Consider the engineering marvel that is your foot. Be it hairy or homely, without its solid support you’d be hard-pressed to walk or jump normally.

Now, researchers at the Stanford University School of Medicine and the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, have identified a change in gene expression between humans and primates that may have helped give us this edge when it comes to walking upright. And they did it by studying a tiny fish called the threespine stickleback that has evolved radically different skeletal structures to match environments around the world.

“It’s somewhat unusual to have a research project that spans from fish all the way to humans, but it’s clear that tweaking the expression levels of molecules called bone morphogenetic proteins can result in significant changes not just in the skeletal armor of the stickleback, but also in the hind-limb development of humans and primates,” said David Kingsley, PhD, professor of developmental biology at Stanford. “This change is likely part of the reason why we’ve evolved from having a grasping hind foot like a chimp to a weight-bearing structure that allows us to walk on two legs.”

Kingsley, who is also a Howard Hughes Medical Institute investigator, is the senior author of a paper describing the work that was published online Jan. 7 in Cell. The lead author is former Stanford postdoctoral scholar Vahan Indjeian, PhD, now head of a research group at Imperial College London.

Adapting to different environments

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.

The researchers identified the area of the genome responsible for controlling armor plate size, and then looked for differences there in 11 pairs of marine and freshwater fish with varying armor-plate sizes. They homed in on a region that includes the gene for a bone morphogenetic protein family member called GDF6. Due to changes in the regulatory DNA sequence near this gene, freshwater sticklebacks express higher levels of GDF6, while their saltwater cousins express less. Strikingly, marine fish genetically engineered to contain the regulatory sequence of freshwater fish expressed higher levels of GDF6 and developed smaller armor plates, the researchers found.