Around 380 million years ago, in the shallow seas of the Devonian Period, this fish was swimming around minding its own business. Little did it know that part of its genetic code would one day help build fingers and toes.
Now, in a new study published in Nature, scientists from the University of Geneva, EPFL, and collaborators in the U.S. have traced the origins of digits not to the fins themselves—but to the genetic machinery that built an entirely different body part: the cloaca, the catch-all excretory and reproductive orifice still found in many animals today.
“The common feature between the cloaca and the digits is that they represent terminal parts,” said geneticist Aurélie Hintermann, co-author of the study and postdoctoral researcher at the Stowers Institute. “Sometimes they are the end of tubes in the digestive system, sometimes the end of feet and hands, i.e., digits. Therefore, both mark the end of something.”
Recycling Evolution
For decades, researchers assumed that digits—the fingers and toes that are hallmarks of tetrapods—emerged from genetic programs specific to fish fins. However, despite lacking fingers or toes, fish still carry versions of the HoxD genes that build digits in mammals. Evolutionary biologists suspected these genes played a role in fin development, but it wasn’t clear exactly what they do.
To solve this, researchers turned their attention to the non-coding regions of the genome, often dismissed as “junk DNA.” These stretches, known as regulatory landscapes, act like molecular control towers; they don’t code for proteins themselves but orchestrate when and where genes switch on. Using a combination of gene-editing, fluorescent tagging, and 3D chromatin mapping, a team led by developmental geneticist Denis Duboule compared the genomes of mice and zebrafish.
They discovered a surprising connection. In mice, genes in the HoxD cluster, specifically Hoxd13, are activated in the developing limb buds to shape fingers and toes. In zebrafish, those same genes were not active in the fins but instead lit up in the cloaca, the shared posterior opening for the digestive, urinary, and reproductive tracts. The team found that the exact same regulatory domain governs Hoxd13 activation in both the mouse digit and the zebrafish cloaca.
To confirm this link, the researchers used CRISPR/Cas9 to delete this regulatory region in embryos. In mice, deleting this region wipes out Hox gene expression in developing digits. In zebrafish, the deletion did nothing to the fins. Instead, it silenced Hoxd13 in the cloaca, which then failed to form correctly.
“Rather than building a new regulatory system for the digits, nature has repurposed an existing mechanism, initially active in the cloaca,” said developmental geneticist Denis Duboule, senior author of the study.
An Ancient Body Plan Rewired
The Hox genes are well-known for orchestrating the body plans of animals. What this study reveals is that the architecture of gene regulation itself can be reused. It’s a bit like taking one component from a machinery and then using it in a completely differnet system. This repurposing, technically called “evolutionary co-option”, isn’t all that rare. But it’s rarely described in such exquisite molecular detail.
The study also suggests that the regulatory landscape controlling the cloaca predates the evolution of limbs and even external genitalia. In other words, the regulatory code for your fingers was once used to build your ancestors’ most humble opening.
“Our results indicate that the regulatory landscape involved in the evolution of genitalia and limbs first arose to drive the formation of the cloaca,” the authors wrote.
That same landscape is now active in multiple body regions in modern animals, including the urogenital sinus in mammals—a structure that forms the foundation of reproductive and urinary systems, and briefly mimics the ancestral cloaca during embryonic development.
What came first?
These findings arrive on the heels of another provocative hypothesis: that the anus itself evolved from the gonopore—the sperm-releasing opening found in primitive marine worms like Xenoturbella bocki. In a preprint posted to bioRxiv, researchers argue that genes marking the anus in higher animals are also active around this ancient sperm-hole in worms.
“Once a hole is there, you can use it for other things,” said Andreas Hejnol, evolutionary biologist at the University of Bergen, in an interview with New Scientist.
While that hypothesis remains under investigation, it echoes the same core idea: evolution doesn’t always start from scratch. It recycles.
The implications of this research go far beyond fingers and fish.
By illuminating how evolution co-opts existing regulatory systems, the study sheds light on how complex anatomical features emerge over time. It also deepens our understanding of the fin-to-limb transition, one of the most iconic leaps in the history of life.
Just as ancient fish were starting to push their way onto land, their genomes were quietly reorganizing old genetic scripts—transforming a cloacal blueprint into the first primitive toes.
