|
January-February 2008
|
< previous | 1 | 2 | 3 | 4 Yet the task of identifying the culprit genes has proved daunting. Although the concordance rate for autism in identical twins is high—with recent estimates ranging from 60 percent for the same diagnosis and 90 percent for related disorders—it is not 100 percent. The fact that identical twins do not always share the disorder indicates that environmental influences are also at play. Furthermore, the variability in the traits and deficits associated with conditions along the spectrum (and often between individuals in a single family) suggests that multiple genes are involved; higher-functioning autism, for instance, may arise through separate genetic mechanisms than lower-functioning autism. These complexities have made cooperation among research teams and among institutions essential. “Autism is a problem that no one person or discipline can figure out alone,” explains James Gusella, Bullard professor of neurogenetics and director of the Center for Human Genetic Research at Massachusetts General Hospital (MGH). Gusella chairs the executive committee of the Boston Autism Consortium, a largely privately funded initiative that began in 2005 to take advantage of the wealth of expertise, technological resources, and patient databases concentrated in the area. The consortium brings together more than 50 researchers from Harvard, MIT, the Broad Institute, MGH, Children’s Hospital, Boston University, Beth Israel Deaconess Medical Center, and Tufts University to tackle different aspects of the disease cycle and to share results. Gene discovery is a top priority. “We’re not saying that it’s all genes,” Gusella is careful to point out, “but the genes will accelerate the search for other factors. They provide the crucial starting point.” The pursuit of autism’s molecular roots has led Christopher Walsh, Bullard professor of neurology and chief of the division of genetics at Children’s Hospital Boston, on a cross-cultural journey. Walsh, who also directs the division of neurogenetics at Beth Israel Deaconess Medical Center, travels regularly to Dubai, Kuwait, and Saudi Arabia to study the genomes of large Middle Eastern families. Because Arab cultures have a strong tradition of first-cousin marriage, the children in these societies have a higher likelihood than other populations of inheriting genetic mutations that can cause a developmental disorder. If both parents carry a recessive gene associated with autism, each child in the family has a 25 percent chance of getting the disease. With an average birth rate of six children per couple, a family in which both parents are carriers may well have more than one child with an autism-spectrum disorder. Walsh uses a technique called homozygosity mapping to look for causative recessive mutations. He checks all the sets of chromosomes in each family member, searching for spots where the affected children have two identical chunks of DNA and unaffected children have something different. Walsh and his team have identified four chromosomal locations in three separate families, and they have begun sequencing the genes in these spots to look for a disabling mutation. “Once we find it,” Walsh explains, “we can sequence any kid anywhere to see if he or she is subject to the same condition.” Inherited mutations hold the promise of explaining some, but not all, of the genetic paths to autism. Walsh points out that many genetic mutations that affect the brain—particularly those involving severe cognitive impairment—are spontaneous. “Mental retardation is frequently not inherited within families because it is so crippling,” he explains. “People with this condition are not likely to have children, so the mutations that cause the disorder are sporadic, rather than inherited.” (Down Syndrome, which arises from the presence of an extra chromosome, is an example of this type of nonhereditary genetic disorder.) Walsh estimates that about 15 to 20 percent of autism cases may fall into this category. In order to identify spontaneous genetic changes that are causally significant, researchers need to look for gains or losses of DNA that are present in children but not in their parents. If they find a change in the child that they can associate with a set of symptoms that is absent in the parents, they can then conclude that the mutation caused the disorder. In the case of autism, however, the isolation of disease-causing mutations has proven particularly difficult because the genetic changes and the clusters of disease traits (phenotypes) do not present a clear one-to-one relationship. “We’ve found that sometimes some of the sub-microscopic changes in the kid’s DNA are also present in one of the parents,” Walsh notes. “And these parents may be either asymptomatic or mildly symptomatic: in some cases, some of the parent’s cells don’t show the mutation, while other cells do, which suggests that the change may have happened part-way through the development of the parent.” The first step, Walsh says, is to determine which of these sub-microscopic changes are meaningful and which aren’t.
Stalking Likely SuspectsToday’s researchers do have some possible signposts to help them navigate the maze of potential routes to autism. There are 10 spots, called chromosomal “linkage peaks,” along the genome, where deletions or insertions of bits of DNA have been statistically correlated with the presence of autistic traits. But hundreds of genes are associated with a single “linkage peak.” Teasing out the causal genes presents a formidable task. Louis Kunkel, professor of pediatrics and genetics and director of the genomics program at Children’s Hospital, is pursuing an unconventional approach to this puzzle. He has joined forces with Isaac Kohane, Henderson associate professor of pediatrics and health sciences and technology, who directs the hospital’s informatics program, to look for irregular patterns in the way genes are expressed in the white blood cells of autistic children. “We’re asking: if gene expression is off-track in the brain, is it also off-track in whole blood?” Kunkel explains. “And can we categorize kids with autism based on gene-expression profiling in blood?” (Gene expression refers to which genes are “on”—giving instructions for how the cell should work—in a given cell.) 1 | 2 | 3 | 4 | continued >  
 
 
|
