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From whence the big toe? Stanford researchers investigate the genetics of upright walking

A tiny armored fish may seem like an unlikely experimental animal to someone interested in understanding how humans may have evolved to walk on two legs.

But developmental biologist David Kingsley, PhD, has made a career out of studying how changes in gene regulation in the aquatic threespine stickleback broadly affect the fish's skeletal structure. His recent research, published today in Cell, pinpoints a stretch of DNA that controls the size of the protective bone plates sported by marine sticklebacks.

As I explained in our release:

The threespine stickleback is remarkable in that it has evolved to have many different body structures to equip it for life in different parts of the world. It sports an exterior of bony plates and spines that act as armor to protect it from predators. In marine environments, the plates are large and thick; in freshwater, the fish have evolved to have smaller, lighter-weight plates, perhaps to enhance buoyancy, increase body flexibility and better slip out of the grasp of large, hungry insects. Kingsley and his colleagues wanted to identify the regions of the fish’s genome responsible for the skeletal differences that have evolved in natural populations.

"So what?" might ask the more jaded, fish haters among us. (Don't count me among them — I recently blogged here about my undying love for the silvery, colorful killifish that's made an undeniable splash in the field of aging research.)

Well, it turns out that this bit of regulatory DNA controls the expression of an important protein involved in bone formation during development. What's more, this regulatory region is shared among animals separated by millions of years of evolution, from mice to chimpanzees.

But you know who doesn't have it? Humans. Further experiments in the Kingsley laboratory suggest that the region specifically drives expression of the protein, called GDF6, in the hind limbs of our nearest evolutionary relatives, the chimpanzee.

From our release:

The fact that humans are missing the hind-limb-regulatory region probably means that we express less of the gene in our legs and feet during development, but comparable amounts in our nascent arms, hands and skulls. Loss of this particular regulatory sequence would also shorten lateral toes but not the first toe of feet. This may help explain why the big toe is aligned with other short, lateral toes in humans. Such a modification would create a more sturdy foot with which to walk upright.

So a tiny change in a bit of regulatory DNA could possibly explain why we walk, run, jump and even climb trees differently than chimps. The research is one more example of how vital differences in gene expression can drive critical steps in evolution (and further reinforces my love of the laboratory fish!).

As Kingsley explains:

These bone morphogenetic proteins are strong signals for bone and cartilage growth in all types of animals. You can evolve new skeletal structures by changing where and when the signals are expressed, and it’s very satisfying to see similar regulatory principles in action whether you are changing the armor of a stickleback, or changing specific hind-limb structures during human evolution.

Previously: Tickled by stickle(backs)It's a blond thing: Stanford researchers suss out molecular basis of hair color and Something fishy: Threespine stickleback genome published by Stanford researchers
Photo by Pawel Loj

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