Abstract:
Why are men diagnosed with autism spectrum disorder at significantly higher rates than women? This phenomenon has long been a research puzzle in the fields of neuroscience and genetics. Current statistics show that boys are about 3 to 4 times more likely to be diagnosed with autism than girls, but genes related to autism are not unique to males. A new study from Boston Children's Hospital found that a special gene on the X chromosome may provide additional protection to the female brain, thereby partially explaining this gender difference.
Researchers hope to understand why hundreds of different genetic variants, each with limited effects, may work together to cause similar traits in the autism spectrum. To this end, the team used neuronal precursor cells cultured in the laboratory to reduce the activity of several autism-related genes one by one and observe the resulting chain changes.
Experiments have found that interfering with different autism-related genes may repeatedly affect the activity of other related genes. The activity of 27 other autism-related genes was reduced in at least 10 experiments. The researchers then used laboratory-grown brain organoids to verify this, further supporting the existence of an interconnected regulatory network between these genes.
By analyzing the regulatory relationship of these genes, the research team focused their attention on a gene located on the X chromosome-ZFX. The gene codes for a zinc-finger transcription factor protein that helps activate other genes, including many associated with autism.
Human females typically have two X chromosomes, but in most cells, many genes on one of the X chromosomes are turned off to avoid overproduction of related proteins. A special exception is ZFX, which is usually active on both X chromosomes. This means that female cells may have higher levels of ZFX expression, helping to maintain the normal activity of the entire gene regulatory network when other autism-related genes are disrupted.
Although men have a Y chromosome gene ZFY that corresponds to ZFX, research has found that ZFY's ability to activate other genes is relatively weak. This difference may mean that female brains have additional buffering mechanisms that males do not have in the face of certain autism-related genetic changes.
The researchers also reanalyzed the gene expression data of previously donated human brain tissue and found that men diagnosed with autism had reduced ZFX activity in excitatory neurons. This result provides further clues as to the possible involvement of ZFX in sex differences in autism.
This research is consistent with the "female protective effect" hypothesis long discussed in the field of genetics. Back in 2014, a genetics study found that although women were diagnosed with autism at lower rates, women who were already diagnosed tended to carry more genetic risk factors related to autism. This suggests that women may need to endure a higher degree of genetic influence before they show characteristics sufficient to qualify for diagnosis.
However, the researchers emphasized that the current findings are not enough to prove that ZFX is the only reason why women are protected from the risk of autism. This experiment mainly used a stem cell line derived from men, and the differences between male and female cells have not yet been fully compared. Future experiments using cells from different gender sources are needed to directly test whether additional ZFX expression can produce a protective effect.
In addition, the difference in autism diagnosis rates between males and females may also be affected by sociocultural factors and diagnostic standards. Some girls may have obvious autistic traits but may go unrecognized because of how they present. A 2012 population-based study found that girls with higher autistic trait scores, without concurrent significant intellectual or behavioral difficulties, were less likely to meet clinical diagnostic criteria.
Some women may also adapt to the surrounding environment by consciously or unconsciously imitating social behaviors and hiding their own characteristics. This phenomenon is often called characteristic camouflage and will also increase the difficulty of identification and diagnosis. Therefore, the fact that more men are diagnosed does not necessarily mean that there is an equal degree of disparity between the true disease status of the two sexes.
The researchers also did not rule out other biological explanations. For example, studies of amniotic fluid from male fetuses later diagnosed with autism have found relatively high levels of steroid hormone activity, suggesting that the hormonal milieu during fetal development may be involved. Other studies have looked at environmental pollutants with hormone-mimicking effects that may also influence autism risk.
This research was also supported by a postdoctoral research grant from Autism Speaks. The organization has been criticized in the past by neurodiversity advocates for describing autism primarily as a condition that needs to be cured. Although organizations have said in recent years that they no longer support research aimed at curing autism, there are still differing views in academia and society on whether autism should be considered a disease or a manifestation of human neurodiversity.
From a scientific perspective, the significance of this study is that it reveals that a single gene may influence the activity of a large number of other genes through regulatory networks and may play different roles in brain development in different genders. However, the extent to which ZFX can explain gender differences in autism remains to be further studied.
Relevant research results have been published in the journal Nature.
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