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The X and Y chromosomes split hundreds of millions of years ago and seem to live very different lives. But new research shows they still regulate the same genes across the genome, quietly shaping biology together.

Biology is often taught in clean categories: two sexes, two chromosomes, two opposing genetic programs. Introductory biology often presents this as XX, labeling female and XY, labeling male. From that contrast, a simple story of difference has grown. But inside human cells, the story is far less binary.

Around 300 million years ago, the mammalian X and Y chromosomes started out as identical partners. As mammals evolved, the Y lost most of its genes and specialized in sperm production. The X kept most of its original DNA. In female cells, one X is mostly switched off through X inactivation, preventing a double dose of its gene activation. What remains of their shared past was a small set of paired genes, including ZFX on the X and ZFY on the Y: two transcription factors that help control gene activity across the genome. 

Although their basic functions were known, for decades these shared genes were viewed as evolutionary leftovers, thought to play only minor or redundant roles. A new study in Cell Genomics by Adrianna San Roman et al. at the Whitehead Institute (now at Duke University) suggests they are anything but. 

San Roman et al. examined hundreds of human cell lines with different numbers of sex chromosomes. Some had only one X, as in Turner syndrome. Others carried two X chromosomes and a Y, as in Klinefelter syndrome. These naturally occurring differences allowed the team to test how changes in X and Y dosage shape gene expression across the genome.

What they found was unexpected. When a cell gained an extra Y chromosome, the activity of many autosomal genes, genes located on non-sex chromosomes, shifted. When a cell gained an extra inactive X chromosome, many of those same autosomal genes shifted in the same direction. Across cell types, the genome did not respond as two opposing systems, but as a shared regulatory network being tuned in slightly different ways.

To trace the source of this shared response, the researchers turned to ZFX and ZFY. These closely related transcription factors share similar DNA-binding structures and bind broadly across the genome, helping regulate large gene networks. When the team suppressed ZFX and ZFY, the coordinated changes in autosomal gene expression largely disappeared. Even the “inactive” X chromosome exerted influence through one of these ancient regulators. Despite hundreds of millions of years of divergence, the X and Y still rely on the same molecular levers to shape gene activity.

Together, these findings challenge a long-standing view of biological sex as two sharply opposing genetic programs: one for males, another for females. Instead, the X and Y appear to regulate a shared landscape, where differences arise through dosage and balance rather than strict opposition. This framework may help explain why people with variation in their sex chromosomes often experience widespread effects on growth, development, and health, as has long been observed in conditions such as Turner and Klinefelter syndromes. It may also shift how scientists think about the genetic roots of sex differences more broadly: not as a simple binary, but as variation within a shared regulatory system.

The X and Y chromosomes may look nothing alike today. But through ZFX and ZFY, they still reach into the same gene networks, quietly tuning how thousands of genes behave. After hundreds of millions of years of evolution, their resemblance has faded, but their connection remains. And in that lingering connection, biology once again resists simple categorization.

Edited by Jameson Blount, Amanda N. Weiss, and Hannah Kubinski