Giraffes’ weirdest feature could unlock new treatments for heart disease

Giraffes are among the giants of the mammalian world. With their infamously long necks and spindly legs, adult male giraffes can reach up to 18 feet tall and weigh 3,000 pounds. They are far bigger than their closest relatives, such as the okapi — a striped creature that is closer in stature to a zebra than a giraffe.

On the surface, the genes underlying why giraffes are so tall may seem far removed from human health, but a new study suggests one gene in particular — known as FGFRL1 — could hold clues to treatments for a host of human health problems, including hypertension and cardiovascular disease.

What’s new — In a study published Wednesday in the journal Science Advances, researchers zoom in on a specific gene known as FGFRL1, which in giraffes, often contains a significant number of mutations.

In the new paper, the researchers theorize that, in giraffes, FGFRL1 may present an instance of pleiotropy at work — this is when one gene produces a multitude of different, seemingly unrelated traits.

Study co-author Qiang Qiu‬ is a researcher at the Chinese Academy of Sciences’ Center for Excellence in Animal Evolution and Genetics. He explains to Inverse that FGFRL1’s pleiotropic nature in giraffes may explain, at least in part, why giraffes have survived for so long, despite the challenges posed by their big bodies.

Essentially, they suggest FGFRL1’s pleiotropic effects likely enables giraffes to deal with high blood pressure, develop strong bones, and be less vulnerable to cardiovascular damage.

How they did it — To come to this conclusion, the researchers first created a map of the giraffe genome and compared it to the genomes of other ruminants, including cattle and the okapi.

From the comparison, the scientists identified certain giraffe-specific mutations which may have enabled these animals to overcome the challenges of maintaining their own bodies.

To test this idea, the researchers induced high blood pressure in wild mice — a control group — and mice that had been genetically modified to carry a variant of FGFRL1 found in the giraffes.

They also conducted CT scans of the mice to examine their bone structure and skeletal growth.

Digging into the details — The analysis revealed stark differences between the genetically modified mice and the controls. Specifically, the mice which carried the giraffe variant of FGFRL1 had better health outcomes overall than did mice in the control group.

“The giraffe-type FGFRL1 mice showed two significant differences from normal mice: they suffered less cardiovascular and organ damage and they grew more compact and denser bones,” Qiu says.

The finding suggests giraffes evolved a suite of adaptations, stemming from variations in FGFRL1, which may have enabled them to survive and thrive.

“Both of these changes are directly related to the unique physiological features of the giraffe — coping with high blood pressure and maintaining compact and strong bones,” Qiu says.

Strong bones may have enabled giraffes to evolve into the tall creatures we know and love today, a trait which offers them several advantages over other ruminants on the savannah — specifically, the ability to use their long necks to scan above the tree canopy for food and predators, as well as the ability to reach tender, juicy leaves on trees out of other creatures’ reach.

The researchers ultimately conclude that “these results show that pleiotropy is a plausible mechanism for contributing to the suite of co-adaptations necessary in the evolution of the giraffe’s towering stature.”

Why it matters — The results suggest variants of FGFRL1 found in giraffes could hold significant implications for human health.

If scientists can understand the biological mechanisms underpinning FGFRL1 — specifically, its effects on blood pressure and the cardiovascular system — then they may be able to use that knowledge to develop new treatments for conditions affecting blood pressure and heart health in humans, such as hypertension and heart disease.

The researchers write:

These results provide insights into the genetic basis of the giraffe anatomy and associated adaptations, with particular implications concerning the cardiovascular system, which may be helpful for treating human cardiovascular disease and hypertension.

Of course, giraffes are very different from humans, so translating these findings to humans is not so simple.

“We must also keep in mind that the effect may be different in different species, so there is some way to go before using it in human intervention,” Qiu says.

In a separate finding, the researchers also found a number of variants in genes to do with giraffes’ vision and eye development which may relate to Usher syndrome in humans. Usher syndrome is a rare genetic disorder correlated with hearing and vision loss. Taken together, the findings point to a potential avenue for further research on the intersection between giraffe evolution and human health.

What’s next — Qiu suggests that the giraffe’s variants of the FGFRL1 gene will be crucial to potentially applying the creature’s biological adaptations to human medicine.

“We know that the giraffe-specific FGFRL1 changes the affinity of certain ligands to bind to a receptor involved in the cardiovascular system, but we do not know for sure how this works,” Qiu says.

But the limitations of the study could pose challenges for this future research, according to the scientists.

For example, the researchers inserted a giraffe-specific variant of the FGFRL1 gene into mice, but mice themselves have a different genetic background to giraffes. As a result, the results in mice can’t be readily applied to broader medical research.

The scientists will first need to conduct further tests on mice that carry the giraffe-FGFRL1 gene to broaden the medical application of their findings, according to Qiu.

“More studies are required to perform detailed physical and medical analysis of the mechanisms behind the observed mouse phenotype, and understand how the giraffe-FGFRL1 affects the cardiovascular system,” Qiu says.

Understanding how FGFRL1 functions on a molecular level — and how it interacts with the animal’s cardiovascular system — is the next step in the scientists’ research.

“We are following up on our findings regarding FGFRL1, trying to understand much better at the molecular level any relevant changes to the cardiovascular system conferred by giraffe-type FGFRL1,” Qiu says.

Abstract: The suite of adaptations associated with the extreme stature of the giraffe has long interested biologists and physiologists. By generating a high-quality chromosome-level giraffe genome and a comprehensive comparison with other ruminant genomes, we identified a robust catalog of giraffe-specific mutations. These are primarily related to cardiovascular, bone growth, vision, hearing, and circadian functions. Among them, the giraffe FGFRL1gene is an outlier with seven unique amino acid substitutions not found in any other ruminant. Gene-edited mice with the giraffe-type FGFRL1 show exceptional hypertension resistance and higher bone mineral density, both of which are tightly connected with giraffe adaptations to high stature. Our results facilitate a deeper understanding of the molecular mechanism underpinning distinct giraffe traits, and may provide insights into the study of hypertension in humans.