Hundreds of genes are thought to be associated with autism, but the precise molecular and cellular mechanisms behind them remain largely unknown. New research published in natureA research team led by Gaia Novallino from the Austrian Institute of Science and Technology (ISTA) aims to uncover these mechanisms, which could lay the foundations for the development of medical therapies.
Autism spectrum conditions, often abbreviated as ASD in the scientific and medical literature, are neurodevelopmental disorders such as epilepsy and intellectual disability, for example. Fundamental changes begin early in brain development, but the first signs are often evident in early childhood and can persist throughout life. ”
Gaia Novalino, Professor and Vice-Rector, Institute of Science and Technology Austria (ISTA)
A key question in this field has been whether the many genetic causes of ASD ultimately converge on the same biological changes in the brain. ISTA graduate Lena Schwarz and colleagues from ISTA’s Novarino group, Medical University of Vienna, University of Vienna, and CeMM have now found a clue.
Lots of mutations, lots of data
Autism is a genetically complex disorder. Some cases are related to rare mutations in individual genes, while others involve a broader combination of factors. “So the biology becomes even more complex,” Schwartz said.
In her doctoral project, she asked whether the different genetic mutations associated with autism could affect brain development in related ways. By comparing molecular changes across several genetic models and developmental stages, this project aimed to identify where these mutations share biological pathways and where they leave distinct molecular signatures of their own.
“Given this overview, we wanted to understand whether different genetic causes of autism may still have overlapping effects, and where those effects differ.” It’s a daunting task that involves truly enormous amounts of data.
Just 10 years ago, such analysis would have been unthinkable. But advances in technology have made it possible. The researchers turned to a technique known as single-nuclear multi-omics sequencing. This name sounds complicated, but it can be broken down.
Instruction manual and recording of individual neuron activity
“Mononuclear” refers to the cell nucleus, the control center of the cell that contains the DNA. The brain contains many types of cells. By looking at individual nuclei, researchers can distinguish between these cell types and learn more precisely what’s going on inside.
“Multi-omics” means examining several layers of information within that core. That is, the DNA itself, RNA-mediated gene activity, and epigenomic chemical modifications on the DNA that control whether genes are switched on or off.
This approach offers significant advantages for questions such as those posed by Schwarz and Novarino. Instead of working with large numbers of samples, the research team can study individual cells to determine which mutations affect which cell types and how autism-related genes show different patterns in the brain.
For Schwartz, this meant analyzing more than 250 samples covering high-risk ASD genes in two different brain regions in male and female mice at different stages of development.
Different mutations, same molecular effects during brain development
The researchers found that although the genes affected varied, the same brain cell types and molecular processes were affected across the models, particularly in the early stages of brain development in mice. At the same time, each model exhibited a unique molecular fingerprint.
These changes primarily manifested as temporary delays in cell maturation and connectivity rather than permanent defects. Around 2 weeks of age, many of these differences began to disappear.
They also found that changes in brain activity reflected molecular processes and that female mice responded differently to ASD-associated mutations.
Looking to the future
The great genetic diversity of ASD makes it difficult to find a one-size-fits-all intervention. Recent research from the Novarino group focuses on changes in brain cells that appear in common across different genetic forms of ASD, pointing to common developmental pathways that could be targets for early intervention.
“Our findings advocate a stage-specific, sex-specific, and trajectory-specific treatment approach. Rather than looking for a single universal intervention, we should consider when to intervene during the stage of development, the biological sex of the individual, and the specific genetic and molecular trajectory that person follows,” Novarino explains.
“Autism spectrum conditions affect many children and families around the world. Understanding what is happening in their brains is important on two levels. It deepens our broader knowledge of human brain development and brings us closer to meaningfully supporting these people.”
sauce:
Austrian Institute of Science and Technology
Reference magazines:
black, los angeles, Others. (2026). Dynamics of cortical development in an autism spectrum disorder mouse model. nature. DOI: 10.1038/s41586-026-10679-1. https://www.nature.com/articles/s41586-026-10679-1
