Researchers find that the genetic causes of autism consist of a wide variety of genetic changes.
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 March 24 online issue of the American Journal of Human Genetics. The findings, they say, 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 sequenced the complete genomes of every family member, including the parents and typically developing siblings. The researchers then looked for 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, PhD, 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, PhD, 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.”
Co-authors include Danny Antaki, Madhusudan Gujral, 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, Lilia M. Iakoucheva, UC San Diego; Lawrence C. Wong, Jasper A. Estabillo, Natacha Akshoomoff, 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.
Funding: 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.
Source: Scott LaFee – UCSD
Image Source: The image is in the public domain.
Original Research: Abstract for “Frequency and Complexity of De Novo Structural Mutation in Autism” by William M. Brandler, Danny Antaki, Madhusudan Gujral, Amina Noor, Gabriel Rosanio, Timothy R. Chapman, Daniel J. Barrera, Guan Ning Lin, Dheeraj Malhotra, Amanda C. Watts, Lawrence C. Wong, Jasper A. Estabillo, Therese E. Gadomski, Oanh Hong, Karin V. Fuentes Fajardo, Abhishek Bhandari, Renius Owen, Michael Baughn, Jeffrey Yuan, Terry Solomon, Alexandra G. Moyzis, Michelle S. Maile, Stephan J. Sanders, Gail E. Reiner, Keith K. Vaux, Charles M. Strom, Kang Zhang, Alysson R. Muotri, Natacha Akshoomoff, Suzanne M. Leal, Karen Pierce, Eric Courchesne, Lilia M. Iakoucheva, Christina Corsello, and Jonathan Sebat in American Journal of Human Genetics. Published online March 24 2016 doi:10.1016/j.ajhg.2016.02.018
Frequency and Complexity of De Novo Structural Mutation in Autism
Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.
“Frequency and Complexity of De Novo Structural Mutation in Autism” by William M. Brandler, Danny Antaki, Madhusudan Gujral, Amina Noor, Gabriel Rosanio, Timothy R. Chapman, Daniel J. Barrera, Guan Ning Lin, Dheeraj Malhotra, Amanda C. Watts, Lawrence C. Wong, Jasper A. Estabillo, Therese E. Gadomski, Oanh Hong, Karin V. Fuentes Fajardo, Abhishek Bhandari, Renius Owen, Michael Baughn, Jeffrey Yuan, Terry Solomon, Alexandra G. Moyzis, Michelle S. Maile, Stephan J. Sanders, Gail E. Reiner, Keith K. Vaux, Charles M. Strom, Kang Zhang, Alysson R. Muotri, Natacha Akshoomoff, Suzanne M. Leal, Karen Pierce, Eric Courchesne, Lilia M. Iakoucheva, Christina Corsello, and Jonathan Sebat in American Journal of Human Genetics. Published online March 24 2016 doi:10.1016/j.ajhg.2016.02.018
