discovered splice forms of autism genes were added to the network, the total number of interactions doubled,” said principal investigator Lilia Iakoucheva, PhD, assistant professor in the Department of Psychiatry at UC San Diego. In some cases, the splice forms interacted with a completely different set of proteins. “What we see from this network is that different variants of the same protein could alter the wiring of the entire system,” Iakoucheva said.

This image a brain and a representation of the networks. The caption best describes the image.

Splicing variants (red) of autism genes were cloned from the brain and screened for interactions. The image on the right represents the network of interactions. Gray lines are interactions from a single isoform; red lines are interactions from additional isoforms of autism candidate genes (yellow circles). Credit UC San Diego School of Medicine.

“This is the first proteome-scale interaction network to incorporate alternative splice forms,” noted Marc Vidal, PhD, CCSB director and a co-investigator on the study. “The fact that protein variants produce such diverse patterns of interactions is exciting and quite unexpected.”

The new network also illuminated how multiple autism genes connect to one another. The scientists found that one class of mutations involved in autism, known as copy number variants, involve genes that are closely connected to each other directly or indirectly through a common partner. “This suggests that shared biological pathways may be disrupted in patients with different autism mutations,” said co-first author Guan Ning Lin, PhD, a postdoctoral fellow in Iakoucheva’s laboratory.

Beyond providing greater breadth and depth around autism proteins, the network represents a new resource for future autism studies, according to Iakoucheva. For example, she said the physical collection of more than 400 splicing variants of autism candidate genes could be used by other researchers interested in studying a specific protein variant. Some of the highly connected network partners may also represent potential drug targets. All interaction data will reside in the publicly available National Database of Autism Research.

“With this assembled autism network, we can begin to investigate how newly discovered mutations from patients may disrupt this network,” said Iakoucheva. “This is an important task because the mechanism by which mutant proteins contribute to autism in 99.9 percent of cases remains unknown.”

Notes about this autism research

Co-lead authors of the study are Roser Corominas, Guan Ning Lin and Shuli Kang of the Department of Psychiatry, UCSD and Xinping Yang of the CCSB, Dana-Farber Cancer Institute. Other co-authors include Yun Shen, Lila Ghamsari, Martin Broly, Maria Rodriguez, Stanley Tam, Shelly A. Trigg, Changyu Fan, Song Yi, Michael A. Calderwood, Kourosh Salehi-Ashtiani, David E. Hill and Tong Hao, CCSB, Dana-Farber Cancer Institute; Murat Tasan and Frederick P. Roth, University of Toronto; Irma Lemmens and Jan Tavernier, Ghent University; Xingyan Kuang, Nan Zhao and Dmitry Korkin, University of Missouri; Dheeraj Malholtra, Jacob J. Michaelson and Jonathan Sebat, Beyster Center for Genomics of Psychiatric Diseases and UCSD Department of Psychiatry; Vladimir Vacic, New York Genome Center; and Steve Horvath, UCLA.

This research was funded, in part, by National Institutes of Health grants R01HD065288, R01MH091350, R01HG001715 and MH076431, the Ellison Foundation, the Dana-Farber Cancer Institute Strategic Initiative, the Simons Foundation Autism Research Initiative, a Canadian Institute for Advanced Research fellowship, the Canada Excellence Research Chairs Program and the National Science Foundation.

Contact: Scott LaFee – UCSD
Source: UCSD press release
Image Source: The image is credited to UC San Diego School of Medicine and is adapted from the UCSD press release
Original Research: Full open access research for “Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism” by Roser Corominas, Xinping Yang, Guan Ning Lin, Shuli Kang, Yun Shen, Lila Ghamsari, Martin Broly, Maria Rodriguez, Stanley Tam, Shelly A. Trigg, Changyu Fan, Song Yi, Murat Tasan, Irma Lemmens, Xingyan Kuang, Nan Zhao, Dheeraj Malhotra, Jacob J. Michaelson, Vladimir Vacic, Michael A. Calderwood, Frederick P. Roth, Jan Tavernier, Steve Horvath, Kourosh Salehi-Ashtiani, Dmitry Korkin, Jonathan Sebat, David E. Hill, Tong Hao, Marc Vidal and Lilia M. Iakoucheva in Nature Communications. Published online April 11 2014 doi:10.1038/ncomms4650

Open Access Neuroscience Abstract

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.

“Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism” by Roser Corominas, Xinping Yang, Guan Ning Lin, Shuli Kang, Yun Shen, Lila Ghamsari, Martin Broly, Maria Rodriguez, Stanley Tam, Shelly A. Trigg, Changyu Fan, Song Yi, Murat Tasan, Irma Lemmens, Xingyan Kuang, Nan Zhao, Dheeraj Malhotra, Jacob J. Michaelson, Vladimir Vacic, Michael A. Calderwood, Frederick P. Roth, Jan Tavernier, Steve Horvath, Kourosh Salehi-Ashtiani, Dmitry Korkin, Jonathan Sebat, David E. Hill, Tong Hao, Marc Vidal and Lilia M. Iakoucheva in Nature Communications. April 11 2014 doi:10.1038/ncomms4650

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