Breakthrough Discovery in Understanding Genetics of Autism Spectrum Disorder
Summary
Researchers have achieved a significant breakthrough in understanding the genetics of autism spectrum disorder (ASD) by focusing on special genetic mutations and their impact on neighboring genes. The study challenges the traditional focus on direct mutations in ASD-related genes and offers new insights into the complex genetic architecture of ASD.
Key Facts
- The study reveals that specific mutations within genome promoters in certain topologically associating domains (TADs) can indirectly affect ASD-related genes.
- This study, involving a large dataset of over 5,000 families, is one of the most extensive genome-wide studies on ASD.
- The discovery has significant implications for future diagnostic and therapeutic strategies in ASD, highlighting the need to consider more than just direct gene mutations.
Breakthrough Research on the Genetics of Autism Spectrum Disorder
Researchers at the RIKEN Center for Brain Science (CBS) have made groundbreaking progress in understanding the genetics of autism spectrum disorder (ASD) by examining mutations in the genomes of individuals and their families. This study, published in the journal Cell Genomics, reveals that a certain type of genetic mutation operates differently from typical mutations, providing insight into the development of ASD.
ASD is a group of conditions characterized by repetitive behaviors and social interaction difficulties. However, despite being familial, the genetics of ASD heritability remain complex and not fully understood.
Prior studies have shown that the high degree of heritability cannot be explained solely by coding regions of the genome. Instead, the answer may lie in the non-coding regions and specifically in genome promoters, which control protein production. The team led by Atsushi Takata at RIKEN CBS focused on exploring “de novo” gene variants, meaning new mutations not inherited from parents, in these promoter regions.
This extensive study involved analyzing a dataset of over 5,000 families, making it one of the largest genome-wide studies on ASD to date. The researchers specifically examined topologically associating domains (TADs), which are three-dimensional structures in the genome that facilitate interactions between nearby genes and their regulatory elements.
The findings of the study suggest that de novo mutations in promoters increase the risk of ASD, but primarily when these mutations are located within TADs that contain ASD-related genes. Because these genes are neighboring and part of the same TAD, the mutations indirectly impact the expression of ASD-related genes.
Therefore, this study provides an explanation for the increased risk of ASD, even when mutations are not located in protein-coding regions or directly control the expression of ASD-related genes. Atsushi Takata, the lead researcher, highlights the significance of their most important discovery, which links de novo mutations in promoter regions to ASD risk. These associations are likely mediated by interactions within the three-dimensional structure of the genome.
The study’s findings were further supported by the researchers’ experiments involving the CRISPR/Cas9 system. By editing the DNA of stem cells with specific promoter mutations, they observed corresponding alterations in ASD-associated genes within the same TAD. The mutations were also found to affect multiple genes linked to ASD and neurodevelopment, suggesting a genomic “butterfly effect” where a single mutation disrupts disease-associated genes scattered across various genomic regions.
Implications for Diagnosis and Treatment
This breakthrough discovery has significant implications for the development of diagnostic and therapeutic strategies in ASD. It highlights the need to consider whole TADs, rather than just ASD-related genes, for genetic risk assessment. Additionally, interventions that correct abnormal promoter-enhancer interactions resulting from promoter mutations may have therapeutic effects on ASD.
Further research involving more families and patients is crucial for better understanding the genetic foundations of ASD. By expanding research, scientists can enhance their understanding of the genetic architecture and biology of ASD, leading to improved clinical management for affected individuals, their families, and society.
Original research: “Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk” by Atsushi Takata et al. can be found in the journal Cell Genomics.
