Alex DeCasien and colleagues have mapped gene activity cell by cell across six regions of the human cerebral cortex, and found that biological sex leaves a small but widespread fingerprint on the brain's molecular profile. Using single-nucleus RNA sequencing on tissue from 30 adults, evenly split between 15 males and 15 females, the team identified more than 3,000 genes showing some degree of sex-biased transcription in at least one cortical region, with 133 genes behaving consistently across regions and cell types.
The size of the effect matters as much as its existence. Sex accounted for only a very small fraction of the total variation in gene expression, meaning male and female cortical tissue looks broadly similar at the molecular level. The differences that did appear were strongest in genes on the sex chromosomes, but the bulk of sex-related variation came from autosomal genes with no chromosomal link to sex - variation the researchers attribute mainly to sex steroid hormones.
That distinction is useful for anyone trying to understand why psychiatric and neurological conditions strike males and females at different rates, ages, and severities. If most of the signal runs through hormones acting on ordinary genes rather than through the X and Y chromosomes themselves, it points research toward hormonal pathways that shift across the lifespan rather than fixed genetic differences. The study's design supports that kind of follow-up work: the researchers deliberately chose some cortical regions already known to differ anatomically between the sexes and others not known to, so molecular findings can be lined up against structural ones.
The researchers are careful to frame sex disparities in brain disease as a product of both biological and social influences. What tipped them toward looking for transcriptional causes was the consistency of these disparities across cultures and their predictable timing during development. This analysis gives the field a high-resolution baseline of where in the cortex, and in which cell types, those biological differences actually show up.