A pair of research teams recently linked large-scale mutations on one of the body's 23 pairs of chromosomes (which carry cells' genetic code) to autism, a finding that helps shed light on a disorder whose genetic underpinnings have confounded scientists for decades. The revelation represents the most concrete evidence to date that structural variations in the genome play a crucial role in the condition's development, marked by symptoms that include a failure to socially connect, communication difficulties and obsessive behavior.

Scientists this month unveiled evidence that an estimated 1 percent of all autism cases may stem from a structural change involving 25 to 30 genes on chromosome 16. On January 9, a team, led by researchers at Massachusetts General Hospital (MGH) and Children's Hospital Boston, announced that it had found copy number variations—deletions of duplications of segments of genetic code that alter the number of copies of a gene a person carries—in 12 of 1,400 autism sufferers it was studying. (A person normally receives two copies of each gene, one from each parent.) The researchers report in The New England Journal of Medicine (NEJM) that they replicated the finding in two other cohorts—one with 500 participants and another with 300 individuals diagnosed with autism. A week later, a Canadian research team announced in The American Journal of Human Genetics that it had uncovered genetic kinks in the same region in a sample of 927 people—427 of whom suffer from autism

The back-to-back findings come amid a stream of evidence pointing to genetic rearrangements as key culprits in autism. (Chromosome 16 is the second instance of a copy number variation to be fingered as a causative mutation of the condition. Scientists first reported a link between a surplus of genetic material on chromosome 15 and autism in 1994, a finding that has since been replicated and confirmed to be a copy number variation.

Less than a year ago the Autism Genome Project (AGP) Consortium, a collective of more than 120 scientists representing various institutions around the world, reported in Nature Genetics that it had found similar chromosomal variants in several autism patients. About the same time, scientists at Cold Spring Harbor Laboratory in Long Island, N.Y., focusing on families with one autistic child, reported that an estimated 10 to 30 percent of all reported cases of autism may be caused by new (or spontaneous) mutations in the number of copies of genes in children (that were not found in either parent).

Citing the growing body of evidence of links between copy number variations and diseases such as autism, an international science consortium announced yesterday that it plans to sequence the genomes of 1,000 people from around the world in an attempt to flush out genetic suspects. "The importance of these variants has become increasingly clear with surveys completed in the past 18 months that show these differences in genome structure may play a role in susceptibility to certain conditions, such as mental retardation and autism," the National Institutes of Health, one of the participant organizations, said in a statement.

Mark Daly, an assistant professor of medicine at Harvard University Medical School and MGH as well as co-author of the NEJM study, notes that "It is extremely unusual to see these spontaneous deletions and duplications in a region that's usually a copy number–stable region. This specific spontaneous mutation, which we found in a sufficient number of cases, announced itself as an autism risk factor."

"I'm really happy because we found the same result on [chromosome] 16 using a Canadian cohort," adds Stephen Scherer, director of The Center for Applied Genomics at The Hospital for Sick Children in Toronto, a co-author on the second study. "Validation of a complex disease is very exciting."

The search for autism-related genes has led to stunning evidence of the complexity of the disease, which is estimated to affect one in every 150 children born worldwide. Autism involves a spectrum of illnesses that all have similar symptoms, including Rett syndrome, which researchers have linked to a specific genetic mutation. The syndrome only strikes girls and is characterized by asocial behavior and cognitive deficits. But the exact causes of the vast majority of autism-related disorders remain a mystery: classic genetic studies, which tie the ailment to single nucleotide polymorphisms (SNPs—deletions, additions or substitutions of one unit in the genetic code), have returned a number of different markers with very few well-replicated candidates.

Some research teams over the past five years have used microarray or gene-chip technology to compare genomes and quickly scan them for variations of copy numbers on each chromosome. Daly says that microarray data provided his team with an early analysis of the vast data sets it is reviewing; he says scientists plan to follow up their initial findings with an SNP-association study. The Canadian researchers—some of whom were members of The AGP Consortium—specifically set out to examine copy number glitches.

Daly believes these structural events are likely behind only some cases of autism. "I think the middle ground is that some of the genetics underlying autism have their roots in these spontaneous deletions or duplications," he says. "At the same time, across our data set, we don't see regions like this. It's a part of the puzzle, but there's a lot more to it than just this type of event."

Michael Wigler, a geneticist at Cold Spring and the senior author of the 2007 Science paper, believes that successfully hunting down these lesions in the genome will prove crucial to unraveling autism. At the least, he says, they will point researchers in the right direction.

"The general approach of looking at copy number variation as the cause for genetic disease has probably taken one of those exponential—it's probably hyper- —exponential leaps," he says. "So, in 2003 we published [a previous] Science paper, which showed that there is [a] relatively large amount of copy number variation among normal, healthy people."

Both of the new studies found that copy number events involving either duplication or deletion of the 25 to 30 chromosome-16 genes—several of which are known to play a role in the developing brain—appear to cause autism. "That region—or rather, a gene in that region—is apparently extremely sensitive to [copy-number] dosage," Daly says. "Too much or too little causes developmental differences."

In the case of a deletion of this DNA segment, the damaged gene likely will not produce enough protein. This can potentially cause myriad malfunctions, because proteins typically work in complexes. Hence, a deficiency of one can hobble the entire collaborative effort. By the same token, a surfeit of one protein caused by duplication would also cause malformed complexes.

There is another wrinkle in the Canadian data set, Scherer says: of the 427 autism sufferers assessed, 7 percent showed evidence of copy number variation. Within that group, 27 individuals (11 percent) had two or more of these spontaneous deletions or duplications (or one of each). One of them had a deletion on chromosome 22 that affected, among other genes, SHANK3, which has been implicated in mental retardation. This deletion was accompanied by a duplication of a genetic segment on chromosome 20.

Scherer calls the mutation on chromosome 20 a "modifier" that adds to the complexity of the phenotype. "There are some of these copy number changes that increase the risk of being autistic, but they may need to be inherited with other changes that culminate," in the disorder, he says. "It's going to vary based on your sex, your genetic background. and possibly the environment." He believes that a person without the chromosome-20 alteration is likely to suffer mental retardation and one who has it is more likely to develop autism.

That is in line with a unified genetic theory of autism proposed by Wigler, who performed a rigorous statistical analysis of a large data set cobbled together by the Autism Genetic Resource Exchange, a group of autism researchers who share data collected from families with autistic children. Wigler proposed the idea of modifying genes partly to account for the disparity in autism incidence between boys and girls. (Boys are four times more likely than girls to develop autism.)

So how significant is the latest finding about chromosome 16? "It's going to be the intense subject of functional studies, studies in model organisms, and genetic follow-up studies in human samples," Daly says. Clinicians monitoring children with the deletion or the duplication of material there, he explains, may eventually be able to find a matching set of specific symptoms that accompany those particular genetic events. "There are folks at the Children's Hospital," Daly notes, who "are already turning this into a critical screening tool."

For Scherer's part, he believes, from his preliminary observations of one family, that a deletion of DNA on the 16th chromosome may result in autism accompanied by mental retardation as well as disruptions in the aortic valve (one of the heart's four valves) that may cause seizures. "In fact," he says, "if you see…[this pair of symptoms], along with autism, it might predict the [chromosome-] 16 deletion."

If that bears out, then looking for the deletion ahead of time could be crucial in early intervention. "We tried to do a thorough study," Scherer says, "so that we could convince people to do a microarray analysis as part of their workup."