Ask Michael Wigler about the genetic basis of autism, and he will tell you that the standard genetic methods of tracing disease-causing mutations in families with multiple affected members are not working. Although most scientists agree that environmental influences play a role in disease onset, autism has a strong genetic component: among identical twins, if one is autistic, there is a 70 percent chance the other will show the disease, a risk factor nearly 10 times that observed in fraternal twins and regular siblings. Yet years of time and bags of money have been spent unsuccessfully looking for genes linked to the condition.
To Wigler, a geneticist at Cold Spring Harbor Laboratory on Long Island, the key to unlocking autism’s genetic mystery lies in spontaneous mutations—alterations in the parental germ line that are novel in offspring. Last year he proved that spontaneous events contribute to some cases of autism and then formed a controversial theory for the genetics of the disorder. It suggests, among other things, that females, who develop autism with a quarter of the frequency with which males do, may carry the genetic profile for the illness, which they then pass on to their children.
As Wigler sees it, conventional genetic studies have failed because they have corralled families that have more than one autistic child to search for differences in one base along the genetic code. These differences, which are presumed to affect neural connectivity, can be an addition, a deletion or a substitution of a base and are known as single nucleotide polymorphisms (SNPs). In autism research, uncovering SNPs shared by affected people would enable scientists to determine who would have an elevated risk for acquiring the disease or passing it on.
The problem is that research groups have rarely fingered the same places on the same genes: they have implicated regions, or loci, on 20 of the 23 pairs of chromosomes in the genome. “We felt like we reached a dead end with SNPs,” says Portia Iversen, the mother of a 15-year-old autistic boy and founder of the advocacy group Cure Autism Now.
“People were really breaking their teeth on this,” explains the 60-year-old Wigler. The SNP people “tried to deal with [the problem] by saying, ‘These are complex disorders caused by the alignment of the planets’—that there would be four or five loci and that if you got the wrong allele configuration of these four or five loci, you would have the disorder.”
Such justifications are unsatisfying to Wigler, who has experienced three decades of success as a geneticist. In 1981 he isolated the superfamily of RAS genes, the first suite of cancer genes ever identified. In the 1990s he conceived of a method to sample segments of a genome, allowing for a quick, inexpensive comparison of the DNA. He then employed this gene-chip technique, now known as representational oligonucleotide micro-array analysis, to scan for DNA disruptions that may lead to cancer.
In his first foray into autism, Wigler, working primarily with his Cold Spring Harbor colleague Jonathan Sebat, set out to determine what role, if any, spontaneous mutations called copy number variations may play in the disorder. These mutations affect the number of copies of a gene a person has. Before scientists sequenced the human genome, researchers thought that an individual always had two alleles, or copies of a gene—one inherited from each parent. In 2004 the Cold Spring Harbor team showed that even in healthy individuals, copies of genes could go missing from (or be added to) the genome via large-scale rearrangements of genetic material. (Such rearrangements have for years been known to account for particular manifestations of many disorders, including Huntington’s disease.) By focusing on families with only one autistic member, the team showed last March that up to 10 percent of noninherited autism cases could be caused by spontaneous copy number variations. Wigler and Sebat found that the structural events were primarily deletions, leaving individuals with only one copy of a particular gene and leading, in some cases, to a disruption of that gene’s function (a condition known as haploinsufficiency).[break]
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.[break]
On recounting the story, Wigler quips: “Sometimes you have a problem, and people don’t see the solution—because they’re not looking at it directly.” But only more data will prove whether his view of autism is truly straight on.