Why Girls May Be Protected From Autism
Genes expressed by the “inactive” X chromosome may confer a female protective effect in autism, contributing to sex bias.
Autism is a neurodevelopmental condition characterized by impairments in social communication and restricted, repetitive behaviors. While there is no single explanation for the cause of autism, several factors—including genetics, metabolic differences, environmental exposures, and the gut microbiome—have been associated with its development.
Roughly four boys are diagnosed with autism for every girl, representing a significant sex bias. This disparity may stem from diagnostic inequities due to research focusing mainly on boys, creating a “male-centric” standard for autism traits that is reflected in screening tools. Girls and women are therefore more likely to be overlooked, misdiagnosed, or diagnosed later in life.
However, the underrepresentation of girls and women in autism research has made it difficult to identify whether the male sex bias is related to sex-differential biological factors like genetics or hormones. If autism’s sex bias is based in biology, major drivers would either be male-specific risk factors or female-specific protective factors.
“Understanding the factors underlying it [male bias in autism] is at the intersection of many different fields of inquiry, including genetics, neuroscience, psychology, and sociology,” Dr. Maya Talukdar, an MD student in the Harvard/MIT MD-PhD program, told Technology Networks. “As a geneticist by training, I was fascinated by understanding the genetic contribution to the male bias and how this might ultimately inform our understanding of how autism develops in general.”
The female protective effect
Hundreds of inherited and de novo gene variants, including structural variants and single-nucleotide polymorphisms, have been associated with autism risk, enabling researchers to study the relationship between genetic risk factors and sex-based differences in autism.
“By studying the factors that underlie the sex bias in autism, we hope to better understand the mechanisms that contribute to autism more broadly.”—Maya Talukdar
DNA sequencing studies of people with autism have revealed that females tend to have more autism-linked genetic variation than males, despite showing the same degree of impairment.
Females may therefore require a higher mutational load to manifest an autism phenotype, and conversely, males are more likely to display autistic impairments because they require fewer genetic variants to reach the same impairment threshold.
“This suggests that females are somehow ‘protected’ from the effects of autism-associated genetic variation, and so this finding has come to be known as the ‘female protective effect (FPE)’,” explained Talukdar.
The FPE provides evidence that genetics contribute to the male sex bias in autism, although the mechanism behind it and the extent of the genetic contribution to autism’s sex bias remain unknown.
The “inactive” X chromosome
Sex chromosomal differences are a compelling avenue for research into the mechanisms behind the FPE and the sex bias observed in autism.
All diploid human somatic cells possess one active X chromosome (Xa). In male cells, this is accompanied by a gene-poor Y chromosome, and in female cells, one X chromosome is inactivated to balance X-linked gene expression levels. The majority of genes on one copy of the X chromosome are silenced in this process.
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However, the inactive X chromosome (Xi) is not completely silent. About a quarter of its genes are active and can regulate genes on Xa and other chromosomes, making critical contributions to human health.
“Our overarching model is that many genes that are implicated in autism are both dosage-sensitive and regulated by genes that are expressed from Xi in females,” said Talukdar. “This means that we have genes that are very sensitive to different regulation being exactly that—regulated differently in males and females.”
In a recent perspective published in Nature Genetics, Talukdar and Prof. David Page from the Whitehead Institute propose that this differential regulation contributes to the FPE and male sex bias in autism.
They pinpointed a subset of X-linked genes that escape silencing during X chromosome inactivation, which are therefore more highly expressed in females due to transcription from both the Xa and Xi chromosomes. Many of these genes regulate key cellular processes that influence other genes, including autism-linked genes. Higher expression levels of these genes may enable females to better tolerate autism-linked genetic mutations.
“We recently demonstrated that an Xi-expressed gene and transcriptional activator ZFX upregulates many genes that tend to be downregulated in autism,” said Talukdar. “Since females express higher levels of ZFX than males, we propose that they are better able to buffer these autism-associated patterns of downregulation.”
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What this means for autism research and beyond
Studying the factors that underlie sex bias could lead to a better understanding of the broader biological mechanisms that contribute to autism and other conditions with a strong sex bias.
“The goal of this work is not to 'cure’ autism or to pathologize neurodiversity.” — Maya Talukdar.
“We are focused on basic scientific questions about how and why autism arises, and why its prevalence and presentation may differ between males and females,” said Talukdar. “In doing so, we also aim to shed light on the broader biological principles underlying sex-biased conditions.”
The FPE is not unique to autism and extends to a range of congenital and developmental conditions, indicating that Xi-linked gene expression may also influence these conditions.
“My hypothesis is that the FPE is particularly likely to arise in conditions whose genetic architecture is driven by rare mutations in highly constrained genes,” noted Talukdar. “This may help explain why many of the disorders in which we observe evidence of an FPE are developmental in nature.”
Understanding how the combined activity of Xa- and Xi-expressed genes shapes disease risk could reframe our understanding of sex differences in human disease. The focus on Xi could also potentially impact treatment and care for conditions with a male sex bias, like autism, or a female sex bias, such as autoimmune diseases.
“What’s next for us is really drilling down mechanistically on the particular pathways regulated by particular Xi-expressed genes in particular male-biased conditions—clearly, a big question, but also one tremendously rich and ripe for future investigation,” concluded Talukdar.
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