Patterns in genetic chaos

Hundreds of genes have been linked to autism, yet the precise molecular and cellular mechanisms behind it remain largely unclear. A new study published in Nature, led by Gaia Novarino at the Institute of Science and Technology Austria (ISTA), aims to uncover these mechanisms—and in doing so, might lay the groundwork for developing medical therapies.

“Autism spectrum conditions, often abbreviated as ASD in scientific and medical literature, are, for example, neurodevelopmental disorders such as epilepsy or intellectual disability. The underlying changes begin during early brain development, while the first signs often become apparent in early childhood and can persist throughout life,” explains Gaia Novarino, Professor and Executive Vice President at the Institute of Science and Technology Austria (ISTA).

A key question in the field has long been whether the many genetic causes of ASD ultimately converge on the same biological changes in the brain. ISTA alum Lena Schwarz and colleagues from the Novarino group at ISTA, the Medical University of Vienna, the University of Vienna, and CeMM have now found clues.

Plenty of mutations, plenty of data

Autism is a genetically complex disorder. While some cases are linked to rare mutations in individual genes, others involve a broader combination of factors. “That makes the biology much more complex,” says Schwarz.

For her PhD project, she asked whether different autism-associated genetic mutations might nevertheless 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 their own distinct molecular signature.

“With such an overview, we wanted to understand whether different genetic causes of autism might still lead to overlapping effects—and where their effects differ.” A daunting task involving truly massive amounts of data.

Just ten years ago, such an analysis would have been unthinkable. But technological advances have now made it possible. The researchers turned to a method known as single‑nucleus multi‑omics sequencing—a complex-sounding name that can be broken down.

Instruction manual and activity log of individual nerve cells

“Single nucleus” refers to the cell nucleus—a cell’s control center that contains its DNA. The brain contains many cell types. By looking at individual nuclei, researchers can distinguish these cell types and examine what is happening inside them more precisely.

“Multi‑omics” means looking at several layers of information within that nucleus: the DNA itself, the gene activity through RNA, and the epigenome—chemical modifications on the DNA that regulate whether a gene is switched on or off.

This approach offers major advantages for questions like those posed by Schwarz and Novarino. Instead of working with bulk samples, the team can study individual cells to determine which mutations affect which cell types and how autism‑related genes show distinct patterns in the brain.

For Schwarz, that meant analyzing more than 250 samples covering high‑risk ASD genes in two different brain regions—from both male and female mice at various developmental stages.

Different mutations, same molecular effects during brain development

The researchers discovered that although the impacted genes varied, the same brain cell types and molecular processes were affected across models—particularly during early brain development in the mice. At the same time, each model showed its own molecular fingerprint.

These changes mostly appeared as transient delays in cell maturation and connectivity rather than permanent defects. Around two weeks after birth, many of these differences began to fade.

They also found that changes in brain activity mirrored the molecular processes and that female mice show different responses to ASD-linked mutations.

Looking ahead

ASD shows immense genetic diversity, which makes the search for a one-size-fits-all intervention difficult. The Novarino group’s recent work highlights the shared changes in brain cells that appear across different genetic forms of ASD, pointing toward common developmental pathways that could become targets for early intervention.

“Our findings advocate for therapeutic approaches that are stage-specific, sex-specific, and trajectory-specific. Rather than looking for a single universal intervention, we need to account for when in development we intervene, the biological sex of the individual, and the specific genetic and molecular trajectory that person is on,” explains Novarino.

“Autism spectrum conditions affect many children and families around the globe. Understanding what is happening in their brains matters on two levels: it deepens our knowledge of human brain development more broadly, and it brings us closer to being able to meaningfully support these individuals.”

 

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Information on animal studies

In order to better understand fundamental processes, for example, in the fields of neuroscience, immunology, or genetics, the use of animals in research is indispensable. No other methods, such as in silico models, can serve as an alternative. The animals are raised, kept, and treated according to the strict regulations of Austrian law. All animal procedures are approved by the Federal Ministry of Education, Science, and Research.

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