Strong genetic mutation overrides female protective effects in autism, researchers discover

Autism spectrum disorder affects males far more frequently than females, with diagnoses occurring roughly four times more often in boys. Scientists have long suspected that females may possess biological protective mechanisms that reduce vulnerability to autism, but direct experimental evidence has remained limited.

Severe mutations challenge sex protection

A joint research team from KAIST, Yonsei University, and the Institute for Basic Science has now uncovered evidence that the severity of autism-related genetic mutations may play a key role in overcoming these protective effects. The researchers developed the world’s first viable homozygous CHD8-mutant mouse model and discovered that stronger mutations can dramatically alter the male–female pattern of autism-related symptoms. The study is published in the journal Molecular Psychiatry.

CHD8 is considered one of the most important genetic risk factors for autism spectrum disorder and other neurodevelopmental conditions. The gene helps regulate the activity of many other genes involved in brain development by remodeling chromatin structure. However, previous animal models carrying only a single mutated CHD8 copy often showed relatively mild symptoms, limiting researchers’ ability to investigate severe forms of the disorder.

Attempts to generate mice carrying mutations in both CHD8 copies had previously failed because the animals died during embryonic development.

Overcoming past model limitations

To overcome this problem, the team introduced the mutation into a hybrid genetic background, allowing the mice to survive. This enabled researchers to directly compare mild and severe CHD8 mutations across brain development, neural activity, behavior, and gene expression.

The results revealed a striking shift in autism-related traits.

Mice carrying only one mutated CHD8 copy showed behavioral abnormalities primarily in males, consistent with previous findings and the higher prevalence of autism in human males. In contrast, mice carrying severe mutations in both CHD8 copies displayed pronounced autism-related abnormalities in both sexes.

Brain and behavior changes in mice

The homozygous mutant mice also exhibited enlarged brain volume, altered cerebral blood flow, disrupted brain rhythms, and widespread transcriptomic changes involving synaptic signaling, RNA splicing, and mitochondrial function—pathways strongly associated with autism and other neurodevelopmental disorders.

“Our findings suggest that females may possess protective biological mechanisms against CHD8-related dysfunction, but severe mutations can overwhelm those protective effects,” said Professor Lee Eunee of Yonsei University. “This provides important insight into why autism severity and sex differences can vary depending on genetic background and mutation strength.”

The researchers found that many male–female differences became progressively weaker as mutation severity increased. This suggests that the biological mechanisms underlying sex differences in autism may not be fixed, but instead depend on the intensity of genetic disruption.

Implications for other brain disorders

Beyond autism, the findings may also help explain sex differences observed in other neurodevelopmental disorders linked to CHD8, including ADHD, intellectual disability, and schizophrenia.

Director Kim Eunjoon of the IBS Center for Synaptic Brain Dysfunctions stated, “Through this study using a viable homozygous CHD8 mutant mouse model, we have comprehensively elucidated the developmental mechanisms of severe autism at both the brain circuit and genetic levels.

“By proving for the first time that sex differences in autism vary according to mutation strength, we have established an important foundation for the future development of precision therapeutics that account for both biological sex and severity.”

Who’s behind this story?

Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021.

Full profile →

Advertisements

Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

Full profile →