Even with Over 1,200 Autism Genes, Brain Changes Converge into Two Patterns [Reading Science]

IBS and KISTI Analyze 17 Mouse Models and 1,008 Brain Datasets,
Identify Differences in Drug Responses

It is known that more than 1,200 genes are associated with autism spectrum disorder. Because there is such a wide variety of genetic causes, it has been difficult to identify common mechanisms underlying disease onset. A Korean research team has discovered that different autism risk gene variants are manifested in the brain as two opposing molecular patterns. This opens a path for understanding autism based on common molecular characteristics, moving beyond individual gene-centered research.

On September 18, the Ministry of Science and ICT announced that a joint research team from the Synapse Brain Disease Research Center at the Institute for Basic Science (IBS) and the Digital Bio-Computing Research Center at the Korea Institute of Science and Technology Information (KISTI) has identified two distinct shared molecular patterns by conducting a large-scale analysis of mouse models carrying autism risk gene variants. The research results were published in the international journal 'Science'.

Two Distinct Molecular Brain States Observed in a Mouse Model with Autism Risk Genes. Analysis of mice carrying different autism risk gene mutations revealed two groups exhibiting opposite changes in genes involved in neural cell signaling and gene regulation. The two groups also showed differences in drug responses, and similar molecular patterns were observed in the brains of human autism patients. Provided by the research team

Diverse Gene Variants Converge Into Two Molecular Patterns

The researchers developed mouse models with mutations in each of 17 different autism risk genes, then analyzed 1,008 sets of RNA sequencing data from the prefrontal cortex. RNA sequencing is a technology used to determine how actively specific genes are functioning.

The analysis revealed that the gene activity profiles of mice with different genetic mutations were divided into two contrasting patterns. In the first group, there was a decrease in the expression of synapse-related genes responsible for neural signaling, accompanied by increased expression of genes involved in gene regulation and RNA processing. In the second group, the opposite pattern was observed.

However, these groups were not strictly determined by the type of gene involved. Even with the same gene mutation, some cases fell into different groups depending on sex or developmental stage. The research team interpreted this not as a fixed classification dividing autism into two types, but as a 'dynamic molecular state' that can change according to specific conditions.

Individual analysis of about one million cell nuclei also confirmed the differences between the two groups. Similar molecular patterns were observed in the brain data of actual autism patients, and 14 key synaptic genes were found to change in the same direction in both mice and humans.

Different Responses to the Same Drug...Possibility for Personalized Treatment Research

The two groups also showed different drug responses. When the antidepressant fluoxetine and the mood stabilizer lithium were administered, the first group tended to show gene expression patterns closer to those of the normal control group. On the other hand, the response in the second group varied by mouse model and gene.

This demonstrates that drug responses may differ according to molecular state, even for the same drug. However, it should be noted that this study confirmed changes in gene expression in mouse models, and did not prove actual behavioral improvement or clinical treatment efficacy.

Research team photo. (From left) Eunjoon Kim, Director of the IBS Synapse Brain Disease Research Center (Co-corresponding author), Mihyun Bae, Research Fellow at the IBS Synapse Brain Disease Research Center (Co-corresponding author), Hyojin Kang, Principal Researcher at the KISTI Digital Bio-Computing Research Center (Co-corresponding author), Junyeop Noh, Senior Researcher at the IBS Synapse Brain Disease Research Center (Co-first author), Yukyung Jeon, Principal Researcher at the KISTI Digital Bio-Computing Research Center (Co-first author). Courtesy of the Ministry of Science and ICT

Eunjoon Kim, Director of the IBS Synapse Brain Disease Research Center (Distinguished Professor at KAIST Department of Biological Sciences), said, "Because the genetic causes of autism are so diverse, studying individual genes alone made it difficult to understand the common mechanisms behind disease onset. Now that a new research framework has been proposed for interpreting various genetic causes through shared molecular characteristics, it will serve as an opportunity to broaden the scope of autism research."

The research team plans to use human-derived cells in future studies to verify the relationship between molecular changes and actual behavior or neural circuit function, and to explore personalized treatment strategies.

Eunjoon Kim, Director of the IBS Research Center, Mihyun Bae, IBS Research Fellow, and Hyojin Kang, Principal Researcher at KISTI, participated as co-corresponding authors, while Junyeop Noh, Senior Researcher at IBS, and Yukyung Jeon, Principal Researcher at KISTI, participated as co-first authors.

This content was produced with the assistance of AI translation services.