Even before hormones arrive, the split is already written. A new study from Cornell researchers shows that male bovine embryos outpace female embryos in their earliest days of development because of fundamental differences in gene activity.
By day seven or eight after fertilization, male blastocysts were already surging ahead, fueled by genes driving energy metabolism. Female embryos, by contrast, emphasized pathways for gonad development, immune response, and regulatory processes. The work, published in Cell & Bioscience, reframes how scientists understand sex-specific development in both livestock and humans.
Fast males, deliberate females
Scientists have known for decades that male embryos in many mammals tend to develop faster than female ones. But the molecular reason has been elusive. By combining ultra-low input RNA sequencing with long-read transcriptome profiling, the Cornell team and collaborators revealed that 837 genes showed sex-biased expression. Of these, 231 were upregulated in males, while 606 were downregulated. The patterns were striking. Metabolic genes predominated in males. Genes tied to female reproductive development and inflammation predominated in females.
“Sex difference has been a factor ignored in a lot of studies and clinical trials,” said Jingyue “Ellie” Duan, assistant professor of functional genomics at Cornell. “And yet, we see that onset and occurrence of many diseases are different in men and women.”
Male blastocysts in vitro appeared hungrier, engaging pathways for amino acid biosynthesis, mitochondrial respiration, and carbon metabolism. Female embryos, by contrast, engaged tight junction formation, TGF-beta signaling, and immune pathways, suggesting a different strategic investment. Both paths matter. One accelerates cleavage, the other lays groundwork for resilience.
X chromosomes and compensation
The team also examined the balance of gene expression between sex chromosomes and autosomes. In female embryos, X-linked genes were overexpressed relative to autosomes, indicating incomplete inactivation of one X chromosome coupled with upregulation of the other. That dosage imbalance, the authors note, may partly explain the slower pace of female development. Several XCI escapee genes, including MED12 and SMARCA1, showed higher activity in females, reinforcing the point that sex bias begins long before gonads form.
The fine print of splicing
Another layer of difference emerged at the level of alternative splicing and isoform use. Over 1,500 sex-biased splicing events were identified, most involving skipped exons. In males, skipped exons clustered in genes linked to metabolism and RNA processing. In females, skipped exons tended to hit genes involved in biosynthetic processes. Novel isoforms uncovered by long-read sequencing revealed more than 1,100 sex-biased isoforms tied to over 1,000 genes, many invisible at the standard gene-expression level. The detail matters. It means the differences between male and female embryos aren’t just in which genes are on, but in which isoform of those genes they use.
“We’re born with this sex-specific genetic regulation that is contributing very differently to cellular behavior, disease onset and immune system development,” Duan said. “And it continues through life all the way to health and aging.”
From cows to clinics
The findings have implications beyond the barn. In cattle, understanding sex-biased development could help refine in vitro fertilization practices critical to dairy and beef production. For human medicine, the message is broader. Drug development, reproductive health, and even our understanding of disease risk must take sex into account at the most basic genomic level. The split begins earlier than most realized—just a handful of days after conception.
Takeaway
This study reveals that male bovine embryos race ahead by activating metabolism-related genes, while females focus on regulatory, immune, and developmental pathways. The work underscores that sex bias is not an aftereffect of hormones but a deeply rooted genomic program shaping life from its earliest moments.
Journal: Cell & Bioscience
DOI: 10.1186/s13578-025-01459-x
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