A study conducted by researchers at the RIKEN Center for Brain Science (CBS) has shed light on the genetics of Autism Spectrum Disorder (ASD). They found that a particular type of genetic mutation contributes to ASD differently than typical mutations. By analyzing mutations in the genomes of individuals and their families, the researchers discovered that the three-dimensional structure of the genome can cause mutations to affect neighboring genes associated with ASD, even without mutations in ASD-related genes. The study was published in the scientific journal Cell Genomics on January 26.
ASD is a group of conditions characterized by repetitive behaviors and social interaction difficulties. Although the condition runs in families, its heritability is complex and only partially understood. According to studies, the high heritability cannot be explained by merely looking at the part of the genome responsible for protein coding. Instead, the answer could lie in the non-coding regions of the genome, particularly in promoters, which control whether proteins are produced. The team led by Atsushi Takata at RIKEN CBS examined "de novo" gene variants, which are new mutations not inherited from one's parents, in these parts of the genome.
Researchers analyzed large ASD whole genome sequencing data and found that promoter de novo mutations in TADs containing ASD genes were specifically associated with the disease.
The researchers analyzed a large dataset of over 5,000 families, making it one of the world's most extensive genome-wide studies of ASD to date. They focused on TADs, which are three-dimensional structures in the genome that enable interactions between nearby genes and their regulatory elements. They found that de novo mutations in promoters increased the risk of ASD only when the promoters were in TADs containing ASD-related genes. Because these mutations are nearby and in the same TAD, they can affect the expression of ASD-related genes. Therefore, the new study explains why mutations can increase the risk of ASD, even when they aren't in protein-coding regions or in the promotors that directly control ASD-related genes' expression.
"Our most important discovery was that de novo mutations in promoter regions of TADs containing known ASD genes are associated with ASD risk, and this is likely mediated through interactions in the three-dimensional structure of the genome," says Takata.
The researchers edited the DNA of stem cells using the CRISPR/Cas9 system to confirm their findings. They made mutations in specific promoters and found that a single genetic change in a promoter caused alterations in an ASD-associated gene within the same TAD. Takata compares the process to a genomic "butterfly effect" where a single mutation affects disease-associated genes scattered in distant regions of the genome.
Takata believes that this finding has implications for developing new diagnostic and therapeutic strategies. "When assessing an individual's risk for ASD, we now know that we need to look beyond ASD-related genes when doing a genetic risk assessment and focus on whole TADs containing ASD-related genes," explains Takata. "An intervention that corrects aberrant promoter-enhancer interactions caused by a promoter mutation may also have therapeutic effects on ASD."
Further research involving more families and patients is crucial 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," says Takata.
JOURNAL Cell Genomics ARTICLE PUBLICATION DATE 26-Jan-2024