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The newspaper of The Johns Hopkins University October 18, 2004 | Vol. 34 No. 8
Hunt for Autism Genes to Be Led by Johns Hopkins Researchers

By Joanna Downer
Johns Hopkins Medicine

With a three-year $3.2 million grant from the National Institute of Mental Health, Johns Hopkins scientists will lead the largest hunt for genetic contributors to autism, a neuropsychiatric condition whose causes are almost as mysterious today as when the condition was first described in 1943.

The researchers will apply new genome-searching technologies to available samples and information from 465 families, including 979 individuals with autism, to identify genetic factors that contribute to the condition.

"Autism is quite likely to result from the combined effects of multiple, very subtle genetic changes that differ considerably from family to family, since no single reliable genetic cause has been found yet," says Aravinda Chakravarti, principal investigator of the project and director of the McKusick-Nathans Institute of Genetic Medicine at Hopkins. "We'll be looking for combinations of genetic mutations and extra or missing gene copies that are much less common, even in the affected group, than most scientists are used to considering. This is a huge undertaking."

Recent research suggests that as many as one of every 500 births is affected by autism, which is characterized by social and communication deficits and restricted and repetitive interests. Understanding the condition's genetic roots may reveal important clues to its biology and hence targets for treating some of its effects or trying to prevent it.

"The molecular genetic study of autism provides one of the best scientific opportunities in medicine: the chance to identify the missing or abnormal signals that prevent full development of a small set of nerve cells in the brain," says project member Edwin Cook, director of the University of Chicago's Laboratory of Developmental Neuroscience and a child and adolescent psychiatrist who sees patients with autism. "Once we know the disrupted signals, we can begin the process of rational development of medical treatment of autism."

One aspect of the new project is to use "DNA chip" or microarray technology from project collaborator Affymetrix that will broaden the hunt for genetic changes behind autism. With these new microarrays, designed to detect the specific building blocks present at about 500,000 locations scattered throughout the genome, the researchers hope to find specific single changes in the genetic sequence — changes known as single nucleotide polymorphisms or SNPs (pronounced "snips") — either associated with autism or perhaps with the condition's risk, severity or constellation of symptoms.

"Conventional family studies have failed to detect autism genes," Chakravarti says. "Our planned studies are far more powerful at gene detection and will give a more complete assessment across all human genes. Because autism is so genetically complex, we're talking about identifying genes that might contribute to only a few percent of cases."

A second part of the upcoming studies is to look for genes that are present in extra copy numbers. Normally, each cell carries two copies of each gene, one from the mother and one from the father, each on its own chromosome. But some preliminary evidence suggests that autism might stem in part from "dose defects" — extra or fewer copies of genes that arise because sections of chromosomes are improperly copied and inserted into or deleted from the genome. Such events could alter normal production of the genes' products, which might damage cells, Chakravarti says.

But unlike those with disorders such as Down syndrome, people with autism don't have extra chromosomes, just — and only perhaps, at this point — extra segments of chromosomes. So existing techniques to count and look at the structure of intact chromosomes aren't enough.

Instead, the team will use digital karyotyping, a technique recently developed by project member Victor Velculescu, assistant professor of oncology in the Johns Hopkins Kimmel Cancer Center. The researchers will use about 400,000 short stretches of DNA to detect extra copies and identify any differences between family members with autism and those without. The techniques will also be used to see whether any extra segment copies were inherited — passed from the parents to the child — or appear spontaneously in the child and aren't found in the parents' genetic material.

To find answers in all these data, David Cutler will lead the project's computational biology aspect. His team will develop some new computer programs and apply some of their existing ones to sift through the data to find and "score" associations between traits and the results of genetic studies. Most studies searching for human disease genes have tended to look at 1,000 or fewer markers because no one was sure they'd be able to make sense of the results of bigger studies.

"Now we know we can do it," says Cutler, an assistant professor in the McKusick-Nathans Institute of Genetic Medicine.

Leaders of the project's various components are Chakravarti, Velculescu, Cutler and Dan Arking, all of Johns Hopkins; and Cook, of the University of Chicago. The family samples and information are publicly available from the NIMH-funded Autism Genetics Initiative Data Archive and the Autism Genetic Resource Exchange.


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