Autism has a significant and enduring sex bias, with roughly four boys diagnosed for every girl. For many years, experts have believed this disparity arises primarily from diagnostic inequities because much of autism research — and the screening tools that grew out of it — has historically focused on boys, effectively setting a male standard for what autism "looks like." As a result, girls and women are more likely to be overlooked, misdiagnosed, or diagnosed much later in life.
This disparity has also shaped the science around autism. When fewer females with the condition are identified, fewer are included in research studies, creating a feedback loop where scientific understanding of autism in females remains limited. Because of this underrepresentation of females, it has been difficult for scientists to disentangle how much of the sex bias in autism reflects social inequities versus underlying biological differences between the sexes.
While the search for biological explanations has largely lagged behind, one leading theory, known as the "female protective effect," proposes that females may be biologically buffered against developing autism in a way males aren't.
The idea can be traced back to studies showing that females diagnosed with autism tend to carry a higher number of genetic mutations or "hits" than males with the condition, meaning that they require a higher load of the same genetic mutations for autism to manifest. But, until now, there's been little clarity on the exact biological mechanism behind this apparent resilience.
Now, a perspective from the lab of Whitehead Institute Member David Page, published March 30 in Nature Genetics, proposes a genetic explanation for the female protective effect and suggests that biological differences between males and females contribute to autism's strong sex bias.
The work is one of many projects from the Page lab uncovering the biological underpinnings of sex bias in everything from heart health and autoimmune disease to certain cancers.
"The fact that we see sex biases in disease all across the body gives credence to the notion that the sex bias in autism isn't simply emerging from diagnostic inequities and gendered expectations of what the conditions looks like," says Page, who is also a professor of biology at Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute (HHMI).
The researchers propose that this protective effect extends beyond autism, and could help explain why 17 other congenital and developmental disorders predominately affect males. By characterizing the biological factors that make one sex more or less 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 trace the female protective effect to the X chromosome. Talukdar is a graduate student in Page's lab and the lead author of the perspective.
Most females have two X chromosomes (XX) while most males 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 a cell, impacting cell function across the entire body.
Historically, scientists believed that the second X chromosome in females is largely inactive. But, in recent years, research out of the Page lab has shown that the so-called "inactive X," also called Xi, plays a crucial role in regulating gene expression on the active X chromosome, and the rest of the chromosomes.
In this perspective, the researchers point to a subset of genes that are expressed from both the active and inactive X chromosome — often known as genes that "escape" X chromosome inactivation. Many of these genes are dosage-sensitive regulators of key cellular processes. These processes influence thousands of other genes across the genome, including many linked to autism.
Because females have an extra copy of these regulatory genes expressed from Xi, Page and Talukdar propose that they may be better able to buffer the effects of autism-associated mutations than males.
The female protective effect beyond autism
This mechanism, the researchers say, extends beyond autism to a range of congenital and developmental diseases with a male bias.
"Many of the other congenital or developmental conditions we're pointing to aren't subject to diagnostic inequities in the way autism is," says Talukdar. "This strengthens the idea that the female protective effect is emerging from genetic differences in males and females."
One example is pyloric stenosis, which like autism, affects four boys for every girl. Infants with the condition experience severe vomiting due to thickening of the pyloric sphincter, the passage between the stomach and small intestine. As with autism, girls with pyloric stenosis appear to require more genetic "hits" in order to develop the condition.
The researchers' new framework of looking at Xi to understand sex differences in disease could impact treatment and care not just for conditions that predominately affect males, but also for those that are more common in women, such as autoimmune diseases.
"Our biology isn't one-size-fits-all," Talukdar says "Sex differences clearly play a huge role in health, and it's so important that we understand them."
ABOUT WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH
Whitehead Institute is a nonprofit, independent biomedical research institute founded in 1982. The institute advances pioneering research in cancer, developmental biology, genetics, genomics, and related fields, with a mission to pursue bold, curiosity-driven science that deepens our understanding of life and improves human health. Led by 24 principal investigators and a global community of trainees and scholars, Whitehead Institute maintains a teaching affiliation with Massachusetts Institute of Technology (MIT) but is fully independent in its research programs, governance, and finances.
