A genomic “butterfly effect” explains the risk of autism spectrum disorders

Researchers at the RIKEN Center for Brain Science (CBS) examined the genetics of autism spectrum disorder (ASD) by analyzing mutations in the genomes of individuals and their families. They discovered that a particular type of genetic mutation works differently from typical mutations in how it contributes to disease.

Essentially, due to the three-dimensional structure of the genome, mutations can affect neighboring ASD-related genes, thus explaining why ASD can occur even without direct mutations in ASD-related genes. This study appeared in the journal Cellular genomics.

ASD is a group of conditions characterized in part by repetitive behaviors and difficulties with social interaction. Although it is hereditary, the genetics of its heritability are complex and remain only partially understood.

Studies have shown that the high degree of heritability cannot be explained simply by looking at the part of the genome that codes for proteins. The answer might instead lie in noncoding regions of the genome, particularly in promoters, the parts of the genome that ultimately control whether proteins are actually produced or not.

The team led by Atsushi Takata of RIKEN CBS looked at “de novo” genetic variants – new mutations that are not inherited from parents – in these parts of the genome.

The researchers analyzed a large dataset of more than 5,000 families, making it one of the largest global genomic studies of ASD to date. They focused on TADs, three-dimensional structures of the genome that allow interactions between different nearby genes and their regulatory elements.

They found that de novo mutations in promoters increased ASD risk only when promoters were located in TADs containing ASD-related genes. Because they are close and in the same TAD, these de novo mutations can affect the expression of ASD-related genes.

In this way, the new study explains why mutations can increase the risk of ASD even when they are not located in protein-coding regions or in promoters that directly control the expression of ASD-related genes.

“Our most important finding was that de novo mutations in the promoter regions of TADs containing known ASD genes are associated with ASD risk, and this is likely mediated by interactions in the three-dimensional structure of the genome,” says Takata.

To confirm this, the researchers edited the DNA of the stem cells using the CRISPR/Cas9 system, by making mutations in specific promoters. As expected, they observed that a single genetic change in a promoter caused alterations in an ASD-associated gene within the same TAD. Because many genes related to ASD and neurodevelopment were also affected in the mutant stem cells, Takata likens the process to a genomic “butterfly effect” in which a single mutation dysregulates disease-associated genes that are scattered throughout distant regions of the genome.

Takata believes that this discovery has implications for the development of new diagnostic and therapeutic strategies. “At the very least, when assessing an individual’s risk for ASD, we now know that we need to look beyond ASD-related genes when assessing genetic risk and focus on entire TADs containing genes linked to ASD,” says Takata.

“In addition, intervention that corrects aberrant promoter-enhancer interactions caused by promoter mutation may also have therapeutic effects on ASD.”

Further research involving more families and patients is essential to better understand the genetic roots of ASD. “By expanding our research, we will gain a better understanding of the genetic architecture and biology of ASD, leading to clinical management that improves the well-being of affected individuals, their families and society,” explains Takata.