Searching in a "Smaller Haystack" Yields Promising Findings in Autism GeneticsConnie Anderson, Ph.D. Date First Published: June 29, 2011
Shrinking the Haystack
How big is the haystack? The human genome contains 20,000 to 25,000 genes,1 and looking for anything within this vast storehouse of information is daunting. Recently, researchers have begun to make the task more manageable by focusing on the exome: the 1% or so of our DNA that contains vitally important protein-coding genes.2 3 This is like shrinking the haystack to about 1% of its original size -- a move that makes the search for any disease-causing genes much more possible. Protein-Coding Genes Pack a PunchThe reason researchers are focusing on mutations in protein-coding genes is that these genes have such important jobs. If something goes wrong with one of them -- so it is producing too little or too much of something, for example -- it can have a very negative effect. Medical research efforts focused on protein-coding genes are showing promise. In April 2011, for instance, cancer researchers examining the exome were able to identify 16 genetic mutations that likely cause melanoma, a form of skin cancer, and were even able to identify one gene as almost certainly a cancer-causing gene.4 5 Autism researchers are taking a similar approach, hoping that a focus on the exome may help them discover autism-causing genetic mutations. Finding Mutations That Matter: Working with "Simplex" FamiliesWe all have a unique genetic code, which is like the blueprint for the person that we are. This code is contained within countless genes, which are themselves contained within 46 chromosomes. This entire blueprint occurs within nearly all of the cells of our body. Among the exceptions are sperm and egg cells, which have only half the code so that, when they come together, there will be just the right amount to make a new person. Because a picture is worth a thousand words:
Everyone has mutations in this genetic material, and most of these "tweaks" are harmless. Some mutations we inherit from our parents. Any "tweaks" our parent had in the half of their genetic material they shared with us, we have, too. Other mutations are the result of a change to genetic material contained in just one sperm or egg. In that case, neither parent has the "tweak" in his or her own genetic code; only the resulting baby does. These types of changes are called de novo mutations because they are new and not shared by a person's parents. (De novo is Latin for "new" or "from the beginning.") De novo mutations are more likely to occur as parents age, which may explain why a number of studies suggest autism spectrum disorders occur more frequently in children born of older parents.6 7 8 Recent research suggests that it is often a de novo genetic change to sperm or egg that results in autism, especially in cases where no one else in the family has any sign of the condition.9 For this reason, researchers interested in de novo genetic change focus on families with just one child on the autism spectrum, also known as simplex families, comparing the genetic material of parents and unaffected siblings with that of the affected child. The aim is to pinpoint mutations in the child with ASD that are not shared by other members of the family and may have contributed to or caused the child's ASD. Autism researchers have recently discovered several new potential autism-related genes by focusing on the exome in simplex families. "In this study," they write, "we sequenced the protein-coding regions of the genome (the exome) to test the hypothesis that de novo protein-altering mutations contribute substantially to the genetic basis of sporadic ASDs."10 The researchers selected 20 families who had participated in the Simons Simplex Collection (SSC), a major autism research initiative gathering genetic material, family histories, diagnostic information, and more from families with just one child on the autism spectrum. They then carefully examined the exome of the child with ASD, the mother, and father. Like all families participating in the SSC, these families had to have a profile that suggested ASD did not run in the family, but arose "out-of-the-blue" in the affected child. The researchers were able to identify 21 de novo mutations in the children, all of which occurred in different genes. Eleven of these were protein-altering. Eight children in the study had two or more de novo mutations. The fact that all of them were from families in which parents were older provides support for the hypothesis that children of older parents are at higher risk of ASD.
Two of the most severely affected children had both a de novo mutation (that only they had) and an inherited mutation (that they shared with a parent). In one case, both mutations were associated with increased risk for epilepsy. "It's like getting hit by lightning twice," said lead researcher Evan Eichler (shown to the left).11 This finding, which provides support for the idea that it may take a combination of harmful mutations involving the same vulnerability to cause the most severe autism, may change our understanding of the genetic basis of ASDs. Simons Simplex Families at the ForefrontAlthough studying 20 families is just a beginning, this effort has shown that focusing on the exome is an efficient way to identify autism-related genetic mutations. The results gained by looking for these very specific "needles" in a much smaller "haystack" have been so promising that the Simons Foundation has funded exome sequencing on 100 additional Simons Simplex Collection families, and is in the process of funding the same for 400 more.12 Dr. Eichler is enthusiastic about the prospects for major new findings based on both exome sequencing and a related effort, the study of copy number variations (CNVs) in autism. (A CNV is when a person does not have the usual two copies of a gene or set of genes, but has one, three, or none at all, doing too much or not enough of what they are supposed to do.13 14 15 ) According to Dr. Eichler, if we can get to the point where we understand exactly what genetic "tweaks" are contributing to a child's challenges, we may be able to directly treat them with individually-tailored drug therapies.11 "You need to know what form of autism your child has if you're going to have a smart therapy that's going to ameliorate some of the symptoms," he says. "The genetic distinctions may be very important going forward."16 Related Articles
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A new approach to studying genetics may permit us to understand what genetic "tweaks" have caused an autism spectrum disorder (ASD) in a specific individual. As we learn more, someday we may be able to develop autism-focused drug therapies tailored to a specific person.
There was a time when autism researchers believed they were searching for a single autism-causing gene in the immense collection of human genetic material known as the human genome. It was like searching for one tiny needle in an enormous haystack. It is now clear that there probably is no single autism-causing gene. Instead, there are likely many different changes to genetic material (called 
Four of the children had de novo mutations the researchers believed were very harmful, and had almost certainly caused their autism. In most cases, these mutations involved genes already known to be linked to ASD, intellectual disability, or epilepsy.
