Giraffe genome holds keys to its peculiar body and clues to hypertension treatments


To biologists, the giraffe’s long neck is a prime example of evolution’s handiwork, cited by both Charles Darwin and Jean-Baptiste Lamarck as support for their evolutionary theories. But it is also an engineering problem. In order to get oxygen up its 2-meter neck to its brain, a giraffe’s heart constantly pumps blood at a pressure roughly 2.5 times higher than is normal in humans. Now, a new giraffe genome is revealing genetic alterations that allow these animals to live happily with hypertension—along with other genes linked to giraffes’ unusual physique.

The findings illuminate “the fascinating evolution of the giraffe form,” says wildlife biologist Monica Bond at the Wild Nature Institute. The researchers also expressed a giraffe gene in mice and showed it protected them from hypertension, perhaps laying the groundwork for new therapies for humans. “It is a beautiful validation of the notion that you can try to assess differences in species by making gene substitutions in mice models,” says molecular biologist Douglas Cavener of Pennsylvania State University, University Park, who published the first giraffe genome 5 years ago.

For the new study, researchers from China, Norway, and Denmark compared the genes of a male Rothschild’s giraffe (Giraffa Camelopardalis rothschildi) with those of 50 other mammals, including the giraffe’s closest relative, the short-necked, zebra-size okapi; the animals diverged about 11.5 million years ago. The new study provides detailed data on about 97% of the giraffe’s DNA, compared with two-thirds of the genome in the earlier sequence. Published in Science Advances this week, the study identifies 490 genes with unique adaptations in the giraffe.

Most of the mutations are in genes linked to cardiovascular features, bone growth, and the sensory system. The team zeroed in on the gene FGFRL1, in which Cavener and his colleagues had found seven unique mutations. In humans and mice, mutations in this gene are linked to cardiovascular and skeletal defects. To find out more, the team used the powerful DNA editor called CRISPR to insert the giraffe mutations into the FGFRL1 gene of mice.

The mutant mice did not grow long necks or show any obvious change in their cardiovascular system. So the team decided to see how the animals would respond to high blood pressure, the normal condition of the giraffe. They gave five of 10 modified mice a drug to induce high blood pressure, and also injected the drug into five normal mice. The normal mice developed hypertension and associated kidney and heart damage. But all the mutant rodents, including those given the drug, stayed healthy, and their blood pressure rose only slightly.

“The FGFRL1 giraffe gene does something to the cardiovascular system that counteracts the effects of hypertension,” says co-author Rasmus Heller, an evolutionary geneticist at the University of Copenhagen. “But we don’t know what yet.”

Further studies on FGFRL1 might point to treatments for hypertension, Heller says. But many genes cause hypertension, and there’s no evidence so far that FGFRL1 plays an important role in the disease in humans, cautions hypertension and precision medicine specialist Bina Joe at the University of Toledo. “If indeed this is a major gene protecting humans from hypertension, it should have come up as a candidate in genomewide association studies,” which scan thousands of people for gene variants linked to a disease. “Talking about therapeutic approaches at this point would be premature,” agrees University of Tennessee Health Science Center nephrologist L. Darryl Quarles, who notes that researchers don’t yet understand how the mutations affect blood pressure.

The study highlights other unique mutations, including those in genes related to eye development and vision. Previous studies have shown that giraffes have the best vision of all hoofed mammals, which together with their stature allows them to scan the horizon effectively. On the other hand, the giraffe has lost at least 53 olfactory genes compared with the okapi. Heller says this could indicate that giraffes have a lousy sense of smell—a sense that is less important when your nose is 6 meters above the ground. “The giraffe … has traded off the sense of smell for improved eyesight,” he notes. “When you upgrade one feature, you often downgrade another.”

The team also found mutations in genes that regulate sleep patterns, which could explain why giraffes in the wild only sleep 40 minutes per day and about 3 to 5 minutes at a time.

Bond notes that giraffes are endangered and in the past 30 years, their population has declined 40%, to 68,000 in the wild. She says knowing more about the animal’s genome can help shape effective conservation strategies based on genes related to fitness, health, and immunity. “Genetics is one more piece of the puzzle in understanding an organism,” she says. “The more we can understand them, the better we can help protect them.”, 17 March 2021