MICHAEL WIGLER SPORADIC THOUGHTS:Proposes that spontaneous mutations, in addition to mutations that follow standard Mendelian inheritance patterns, can explain autism's puzzling heredity and perpetuation.

MYSTERY DISORDER:Autism symptoms range from cognitive deficiencies to asocial and obsessive behavior. It afflicts one out of every 150 children born in the U.S.

CASTING A WIDE NET:Believes that his unified theory of autism may also help explain other complex genetic diseases, such as schizophrenia, depression, morbid obesity and diabetes.
BRIAN MARANAN PINEDA

When Michael Wigler saw researchers using classical genetic methods "breaking their teeth" on the underpinnings of autism, he took a different approach. By looking at large genetic events, he developed a unified theory of autism that would recharge the field.

The search for single nucleotide polymorphisms (SNPs)—substitutions, deletions or additions of a single base along the genetic code—associated with autism has yielded minimal insight into the genetic footprint of the disorder. Drawing on his work with cancer, Michael Wigler thought that by looking at bigger events—specifically copy number variations, where large segments of DNA are duplicated or deleted—that arose spontaneously in a child (without appearing in a parent) could help jump-start the field. In a study published last March in Science, he and colleagues showed that these larger genetic rearrangements could account for more than 30 percent of autism cases. He followed that up in July with a second paper, appearing in Proceedings of the National Academy of Science USA, which rolled out a unified theory for the genetics of autism, ascribing 75 percent of the disorder to spontaneous mutation.

For the Insights story, "A Maverick against the Mendelians," appearing in the February 2008 Scientific American, Nikhil Swaminathan talked with Wigler about the reception to, the genesis of, and the effect he hopes to have with his controversial theory. Here is an expanded interview.

SciAm: How has your unified genetic theory of autism been accepted by colleagues and the general public?

Wigler: At a personal level, I haven't gotten any death threats. I haven't had any colleagues calling me on the phone and telling me that they think I am an idiot. I've gotten a few colleagues sending me e-mails congratulating me on a marvelous integration of facts. And I've gotten a number of calls from journalists who wanted explanations of things. And, in general, I have been more or less disappointed by the media coverage because it doesn't really capture what we're saying, but what we're saying is kind of complicated. So that's excusable, I guess. Some of the worst offenders were saying that we were blaming mothers. That was a little horrifying.

In general, I don't think the publication has had the impact that I would have liked to have had. I think that there should have been more controversy about the implication of these certain mixed de novo mutations and inherited models on other disorders like schizophrenia. I don't think it's really penetrated very far. I think its penetrated pretty far in the autism community among geneticists. But there's really no other game in town right at the moment besides our approach.

So, it doesn't matter if the model is right. Because everybody is looking at copy number variation because the methods for looking for SNP associations are pretty much acknowledged as … worthless. The other kinds of approaches in autism that show promise are in families with a lot of inbreeding where you can use more classical methods. The fellow who's doing that is Chris Walsh. He's gone off to the Middle East where there's still a lot of consanguineous marriages and tried to use those families.

But, ultimately, looking at marriage within the same bloodlines has a limited scope, right?

Well, yes and no. Our major hypothesis is in fact that there are up to a hundred or perhaps even more loci. There isn't any one locus that's going to be the common etiologic factor. So, any particular gene that tells us something is valuable.

Basically, we divide the genetic task into two parts: Part one is finding genes at very high penetrance—that is, when those genes are mutated, then your odds of getting autism are very high, if you're a boy. Those will tell us something about the underlying basic mechanisms. There are another class of genes that are modifiers and the evidence that they exist comes from the observation that girls don't show autism with the same frequency. Those could be of small effect, that they change the odds of you being autistic—each one may be a minor thing, but, in total, they add up to a lot. They're harder to find.