Autism: Link to increased genetic change in regions of genome instability

These microscopic images were taken as part of research to explore rearrangements of DNA in one of the "hotspots" of the human genome, where deletions and duplications occur at higher rates. 

Credit: Betsy Hirsch/University of Minnesota and Scott Selleck /Penn State University

Children with autism have increased levels of genetic change in regions of the genome prone to DNA rearrangements, so called "hotspots," according to a research discovery to be published in the print edition of the journal Human Molecular Genetics.

The research indicates that these genetic changes come in the form of an excess of duplicated DNA segments in hotspot regions and may affect the chances that a child will develop Autism—a behavioural disorder that affects about 1 of every 88 children in the US, according to the Centers for Disease Control (CDC).

Earlier work had identified, in children with Autism, a greater frequency of rare DNA deletions or duplications, known as DNA copy number changes.

These rare and harmful events are found in approximately 5 to 10 percent of cases, raising the question as to what other genetic changes might contribute to the disorders known as autism spectrum disorders.

The new research shows that children with autism have—in addition to these rare events—an excess of duplicated DNA including more common variants not exclusively found in children with autism, but are found at elevated levels compared to typically developing children.

The investigators also found that the balance of DNA duplications and deletions in children with autism was different from that found in more severe developmental disorders, such as intellectual disability or multiple congenital anomalies, where the levels of both deletions and duplications are increased compared to controls, and are even higher than in children with autism.

They also found that children who had more difficulty with daily living skills also had the greatest level of copy number change throughout their genome.

Scott Selleck

"These measures of adaptive behaviour provide an indication of the severity of the impairment in the children with autism. These behaviours were significantly correlated with the amount of DNA copy number change," Selleck said, emphasizing that the research revealed "clear and graded effects of the genetic change."

"These results beg the question as to the origin of this genetic change," Selleck said. "The increased levels of both rare and common variants suggests the possibility that these individuals are predisposed to genetic alteration."

The research collaboration includes groups led at Penn State by Scott Selleck; at the University of California Davis /MIND Institute by Isaac Pessah, Irva Hertz-Picciotto, Flora Tassone, and Robin Hansen; and at the University of Washington by Evan Eichler.

CHARGE
The University of California Davis /MIND Institute group directs a large population-based case-control study of autism called CHARGE (Childhood Autism Risks from Genetics and Environment).

In this multiyear study, clinical history, environmental, nutritional, family, and medical data are collected from the families of children with autism and other developmental disorders, as well as from randomly selected control children from the general population.

The research took advantage of the CHARGE study, supported by the National Institute of Environmental Health Sciences and the Environmental Protection Agency.

"The CHARGE study is a true population-based case-control cohort for the study of autism, the only one of its kind that I am aware of " says Selleck, and allows for comparisons between the children with autism and controls matched for geographical location and time of birth.

The research team plans to continue its collaboration to further characterize the more common genetic variants found to be associated with autism and to explore the relationship between genome variation and environmental exposures.

Reference
Global increases in both common and rare copy number load associated with autism;  hmg.ddt136.abstract