A Massive Search for Autism Genes Begins

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A Massive Search for Autism Genes BeginsNew gene chips could finally bring clues to this complex disorder.Source: Technology Review,http://www.technologyreview.com/read_article.aspx?id=17332 & ch=biotechThe hunt for the genetic basis of autism may soon be closing in onits elusive target. Scientists at 11 Boston-area institutions,including MIT and the Broad Institute, will use new tools to analyzeDNA samples from thousands of autistic people and their families. Itis expected to be the largest search to date for the genetic causesof autism and may yield candidate genes in as little as six months."This project will allow us to study the genome with an unprecedentedlevel of detail," says Mark Daly, a researcher at the Broad Institute<http://www.broad.mit.edu/> who is participating in the project."Once we have an understanding of the genes and causal pathwaysunderlying the disease, we can focus research and development oftherapeutics for those genes."Scientists know that autism, which occurs in about one in 166children, has a genetic component; siblings of autistic people have amuch higher chance of developing the disorder than the generalpopulation. But the disease probably has a number of causes,including environmental influences and multiple genes. As with othercomplex genetic diseases, pinpointing the genes that increase riskhas been enormously difficult.Previous studies have identified large regions of the genome thatappear to contain genetic variations linked to autism. That regionmight contain hundreds of genes, however, and the limits

ofDNA-analysis technology have made identifying the specific culprit achallenge. In such situations, scientists usually make a guess basedon the known biology of the disease. "It's very frustrating," saysRudy Tanzi <http://adams.mgh.harvard.edu/cagn/faculty/tanzi.html>, aneurologist at Harvard Medical School and a collaborator on theproject. "The odds are low that you've picked the right gene."But scientists can now scan the genome much more thoroughly usingnewer varieties of gene chips, tiny glass slides coated withparticular sequences of DNA that can identify sequences in a sampleby binding to them. The latest chips can quickly detect more DNAsequences than ever before -- hundreds of thousands of them at atime. "Now we can find diamonds among the glass," says Tanzi.The new

study will use a chip developed by Affymetrix<http://www.affymetrix.com/>, a DNA-analysis company based in SantaClara, CA, that searches for 500,000 specific genetic variations, orSNPs (single nucleotide polymorphisms), in a single experiment.Scientists will analyze the DNA of 3,700 autistic people and theirfamilies for SNPs that appear more frequently in those with thedisorder, compared with nonaffected participants in the study.Because the chip detects so many SNPs, almost every one can be tracedto a location near or within a specific gene in the genome. "Each hitcan get you right to the gene of interest," says Tanzi. "That'sreally a quantum leap forward, like going from Little League to themajor leagues."As soon as the researchers find a candidate list of genes, which theythink could happen in as little as six

months, they will make the datapublicly available, allowing other scientists to study the genes andtheir role in autism. Experts expect the project to point towardgenes and pathways no one has ever considered in autism -- pathwaysthat, in fact, might lie at the root of the disorder.Indeed, studies using advanced DNA chips have uncovered surprisingcauses of other diseases. According to Daly, a similar study ofage-related macular degeneration (the leading cause of blindness inpeople older than 55 in the United States) highlighted genes involvedin the function of the immune system rather than genes specific to theeyes or brain. "The genetics led us to a biological pathway thatpeople had not been focused on," says Daly. "It gives a foundationthat allows the research community to focus on what's really causal,rather than simply an effect of the disease."Other planned or ongoing studies that use the new Affymetrix

chip,which went on the market last September, are targeting disordersincluding diabetes, obesity, and Alzheimer's disease. Tanzi hasalready completed initial analysis in Alzheimer's patients andexpects to have a list of candidate genes in a month.So will these gene chips finally force complex genetic diseases tosurrender to DNA analysis? "I'm very confident we're going to findgenes associated with complex disorders," says Daly. "I'm equallyconfident we won't find all of them, maybe not even a majority. Butfor neuropsychiatric disorders, such as autism or schizophrenia,where we don't know any of the genes or have any insight into thecausal basis of the disorder, uncovering even a single gene could betransforming."For those facing the daily mysteries of a disease like autism, thatis welcome news. "This is really on the cutting edge of technology,"says Andy Shih, chief scientific officer at Autism

Speaks, anadvocacy group based in New York City. "The fact that people arewilling to apply this technology to autism is exciting."

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