The cortex is not the part of the brain you typically think of when you think about sex differences.
A landmark study of human brain tissue has revealed that more than 3,000 genes express themselves differently in male and female cerebral cortices — a region long assumed to stand apart from the biology of sex. Published in Science, the work uses single-cell transcriptomics to map molecular variation across six cortical regions in thirty donors, surfacing patterns that may quietly underlie why conditions like multiple sclerosis and autism fall so unevenly across the sexes. The findings invite both hope and humility: they narrow the search for disease mechanisms while reminding us that a difference at one level of biology does not yet explain the full human story above it.
- Scientists expected the cerebral cortex to be neutral territory in the study of sex differences — finding over 3,000 differentially expressed genes there has upended that assumption.
- 119 of the 133 most consistent genes sit on autosomes, chromosomes both sexes carry identically, meaning the molecular machinery driving these differences is more cryptic and complex than sex chromosomes alone.
- Genes more active in female brains cluster around variants that raise women's risk for multiple sclerosis, while the region showing the largest sex differences — the fusiform gyrus — is already implicated in autism, a condition diagnosed four times more often in boys.
- Despite the scale of the discovery, sex accounts for only 0.3 percent of total gene expression variance, a paradox suggesting that small molecular differences accumulate quietly into large clinical disparities.
- Researchers are pushing toward organoid studies involving atypical sex chromosome profiles and hormone-mapping across life stages, aiming to disentangle sex chromosomes, sex hormones, and gender-shaped environment as distinct variables.
A new study published in Science has found that more than 3,000 genes behave differently in male and female brains — a discovery that challenges long-held assumptions about the cerebral cortex. Researchers used single-cell transcriptomics to analyze tissue from 30 donors across six cortical regions, a part of the brain historically considered neutral ground in the study of biological sex. Neuroscientist Tomasz Nowakowski of UCSF called the result "a pretty dramatic shift" and a landmark finding.
Of the thousands of genes identified, 133 showed consistent sex differences across every cell type and region studied. Strikingly, 119 of these sit on autosomes — chromosomes that men and women carry in equal copies — meaning they should, in theory, express equally. That they do not points toward complex regulatory mechanisms involving sex hormones and the X chromosome. Armin Raznahan of the National Institute of Mental Health described these autosomal genes as "ground zero for molecular sex differences in the brain."
The clinical implications are significant but carefully bounded. Female-biased genes show enrichment for variants linked to multiple sclerosis risk, and the fusiform gyrus — a region implicated in autism — displays the study's largest sex differences. Researcher Matthew Oetjens noted the findings reduce the search space for understanding why autism is diagnosed far more often in boys. Yet lead researcher Alex DeCasien cautioned that a difference at one biological level cannot be assumed to explain behavioral or clinical outcomes, especially since male- and female-biased genes often occupy the same cellular compartments and may counterbalance one another.
A further paradox: sex explains only 0.3 percent of gene expression variance across samples, yet remains one of the strongest population-level predictors of neurological disease. The study also identified, for the first time using brain tissue directly, X-chromosome genes that escape normal silencing in females — known hotspots for neurodevelopmental differences. Next steps include organoid studies from donors with atypical sex chromosome profiles and efforts to map hormonal influences across life stages, as researchers work toward treating sex chromosomes, hormones, and gender-shaped environment as the distinct variables they are.
A new study has found that more than 3,000 genes behave differently in the brains of men and women, a discovery that may finally explain why certain neurological conditions strike one sex far more often than the other. Researchers analyzed brain tissue from 15 men and 15 women, aged 26 to 78, using single-cell transcriptomics to map gene activity across six regions of the cerebral cortex. The work, published in Science, reveals a landscape of molecular sex differences that most neuroscientists did not expect to find in the cortex itself—a region long considered neutral ground in the study of sex and the brain.
The sheer scale of the finding has caught the attention of researchers outside the study. Tomasz Nowakowski, a neuroscientist at the University of California, San Francisco, calls it "a pretty dramatic shift in how we're thinking about sex differences." For decades, sex-based biology in the brain was thought to live primarily in deeper structures, where sex hormones exert their influence. The cortex, the brain's outer layer responsible for higher cognition, seemed like an exception. "The cortex is not the part of the brain that you typically think of when you think about sex differences," Nowakowski says. "I think it's a landmark."
