Sex chromosome overload sparks to a common developmental faultline

Whether it is an extra X or an extra Y, new research shows that additional sex chromosomes can scramble the genetic script in surprisingly similar ways.

In a first-of-its-kind stem cell study, researchers found that two of the most common sex-chromosome anomalies in males hijack the same genetic pathways^[1]. This alters key brain-related genes in ways that could help explain their overlapping cognitive and developmental symptoms.

Led by Antonio Adamo, the KAUST team used patient-derived induced pluripotent stem cells (iPSCs) to model early development in the lab, converting them into neural precursors that preserved the unique genetic makeup of their donors.

The researchers created the world’s first iPSC lines from individuals with Jacobs syndrome, a condition affecting approximately one in 1,000 males, in which boys inherit an extra Y chromosome in addition to the usual X-Y pair. These were compared to iPSC-based models of Klinefelter syndrome, in which males inherit two X chromosomes plus a Y. Notably, participants of Saudi origin were included, broadening the genetic diversity often represented in such studies.

Adamo’s team observed that gene regulation begins to unravel almost immediately in cells carrying extra sex chromosomes — and that these disruptions converge on the same molecular networks, particularly those tied to brain development, hormone signalling, and metabolism. All three pathways are commonly affected in individuals with sex chromosome abnormalities.

The findings suggest that, despite their distinct chromosomal profiles, both Jacobs and Klinefelter syndromes may disrupt genome regulation through a shared mechanism, tipping the balance that normally keeps gene expression in check.

“When cells carry an extra X or Y chromosome, the balance of gene activity is disrupted in a similar way, ultimately affecting the entire genome,” Adamo says. “Our findings highlight the Y chromosome’s unexpected and essential role in regulating the genome, challenging the long-standing view of it as a minor player in human biology.”

Researchers focused on a little-studied gene called UTY, one of the few active genes on the Y chromosome during early development. UTY was predictably overexpressed in cells from individuals with Jacobs syndrome who harbor two copies of the Y chromosome. What surprised the researchers was its apparent influence on KDM6A (also known as UTX), an X-linked gene known to play a critical role in brain development and associated with neurodevelopmental disorders such as autism.

“The two genes appear to be engaged in ‘transcriptional crosstalk,’ with imbalances in either one reverberating through critical developmental pathways, ultimately contributing to the same kinds of molecular misfires seen in both syndromes,” Adamo explains. “Our results both support and refine existing models of how epigenetic mechanisms respond to changes in sex chromosome number.”

Beyond shedding light on the fundamental biology of sex-chromosome aneuploidies, the study also points to a promising therapeutic lead.

“Because UTY encodes an enzyme involved in gene regulation, it offers a rare, actionable drug target in an area of medicine where treatment options remain scarce,” notes study co-author Veronica Astro, a research scientist in Adamo’s group. “Controlling its activity with specific inhibitors might be possible, opening new paths for targeted therapy of sex chromosome aneuploidies.”

Reference

1. Astro, V., Cardona-Londoño, K. Y., Cortés-Medina, L. V., Alghamdi, R., Ramírez-Calderón, G., Kefalas, F., Dilmé-Capó, J., Radío, S. & Adamo, A. An iPSC-based model of 47,XYY Jacobs syndrome reveals a DNA methylation-independent transcriptional dysregulation shared with male X aneuploid cells. Genome Research 35, 1503-1517. | article