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Scientists found a mutant zebrafish with extra bones that formed a limb-like joint. On Twitter, M. Brant Hawkins says the team named the mutant zebrafish Rephaim, after the biblical giants with extra fingers and toes. Photo by Inga Spence/Alamy Stock Photo

An Unexpected Hint of a Limb Found in a Fish’s Fin

By flicking a genetic switch, scientists showed how one long-dormant gene gives fish limb-like structures.

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by Chris Baraniuk

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It’s a moment in evolutionary history so notorious it has even been spoofed on The Simpsons: somehow, somewhere, around 370 million years ago, an aquatic animal reached out a stumpy limb and crawled onto land. Had it not, there would be no lions, no pandas, no giraffes—no us. But how exactly did flappy fins turn into limbs? It’s a mystery that has long challenged biologists.

Scientists definitely know that this crucial transition happened—the fossil record makes it very clear. But what hasn’t been determined is precisely how. New research led by M. Brent Hawkins, a doctoral candidate in genetics and evolutionary biology at Harvard University in Massachusetts, may have just uncovered a crucial genetic pathway that made this shift possible.

Hawkins and his colleagues discovered a mutant zebrafish with an unusual pair of additional bones at the base of its pectoral fins. The bones are integrated into the rest of the fish’s body, forming what the scientists call a limb-like joint, replete with muscle connections. The bones sit awkwardly below the zebrafish’s fins, pushing up one end of the entire structure.

But what really makes these out-of-place bones important is how they got there and what that may mean for the evolution of limbs.

Hundreds of millions of years ago, fish effectively split into two lineages: ray-finned fish and lobe-finned fish. Ancient members of the lobe-finned group (which includes the serious-looking coelacanth and all lungfish species) later evolved into species with limbs. The ray-finned fish went their own way and never evolved limbs.

The extra bones discovered in the mutant zebrafish, known as “intermediate radials,” are commonly found in four-limbed species, tetrapods, albeit in a larger and more useful form. But a zebrafish is a ray-finned fish: there is no sense in these extra bones being there. The fact that they are says something very interesting.

According to the work of Hawkins and his colleagues (which has not yet been peer reviewed), the development of the mutant bones in the zebrafish appears to be regulated by the same group of genes—HOX11—that regulate the development of forearm bones in tetrapods, including humans.

Zebrafish may be ray-finned fish, but they share a distant ancestor with lobed fish. Discovering that the HOX11 gene triggers the development of nascent limb-like structures is like reactivating a 400-million-year-old genetic sequence.

When contacted, the authors of the new paper declined to comment, but their work has already garnered attention in the biology community after they uploaded an early copy of their paper online.

Joost Woltering, a biologist at the University of Konstanz in Germany, praises the quality of the research. He says the tiny zebrafish bones are an example of an atavistic trait: a structure or function that existed in an organism’s ancestors and was lost but can be prompted to reappear. (A famous example of another atavistic trait: in 2006, researchers showed that chickens can be prompted to grow alligator-like teeth.)

In their paper, Hawkins and his colleagues describe how they sequenced the genome of their mutant fish and compared it against the genes of fish without the extra bones. They found that one particular gene, waslb, was different in the mutant fish.

The scientists then used CRISPR—a gene editing technique—to confirm in other fish that waslb did not have an obvious role in generating normal fins but did interact with HOX11 in mutants that had intermediate radials.

The scientists flicked a genetic switch and activated an extremely basic form of a limb—the same switch that may have flicked millions of years ago in the ancestors of tetrapods.

Matthew Wills, a paleobiologist at the University of Bath in England, explains that the earliest limbs that evolved in aquatic species were likely not useful for exploring land—instead, they were perhaps used for other activities, such as groping through underwater vegetation. Though these early bony structures originally had other uses, they eventually evolved into more complex limbs.

Should the finding stand up, Wills says, it would suggest that genes that already existed were “adapted and modified and reused in the development of limbs.”

To confirm the finding, Woltering suggests a follow-up study to see if the same genes are at play in lobe-finned fish species, such as lungfish, which have articulated fins vaguely similar to the zebrafish mutants.

Wouter Masselink, a molecular biologist at the Research Institute of Molecular Pathology in Austria, calls the work a “technical first.” Because lungfish “represent an intermediate state of fin to limb transition,” he agrees with Woltering’s suggestions for confirming the finding.

Unraveling evolutionary history hundreds of millions of years later is no easy task. But genetic networks, passed down through billions of generations, do allow scientists to occasionally peer far into the past. Thanks to a mutant zebrafish, we may have just caught a glimpse, a whispered echo, that takes us back to one of evolution’s most important moments.