Music of the genome hits a discord with autism

We still do not know what causes autism, but insights from the burgeoning field of epigenetics are helping to reveal the subtle factors that can contribute to the disorder.

Autism spectrum disorder (autism for short) is a term that describes a diverse set of conditions, including problems with social communication, social interaction and repetitive/restrictive behaviours. It affects around one in 135 children under 7, and is four times more common in males than females.

What we do know about autism is that it affects brain development. And recent reports have led us to believe that autism is caused by faulty genetics.

But there is more to life than just a genetic sequence. Our genes, like the keys on a piano, are played with a different melody in different individuals. This variation in which genes are “played” contributes to our individual differences in health, even between identical twins.

Epigenetic musicians

We study the various epigenetic influences that switch genes on and off – the “musicians” that tinkle the keys of our genome. In reality, these are tiny molecules that are essential for making each tissue in our body different, despite them having identical genes.

Our research team wanted to explore how these epigenetic factors influence autism. First we reviewed the hundreds of genes whose sequences have already been linked with autism.

Thankfully, the Simons Foundation had already done this hard work for us. They had even ranked the genes based on accumulated evidence for their contribution to autism.

Interestingly, of the 16 genes that were most strongly associated with autism, half code for proteins that influence how other genes work – the epigenetic musicians, as it were. Many of these genes also play a role in brain development.

Next we asked what is known about the physiology of people with autism. Among other things, it turns out that their immune systems are more easily disrupted than those without autism. They are more likely to experience inflammation in the blood and the brain.

This may explain why immune suppressants have been shown to temporarily reduce some symptoms of autism.

Out of tune

As gene activity contributes much to the physiology of a person, we also looked for studies that had measured gene activity in people with autism. Those genes most frequently “played” too loud or too quiet were associated with brain development and function and, again, with immune state in the blood and brain.

Finally, we directed our attention mostly on the epigenetic musicians that play the genes themselves. A few researchers had taken a guess at which genes weren’t being played very well. Looking mostly in the brain, they found four or five genes whose musicians weren’t working properly.

The clearest evidence was for the oxytocin receptor gene, for which two studies showed differences in the blood and brain of those with autism.

Oxytocin, often referred to as the “love hormone”, regulates many of the behaviours associated with autism. Therefore, the level of oxytocin receptor is a plausible candidate for causing some of the characteristic features of autism.

Many melodies

The quickest way to find genes associated with autism is to look everywhere in our genomes, and current technology is advanced enough to do this. Therefore, we reviewed seven such genome-wide studies.

It wasn’t easy though, as different researchers have favourite techniques. What we had to work with were three studies of the brain, three of blood and one of cheek cells. Yet again, genes involved in brain development and the immune system floated to the top in all tissues studied.

To sniff out evidence for individual autism-associated genes, we searched for those identified by two independent studies. Four genes emerged. None had been indicated previously as autism-related, which was a surprise. For two of these genes, we don’t actually know what they do in the body.

Of the other two, one is likely to play a role in the sense of smell. Interestingly, a common feature of autism is a lower sensory threshold –- senses, including smelling, work overtime.

The second gene codes for an epigenetic musician required for early development. Intriguingly, this gene has its own epigenetic musicians changed in children whose mothers had low levels of folate during pregnancy. Low folate levels have also been linked with risk for autism, so even more connections were emerging.

Finding the composers

So, what does all this information tell us? Firstly, as Aristotle said: “One swallow does not a summer make, nor one fine day.” This means that we need to gather a lot more evidence to determine whether epigenetic changes in such genes are truly associated with autism.

We should also bear in mind the possibility that such changes could result from autism rather than cause autism.

This information also tells us that researchers around the world should start giving more attention to these candidate genes and epigenetic musicians. They should also focus more on physiological processes, such as inflammation, that have not been identified from genetics alone.

But should we be thinking of ways to minimise inflammation during pregnancy to lower the risk of autism? Should we be focusing on raising our children in low inflammatory environments?

Furthermore, could the “molecular melodies” of the epigenetic musicians be selectively edited to prevent or treat the symptoms of autism? There is currently insufficient evidence available for us to answer these questions. But we are working to listen to the whole symphony to find out.

Jeffrey Craig receives funding from The Brockhoff Foundation, the National Health and Medical Research Foundation and the Financial Markets Foundation For Children.

Anthony Hannan receives funding from the National Health and Medical Research Council (NHMRC) of Australia, Macquarie Foundation and Walter Cottman Endowment Fund (Equity Trustees) .

Yuk Jing Loke does not work for, consult to, own shares in or receive funding from any company or organisation that would benefit from this article, and has no relevant affiliations.