By Geri Dawson, Chief Science Officer, Autism Speaks
Science moves so slowly and is so labor-intensive that we don’t often have moments to celebrate an achievement or breakthrough that has resulted from our investments. With this week’s announcement of Phase 2 results from the Autism Genome Project, we are celebrating such an achievement.
Several years ago, when I was a professor at the University of Washington, I remember a phone call from Andy Shih, Ph.D. (Autism Speaks VP, Scientific Affairs) who asked if he could take my colleague, Jerry Schellenberg, and me out to breakfast. Over coffee, Andy described to us an idea he had: Would we be willing to collaborate with other scientists around the world and add the genetic data we have been collecting to a combined database? While each of us at that time had been working independently to try to discover autism risk genes, we knew that ultimately we would need much larger samples to deal with the significant heterogeneity that exists in autism spectrum disorder. After a lot of discussion and questions, Andy convinced us that this would be a worthwhile effort and thus we became part of what became known as the “Autism Genome Project,” or the AGP. Eventually, Andy talked with over 50 groups worldwide and cajoled each of them to join the effort. What ensued was a series of monthly conference calls, complex negotiations and agreements that Andy helped broker, the creation of a combined database, and yearly meetings during which the goals for analysis and future data collection would be discussed. Today, the AGP is considered a driving force in autism genetic research.
Meanwhile, Clara Lajonchere, Ph.D. (Autism Speaks VP, Clinical Programs) was spearheading an effort to create a database of multiplex families called the Autism Genetic Resource Exchange (AGRE). She was leaving most of us collecting similar samples in the dust as she quickly assembled the largest private genetic individual data base that exists. Her ability to form partnerships with families, engaging them in the process of scientific discovery, was a model for us all. Not surprisingly, Clara readily agreed to join the AGP since AGRE’s basic premise was “collaboration and data sharing.”
Fast forward to this week when the AGP published the largest and most comprehensive study of copy number variations (CNV) – small deletions or duplications in our genome that can disrupt gene function – in autism families. By comparing CNVs found in 1,000 individuals with autism with those from 1,300 individuals without autism, the AGP reported the following:
- Several novel ASD genes were discovered, and many genes previously implicated by other studies were confirmed. Some of these genes are involved with communication between neurons, while others help regulate cell growth and how they respond to environmental stimuli.
- It was confirmed that autism risk genes are rare variants in our genome that occur very infrequently or not at all in the general population, and each person with ASD may have a unique risk gene or set of risk genes. Some of these genes are “highly penetrant” meaning that, if you carry this risk gene, you very likely will develop ASD, whereas other only raise the risk for ASD and need to combine with other genetic and/or environmental risk factors to cause ASD. Some of these are inherited, but many appear “de novo” meaning that they only exist in the child and not the parents.
- In the not-so-distant future, we will start to see more comprehensive genetic testing being conducted in the clinic to provide parents with information about whether their child may be at risk for ASD, so they can watch for signs or better understand the cause of their child’s ASD. It will be important to consider carefully what tests are appropriate and interpret them in a manner that is responsible and helpful for parents.
- Although the fact that so many rare genes can be related to risk for autism seems to form an overwhelmingly complex picture of autism, there is a path forward: These genes appear to cluster around specific biochemical pathways in the brain and, thus, point to new directions for developing drugs that could potentially help recover function of these pathways. This is good news for families.
Most of all, I see the publication of this report as a celebration of the fruitful partnership between the families and the scientific community. While Autism Speaks staff like Andy and Clara helped create and implement unique and productive scientific endeavors like the AGP, ultimately, it is the families who contributed their time and literally a part of themselves that is helping us put together this puzzle called autism piece by piece.
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our ninth item, Copy Number Variations, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
Three studies published in 2007 pointed autism researchers toward the importance not only of mutations within the DNA code of specific genes, but also of variations in the number of copies of genes, known as Copy Number Variations (CNV). Created by submicroscopic deletions or duplications of DNA sequences, recent advances have only now allowed CNV to become routinely detectable, establishing an entirely new avenue of genetic research.
Armed with the latest technology and three different collections of patient DNA, including Autism Speaks’ Autism Genetic Resource Exchange (AGRE), researchers at Cold Spring Harbor scanned the genome for the presence of CNV in autism. In February 2007 they reported that not only do individuals with autism have more CNV than individuals without autism, but that CNV in autism occur more often as “de novo” or spontaneous mutations (mutations not found in the DNA of either parent). They also found that these spontaneous CNV appear to be more common in families with only one child with autism (simplex) than those with multiple affected children (multiplex).
With their data suggesting that genetic mechanisms may be different in different types of autism, the researchers then carefully studied the inheritance pattern of autism in the many families in Autism Speaks’ AGRE and IAN databases. In July they published that they could fit the data to a model in which there are at least two distinct ways that genes may play a role in the development of autism: spontaneous CNV might help to explain autism in simplex families, whereas inherited gene mutations may be at the root of autism spectrum disorders in a greater portion of multiplex families. Such a model is significant because although autism has been thought to have a strong genetic component, so far it has not been shown to be as clearly inherited as other simple genetic disorders.
The team from Cold Spring Harbor has provided a new theory of autism risk that stands to influence how future autism genetic research is conceptualized. Although their results require replication, it also now leads to the question of what causes this increase in spontaneous CNV, opening the door to an exploration of the interplay between genetics and environmental factors. Possible risk factors include age of the parents, specific toxicological factors and accumulated exposures, as well as genetic predisposition.
Update since this story was first run: Improvement in DNA technology since the publication of this first major autism CNV study has meant that new insights into the role of CNV are actively being pursued. The largest and most comprehensive autism CNV study to date was published in April 2009 in the top research journal, Nature. The new study focused on inherited rather than spontaneous CNV, with the researchers finding CNV variations in genes important for neural development [for more details, see http://www.autismspeaks.org/science/science_news/top_ten_autism_research_events_2009_cnv.php]. Researchers in autism are continuing to lead geneticists in other fields with an intense focus on CNV and early recognition of their importance as potential disease risk factors.