immense heterogeneity of autism,” says
geneticist Huda Zoghbi of Baylor College
of Medicine in Houston, who was not
involved in the studies. “We suspected
it, but these data show it clearly.”
Results described by Wigler’s team
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 har-
bors more of these rare
autism-associated genome
duplications and deletions, the
researchers found. And these anomalies
aren’t just more abundant in girls; each
change interrupts more genes. For a girl
with autism, each duplication or dele-
tion disrupted a median of 15. 5 genes,
while for a boy, the number disrupted
was just two.

Through some mysterious process, girls are just more resistant than boys to the genetic causes of autism, the results suggested. “Overall, it does look like a girl can have the same genetic insult as a boy, but not be diagnosed with autism,” Wigler says.

For the most part, each duplication or deletion was specific to each affected child. Although copy number variations of one particular region of chromosome 16 were observed in multiple children in both studies, changes to this region still accounted for only slightly more than 1 percent of autism cases.

“Some people will see that as glass-is-half-empty, but we see it as glass-is-half-full,” State says. “It shows that there are a lot more clues to be had.” State and his colleagues are now combing through 1,000 more samples from the Simons Simplex Collection, conducting more targeted studies to find out how some of these genes may contribute to the disorders.

While single, severe abnormalities in parts of the genome are clearly important for certain cases of autism, in some people the disorder could be caused by more numerous mild genetic changes. A new study from Zoghbi and her colleagues finds that children with autism

are more likely than unaffected children to have double hits: mutations in two of 21 autism-implicated genes.

Just one of these mutations is not severe enough to completely scramble or eliminate a gene’s functions, nor is it strong enough to affect the parent, who oftentimes carried it as well. “Each parent is fine, but those two together now in a child can perhaps increase the possibility of having autism,” Zoghbi says. Once a certain mutational threshold is reached, the disorder appears, the researchers suggest in a paper to appear in an upcoming Human Molecular Genetics.

Linking up

Other researchers are taking a different tack: Instead of searching for DNA changes to identify related genes, they study how genes behave. For instance, a recent study by neurogeneticist Daniel Geschwind of UCLA focused on gene activity — measured by the amount of RNA molecules shuttling information from a particular gene to the protein-producing parts of cells.

Hundreds of genes behaved differently in the brains of people with autism compared with unaffected people, Geschwind and his colleagues reported online May 25 in Nature (SN: 6/18/11, p. 5). Many of these genes were involved in maintaining the complex and sensitive links called synapses, the junctions between nerve cells.

Wigler and his colleagues have also found that in children with autism, deletions and duplications tend to strike genes whose products are essential for nerve cell communication. The study, published in the June 9 Neuron, adds to a growing body of evidence that nerve cell signaling is profoundly altered in people with autism.

With better ways to uncover the bio-
chemical networks in which genes, RNA
and proteins are players, scientists can
now study such nerve cell malfunctions
with precision. Wigler and his team ana-
lyzed how genes in DNA regions that have
duplications or deletions associated with
autism interact with one another. Among
other things, some of the affected genes
tell nerve cells how to grow a signal-
sending axon and how to find the right
partner to send signals to. Others oversee
the chemical messages that carry signals
across synapses from cell to cell.