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Exploring Autism’s Genetic ‘Dark Matter’

Guest post by Nir Oksenberg, a 2011 Dennis Weatherstone predoctoral fellow at the University of California, San Francisco. His research project involves deciphering the function and regulation of AUTS2, a gene linked to increased risk for autism.

According to common understanding, genes “code,” or provide instructions, for building proteins. Proteins, in turn, direct the building and function of our cells and body. But this sort of active coding gene accounts for only 2 percent or so of our genome (all the DNA that makes up our hereditary material).

The rest is the non-coding portion of the genome – once called “junk DNA.” Non-coding DNA is somewhat mysterious. But we know that much of it helps to regulate our genes. This includes telling them when, where and at what levels to turn on and off. 

Why is this important to autism research? We know that the genetics behind the development of autism is very complex. Often it involves changes in the level of gene activity in different types of cells. For the most part, this “fine tuning” of gene activity is determined by the non-coding, regulatory elements of our genome. Yet relatively little research has focused on this type of DNA.

In our study, we looked at how non-coding, regulatory DNA influences the activity of a gene called autism susceptibility candidate 2 (AUTS2). As its name suggests, this gene influences autism risk. We also know that it’s active in developing brain cells.

Our first goal was to better understand what this gene does. To do so, we used one of modern genetics’ favorite tools: the zebrafish. Despite the vast differences between humans and zebrafish, there are important similarities in their brain structure. Zebrafish also have see-through bodies! This allows us to use phosphorescent tags to monitor gene activity. (See images below.)

Using zebrafish, we confirmed that AUTS2 plays an active role in brain development. We then disabled, or “knocked down,” the gene to see what would happen. First, we saw that the fish without the functioning gene had fewer brain nerve cells, or neurons. (See images at right.) This told us that this gene is vitally important to normal brain development. We also noticed that the “knock-down” fish had fewer motor and sensory neurons in particular. Not surprisingly, they moved less than the normally developing zebrafish did.

Next we set out to determine which non-coding DNA sequences enhanced AUTS2’s activity. Using genetic engineering, we injected zebrafish embryos with DNA segments that might be regulatory elements. In all, we found 10 AUTS2 regulatory elements that were playing an active role in brain development. This tells us that the activity of the AUTS2 gene is normally very tightly regulated during brain development. It also suggests that there may be many places to disrupt this gene’s normal control and, so, increase the risk of autism.

The take-home message? In seeking to better understand the causes of autism, we need to look beyond coding genes (those that direct the production of proteins). We must explore more of the genome’s so-called “dark matter” – its noncoding regulatory DNA.

This may seem like a daunting task, given that this little-understood DNA makes up some 98 percent of our genome. The good news is that whole genome sequencing technology is becoming cheaper and easier to perform every year. Now is the time to begin examining the whole genomes of many more individuals with autism and their families.

This holds the potential to revolutionize our understanding of what causes autism. Importantly, it will allow us to improve our ability to recognize autism risk and diagnose autism earlier in life, as well as develop individualized treatments.

I want to thank Autism Speaks and the Stavros Niarchos Foundation for establishing the Dennis Weatherstone Pre-Doctoral Fellowship Program and supporting my research.

Click here for more information about the Dennis Weatherstone Predoctoral Fellowship, and here for information on the 2011 Weatherstone fellows and their research projects. Also see these blogs, profiles and videos by Weatherstone Fellows Allison Wainer, Cara Damiano, Elaine Hsiao and Katherine Stavropoulos

The Autism Speaks blog features opinions from people throughout the autism community. Each blog represents the point of view of the author and does not necessarily reflect Autism Speaks' beliefs or point of view.