Researchers at the RIKEN Center for Brain Science (CBS) have made a significant breakthrough in understanding the genetics of autism spectrum disorder (ASD), according to a study published in the journal Cell Genomics. By focusing on special genetic mutations and their impact on neighboring genes, the study challenges traditional beliefs about the genetic architecture of ASD.

The study examined mutations within promoters, the parts of the genome that control the production of proteins, in specific genome regions. Researchers found that these mutations can indirectly affect ASD-related genes due to the three-dimensional structure of the genome. This suggests that mutations in non-coding regions, particularly promoters, play a crucial role in the development of ASD.

To conduct the study, the researchers analyzed an extensive dataset of over 5,000 families, making it one of the largest genome-wide studies on ASD to date. They focused on topologically associating domains (TADs), which are three-dimensional structures in the genome that allow interactions between nearby genes and their regulatory elements.

The findings revealed that de novo mutations in promoters within specific TADs can impact ASD-related genes. Even if the mutations are not located in protein-coding regions or directly controlling the expression of ASD-related genes, they can still increase the risk of ASD. This highlights the complexity of the genetic architecture of ASD and the need to consider more than just direct gene mutations.

To further confirm these findings, the researchers used the CRISPR/Cas9 system to edit the DNA of stem cells, specifically targeting the promoters. As expected, they observed that a single genetic change in a promoter caused alterations in an ASD-associated gene within the same TAD. This suggests a "genomic butterfly effect," where a single mutation can dysregulate disease-associated genes scattered in distant regions of the genome.

The implications of this breakthrough are significant for the development of new diagnostic and therapeutic strategies for ASD. Lead researcher Atsushi Takata emphasizes the need to look beyond ASD-related genes and focus on whole TADs that contain these genes when assessing an individual's risk for ASD. Correcting aberrant promoter-enhancer interactions caused by promoter mutations could also have therapeutic effects on ASD.

While this study sheds new light on the genetics of ASD, further research involving more families and patients is crucial for a better understanding of the genetic roots of ASD. Expanding research in this field will ultimately lead to improved clinical management and enhance the well-being of those affected by ASD, their families, and society as a whole, concludes Takata.

In summary, this groundbreaking study has revealed that mutations in promoters within specific genome regions can indirectly impact ASD-related genes, challenging the traditional focus on protein-coding regions and direct mutations in ASD-related genes. This new understanding of the complex genetic architecture of ASD opens up new avenues for research and has potential implications for future diagnostic and therapeutic approaches.