Study suggests genetic basis for strong sex bias in autism

Autism has a significant and persistent sex bias, with approximately four boys diagnosed for every girl. For years, experts have believed that this disparity stems primarily from a lack of diagnosis because most autism research — and the diagnostic tools that came out of it — have focused on boys, effectively setting male standards for what autism “looks like.” As a result, girls and women are more likely to be neglected, neglected, or neglected later in life.

This difference has also shaped the science of autism. When fewer women with this condition are known, fewer are included in research studies, creating a wave of opinion where the scientific understanding of autism in women remains limited. Because of this underrepresentation of women, it has been difficult for scientists to distinguish whether the overwhelming sex bias in autism reflects social inequality versus natural differences between the sexes.

Although research into biological explanations has lagged behind, one leading theory, known as “female immunity,” suggests that women may be more susceptible to autism than men.

The theory can be traced back to studies that show that women diagnosed with autism tend to carry a higher number of genetic changes or “hits” than men with the condition, which means that they need a higher load of the same genetic changes for autism to manifest. But, until now, there is little clarity about the exact biological mechanism behind this apparent robustness.

Now, a view from the lab of Whitehead Institute Member David Page, published on March 30 Nature Genetics, provides a genetic explanation for the female protective effect and suggests that biological differences between males and females contribute to the strong sex discrimination of autism.

The work is one of several projects from Page’s lab that are uncovering the biological basis of sex bias in everything from heart health and autoimmune disease to some cancers.

The fact that we see a sex bias in diseases all over the body lends credence to the idea that sexism in autism doesn’t just arise from disparities in diagnosis and gendered expectations of what the condition looks like. ”

David Page, professor of biology at the Massachusetts Institute of Technology and researcher, Howard Hughes Medical Institute (HHMI)

The researchers suggest that this protective effect extends beyond autism, and may help explain why 17 other birth and developmental disorders affect men more. By elucidating the genetic factors that make a person of the same sex more likely to develop certain health conditions, scientists see an opportunity to improve how these conditions are diagnosed and how people receive care.

Page and Harvard-MIT MD-PhD student, Maya Talukdar, are testing the female immunity on the X chromosome. Talukdar is a graduate student in Page’s lab and senior visual author.

Most women have two X chromosomes (XX) while most men have one X and one Y chromosome (XY). Sex chromosomes can dial up and down the expression of thousands of genes on the other 22 pairs of chromosomes in the cell, affecting the cell’s function throughout the body.

Historically, scientists believed that the second X chromosome in women is not very active. But, in recent years, research from Page’s lab has shown that the so-called “inactive X,” also called Xi, plays an important role in controlling gene expression on the active X chromosome, and other chromosomes.

In this view, researchers identify the subset of genes that are produced from the active and inactive X chromosome – commonly known as genes that “escape” X chromosome activation. Many of these genes are passive regulators of important cellular processes. These processes influence thousands of other genes throughout the genome, including many associated with autism.

Because women have an extra copy of the regulatory gene expressed in Xi, Page and Talukdar propose that they may be more immune to the effects of autism-related mutations than men.

Female immunity over autism

This mechanism, the researchers say, extends beyond autism to many birth and developmental disorders with a male bias.

“Many of the other congenital or developmental conditions we identify are not based on diagnostic disparities in the way that autism is,” says Talukdar.

Another example is pyloric stenosis, which, like autism, affects four boys for every girl. Babies with this condition vomit a lot because of the narrowing of the pyloric sphincter, the passageway between the stomach and the small intestine. Like autism, girls with pyloric stenosis appear to need genetic “hits” to develop the condition.

The researchers’ new plan to look at Xi to understand sex differences in disease could affect the treatment and care of not only conditions that affect men more, but also those that are more common in women, such as autoimmune diseases.

“Our biology doesn’t fit,” says Talukdar, “It’s clear that sex differences play a huge role in health, and it’s very important that we understand it.”