"A Unified Genetic Theory for Sporadic and Inherited Autism" -- First Research Paper to Use IAN Data
On April 18, 2007, only two weeks after the Interactive Autism Network's official launch, Dr. Michael Wigler of the Cold Spring Harbor Laboratory (CSHL) was the first researcher to use IAN data. He and his team have now published their groundbreaking article, "A Unified Genetic Theory for Sporadic and Inherited Autism," in the Proceedings of the National Academy of Science. This is the very first publication based, in part, on IAN data.
The article describes a new genetic model for understanding how autism is acquired. Unlike previous genetics efforts, which were largely focused on looking for an autism susceptibility gene --a gene or genes that cause autism in many families around the world-- the new model sees the underlying cause of autism as the spontaneous, new mutation of a gene.
In the majority of cases, according to this theory, individuals acquire autism through a spontaneous mutation affecting genetic material within their parent's sperm or egg cell. In other words, a gene is altered within a single sperm or egg cell at some point during the parent's life. If a child is conceived with that particular sperm or egg, the child may be autistic. (The mutation was present in only one sperm or egg cell of the parent, but it will be present in virtually every cell of the resulting child.)
Although they account for the majority of autism cases, such mutations are fairly rare, and are unlikely to happen to the same family twice. This makes sense when you consider that the mutation was in only one sperm or egg cell. You'd have to have another spontaneous autism-causing mutation in another sperm or egg cell to have a second child with autism.
However, the authors of this paper theorize, autism is inherited in a minority of cases. In such instances, an autism-causing genetic mutation is already present in the family. A parent who has inherited it carries a mutated gene in virtually every cell in their body, including half of their sperm or egg cells. They will pass the altered gene on to their offspring 50% of the time in what is known as an autosomal dominant pattern. (For an explanation and chart explaining autosomal dominant inheritance, please see the Genetics Home Reference.)
In a family like this, we would expect to see multiple cases because male children would have a 50/50 chance of developing an ASD. (As we know, boys develop autism much more frequently than girls. Therefore, women carrying such a gene are much more likely than men who do so to function normally and to have children. They can then pass the gene to their sons and daughters. Similarly, male children inheriting the gene are more likely to develop ASDs than daughters who might inherit it.)
These findings may account for gaps in previous genetic models of autism. They also provide a fascinating possible link between genetic and environmental explanations for autism, for one must ask: What in the environment may be causing genes to mutate in the first place?
The researchers working on this theory hypothesized that, if they were right about spontaneous mutation and autism, a certain mathematical pattern would be found in large sets of autism data. They found it first in the Autism Genetic Research Exchange (AGRE), which contains data only from families with more than one child with an ASD. They then used data from the Interactive Autism Network (IAN) to check their theory against a data set including both families with more than one person with an ASD and families with only one person with an ASD. They found exactly the pattern they had predicted –a major scientific finding.
View the full article, "A Unified Genetic Theory for Sporadic and Inherited Autism", in the Proceedings of the National Academy of Science.
A Deeper Look at the Unified Genetic Theory of Autism: Concepts and Questions
We had many questions about this fascinating and complex article, and are sure our readers will, too.
Before exploring these questions, however, we'd like to review some key scientific concepts that will help put the article into context.
The authors of this article are proposing a theory about genetics and autism.
What is a theory? Coming up with theories is at the heart of the scientific process. In simplest terms, observations of a phenomenon lead to an educated guess about what is causing it or how it works. Experiments or other forms of research then test this guess or hypothesis. If these guesses are confirmed, a theory emerges. If it's a powerful one, it will both explain, telling you why something is happening in such-and-such a way, and predict, telling you what should happen next. Theories may be abandoned or modified as researchers learn from both their successes and their failures.
The authors of the article have also developed a mathematical model based upon their theory.
What is a model? Researchers who have developed a theory may create a model –a simplified representation of what they are studying and how they expect it to behave. In the case of the Unified Genetic Theory of Autism study, the researchers developed a mathematical model. The researchers were saying: "If my theory is correct, I should find a certain mathematical pattern in the data."
The authors of the article tested their theory by looking at data collected from families containing one or more children with autism to see if it fit their mathematical model.
What is testing? Testing is when you collect data to see if it matches your model. This new study is so exciting because the researchers found patterns that fit their mathematical model not just in one data set, but in three. Those three data sets were from the University of Michigan, the Autism Genetic Research Exchange (AGRE), and the Interactive Autism Network (IAN).
When learning about the study, remember that the researchers are both proposing a new theory and providing some evidence that supports it. Now other researchers will use a variety of different approaches to further test the new theory. Will the theory stand up over time? That will depend on whether future scientific work refutes or supports it.
Questions we had…and thought you might have, too.
- What's making people have "spontaneous mutations" of their genes? Is it something in the environment that could be causing this?
