New Limbs from Old Fins, Part 5

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In the previous post, we explored molecular genetic evidence that suggests homology between fish fins and tetrapod limbs. Combined with observations of shared anatomical structurecurious fossil intermediates, and oddly conserved signaling systems, the remarkable genetic similarities complete a set of data that is coherently explained by common ancestry. Animal limbs have their historical roots in the fins of ancient fish.

But we left off with a very interesting unanswered question: to what extent do tetrapod limbs arise from fish fins? Detailed developmental studies of developing limbs led to a model of early limb emergence that identifies a process occurring in three phases. As we saw in the previous post, the first phase lays the groundwork for the upper arm, the second phase outlines the lower arm, and the third phase is associated with the most highly specialized structures in a limb: the digits. The first two phases display clear homology with fin development in fish, but Phase III was thought to be a new development – a tetrapod-specific innovation.

Did hands and feet evolve from fins, too?

Until quite recently, there were fairly compelling reasons to think that the development of hands and feet involved completely new processes. Hands and feet are highly specialized for various tetrapod lifestyles, suggesting evolutionary novelty (at the time). More importantly, today's fish – even those thought to be most closely related to tetrapods – seem not to have structures that resemble digits, nor were such structures observed in potential ancient ancestors. And finally, the genetic systems that control digit development seemed to differ in important ways from those that control fin development. Beginning just a few years ago, however, new data began to point to a different conclusion. Let's review those recent findings, concluding with a detailed look at some fresh new results from some fascinating experiments.

Look again: proto-fingers found in an ancient fish fin

Recall that the fossil record includes some intriguing evidence for a fins-to-limbs transition. Tiktaalik appears to be a tetrapod with fishy characteristics, and Tiktaalik had tetrapod-like "hands." But then there's the ancient fish Panderichthys, the transitional ancestor that appears to be closer to fish than to tetrapods. Panderichthys seemed not to have anything resembling hands, strengthening the conclusion that hands and digits were invented in the tetrapod lineage. But in 2008, as genetic evidence to the contrary was mounting (see below), Per Ahlberg and his colleagues took a closer look at Panderichthys using a CT scan. (Also known as CAT scanning, this is a technique that uses X-rays to build a 3-dimensional image of a solid structure. Its most familiar use is in medical imaging.) They found that previous analysis of the fossil had missed key features of its skeletal anatomy. Specifically, they found proto-fingers at the end of the creature's preserved fin. Have a look at the color-coded image below, from their paper. The green section at the top is the humerus. The yellow and the turquoise are radius and ulna. The rust-colored shapes at the bottom are the proto-fingers. There they are: one bone, two bones, blobs, digits.

Ancient gene expression patterns in hands and fins

The genetic story is somewhat more complicated. Early molecular genetic studies had led biologists to suspect that the ends of limbs were distinct from the ends of fins, although there was never a strong consensus around that view. But about 5 years ago, around the time that Tiktaalik was revealed, several different labs reported data that began to tip the scales. Looking at the development of fish of various types chosen based on their evolutionary relationships, all of these labs found striking similarities between the gene expression patterns in fins and the patterns in limbs. In each case, biologists discovered Hox gene expression patterns that strongly resembled Phase III patterns in mice and chicks. It was unmistakable: whether in standard fish like zebrafish, or distant relatives likepaddlefish or even sharks, the three-phase pattern of Hox gene expression lays the groundwork for the development of a fin, just like it does in the development of an arm – and a hand.

Taken together, the fossil evidence from an ancient fish and the surprising homology of Hox gene expression patterns strongly suggest that even the blobs and the digits are modified versions of very ancient structures in fish. But a question remained: just how much functional similarity exists between those genetic patterning systems? In other words, to what extent is that Phase III expression pattern truly homologous between fish and tetrapods? One possibility is that the Phase III Hox expression patterns are similar only superficially; perhaps somehow the pattern emerges from other conserved processes, and the similarities don't mean much. And the other possibility is that the pattern is set by an ancient genetic switch, inherited by both fish and tetrapods from a common ancestor.

Recent experiments on interchangeable genes: chick genes and mouse paws

Biologists in Neil Shubin's lab addressed this question in some elegant experiments published in August 2011. They already knew that the Phase III pattern was controlled in mice by a genetic switch called an enhancer, and they knew roughly where the enhancer was located in the mouse genome. Because they knew the DNA sequence of the enhancer, they were able to find regions of other genomes that are similar in sequence and located near the Hox genes of interest. They looked in mouse, chicken, frog, zebrafish, and skate, animals chosen based on likely evolutionary relationships. And they found the switch in each of those animals. Their question, then, was this: does that switch do the same thing in fish as it does in mice? In other words, will the switch turn on Phase III Hox gene expression patterns in each animal?

