A new study has been published. Scientific advances A complex mechanism behind sex differences in autism has been uncovered. The study suggests that increased amounts of a gene called Ube3a may affect autism-related traits differently in men and women. By studying mice with extra copies of this gene, researchers found significant sex-specific effects on brain connectivity and behavior, providing insight into why autism is more prevalent in men.
Autism, or Autism Spectrum Disorder (ASD), is a complex neurodevelopmental disorder characterized by challenges with social interaction and communication, and a tendency to engage in repetitive behaviors. These symptoms vary in severity and manifestation, making autism a spectrum disorder.
Despite extensive research, the exact cause of autism remains unknown. It is believed to be due to a combination of genetic, environmental, and neurological factors. One interesting thing about autism is that it is more prevalent in men; for every 1 woman, 4 men are diagnosed with autism. This large gender gap has led scientists to investigate possible genetic and biological mechanisms that could explain this discrepancy.
One genetic mechanism that may contribute to the male bias in autism is the Ube3a gene, which is known to be involved in neurodevelopment and is located on chromosome 15. Mutations in the Ube3a gene have been associated with several neurodevelopmental disorders, including autism; however, its role in interacting with gender-specific mechanisms has not been thoroughly investigated.
“My lab has long been investigating the genetic and biological causes of autism, in particular the altered brain connectivity that characterizes these disorders. As part of this work, we have been scanning the brains of mice that carry a duplication of the autism risk gene Ube3a,” said the study authors. Alessandro GozziSenior Scientist and Director of the Institute of Functional Neuroimaging at the Italian University of Technology.
“Through these investigations, we serendipitously discovered that sex had a significant impact on the patterns of changes we had mapped; male and female mice showed distinct and different effects. This finding intrigued us and prompted us to further investigate the function of Ube3A. We then realized that this gene plays a less explored role in controlling the expression of other genes in a sex-dependent manner. Upon further investigation, we found that Ube3A acts as a sex-specific switch that controls the expression of many other genes important for autism in both rodents and humans.”
To investigate the effects of increasing the dosage of the Ube3a gene, the researchers used a genetically modified mouse model to mimic the human condition known as 15q duplication syndrome, which involves a duplication of the Ube3a gene and is associated with autism. Specifically, the researchers used Ube3a2X mice, which have two extra copies of the Ube3a gene, and compared them to wild-type control samples.
Functional magnetic resonance imaging (fMRI) was used to study brain connectivity: both male and female mice underwent resting-state fMRI (rsfMRI) to measure functional connectivity between different brain regions, and structural MRI was also performed to examine brain anatomical changes.
fMRI results revealed significant differences in brain connectivity between male and female Ube3a2X mice. Female mice with increased Ube3a dosage had decreased connectivity in key brain regions, including the hypothalamus and prefrontal cortex. In contrast, male mice had increased connectivity in these regions. These results suggest that Ube3a gene dosage differentially affects brain connectivity in males and females, which may contribute to the gender-specific prevalence of autism.
“It was really striking and surprising that the same mutation had such different effects on rodent brain function, and it provided a great clue for our subsequent research,” Gozzi told PsyPost.
To assess autism-related behaviors, the researchers conducted a series of behavioral tests, including an open-field test to measure locomotion and anxiety, a rotarod test to evaluate motor coordination, and a self-grooming scoring to observe repetitive behaviors. Additionally, social behavior was assessed using the habituation/dishabituation social interaction test and the three-chamber social interaction test.
Male Ube3a2X mice exhibited a significant increase in repetitive behaviors, including excessive grooming, compared to wild-type mice. This increase in stereotyped behavior was not observed in female Ube3a2X mice. The rotarod test also revealed impaired motor coordination in Ube3a2X mice, which was not sex-specific. Regarding social behavior, no significant differences were found in social interactions between Ube3a2X mice and wild-type controls, regardless of sex, in both the habituation/dishabituation test and the three-chamber test.
The researchers performed RNA sequencing to analyze gene expression in specific brain regions, specifically the prefrontal cortex and hypothalamus, which allowed them to identify differences in gene activity between Ube3a2X and WT mice, and between males and females.
Gene expression analysis provided further insight into the gender-specific effects of increased Ube3a dosage. In the frontal cortex, many autism-related genes were abnormally expressed in a gender-dependent manner. For example, some genes were upregulated in male Ube3a2X mice but downregulated in females, and vice versa. These differences in gene expression were particularly pronounced for genes located on the X chromosome and genes affected by sex steroid hormones, such as androgen and estrogen receptors.
“The main point is that the gender bias in autism (four times more common in boys than in girls) may be explained by genetic mechanisms, particularly interactions with sex hormones,” Gozzi explained. “This finding adds to a growing body of evidence suggesting that autism is in many ways a genetic disorder.”
The discovery improves our understanding of the genetic and biological factors underlying sexism in autism. However, Gozzi noted that “this is only one of many genetic mechanisms that may lead to sexism in autism. The challenge now is to understand which, and how many, other genetic and biological mechanisms contribute to this phenomenon.”
“Our long-term goal is to better understand how genetic variants that confer risk for developing autism alter brain function. This remains a major knowledge gap that we need to address.”
the study, “Gender-biased effects of autism-associated Ube3a gene overdosing at connectomic, behavioral, and transcriptomic levels” is written by Caterina Montani, Luigi Balasco, Marco Pagani, Filomena Grazia Alvino, Noemi Barsotti, A. Elizabeth de Guzman, Alberto Galbusera, Alessia De Felice, Thomas K. Nickel-Yokshut, Sara Migliarini, Simona Casarosa, Pierre Lau, Lorenzo Mattioni, Massimo Pascretti, Giovanni Provenzano, Yuri Bozzi, Michael V. Lombardo and Alessandro Gozzi.