Spontaneous means "arising without apparent cause; coming out of the blue." When speaking of genetics, a mutation means a permanent change in the DNA sequence that makes up a gene.
Spontaneous mutations are permanent changes in a person's DNA that arose "out of the blue." When a mutation happens to just one gene in one cell somewhere in a person's body, that change rarely has much effect. When a mutation happens to a sperm or egg cell, though, the change will be programmed into virtually every cell in any child arising from that sperm or egg. It becomes part of the genetic code for that child.
Spontaneous mutations happen all the time, and can be caused by a variety of factors. For example, genes can be damaged by ultraviolet radiation from the sun, environmental toxins, or the process of aging. Indeed, this research has the potential to link genetic and environmental concerns, as well as to explain why it has been observed that older parents seem to have a higher risk of having children with ASDs.
- How can a variety of different spontaneous mutations all lead to autism in so many people?
Actually, the notion that spontaneous mutations cause autism would help explain why there is such great variation across the autism spectrum.
Genes have jobs. One of their most essential jobs is to make the proteins that run the millions of processes upon which the human brain and body depend. A mutated gene may not make a protein the way it is supposed to. It may not make it at all, or make too much of it, or make it incorrectly. If the problematic protein plays a critical role, it may disrupt normal development and cause disease.
Many different mutated genes may interfere with the same ultimate process, whether that be hearing, liver function, or brain function. A variety of genes, when working improperly, could lead to some kind of Autism Spectrum Disorder.
Think of cancer. Not so long ago, it was thought of as a single disease that probably had a single cause, but no single cause was found. Instead, many different variations of cancer were found, each with a different ultimate cause or causes.
Sometimes, risk can be assessed by looking at people's genes and family medical history. There are genetic tests, for example, that look for mutations in the breast cancer genes, BRCA1 and BRCA2, to help assess if a person has a high risk of breast cancer. Someday, similar tests may become available to assess the risk of having a child with autism.
- What do you mean, "mothers are the carriers"? Can fathers be carriers, too?
According to this new theory, most parents are not carriers of any genetic change. If a spontaneous mutation has led to a child's autism, it did not come from a parent's overall genetic code, the one present in each and every cell in his or her body. It happened randomly, and only to one sperm or egg cell that then resulted in an autistic child. This is the case for the majority of children with ASDs.
Also according to this theory, autism can be inherited in families where such a mutation has become part of the genetic code and is being passed down through generations. For such families, who are in the minority, the odds of having more than one child with autism are much higher.
Both men and women who carry such an altered gene may pass that mutation on to their children. Women, however, are more likely to do so. Why is this?
A woman with such a mutation probably won't show signs of autism herself because women, for whatever reason, are less vulnerable to autism. A person who is not autistic is more likely to have children than a person who is, which is why the researchers say that women tend to be carriers (even though men can be, too). Men carrying the mutation will be more likely to show signs of autism and less likely to have children. Still, mildly affected men with such a mutation can also pass on the gene to any children they have.
- They say a man or woman who carries an altered autism-causing gene will pass it on about 50% of the time. Why is this?
We each have two copies of every gene. For a child to end up with two copies, they need to get one copy from mom and one from dad. (That's why most cells have 46 chromosomes, but sperm and egg cells only have 23. They'll have 46 when they come together.)
A parent with a mutated gene will generally have one mutated copy and one normal copy in most cells in their body. In their sperm or egg cells, however, they will have only one copy, the mutated one or the normal one. Therefore, each of their children will have a 50/50 chance of receiving either the mutated gene or the normal gene.
Boys who end up inheriting the mutated gene will tend to be autistic. Girls inheriting the mutated gene will tend to be carriers, with the potential to pass ASD down to the next generation. In a family passing down such a mutation, you would expect autism to show up quite often –in about half the sons.
One way this theory may be tested is by collecting data from at least three generations within families that have a child with autism. If the theory is correct, families that do have "carriers" should have a very distinct pattern of ASD in their family tree over time.
- If a mother or father carries an autism-causing genetic mutation, does that mean their daughters have a 50% chance of carrying the mutated gene and giving it to their own sons?
Yes. If a mom or a dad has an autism-causing genetic mutation, each of their children will have a 50/50 chance of inheriting it and then passing it on. If a girl does inherit it, she will probably not show signs of autism, but will nevertheless carry the mutation on, with the potential to pass it to her own children 50% of the time. Again, her daughters who inherit it will be far less likely to show signs of autism than her sons.
- Is there a genetic test that will tell me if my partner or I carry an autism-causing gene?
This research is all brand new, so there is currently no genetic test available.
Keep in mind that this is a new theory. It will now be tested and evaluated by other researchers. As we learn more about the genetics of ASD, we hope that methods will be developed to help families assess their risk of having a child with ASD.