summary: Researchers have made major advances in understanding the genetics of autism spectrum disorders (ASD) by focusing on specific genetic mutations and their effects on neighboring genes.
This study shows that due to the three-dimensional structure of the genome, mutations within the promoters of specific genomic regions can indirectly affect ASD-related genes.
This finding questions the traditional focus on protein-coding regions and direct mutations in ASD-associated genes and provides new insights into the complex genetic architecture of ASD.
Important facts:
- This study found that novel mutations in genomic promoters within specific topologically associated domains (TADs) can impact ASD-related genes.
- The researchers used a large dataset of more than 5,000 families, making this one of the most extensive genome-wide studies of ASD.
- This finding has implications for future diagnostic and treatment strategies for ASD and suggests the need to look beyond direct genetic mutations.
sauce: RIKEN
Researchers at the RIKEN Brain Science Center (CBS) investigated the genetics of autism spectrum disorder (ASD) by analyzing genomic variations in individuals and their families.
They discovered that special types of genetic mutations work differently than typical mutations in how they contribute to symptoms.
Essentially, due to the three-dimensional structure of the genome, mutations can affect neighboring genes associated with ASD, explaining why ASD can occur even in the absence of direct mutations to ASD-associated genes. Masu.
This study was published in the journal cell genomics.
ASD is a group of conditions characterized in part by repetitive behaviors and difficulties with social interactions. Although it occurs in families, its heritable genetics are complex and still only partially understood.
Research has shown that high levels of heritability cannot be explained simply by looking at the parts of the genome that code for proteins. Rather, the answer may lie in non-coding regions of the genome, particularly promoters, the parts of the genome that ultimately control whether a protein is actually produced.
A team led by Jun Takada at RIKEN CBS looked for “de novo” genetic mutations in these parts of the genome, meaning new mutations that are not inherited from parents.
Researchers analyzed an extensive dataset of more than 5,000 families, making this one of the world’s largest genome-wide studies of ASD to date. They focused on TADs, three-dimensional structures within the genome that enable interactions between different genes and their regulatory elements in close proximity.
They found that de novo promoter mutations increase the risk of ASD only if the promoter is located in a TAD containing ASD-related genes. These novel mutations may affect the expression of her ASD-related genes, as they are close and within the same her TAD.
Thus, the new study explains why mutations may increase the risk of ASD even though they are not located in protein-coding regions or promoters that directly control the expression of ASD-related genes. There is.
“Our most important finding is that novel mutations in the promoter regions of TADs, including known ASD genes, are associated with ASD risk, and this may be mediated through interactions in the three-dimensional structure of the genome. “It was said that it was high,” says Professor Takada.
To confirm this, the researchers used the CRISPR/Cas9 system to edit the DNA of stem cells and make mutations in specific promoters. As expected, they observed that single gene changes in the promoter caused changes in ASD-related genes within the same TAD.
Because a large number of genes associated with ASD and neurodevelopment were also affected in the mutant stem cells, Prof. Takada explained how a single mutation can cause dysregulation of disease-associated genes scattered in distant regions of the genome. He likens it to the “butterfly effect.”
Professor Takada believes this discovery will have implications for the development of new diagnostic and therapeutic strategies.
“At the very least, we know that when assessing an individual’s risk for ASD, genetic risk assessments need to go beyond ASD-related genes and focus on TADs as a whole, including ASD-related genes.” Professor Takada explains.
“Furthermore, interventions that correct aberrant promoter-enhancer interactions caused by promoter mutations may also have therapeutic effects in ASD.”
Further research involving more families and patients is essential to better understand the genetic roots of ASD.
“Expanding our research will lead to a deeper understanding of the genetic makeup and biology of ASD, leading to clinical management that enhances the well-being of affected individuals, their families, and society,” says Takada.
About this autism and genetics research news
author: Atsushi Takada
sauce: RIKEN
contact: Atsushi Takada – RIKEN
image: Image credited to Neuroscience News
Original research: Open access.
“Topologically related domains define the impact of de novo promoter variants on autism spectrum disorder risk” Written by Atsushi Takada et al. cell genomics
abstract
Topologically related domains define the impact of de novo promoter variants on autism spectrum disorder risk
highlight
- Analysis of promoter DNVs in 5,044 ASD and 4,095 siblings by WGS using TAD information
- Specific association between ASD and promoter DNVs within TADs containing ASD genes
- Identification of TADs by enrichment of promoter DNVs in ASD
- Experimental verification of the effects of single promoter DNV on multiple genes
summary
Whole-genome sequencing (WGS) study of autism spectrum disorder (ASD) demonstrates role for rare promoter de novo Variant (DNV). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes.
In this study, which analyzed WGS data from 5,044 ASD probands, 4,095 unaffected siblings, and their parents, promoter DNVs within the topologically associated domain (TAD) containing the ASD gene were significantly and differentially associated with ASD. showed that they are related. Analysis considering TADs as functional units identified specific TADs enriched in promoter DNVs in ASD, and showed that common variants in these regions also confer heritability of ASD.
Experimental validation using human induced pluripotent stem cells (iPSCs) shows that potentially deleterious promoter DNV in ASD affects multiple genes within the same TAD, resulting in global dysregulation of ASD-related genes. It has been shown that it is possible.
These results highlight the importance of TADs and gene regulatory mechanisms in better understanding the genetic architecture of ASD.