They answered this question in somewhat dramatic fashion by doing what we'll call a genetic transplant experiment. They took the switch from one animal and put it into another. That alone is awfully cool, but they did the transplants in such a way that the activity of the transplanted genetic switch could be easily visualized. So, whenever the transplanted switch turned on gene expression, the pattern would be visually apparent.

In one set of experiments, the mouse switch was transplanted into fish embryos. The picture below shows the result. The developing fin is outlined, and the arrowhead points to gene expression that was turned on by the mouse switch. The genes are being expressed at the fringe, in a pattern similar (but not identical) to the Phase III pattern normally seen in developing fish fins. Think about this, because it's really remarkable: a mouse genetic switch turned on a very specific genetic system in a fish, and in the same place and time as it would in the mouse. This is very strong evidence that the two switches (mouse and fish) are the same. They are homologous.

Then, in another set of experiments, switches from chick, fish, and skate were transplanted into developing mouse embryos. In each panel below, you're looking at the developing limb of a mouse; notice the paddle-like shape of the soon-to-be paw. The blue color represents gene expression that was turned on by the transplanted switch. When the chick switch is put into the mouse, we see blue right at the end of the limb, at the base of the paw. That's the same pattern as the one generated by the mouse's own switch. And that result is notable by itself: it means that the tetrapod switches are interchangeable to a large extent. But more remarkable are the effects of the switches from the fish and the skate. Both are also capable of turning on a Phase III-like pattern of gene expression, as indicated by the appearance of blue at the base of the paw. To learn why the skate switch seems "better" than the zebrafish switch, try reading the article, which is freely available at the journal's web site.

A deep shared history

In conclusion, we see that studies of the molecular genetics of animal development strongly indicate common ancestry of fish fins and tetrapod limbs. We've looked at shared anatomical structure, curious fossil intermediates, oddly conserved signaling systems, and, now, remarkable genetic similarities that extend to the end of the fin or limb and deep into their shared history. It's a large collection of varied observations, a collection that we have merely sampled. Descent from common ancestors offers a cohesive and compelling explanation that no competing explanation can match.

In the final post in the series, we'll discuss even deeper homology among animal appendages, explore snakes and whales as examples of tetrapods that don't have all four limbs, and delve into the meaning of design in the context of limbs and common descent.

Further Reading

Neil Shubin (2009) Your Inner Fish: A Journey Into the 3.5-Billion-Year History of the Human Body. New York: Vintage Books.

Brian K. Hall, editor (2007) Fins into Limbs. Chicago: The University of Chicago Press.

Scott F. Gilbert (2000) “Chapter 16. Development of the Tetrapod Limb.” In Developmental Biology, 6th Edition. Sunderland (MA): Sinauer Associates.

John Gerhart and Marc Kirschner (1997) Cells, Embryos, and Evolution. Malden (MA): Blackwell Scientific.

Laura Hoopes, editor (2011) Gene Expression and Regulation at Nature's Scitable site. Part of a large and excellent educational resource in genetics.


Image credits:

Panderichthys fin from Figure 2a of Boisvert et al. (2008) Nature 456:636-638.
Mouse switch in zebrafish fin from Figure 2H; other switches in mouse limbs from Figures 3B, 3D, and 3F of Schneider et al. (2011) PNAS 108:12782–12786.




Matheson, Stephen. "New Limbs from Old Fins, Part 5" N.p., 6 Oct. 2011. Web. 26 February 2017.


Matheson, S. (2011, October 6). New Limbs from Old Fins, Part 5
Retrieved February 26, 2017, from

About the Author

Stephen Matheson

Stephen is a biologist, baseball fanBardolator, beer enthusiast, and bicyclist – and he’s also Senior Editor at Cell Reports and Editor of CrossTalk. Originally from the Wild West (Arizona), he now prefers the chaos of Cambridge (Mass.) and is enamored with the culture of Scotland, the cuisine of India, and all kinds of music. Fascinated by all of science, he has strong interest in neuroscience, evolution, development, and systems biology. He earned a PhD in neuroscience from the University of Arizona and did a postdoctoral fellowship at MGH/Harvard Medical School.

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