Short answer: not literally. A 2025 Nature study found that a large region of regulatory DNA around HoxD genes controls gene activity in a fish cloaca and in mouse digits and urogenital tissue. The authors propose that the lineage leading to tetrapods—including humans—co-opted an older cloacal gene-regulation program as digits and external genital structures evolved. A fish’s cloaca did not physically turn into a hand, and the experiments did not test an animal from 380 million years ago.
What “a fish’s butthole helped make fingers” means
The headline compresses an evolutionary-developmental idea into a vivid image. The study is about regulatory DNA: stretches of the genome that help turn nearby genes on in particular tissues and at particular times. The genes at issue belong to the HoxD cluster, which helps provide positional instructions during development.
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A cloaca is a shared chamber or opening used for excretion and reproduction in many vertebrates. It is not the same structure as a hand or finger. The proposed connection is that some ancient DNA control circuitry active in cloacal development was later reused, or co-opted, in the developing distal limbs of tetrapods.
The final report appears in Nature, volume 648, pages 109–116 (2025): “Co-option of an ancestral cloacal regulatory landscape during digit evolution.”
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What the researchers actually tested
The researchers deleted corresponding HoxD regulatory landscapes in zebrafish and compared the results with the known role of equivalent regions in mice. “Regulatory landscape” is important wording: this was a broad genomic region containing multiple enhancers, not one isolated on/off switch.
| Experimental context | Tissue examined | Intervention | Observed effect |
|---|---|---|---|
| Zebrafish | Distal fin and cloaca | Full deletion of corresponding HoxD regulatory landscapes | Distal-fin hoxd transcription was not disrupted in the way the equivalent landscape is required for mouse digits; cloacal hoxd expression was eliminated, and distal hox13 genes were essential for correct cloacal formation. |
| Mouse | Developing digits and urogenital sinus | Functional comparison with the digit-associated regulatory region | The same genomic neighborhood contributes to digit regulation and also contains enhancers active in the urogenital sinus. |
The authors summarize the fish–mouse difference this way: “We show that, unlike in mice, deletion of these regions in fish does not disrupt hoxd gene transcription during distal fin development.”
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Why the fish and mouse results matter
If the zebrafish regions had controlled distal-fin hoxd activity exactly as the corresponding regions control mouse digits, the ancestral-to-digit story would be less distinctive. Instead, the deletions exposed a strong cloacal role in fish while showing that distal-fin regulation is organized differently from digit regulation in mice.
That contrast supports a model in which tetrapod evolution did not simply preserve a fin program and stretch it into fingers. It may have recruited an older regulatory system—one already active in a cloacal developmental context—and integrated it with newer limb and genital regulatory networks.
The evolutionary hypothesis: co-option, not transformation
In evolutionary biology, co-option means using an existing biological component in a new context. A gene, enhancer, or developmental program can acquire an additional role without losing its older one.
Applied here, the authors propose that an ancestral cloacal regulatory landscape was redeployed during the emergence of digits and external genital structures in early tetrapods. The evidence is comparative and functional: deleting the regions in living fish reveals their cloacal role, while mouse experiments show related regulatory activity in digits and the urogenital sinus.
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This does not identify a single “finger gene.” Digit formation involves many genes, enhancers, signaling pathways and tissue interactions. The study addresses how one important regulatory neighborhood may have been reused within that larger developmental system.
What “380 million years ago” does—and does not—tell us
The 380-million-year figure places the proposed evolutionary transition in deep time, around the period when early tetrapod traits were emerging. It is context for the hypothesis, not a measurement made by this experiment.
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The researchers worked with modern zebrafish and mice. They did not recover ancient DNA, edit a 380-million-year-old fossil, or observe a prehistoric cloaca becoming a digit. Fossils and comparative genetics provide the broader evolutionary setting; the laboratory tests examine whether living organisms still reveal compatible regulatory functions.
Independent reader supportYour contribution helps us test, update, and keep practical guides available for everyone.How strong is the evidence?
- Directly shown: deleting the tested zebrafish regulatory landscapes affects cloacal hoxd expression and cloacal development, while not producing the same distal-fin transcription defect expected from the mouse digit system.
- Also shown in the mouse comparison: enhancers in the relevant genomic neighborhood are active in the urogenital sinus as well as in digit development.
- Proposed interpretation: tetrapods co-opted an ancestral cloacal regulatory program during the evolution of digits and genitals.
- Not shown: that one switch made human fingers, that a fish cloaca anatomically became a hand, or that the exact sequence of events in a 380-million-year-old animal has been reconstructed.
The earlier related article is available through PubMed Central, with an indexed record at PubMed. The final publication is indexed at PubMed.
Why this matters for understanding evolution
Evolution often modifies existing developmental systems rather than inventing every structure from scratch. Regulatory DNA is especially useful for this kind of change because an enhancer can alter where or when a gene acts while leaving the gene’s basic biochemical function intact.
The study therefore offers a concrete example of how anatomical novelty can arise through changes in gene regulation. It links a developmental program associated with an ancestral body opening to the regulatory architecture of tetrapod digits without claiming that the structures are anatomically equivalent.
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The study supports a precise, limited conclusion: an ancient cloacal regulatory landscape may have been co-opted into the developmental networks that produced tetrapod digits. “A fish’s butthole made human fingers” is memorable shorthand, not a literal account of anatomy or a claim that one DNA switch independently built the human hand.
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