Maverick Against the Mendelians

Using standard inheritance theory, scientists have searched for the genes underlying autism with little success. Michael Wigler thinks he knows why - and how the disorder persists over generations
Supplement: Working around the Mendelians: A Q&A with Michael Wigler


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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).

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