Genetic Changes that Cause Autism Are More Diverse Than Previously Thought

Published April 7, 2016

Written by Scott LaFee (UC San Diego Health Sciences) and Warren Froelich (SDSC)

The types of gene mutations that contribute to autism are more diverse than previously thought, report researchers at University of California, San Diego School of Medicine in the current issue of The American Journal of Human Genetics. The findings, created with the aid of the Comet supercomputer based at the San Diego Supercomputer Center (SDSC) at UC San Diego, represent a significant advance in efforts to unravel the genetic basis of autism spectrum disorder (ASD).

To conduct their study, researchers enrolled hundreds of volunteers from families with one child affected by ASD and, using Comet, sequenced the complete genomes of every family member, including the parents and typically developing siblings.

“Comet provided the added computer power and flexibility needed to implement a rapid whole genome sequencing analysis pipeline required for this project,” said Mahidar Tatineni, director of SDSC’s User Service Group. Wayne Pfeiffer, a SDSC Distinguished Scientist, also participated in this project.

Added Madhusudan Gujral, a co-author of the paper: "Prior to the commissioning of Comet, we could process and analyze, at the most, about few hundred whole genomes every year. 

"Now we can undertake much larger projects and look at the de novo variants of the thousands of affected kids and their healthy siblings every year. This will allow us to understand the patterns of genetic variation and help us identify the likely cause of the autism spectrum disorder (ASD) in some cases.”

The researchers focused their efforts on de novo mutations, gene alterations that appear spontaneously in one’s offspring and are due to a mutation in a father’s sperm or a mother’s egg. Based on the authors’ previous discoveries, it is known that de novo mutations contribute to risk, particularly in sporadic cases where there is no family history of autism.

The most common type of de novo mutations are spelling mistakes that change a single letter of the DNA code. However, in their new study, the researchers discovered many other mutations that introduce changes that are more complex. Called structural variants, these alterations involve the insertion or deletion of entire words or sentences of the DNA code.

The research team found a surprising variety of spontaneous mutations, from simple deletions or insertions to “jumping genes” – elements of DNA that copy and paste themselves into other parts of the genome. They also found that structural mutations sometimes occur in tight clusters where a combination of different mutations occur all at once.

“These mutations can insert, delete or in some cases scramble the DNA sequence,” said senior author Jonathan Sebat, associate professor of psychiatry and cellular and molecular medicine and director of the Beyster Center for Genomics of Psychiatric Disease at UC San Diego School of Medicine.

Sebat and colleagues discovered that spontaneous structural mutations occurred at a surprisingly high rate in individuals – 20 percent – and mutations in autism tended to disrupt genes. “Children with autism do not have more mutations overall,” said Sebat, “but their mutations are more likely to disrupt genes involved in brain development.”

The study, Sebat noted, highlights several genes that could play a key role in brain development. For example, the scientists identified a deletion in one gene called “stargazin” that is required for regulating the transmission of signals between neurons in the brain.

“Mutations in stargazin are very rare,” said first author, William Brandler, a postdoctoral scholar in Sebat’s lab, “but they point us to a biochemical pathway that may be important for social development. In the future, discoveries like this could lead to more effective personalized treatments for autism.”

Funding for this research came, in part, from the National Institutes of Health (grants MH076431, HG007497, HD065288, MH104766 and MH105524), the Simons Foundation, the Autism Science Foundation and NIH predoctoral training grant T32-GM008666.

Co-authors include Danny Antaki, Amina Noor, Gabriel Rosanio, Timothy R. Chapman, Daniel J. Barrera, Guan Ning Lin, Dheeraj Malhotra, Amanda C. Watts, Therese E. Gadomski, Oanh Hong, Karin V. Fuentes Fajardo, Abhishek Bhandari, Michael Baughn, Jeffrey Yuan, Terry Solomon, Alexandra G. Moyzis, Michelle S. Maile, Gail E. Reiner, Keith K. Vaux, Kang Zhang, Alysson R. Muotri, Karen Pierce, Eric Courchesne, and Lilia M. Iakoucheva (UC San Diego); Lawrence C. Wong, Jasper A. Estabillo, Natacha Akshoomoff, and Christina Corsello (Rady Children’s Hospital-San Diego); Renius Owen and Charles M. Strom (Quest Diagnostics Nichols Institute); Stephan J. Sanders (UC San Francisco); and Suzanne M. Leal (Baylor College of Medicine.)

About SDSC

As an Organized Research Unit of UC San Diego, SDSC is considered a leader in data-intensive computing and cyberinfrastructure, providing resources, services, and expertise to the national research community, including industry and academia. Cyberinfrastructure refers to an accessible, integrated network of computer-based resources and expertise, focused on accelerating scientific inquiry and discovery. SDSC supports hundreds of multidisciplinary programs spanning a wide variety of domains, from earth sciences and biology to astrophysics, bioinformatics, and health IT. SDSC’s Comet joins the Center’s data-intensive Gordon cluster, and are both part of the National Science Foundation’s XSEDE (eXtreme Science and Engineering Discovery Environment) program, the most advanced collection of integrated digital resources and services in the world.