Michael Wigler
Genetics Professor, Cold Spring Harbor Laboratory

A "Unified Theory of Autism"

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Why is the risk of autism higher in boys than girls? Why do older parents tend to have more autistic children? New genetic research attempts to answer some of the major questions surrounding the disorder.

Michael Wigler

Dr. Michael Wigler has made wide-ranging contributions to biomedical research in genetics, cancer, and cognitive disorders. Dr. Wigler attended Princeton University as an undergraduate, majoring in Mathematics, and Columbia University for graduate studies in Microbiology. After receiving his Ph.D., he began his scientific studies at Cold Spring Harbor Laboratory, where he continues his work to this day as an American Cancer Society Research Professor.

Early in his career, Dr. Wigler developed methods for engineering animal cells with his collaborators at Columbia University, Richard Axel and Saul Silverstein. These methods are the basis for many discoveries in genetics, and the means for producing medicines used to treat heart disease, cancer, and strokes. Dr. Wigler continued his genetic explorations, and in the early 1980s isolated the first human cancer genes. In the mid 80s, Dr. Wigler and his collaborators demonstrated conservation of cellular pathways in humans and yeast, thereby providing deep insights into the function of the cancer genes.

In the early 1990s, Drs. Wigler and Clark Still developed a method for building vast chemically indexed libraries of compounds, an approach that is still in use for drug discovery. During the same period, Wigler’s group developed the concept and applications of representational analysis, RDA, which led to identifying new cancer genes and viruses. He later enhanced this concept through use of microarrays, a method now widely used commercially for genetic typing.

Dr. Wigler’s research is presently focused on the genomics of cancer and genetic disorders. He expects this work will eventually improve the targeting of cancer treatment and lead to early detection tests for cancer. His studies in human genetics led to the discovery of a vast source of genetic variability known as copy number variation (CNV), and to the breakthrough that spontaneous germline mutation is likely to be a contributing factor in autism. His genetic theories and methods suggest to new approaches to understand many other cognitive and physical abnormalities.

For his fundamental contributions to biomedical research, Dr. Wigler is a recipient of numerous awards and honors and is a member of the National Academy of Science and the American Academy of Arts and Sciences.

Question: What is the “unified theory of autism” that you’ve developed?

Michael Wigler: The unified theory of autism attempts to reconcile several observations.  The first observation is that having siblings with autism is more common than one would expect if each incidence of autism was random.  So, if a child is born has autism, a brother is born, the chances that that brother has autism are much higher than a male born to another family. 

And twins, identical twins have an extremely high concordance.  Something like 90%.  There is no other cognitive disorder whose concordance among identical twins is as high. 

So, those two facts tell you that there is a genetic component to autism.  However, there are families that have autistic children and there are large families and only one child will have autism.  So, the genetics would look to be complicated.  There’s an inherited component because siblings have a higher rate of concurrence, but there might also be a sporadic component.  So, the issue is how to reconcile that. 

I think that prior to our serious involvement in the field, people assumed there was what was called this complex inherited model.  That there are many genes that may be in the wrong state in the parents that come into some combination in the child, so the children of these parents have a higher chance of having autism.  But it’s not a classical Mendelian pattern where half of your kids have it, or a quarter of your kids have it.  Half will have it if it’s a dominant, a quarter if it’s recessive.  The pattern seems more complicated than that. 

What we did was come in and say, well, you know, it could be a combination of both.  In some families, it is perhaps simple Mendelian and in other families it’s spontaneous.  And if you assume that there are a large number of genes that can give you autism, then you could have a very large proportion of autism being generated by spontaneous mutation.  But if the mutations don’t all have complete, what’s called complete penetrance, that is, you can pass on the mutation and the child can carry it and not show the disorder, then his or her children could then be at risk in a Mendelian way of inheriting that gene.

So combining these two ideas that the sibling risks is really a combination of simple Mendelian in some families with other families being spontaneous mutation unifies these two observations and does so in a coherent model.  So, the coherent model is that humans are mutating, the rate of new mutation giving rise to autism is perhaps on the order of 1 in 200 kids, and something like half of those kids actually don’t come down with a diagnosis, they mature, they get married, they have children and those children are then at risk from the carriers. 

Now, one of the very important clues that is compatible with this model is that the risk of autism is much higher in boys than in girls.  If the model, almost any model would predict that whatever genetic abnormalities exist in the boy, those abnormalities will exist in the girl.  So girls have something that makes them resistant.  So girls, in fact, could be natural carriers of genes that in the boy would give the boy autism.  And that girl might grow up and be a healthy and desirable mate and have children and her children, particularly her male offspring might be at high risk because they might inherit the gene that she safely carries.  That’s the essence of unified theory.  It does not explain why autism, why boys are at higher risk than girls.  But it does suggest that you can have two forms of genetic involvement; an inherited involvement from a carrier parent and also those rare mutations that destroy a gene in the germ line. 

Now, I should say, and I really have to mention this, that in the model we’re not saying that only women are carriers.  In fact, there’s well-known example that’s been in the news of a male sperm donor who had something on the order of 20 male offspring and half of them had autism.  So, that’s clearly a case where the sperm donor, who I guess was judged to be normal, probably maybe even brilliant or even genius, was a carrier of a simple dominantly inherited Mendelian trait.

Question: Why do older parents tend to have more autistic children?

Michael Wigler:  The incidence of autism goes up with the age of the parent, and that’s entirely consistent with the new mutation idea.  Because it’s already well established in males that the number of point mutations found in the male’s offspring go up with the age of the father.  And there’s also a correlation with the age of the mother.  So, there may be a mild increase in the rate of autism in those cultures where having children is differed and delayed.  The magnitude of that effect is not going to explain the overwhelming explosion in the number of diagnoses, but there may be a mild increase in the rate of autism due to that.  And the age dependence on the parents is consistent with the new mutation hypothesis.

Recorded April 12, 2010