Home Medizin Studie zeigt, wie einzelne Veränderungen das Autismus-Gen-Netzwerk auslösen

Studie zeigt, wie einzelne Veränderungen das Autismus-Gen-Netzwerk auslösen

von NFI Redaktion

Researchers from the RIKEN Center for Brain Science (CBS) explored the genetics of autism spectrum disorder (ASD) by analyzing mutations in the genome of individuals and their families. They discovered that a particular type of genetic mutation has a different effect than typical mutations and contributes to the condition in a unique way. Due to the three-dimensional structure of the genome, mutations can essentially affect neighboring genes associated with ASD, explaining why ASD can occur even without direct mutations to ASD-related genes. This study was published in the journal Cell Genomics on January 26th.

ASD is a group of disorders characterized in part by repetitive behaviors and difficulties in social interaction. While it runs in families, the genetics of its inheritance are complex and only partially understood. Studies have shown that the high degree of heritability cannot be solely explained by looking at the part of the genome that codes for proteins. The answer may instead lie in the non-coding regions of the genome, specifically in the promoters, parts of the genome that ultimately control whether proteins are actually produced or not. Atsushi Takata and the team at RIKEN CBS investigated „de novo“ gene variants – new mutations that are not inherited from the parents – in these parts of the genome.

The researchers analyzed an extensive dataset of over 5,000 families, making this study one of the largest genome-wide studies on ASD. They focused on TADs – three-dimensional structures in the genome that enable interactions between different neighboring genes and their regulatory elements. They found that de novo mutations in promoters only increased the ASD risk if the promoters were located in TADs containing ASD-related genes. Because they are close to each other and are in the same TAD, these de novo mutations can affect the expression of ASD-related genes. Therefore, the new study explains how mutations can increase the ASD risk even if they are not located in protein-coding regions or in the promoters directly controlling the expression of ASD-related genes.

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

Atsushi Takata at RIKEN CBS

To confirm this, the researchers edited the DNA of stem cells using the CRISPR/Cas9 system and generated mutations in specific promoters. As expected, they observed that a single genetic change in a promoter caused changes in an ASD-associated gene within the same TAD. Since numerous genes affected in the mutated stem cells are related to ASD and neurological development, Takata compares the process to a genomic „butterfly effect“, where a single mutation misregulates disease-associated genes scattered in remote regions of the genome.

Takata believes that this insight will have implications for the development of new diagnostic and therapeutic strategies. „When assessing an individual’s ASD risk, we now know that in genetic risk assessment, we need to look beyond ASD-related genes and focus on whole TADs containing ASD-related genes,“ explains Takata. „Furthermore, an intervention that corrects aberrant promoter-enhancer interactions caused by a promoter mutation can also have therapeutic effects on ASD.“

Further research involving more families and patients is crucial for a better understanding of the genetic roots of ASD. „Expanding our research will lead to a better understanding of the genetic architecture and biology of ASD, ultimately leading to clinical treatment that improves the well-being of affected individuals, their families, and society,“ says Takata.


Journal reference:

Nakamura, T., et al. (2024). Topologically associating domains define the influence of de novo promoter variants on autism spectrum disorder risk. Cell Genomics. doi.org/10.1016/j.xgen.2024.100488

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