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 there are more than 1,200 genes associated with autism spectrum disorder. Due to this wide variety of genetic causes, it has been difficult to identify a common mechanism for the disorder. A Korean research team has discovered that different autism risk gene mutations manifest as two opposing molecular patterns in the brain. This finding paves the way for understanding autism based on shared molecular characteristics, rather than focusing on individual genes.

On September 18, the Ministry of Science and ICT announced that a joint research team from the Synapse Brain Disease Research Division of the Institute for Basic Science (IBS) and the Digital Bio-Computing Research Division of the Korea Institute of Science and Technology Information (KISTI) had identified two common molecular patterns by conducting large-scale analyses of mouse models carrying autism risk gene mutations. The findings 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

Different Gene Mutations Converge into Two Molecular Patterns

The research team created mouse models with mutations in each of 17 different autism risk genes and analyzed 1,008 RNA sequencing datasets collected from the prefrontal cortex of the brain. RNA sequencing is a technology that determines how actively specific genes are functioning.

The analysis revealed that the gene activity states of mice with different mutations split into two contrasting molecular patterns. In the first group, the expression of synapse-related genes responsible for transmitting signals between neurons decreased, while the expression of genes involved in gene regulation and RNA processing increased. The second group exhibited the opposite phenomenon.

However, the groups were not strictly determined by gene type. The same gene mutation could fall into different groups depending on sex or developmental stage. The research team interpreted this as a "dynamic molecular state," meaning a flexible classification depending on conditions, rather than a fixed division into two types of autism.

Analysis of approximately one million individual cell nuclei also confirmed the distinction between the two groups. Similar molecular patterns were observed in brain data from actual autism patients, and 14 core synaptic genes that change in the same direction in both mice and humans were identified.

Different Responses to the Same Drug: Potential for Personalized Treatment Research

The two groups also showed differences in their responses to drugs. When the antidepressant fluoxetine and the mood stabilizer lithium were administered separately, the first group showed a tendency for various gene expression patterns to return to levels similar to the normal control group. In contrast, the response in the second group varied depending on the mouse model and gene involved.

This demonstrates that the response to the same drug can differ according to molecular state. However, it should be noted that these findings come from observing gene expression changes in mouse models; improvements in actual behavior or proven clinical therapeutic effects were not confirmed by this study.

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 Division (and Distinguished Professor at KAIST's Department of Biological Sciences), stated, "Because there are so many different causative genes for autism, it has been difficult to understand the common mechanism of onset through individual gene studies alone," adding, "With this new research framework interpreting various genetic causes through common molecular features, we hope to broaden the horizons of autism research."

The research team plans to further investigate the relationship between molecular changes and actual behaviors or neural circuit function using human-derived cells and to explore personalized treatment strategies.

This study was led by Eunjoon Kim, Director of the IBS Synapse Brain Disease Research Division; Mihyun Bae, Research Fellow at IBS; and Hyojin Kang, Principal Researcher at KISTI, as co-corresponding authors. Junyeop Noh, Senior Researcher at IBS, and Yukyung Jeon, Principal Researcher at KISTI, contributed as co-first authors.

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