Does the autistic spectrum affect men more than women? They look for answers in the chromosomes

BarcelonaFor every four boys diagnosed with autism spectrum disorder (ASD), there is one girl with the recognized condition. For many years, the scientific community has argued that the difference lies mainly in underdetection. On the one hand, because there is a gender bias in standard assessment instruments – the tools used or the symptoms described as typical are based on a masculinized perspective and are less sensitive to female particularities –, and on the other hand, because they tend to mask more subtle symptoms, causing their case to go unnoticed or to be detected late or incorrectly. But is it possible that there are specific biological mechanisms that have gone unnoticed until now?

Given that ASD is considered a disorder with a strong genetic – with hundreds of genes involved – and cerebral basis, researchers at the Whitehead Institute suggest that women may be biologically more protected against autism and would require a higher burden of genetic mutations for autism to manifest. According to a team led by American geneticist David C. Page, a clue to follow would be chromosomes.

David C. Page works at the Whitehead Institute, an independent biomedical research center closely linked to the Massachusetts Institute of Technology (MIT), and is known for studying sex chromosomes (X and Y). Specifically, the biological foundations that can bias the knowledge of multiple diseases, from cardiac and autoimmune to oncological, due to sex. According to a study published this Monday in Nature Genetics, the team led by Page proposes a genetic explanation for the female protective effect and suggests that biological differences between men and women contribute to the strong sexual bias of autism. According to what? With the combination of X and Y chromosomes, which biologically distinguishes men and women.

From a purely biological point of view, most women have two X chromosomes (XX), while most men have one X chromosome and one Y chromosome (XY). These chromosomes can increase or decrease the expression of thousands of genes from the other 22 pairs of chromosomes in a cell. However, historically, scientists believed that the second X chromosome in women is largely inactive. Now, research from the Page laboratory aims to demonstrate that it could actually play a relevant role in the regulation of some key genes.

Compensate for genetic errors?

This scientific thesis –which should not be understood as a definitive explanation, but as a plausible hypothesis– is not new: it is called the female protective effect and proposes that women may be biologically more protected against the development of autism than men. The idea dates back to studies conducted at the beginning of the century which indicate that women diagnosed with autism tend to have a higher number of genetic mutations than men with the condition. In fact, Whitehead researchers propose that they might require a higher load of the same genetic mutations for the disorder to manifest. Although it has been studied, until now there has been little clarity on the biological mechanism behind this apparent female resilience.

To simplify greatly, researchers argue that some subgenes on the X chromosome always function, both on the active chromosome and on the one that is normally inactive. Furthermore, many of these genes control very important processes within cells, including some related to ASD. In this regard, the study indicates that since women have an extra copy of these regulatory subgenes, this could help mitigate the effect of genetic risk variants associated with ASD, while men have fewer and are therefore more vulnerable. In short, they propose, they might have a greater capacity to buffer the effects of autism-associated mutations than men.

Researchers propose that this protective effect extends beyond autism and they want to explore whether a similar mechanism could contribute to the sexual bias of 17 congenital and developmental disorders that predominantly affect men, although this is still a hypothesis. One example is pyloric stenosis: caused by a narrowing of the muscle between the stomach and the small intestine (pylorus), this disorder prevents the passage of food and causes intense "projectile" vomiting, constant hunger, and weight loss. As with autism, girls with pyloric stenosis appear to require more genetic mutations to develop the disease, the authors of the article emphasize.

The study also highlights that all of this has made it difficult to include women with the condition in research, where they are underrepresented, "which creates a feedback loop where the scientific understanding of autism in women remains limited." The researchers' new framework for analyzing the inactive X chromosome to understand sex differences in diseases could also improve the information, care, and treatment of diseases more common in women, such as autoimmune diseases. "Our biology is not unique to everyone. Sex differences play a very important role in health, and it is very important that we understand them," predicts Harvard-MIT medical doctoral student Maya Talukdar, who participated in Page's research.