As a bold follow-up, Wigler published a paper in late July that unveiled a unified genetic theory for autism, which he cobbled together by examining data from families with multiple autistic individuals and incorporating both hereditary as well as spontaneous events. Focusing on families where the first two children were affected, he found that third-born male children have a 50 percent risk of acquiring the disorder, whereas the risk for third-born girls is closer to 20 percent.
From that data point, Wigler developed a simple two-tiered hypothesis: The vast majority of families fall into the low-risk category, in which affected children have a spontaneous mutation, either a copy number variation or a point mutation. On the other hand, high-risk families—which make up 25 percent of all autism cases, according to Wigler’s numbers—manifest the disease when an unaffected individual, most likely a female, carries a sporadic mutation and passes it down as a dominant allele. If the offspring happens to be male, Wigler estimates that his chance of developing autism is roughly 50 percent.
Deborah Levy, director of the psychology research laboratory at Harvard Medical School’s McLean Hospital, calls Wigler’s theory “a completely different framework” for looking at the disorder. “Rather than having multiple genes of small effect,” she says, “you have a single gene that’s accounting for the disorder,” although many different genes—up to 100, by Wigler’s estimate—can play that role.
Wigler explains that some sporadically altered or deleted genes have high penetrance (conferring high risk), especially for males. These particularly nasty mutations typically disappear within two to three generations, but autism will likely persist as a phenotype because carriers, mostly women, have modifying genes that protect them. Such genes, however, are less likely to shield male descendants. “The rates of autism are really quite high, and it would be a striking thing to say that most of autism is spontaneous mutation,” Wigler explains. “It says that we are living with evolution.”
Although some autism investigators see Wigler’s spontaneous mutation model as a simpler way to view the genetics of the disease, others find it incomplete. According to behavioral scientist David Skuse of University College London, critics note that it does not account for observations of families with an autistic child in which either second- or third-degree relatives are also affected or in which first-degree relatives show mild symptoms of the disorder. And the model fails to explain why girls do not get autism with the same frequency as boys.
Wigler believes that more statistical data might help prove his theory (which he views as a boast). For instance, the girl-boy discrepancy could be explained if the genetic modifiers are sex-specific, an effect that might become apparent if, he says, researchers look at cases in which a normal mother has an autistic daughter. “This is not the kind of theory where you can comfort yourself with it and say the mystery is solved,” he says. “It’s the kind of theory that gets you out of bed and doing something.”
On a Friday afternoon in his office, Wigler chats excitedly about a movie he just received from Netflix. “Have I told you about my first intellectual awakening?” he asks. He is referring to the film Alexander the Great, Robert Rossen’s 1956 tale of the Macedonian conqueror, which his grandfather took him to see when he was nine years old. In it, Alexander (played by Richard Burton) is confronted with the Gordian knot, a tangle of bark rope that mythology foretold would grant to the one who managed to unravel it the legacy of conquering all of Asia. Rather than grappling with the intractable bulge, Alexander draws his sword and hacks through it.