By studying gene regulation in a tiny little fish, researchers believe they 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. [iStock/Xrisca30]
By studying gene regulation in a tiny little fish, researchers believe they 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. [iStock/Xrisca30]

Be it flat, arched, beautifully adorned, or Fred Flintstone-esque, the foot is a grand achievement of evolutionary engineering. The shift toward a flatter weight-bearing appendage not only afforded humans the ability to walk upright and bipedally; in a much broader sense allowed the species to traverse large distances more easily, ultimately leading to the migration of humans across the globe.

Researchers at the Stanford University School of Medicine and the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, have identified a variation in gene expression between humans and primates that may have aided early humans in the development of upright walking. Interestingly, the researchers' findings came about after studying variations among a tiny fish called the threespine stickleback, which has evolved radically different skeletal structures to match their different 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,” explained senior study author David Kingsley, Ph.D., HHMI researcher and 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.”

The findings from this study were published recently in Cell through an article entitled “Evolving New Skeletal Traits by cis-Regulatory Changes in Bone Morphogenetic Proteins.”

The threespine stickleback is a remarkable little fish, having adapted many different body structures to equip it for life in various parts of the world. It sports an exterior of bony plates and spines that act as armor to protect it from predators; the plates are large and thick in marine environments, smaller and lighter in freshwater regions. Given these adaptations, the investigators looked to identify the areas within the fish's genome responsible for the skeletal differences that have evolved in natural populations.

Using 11 pairs of marine and freshwater fish with varying armor plate sizes, the scientists honed 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. Moreover, marine fish genetically engineered to contain the regulatory sequence of freshwater fish expressed higher levels of GDF6 and developed smaller armor plates.

The researchers wondered whether changes in GDF6 expression levels might have also contributed to critical skeletal modifications during human evolution, so they began to compare differences in the genomes of chimps and humans. From previous studies, the research team found over 500 spots where humans have lost regulatory regions that are conserved in chimps and many other mammals. To their amazement, two of the regions occur near the GDF6 gene. 

“This regulatory information was shared through about 100 million years of evolution,” noted Dr. Kingsley. “And yet, surprisingly, this region is missing in humans.”

In order to learn more about what GDF6 might be controlling, the researchers used chimp regulatory DNA to control the production of a protein that was easy to visualize in mice. The researchers found that these genetically engineered mice strongly and specifically expressed the protein in their hind limbs and lateral toes, but not their forelimbs or the big toes of the hind limbs. Conversely, mice genetically engineered to lack the ability to produce GDF6 had skull bones that were smaller than normal, and their toes were shorter than those of their peers. Taken together, these findings provided insight that GDF6 might play a critical role in limb development and evolution.

That humans are missing the hind limb regulatory region suggests that we express less of the gene in our legs and feet during development, but comparable amounts in our young 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.

“These bone morphogenetic proteins are strong signals for bone and cartilage growth in all types of animals,” Dr. Kingsley concluded. “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.”








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