VICTIM OF A REARRANGEMENT?: Researchers are beginning to take a new tack in finding autism genes, looking at large-scale disruptions in copy number, where several genes deleted or duplicated in one fell swoop.
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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."