Researchers at the RIKEN Center for Brain Science (CBS) have 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 acts differently from normal mutations in how it contributes to the condition. In essence, due to the three-dimensional structure of the genome, mutations are able to affect neighboring genes associated with ASD, thus explaining why ASD can occur without direct mutations in ASD-related genes. This research has been published in the scientific journal Cell Genomics On 26 January.
ASD is a group of conditions characterized in part by repetitive behaviors and difficulties in social interaction. Although it runs in families, the genetics of its inheritance are complex and only partially understood. Studies have shown that high degrees of heritability cannot be explained solely by looking at the part of the genome that codes for proteins. Rather, the answer may lie in non-coding regions of the genome, particularly in promoters, parts of the genome that ultimately control whether proteins are produced. The team led by Atsushi Takata at RIKEN CBS examined “de novo” gene variants in these parts of the genome-;new mutations that are not inherited from one’s parents-;
The researchers analyzed an extensive dataset of more than 5,000 families, making it one of the world’s largest genome-wide studies to date. They are TADs-; focused on the three-dimensional structure of the genome that allows interactions between various nearby genes and their regulatory elements. They found that de novo mutations in promoters increased the risk of ASD only when the promoters were located in TADs containing ASD-related genes. Because they are close and in the same TAD, these de novo mutations may affect the expression of ASD-related genes. Thus, the new study explains why mutations may increase the risk of ASD even if they are not located in protein-coding regions or in promoters that directly regulate the expression of ASD-related genes.
“Our most important discovery was that de novo mutations in the promoter regions of TADs, known as ASD genes, are associated with ASD risk, and this is likely mediated by interactions between the three-dimensional structure of the genome.”
Atsushi Takata at RIKEN CBS
To confirm this, the researchers edited the stem cell’s DNA using the CRISPR/Cas9 system, creating mutations in specific promoters. As expected, they observed that a single genetic change in a promoter caused a change in an ASD-related gene within the same TAD. Because numerous genes associated with ASD and neurodevelopment were also affected in the mutant stem cells, Takata compared the process to a genomic “butterfly effect” in which a single mutation controls disease-related genes that spread to distant regions of the genome.
Takata believes this finding has implications for the development of new diagnostic and therapeutic strategies. “At least, when assessing an individual’s risk for ASD, we now know that when assessing genetic risk we need to look beyond the ASD-related genes, and focus on the entire TAD that contains the ASD-related genes,” He explained the money. “Furthermore, an intervention that corrects aberrant promoter-enhancer interactions caused by a promoter mutation may also have therapeutic implications in ASD.”
More research on families and patients is important 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 enhances the well-being of affected individuals, their families, and society,” Takata said.
Nakamura, T., etc. (2024). Topologically associating domains define the effect of de novo promoter variants on risk for autism spectrum disorders. Cell Genomics. doi.org/10.1016/j.xgen.2024.100488