Science ministry says researchers map two molecular patterns for autism

The science ministry said Thursday that a joint research team has identified two common molecular patterns underlying the genetic diversity of autism spectrum disorder. The findings, derived from analyzing the world's largest scale of mouse models with autism risk gene mutations, offer a new framework for understanding the condition beyond individual gene studies.

Researchers from the Institute for Basic Science and the Korea Institute of Science and Technology Information found that diverse gene mutations converge into two opposing transcriptome states in the brain. While previous studies focused on specific genes or small animal models, this comprehensive analysis revealed universal biological principles connecting various genetic causes to the disorder.

The study selected 17 autism risk genes involved in functions such as synapse function and cell signaling. By analyzing 1,008 RNA sequencing data points from the brain prefrontal cortex, the team discovered that mice with different mutations all fell into one of two distinct groups based on gene activity levels.

In the first group, gene expression related to synaptic signal transmission decreased while genes regulating expression and RNA processing increased. The second group displayed the opposite pattern, with heightened synaptic gene activity and reduced regulation.

Drug response tests highlighted the distinction between the two groups. When administered the antidepressant fluoxetine and the mood stabilizer lithium, the first group showed consistent recovery in molecular abnormalities across multiple genes. In contrast, the second group exhibited varied responses depending on the specific gene, indicating that treatment efficacy may depend on a patient's underlying molecular state.

The researchers validated these results using single-nucleus RNA sequencing of approximately 1 million cell nuclei and gene correlation analysis. Similar molecular patterns were observed in additional autism mouse models and actual brain transcriptome data from patients.

Eunjoon Kim, head of the IBS Center for Synaptic Brain Dysfunctions, noted that the diversity of causal genes had previously limited the understanding of common disease mechanisms. He stated that presenting a new research framework to interpret diverse genetic causes through shared molecular features will broaden the horizons of autism research.

Mi-Hyun Bae, an IBS research fellow who led the study, said the work will systematize comparative evaluations of candidate therapeutic substances. She added plans to expand the research scope using human-derived cells to refine strategies for treating the disorder.

Sungsoo Kim, director of the R&D Planning Office at the ministry, described the achievement as meaningful for linking large-scale life science resources with advanced data analysis capabilities. He pledged continued support for fundamental research into life phenomena to overcome intractable diseases.

The study was conducted through the ministry's support program for IBS basic science research groups, utilizing computing resources from the National Bio Data Station. The results were published in the journal Science on September 18.