A plethora of genetic changes contributes to autism spectrum disorders, three new studies find. The new genetic data illustrate why researchers have struggled to find a single cause for the baffling suite of developmental and behavioral conditions, and may help point the way to a unifying process underlying them. The studies also begin to explain why autism spectrum disorders are more common in boys than girls.
Though the specific genetic changes identified by a trio of papers in the June 9 Neuron account for only 5 to 8 percent of autism cases, what they reveal about the biology of autism may have much wider implications.
“I think we’re still scratching the surface,” says Steve Scherer of the Hospital for Sick Children in Toronto, who wasn’t involved in the studies. “But we’re getting there, and I think these are very important papers.”
Two of the studies examined DNA samples taken from carefully screened families, a cohort called the Simons Simplex Collection. Each family included two unaffected parents and one high-functioning child diagnosed with autism spectrum disorder. For most families, an unaffected sibling was also included. By studying genetic changes in unaffected family members, the researchers could find abnormalities — specifically, duplications and deletions of DNA called copy number variations — that were not passed down from parents but arose spontaneously in the genomes of affected children.
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“What was surprising is how unique each of the variants is,” says geneticist Huda Zoghbi of Baylor College of Medicine in Houston. “This really speaks to the immense heterogeneity of autism. We suspected it, but these data show it clearly.”
The results may also help explain why autism spectrum disorders are much more common in boys. Autism strikes four boys for every girl, yet girls’ DNA actually harbors more of these rare autism-associated genome duplications and deletions, a study led by Michael Wigler of Cold Spring Harbor Laboratory in New York shows. And these genetic anomalies aren’t just more abundant in girls; they are also more severe. For a girl with autism, the median number of genes scrambled by duplication or wiped out by a deletion was 15.5, while for a boy with autism, the number was just two.
Through some mysterious process, girls are just more resistant than boys to the genetic causes of autism, the results suggest. “Overall, it does look like a girl can have the same genetic insult as a boy, but not be diagnosed with autism,” Wigler says.
The scientists can’t explain why girls might be more protected. Some researchers have proposed that sex hormones or some unidentified effects of genes on the X chromosome may play a role. Boys have only one copy of the X chromosome, so a genetic aberration there may be particularly dangerous for them.
In one of the three studies, Wigler and his colleagues analyzed how genes in DNA regions that have duplications or deletions interact with one another. In girls, this massive network of interrelated genes requires a much stronger hit to go haywire. In boys, it is relatively easy to perturb the network. This same analysis also revealed that children with autism tended to have more duplications or deletions in gene regions involved in nerve cell communication compared with other functions.
One of the studies using the Simons Simplex Collection, coauthored by child psychiatrist and geneticist Matthew State of the Yale University School of Medicine and his colleagues, included 1,124 families and estimated 130 to 234 genome regions in which copy number changes were linked to autism. Wigler’s study, which looked at 887 families, put the number at 250 to 300.
Deletions and duplications of one particular region of chromosome 16 were the most commonly observed changes. But, as is typical for such a diverse disease, changes to this region still accounted for only slightly over 1 percent of autism cases.
The studies also found that having extra copies of DNA on a part of chromosome 7 may be tied to autism. Children completely lacking the same region of DNA have Williams syndrome, a disorder marked by hypersocial and friendly behavior. “That suggests that this one small region of the genome contains genetic information that is really fundamentally important in the development of social circuitry,” State says.
Scientists don’t yet know which particular genes located in this section of DNA, if any, are behind the behavioral changes seen in autism spectrum disorders. But figuring that out will be tremendously important for understanding how genes can control human behavior, State says.