Of the thousands of genes flagged, 133 showed consistent sex differences across all cell types in all six regions studied. Two of these regions—the fusiform gyrus and the inferior lateral temporo-occipital cortex—have more gray matter in men according to previous brain imaging studies. Two others, the caudal insula and intraparietal sulcus, show more gray matter in women. The remaining two regions show no sex bias in structure at all. What makes this pattern particularly striking is that 119 of the 133 consistently different genes are autosomal—they sit on chromosomes that men and women both carry in identical copies. In theory, these genes should be expressed equally. Yet they are not. Armin Raznahan, chief of the Section on Developmental Neurogenomics at the U.S. National Institute of Mental Health, calls these autosomal genes "ground zero for molecular sex differences in the brain."
Many of the 3,000 genes identified play roles in how the brain develops and are regulated by sex steroid hormones and the X chromosome itself. When researchers compared their findings to genetic studies of disease risk, a pattern emerged: genes that are more active in females show enrichment for genetic variants that increase women's risk of multiple sclerosis, for example. This alignment suggests the study may have identified some of the molecular machinery underlying sex-based disease disparities. Matthew Oetjens, a developmental medicine researcher at Geisinger College of Health Sciences, notes that while the work "doesn't necessarily implicate a gene, I think it's reducing that search space" for understanding why conditions like autism are diagnosed roughly four times more often in boys than in girls.
Yet the researchers themselves urge caution. The biggest sex differences in gene expression appear in the fusiform gyrus, a region involved in facial recognition and implicated in autism. But Alex DeCasien, a Stadtman Investigator at the U.S. National Institute on Aging and a lead researcher on the study, emphasizes that finding a difference at one biological level does not automatically explain behavioral or clinical differences. "When we find something at a specific biological level, that's all we can know," DeCasien says. "We can't make assumptions about the underlying drivers or the downstream consequences." The picture grows more complex when considering that male-biased and female-biased genes often overlap in the same cellular compartments and biological processes, potentially counterbalancing each other in ways that leave no visible trace at higher levels of brain organization.
Another surprise emerged from the data: sex explains only 0.3 percent of the variance in gene expression across the samples studied. Yet at the population level, sex is one of the strongest predictors of whether someone will develop certain neurological conditions. This paradox hints at how molecular differences, though individually small, can accumulate into large clinical disparities. Genes on the sex chromosomes themselves showed the largest expression differences, which aligns with earlier findings and serves as a kind of validation. Some genes on the X chromosome escape the normal silencing process that typically occurs in females, and DeCasien notes that the study was able to identify these genes for the first time by looking directly at brain tissue rather than relying on blood samples or cell cultures. These escapee genes are already known to be hotspots for sex differences at the molecular level and are implicated in neurodevelopmental conditions.
The researchers plan next steps that include studying organoids grown from people with atypical sex chromosomes, such as those with Klinefelter syndrome or trisomy X. But DeCasien also articulates a larger ambition: to move beyond sex as a simple investigative category. Currently, researchers use "sex" as shorthand for sex chromosomes, sex hormones, and environmental factors shaped by gender—three things that do not always align. Untangling these threads will require new approaches, such as mapping the relationship between circulating hormones and brain gene expression at different life stages. The study opens a door, but the full picture of why sex matters so much in the brain remains incomplete.
Notable Quotes
A pretty dramatic shift in how we're thinking about sex differences.— Tomasz Nowakowski, UC San Francisco neuroscientist
When we find something at a specific biological level, that's all we can know. We can't make assumptions about the underlying drivers or the downstream consequences.— Alex DeCasien, lead researcher, National Institute on Aging
The Hearth Conversation Another angle on the story
Why does it matter that these genes are autosomal? Shouldn't men and women have the same dosage anyway?
That's exactly the puzzle. They should, in theory. But they don't. That's what makes these 119 genes so interesting—they're telling us that sex differences in the brain aren't just about having different sex chromosomes. Something else is regulating them.
Like what? Hormones?
Hormones are part of it, yes. But the study doesn't fully explain the mechanism yet. That's what makes it a landmark finding but also incomplete. They've mapped the territory; now they have to understand why the map looks this way.
The study says sex explains only 0.3 percent of gene expression variance. That sounds tiny. Why should anyone care?
Because that tiny percentage at the molecular level translates into huge differences at the clinical level. Autism is diagnosed four times more often in boys. Multiple sclerosis hits women harder. Those aren't small disparities. The researchers are saying: look, the molecular differences are real, but they're subtle. They layer on top of each other.
So you can't just point to one gene and say, "That's why girls don't get diagnosed with autism as much."
Exactly. DeCasien is very clear about that. Finding a difference at one biological level doesn't tell you what it means for behavior or disease. That's the caution they're building in.
What happens next?
They want to study people with unusual sex chromosomes—Klinefelter syndrome, trisomy X—to see if the pattern holds. And they want to separate out what "sex" actually means in research. Right now it's a catch-all for chromosomes, hormones, and gender environment all mixed together. Untangling that is the real work ahead.