Much of the coverage of autism in the media focuses on the arguments of advocates, scientists, and government officials over the relationship between vaccines and autism. But out of the spotlight, a bigger story is brewing: the hunt for autism genes, a technically difficult hunt which is pressing forward using all of the tools modern genetics has to offer. If you are like me, news stories about autism have left you with only a vague impression of the current scientific state of understanding, the impression that researchers strongly deny any link between autism and vaccines, but have little else to say about what the real cause of autism might be.
If that is your impression, you'll perhaps be surprised to learn that roughly 20% of autism cases in the US are linked to known genetic changes, a minor fraction of autism cases to be sure, but much higher than I would have guessed. That autism has a genetic basis is a well-established finding, and while this by no means rules out environmental factors, genetics is at the core of the recent progress scientists have made in understanding autism. The genetics of autism, however, is not simple - no surprise, since autism involves our most complex organ, the brain, in one of its most complex functions, social interaction. Untangling the genetic and environmental factors that underlie autism will be tough, but in the process we will learn more about how many different genes work together in a child to control the developing brain.
Thirty years ago, autism was a complete mystery, with vaguely defined criteria for diagnosis, but in the early 1980's, scientists picked up some big clues. Most importantly, autism researchers established that autism has a strong genetic basis. Without knowing the genes involved, how do you know autism has a genetic basis? There are several telltale indicators that scientists check. For example, siblings of autistic children have a higher risk of themselves being autistic - suggesting that a shared genetic background is responsible. Keep in mind that in general, the risk of autism is relatively low, so that even in families with an increased risk, no more than one child will usually have the disorder. But as you look at thousands of families, the genetic pattern emerges, even if you don't know which genes are involved. The genetic roots of autism also show up in twin studies - identical twins are more likely to both be autistic than fraternal twins. So it has been clear for over 20 years that autism has a strong genetic basis, but finding the actual genes involved is much more difficult.
With Genotypes and Phenotypes You Can Do Genetics
The hunt for autism genes has been given a big boost by the amazing advances in DNA analysis technology, and by improved criteria for diagnosis. This is no surprise: the key to successful genetic research is the ability to get genotypes - the actual DNA variants present in your study subjects, and phenotypes, such as specific autism characteristics in your subjects that you can reproducibly measure. Thanks to the availability of the human genome sequence as a reference, extensive maps of human genetic diversity, and technologies like DNA chips and modern sequencers, we can now easily get the genotypes of thousands of people, such as groups of autism patients and their family members. And improvements in making an autism diagnosis have made phenotypes in these genetic studies much more consistent. Doctors can recognize full-blown autism, as well as a range of other similar, but not identical syndromes, like Aspberger's syndrome, now all put under the umbrella term Autism Spectrum Disorders (ASDs).
How do you use genotype and phenotype information together to find autism genes? One of the best ways is to look at families. In a family with an autistic child, you obtain phenotype information from all of the children in that family, something measurable, such as the age at which the child first spoke (delayed speech is sometimes a hallmark of autism spectrum disorders). You also get genotype information from those same children, perhaps using a DNA chip to look at several hundred thousands places in the genome where potential changes might be located. Then you look for genetic changes that correlate with your phenotype - maybe the children who first spoke at a late age have a genetic variant not found in the kids who starter speaking earlier. You repeat this process for as many families as you can find, and hope that in the end you find enough families to give your study the statistical power you need to convincingly find genetic variants connected to autism.
One research group, led in part by Dr. Christopher Walsh from Harvard Medical School, has found a rich source of families with Autistic children to study: the Persian Gulf. In many Gulf states, like Saudi Arabia, first-cousin marriage is relatively common, and families tend to have large numbers of children. This makes genetic studies much easier, so the Harvard team, collaborating with native scientists in the Gulf region, are looking for genetic mutations are more likely to show their effects in children of first cousin marriages. In an extended family that has multiple potential Autism mutations in its gene pool, first cousin marriages are much more likely to produce children who have the right combination of unlucky genes for full-blown autism. The Harvard group's research is still in progress, but so far they have managed to find at least one candidate ASD mutation to add to the growing list.
