Fetal brain wiring sets up life-long sex differences in gene activity, study shows microbiologystudy

A large international study led by scientists at FIMM, University of Helsinki, shows that many of the molecular differences between male and female brains are already established during the first trimester of pregnancy and linger throughout life.

The study is published in the journal Cell Genomics.

By analyzing RNA sequence data from 1,899 human fore-brain samples, the team built a unique developmental timeline of sex-biased gene expression.

The study used public RNA sequencing datasets, containing both prenatal specimens collected between five and 17 weeks post-conception (Human Developmental Biology Resource) and adult samples from people aged 20–79 years.

The analysis uncovered more than 3,000 genes whose activity differed between male and female fetal brains, compared with approximately 1,000 such genes in the adult fore-brain.

Statistical modeling revealed that almost two-thirds of these differences are unique to early development, while less than 1% emerge only in adulthood. The rest persist across both life stages, although usually with smaller effects in adults.

Digging into potential drivers, the researchers found that prenatal-specific sex differences were enriched for binding sites of androgen and estrogen receptors, highlighting the early hormonal influences in shaping sex-biased brain biology.

“Our results show that the male–female gap in brain gene activity opens remarkably early, long before birth, and many of those early signatures stay with us,” says the first author of the paper, Clara Benoit-Pilven, a post-doctoral researcher at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki.

“To understand why neurological conditions often look different in men and women, we have to pay attention to these fetal origins.”

Although the sex-biased genes themselves were not associated with neurological diseases, they seem to be over-represented in co-regulation networks linked to disorders such as schizophrenia and multiple sclerosis. These results hint at the possibility that subtle expression differences may modulate the activity of disease-associated gene networks.

The study also showed that those X-chromosomal genes that escape X-inactivation showed consistent female-biased expression throughout life, underscoring the stable role of sex chromosomes in the brain.

“The findings underscore the importance of studying gene expression dynamics across development and aging to gain deeper insight into the molecular factors shaping phenotypic differences,” says Dr. Taru Tukiainen, former FIMM Group Leader and senior author of the study.