The real workhorse is the April 2007 paper [published in Science], which says spontaneous mutation is higher in autism.
What percent of autism cases did you predict were due to spontaneous mutation in that paper?
In PNAS, we said 75 percent; in the Science paper, we said that 30 percent would be spontaneous mutations of the copy number variety. The PNAS paper says that 75 percent of autism may be caused by spontaneous mutation, not necessarily by the copy number variant. It could be a new SNP.
Going back to the issue of what does the theory do to scientific practice: It makes a boast in some sense. It says just stay doing this sort of stuff, looking for spontaneous mutation and you'll find your answers. You can believe it or not believe it. if it's correct, those who believe it will win. If it's incorrect, those who believe it will lose.
It provides a way of developing models that incorporate spontaneous mutation and Mendelian inheritance, but it also does something which says: How do you look for modifier genes? So, at the end of the paper, we're left with this really outstanding, unexplained fact, which is: Girls don't get it with the frequency of boys. It suggests that there must be genetic modifiers of that. It might be merely estrogen. Even it were estrogen, it's not going to be all in the effects of estrogen; it would have to be something specific. It really raises the most profound questions about what is different about the male and female brain[s]. To me, it suggests that there are going to be simple, genetic modifiers and suggests if you read into it, how to look for those.
In earlier versions, we stated how to go looking for these things. If you have this model in mind, you want to compare mothers and daughters; mothers that you think are carriers and daughters who have the disease. That gives you a pair to compare with classical genetics.
Everything is a signal-to-noise game. If you're looking at the whole world, your signal is submerged in things other than what is going to show up as a strong genetic signal. If you focus on the right population subclass, these methods might work. So, one is to look at mother–daughters. And the other is to look at brothers both of whom have autism—one who has it severely and the other who doesn't—which I don't think the geneticists were doing. If you're a Mendelian, and you have two brothers who have autism, what do they have in common, because that's causing their autism. But, I am asking, "How do they differ, if they are at different ends of the spectrum?" That's going to yield you the heritable genetic things—because presumably they have inherited the same major causative allele.
The people who really should be paying attention to this model, if they think it's correct, are the people who are interested in leveraging the Mendelian approaches to find modifying genes.
And you got to this point thanks to your work on cancer?
I don't think that we have had the model that we have or the approach to autism that we had without being conditioned by our experience in cancer. My first experiments when I came to Cold Spring Harbor were isolating oncogenes. These oncogenes were activated by point mutations. The laboratory that I came out of before that, everything was directed to mutational hypotheses. How is it that mutations cause cancer? And one of the first, big biological hypotheses that I was in relationship to was the idea that point mutations in normal genes have the potential to create cancers.
So, my orientation to begin with was not Mendelian, but more oriented towards the effects of spontaneous mutation. And then as we began to analyze, as our tools became more powerful, it was clear that there a lots mutations in cancers, but some of these mutations go away when you compare the cancer to normal. So the person was abnormal relative to what was then thought of as the standard human genome. And that was actually the first indication that there was more variety of the type that we subsequently went after directly, resulting in the Science paper of 2003. But, the way we first saw that was in cancer.
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Add CommentAs a biochemist/molecular biology scientist and mother of an autistic 7 year old girl I am very interested in this new vision. It has been very frustrating the wait during the autism gene hunting leading to more and more unanswered questions rather than answers. I am glad Dr. Wigler and colleagues are seriously looking at the problem coming with the cancer genetics experience. I am a mother daugther pair looking for answers. I see a cluster of traits in my family: ADD, depression, anxiety,panic disorder more ADD among us parents and older daugther. One girl only with autism and ADHD with no mental retardation and no epilepsy in her. Count me in, in donating tissue samples.
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