A "butterfly effect" may help explain how autism-related genes in DNA get switched on. A new study suggests that, through this complex ripple effect, mutations in genes unrelated to autism end up influencing the activity of genes tied to the disorder.
How does this work? DNA contains genetic material called promoters, which essentially switch genes on and off. Because DNA is twisted and coiled in a 3D shape, these promoters can control genes that are located far away from them in the DNA's sequence. In other words, if you stretched out all the kinks in the DNA, the promoter and genes would be far apart, but introducing folds in the molecule brings them close together. The promoter and the genes it controls form a regulatory "unit" called a topologically associated domain (TAD).
Because of this complex mechanism, someone who doesn't have mutations in autism-linked genes may still develop the disorder due to mutations elsewhere in their genome — in promoters. That's the idea explored in the new study, published Friday (Jan. 26) in the journal Cell Genomics.
Autism is highly heritable — it's estimated that between 40% and 80% of cases are tied to genes passed down through families. However, autism can also be caused by mutations that spontaneously arise in DNA.
Such mutations have recently been discovered in "non-coding" regions of DNA, which comprise about 98.5% of the genome. These regions include promoters and are known as "non-coding" because they don't contain instructions to build proteins, like genes do.
Until now, little was known about how mutations in non-coding DNA impact someone's likelihood of having autism spectrum disorder (ASD). The new study begins to address that question.
The study authors analyzed the genomes of more than 5,000 people with autism, along with those of their siblings who didn't have the condition and acted as a comparison group. The team were specifically looking for the presence of non-heritable mutations. They used specialized techniques to capture the 3D configuration of the genome and define TAD boundaries around autism-linked genes.
The team found a direct association between autism and TAD-related gene regulatory mechanisms — specifically TADs that contain genes known to be linked to autism.
Sometimes, changing just one "letter," or base, in DNA's code was linked to a higher likelihood of autism, senior study author Dr. Atsushi Takata, a researcher at the Riken Center for Brain Science in Japan, told Live Science in an email.
"The results showed that just a single base of DNA sequence difference in a non protein-coding region can affect the expression of nearby genes," he said, "which in turn can alter the overall gene expression profile of distant genes in the genome, leading to an increased risk of ASD."
Takata likened this to a physics phenomenon known as the "butterfly effect," in which a slight change in the initial state of a complex system makes a big difference later on — for example, a butterfly flaps its wings, and weeks later, miles away, a tornado tears through a town. Similarly, a subtle mutation in a promoter can have big impacts on gene expression elsewhere.
In a separate experiment in human stem cells, the researchers induced mutations in specific TAD promoters using CRISPR gene-editing technology. They discovered that a single mutation that reduces activity in a promoter could drive changes in the activity of an autism-linked gene within the same TAD. This helped validate their earlier findings in people.
"This is an interesting paper that attempts to extend our understanding of the contribution of rare, de novo [non-heritable] variation to ASD risk in regions outside the protein-coding genome," Dr. Daniel Rader, a professor of molecular medicine at the University of Pennsylvania who was not involved in the research, told Live Science in an email.
The findings could have potential therapeutic implications, Rader said. For example, there may be ways to modulate the activity of specific promoters so that multiple autism-linked genes are regulated at the same time, he suggested. In theory, this could help alleviate symptoms of ASD, he said.
The researchers now hope to identify other types of non-coding mutations that may impact someone's likelihood of having autism, Takada said.
This article is for informational purposes only and is not meant to offer medical advice.
Ever wonder why some people build muscle more easily than others or why freckles come out in the sun? Send us your questions about how the human body works to firstname.lastname@example.org with the subject line "Health Desk Q," and you may see your question answered on the website!
Sign up for the Live Science daily newsletter now
Get the world’s most fascinating discoveries delivered straight to your inbox.
Emily is a health news writer based in London, United Kingdom. She holds a bachelor's degree in biology from Durham University and a master's degree in clinical and therapeutic neuroscience from Oxford University. She has worked in science communication, medical writing and as a local news reporter while undertaking journalism training. In 2018, she was named one of MHP Communications' 30 journalists to watch under 30. (email@example.com)