A Unified Theory of Autism

by Kristina Chew, PhD on January 18th, 2008

Geneticist Michael Wigler has proposed a “unified genetic theory of autism.” Drawing on his work studying cancer genetics, Wigler took a different approach than that of researchers using classical Mendelian genetics; last year he published two articles about spontaneous mutation and autism. A March 2007 paper in Science suggested that large genetic events—”copy number variations, where large segments of DNA are duplicated or deleted–that arose spontaneously in a child (without appearing in a parent)“—could account for more than 30 percent of cases of autism. A July paper in the Proceedings of the National Academy of Science USA stated that spontaneous mutation accounts for 75 percent of cases and noted why some families might be at “high risk” or “low risk” to have an autistic child. Previous studies on autism genetics have searched for “single nucleotide polymorphisms (SNPs)–substitutions, deletions or additions of a single base along the genetic code.”

The January 17th Scientific American interviews Wigler. He notes that, though his theory is controversial in the field of genetics, it has not (yet) had “the impact that [he] would have liked to have had.” But—I would hazard saying in light of recent discussions about what direction autism research should take and about who is making the decisions—-Wigler’s research make quite an impact and, too, goes right to the heart of some controversial and contentiously debated questions about autism: Is it genetic or caused by something in the environment? Should more research funds be allocated to research about genetics that does not (some say) lead directly to new treatments for autistic children, but rather on biomedical and environmental research that (some claim) would have a direct impact on the health of autistic children and the lives of their families? Some excerpts from Scientific American:

On sporadic cases of autism:

The model is that most sporadic cases are in fact these lightning strikes, which nobody likes to think about. I’m used to thinking about it because I’m a cancer researcher and when you get cancer, it’s a lightning strike. You hear people say, “Oh I eat all the right things, I exercise, I don’t smoke,” and they still get cancer. I think it’s natural for people to want to finger some cause that’s controllable, but random processes are not controllable. People are very reluctant to accept randomness as a factor in their lives.

On the role of environmental factors and his unified genetic theory of autism:

Just because something is genetic doesn’t mean it’s not environmental—that’s number one. If you have 100 people and they’re all exposed to the same environment and one reacts badly to it, that’s genetics and environment. So, just by saying something is genetic says nothing about that it might not be also environmental. That’s the main point. The secondary point, we said our model assumes that—the population genetic analysis that we did makes an assumption that—it’s genetic. You can’t turn around then and say it proves that it’s genetic.

On seemingly normal children “regressing” into autism:

There is a subjective sense that the child regresses in about 25 percent of the cases, but it’s not really that the child is regressing, but the subjective experience of it. In fact, I’ve met scientists who told me a story about their three-year-old child who was developing very well, and then the child did regress. And this was from a trained observer, so I think there is little question that there are cases where little children regress. And that doesn’t necessarily mean that something is environmental, although that would seem to be the logical conclusion, because I think in many cases, for example, where there are storage diseases. The body’s buffer can accumulate. The child continues along normal development. The buffer gets filled and then catastrophe strikes.

The cases where there is regression are extremely interesting. It suggests a different molecular mechanism, but it doesn’t necessarily suggest that a kid has been vaccinated and he’s having an immunological reaction.

On focusing on large genetic events instead of focusing on the “genome from a SNP level”:

Autism was an example of what people call a complex, genetic disorder that was failing to be conquered by Mendelian SNP association studies. People were really breaking their teeth on this. To groups would rarely come up with the same conclusion. And it was fairly easy for me to believe that this was not the right approach to autism or to other complex genetic diseases, like schizophrenia or obesity—any large number of things. There were two things that I thought were being missed: one was the possible role of spontaneous mutation. There were really three things: the possibility of spontaneous mutation; the possibility of rare variants that don’t exist in the population for very long because they’re eliminated quickly; the possibility of there being many loci that could contribute to the disorder. And those three things were generally missed, and the way the Mendelians tried to deal with this was to say: “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 at these four or five loci, you would have the disorder. This was sort of the hypothesis you heard to explain why they had failed.

And it was a very unsatisfying hypothesis because first of all it’s not testable. Second of all, it gave them reason to hope that they could continue to use their methods, just scale them up and eventually they’d get [a] signal. So, it was sort of self-serving. So, I really didn’t like it. I really disliked it. There were huge amounts of money that were going into supporting giant efforts of that type.

So, it seemed to me that there were simpler hypotheses. All we had to do was admit to the possibility that there multiple loci and multiple mutations, each one of strong impact and high penetrance, and you could still get the failure of the Mendelian methods.

Thanks to Marita for pointing out the Scientific American article to me!

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