Unfortunately, the genetic variants that most studies have turned up so far each account for only a small number of cases, and many of them don't appear to be inherited in a family through multiple generations, which makes some classic genetics studies difficult. Unlike a genetic disease such as cystic fibrosis, in which one mutation in one gene accounts for most of the disease, each autism mutation that has been found accounts for only 1-2% of autism cases. All together, these rare mutations show up in about 20% of autism cases. So instead of a hunt for The autism gene, it looks like the search is going to be a long slog to find many different genetic variants that may interact with each other and the environment to produce autism. Autism is a complex disorder, involving a complex function of our complex brains, so it should be no surprise that Autism is genetically complex as well.
Broken Genes that Add Up To A Biological Picture of Autism
There may be many different mutations that can produce autism, but do these mutations have anything in common? Researchers have looked to see what type of molecular machinery is involved, and although we have a few leads, the big message again is that the biological cause of autism is complex. One way to untangle this complexity is to look at syndromes where one major broken gene produces many effects that include autism itself. One of these diseases is Timothy Syndrome, caused by a broken calcium transporter gene. Patients who suffer from Timothy Syndrome have webbed hands, problems with electrical conduction in the heart, and, interestingly, 60-80% of these patients also have an ASD. A variety of syndromes like this, where one broken gene produces multiple effects including autism, have helped researchers zero in on the types of brain processes that might be involved in ASDs, such as abnormal communication across synapses, the connection points between neurons. Genes involved in the function of synapses turn up over and over again in autism genetics, but the generation of new synapses during childhood brain development is an extremely complex process, so it has been difficult to know just where the identified Autism mutations fit in.
All of this may strike you as terribly vague - we have a list of genes, each of which accounts for only a small number of cases, and many of these genes somehow relate to the function of synapses. It's clear that researchers are a long way from a good understanding of what causes the complex symptoms of ASDs, in part because some of the more sophisticated technologies for doing genetic studies have been available only for a few years.
Yet a big picture is emerging, and it suggests that the genetic causes may be more simple than people previously believed. There are two possible genetic scenarios for autism that researchers have considered: children with an ASD are born with an unlucky combination of multiple genes that together have a negative effect on certain aspects of brain development (the complex genetic explanation), or, instead of a combination of unlucky genes, autistic children have inherited one big unlucky mutation that spontaneously arose in their parents reproductive cells (a much more simple explanation). A recent study, analyzing the pattern of genetic results we have so far, suggested that the majority cases of ASDs may be the result of spontaneous, big mutations in the reproductive cells of parents. This explains why the risk of having an autistic child increases with the age of the parents - as you age, you are more likely to have mutations in sperm or egg cells, and some of these mutations give rise to autism. There are probably many different ways to break brain development, which is why spontaneous mutations in so many different genes have been linked to ASDs.
This also means that, as the mutations linked to ASDs accumulate, we will have a list of mutations which we can use to identify high risk children. Unfortunately, there is little we can do for those children now, but as the autism gene list grows, the biological picture should become more clear. Researchers will narrow in on the biological processes that go awry as an autistic child's brain develops, the hope is that we'll gain the ability to modify those biological processes to restore the normal sequence of brain development.
One final point: the fact that autism has a strong genetic component does not mean that environment has no role. Genes interact with their environment, and the better we understand the genes, the better we'll understand how the environment affects the developing brain. Right now, genetic research is the most promising, and it offers the most potential for identifying just which molecular events in the brain are off in ASDs. With the genetic foundation in place, we may eventually put together the whole neurobiological picture, learning in the process how both normal and autistic brains develop, and with luck, discovering a way to steer that developmental process in the right direction.
For further reading, see this review in Nature Reviews Genetics.
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