ABOVE: Giraffes appear to be just as strange on the inside as they are on the outside. A new study reveals how these animals have evolved highly mutated genes in order to support their odd physique.

With their long necks, giraffes are a poster child for evolutionary oddities, but scientists know very little about the genetic underpinnings of such an extreme adaptation. An updated giraffe genome, published March 17 in Science Advances, reveals new insights into how the species accommodates what Rasmus Heller, an evolutionary geneticist at the University of Copenhagen and an author on the new study, calls a “blatantly strange body architecture.” Giraffe’s bones grow faster than any other animal, for instance, and the blood pressure required to pump blood up its six-foot neck would be fatal to humans. “If you’re an evolutionary biologist, it’s a no-brainer to try to explain what drove that...

Several years ago, Heller and his colleagues launched the Ruminant Genome Project (RGP), a multi-team effort to flesh out the genomes of all even-toed, hoofed mammals. While the genomes of commercially important species such as cattle are well-studied, wild species receive far less attention. The first giraffe genome was published in 2016, with few related genomes to analyze it against. In that research, the researchers aligned the giraffe’s genome with the genome of a cow, a dog, and a human. With the release of three papers in 2019 by researchers linked to the RGP, the total number of ruminant genomes available for comparison jumped from six to 50.

To generate a more robust giraffe genome, the team used several sequencing technologies, ultimately mapping almost 98 percent of the giraffe’s DNA, compared to roughly two-thirds in the earlier genome. The gap between the two has largely been filled by the advent of sequencing technologies that can generate longer DNA sequencing reads, combined with the additional ruminant genomes that can now be used to align the giraffe genome and annotate its genes. 

What we tentatively hypothesize is that . . . this gene is doing something to help the giraffe grow strong bones despite having the fastest growth rate of bones of any known animal.

—Rasmus Heller, University of Copenhagen

When scanning for what makes giraffes unique, it helps to be able to look at what separates them from their nearest relatives, rather than from distantly related species. At the chromosome level, giraffes differ from their distant ruminant cousins, separated as they are by 11.5 million years from their nearest relative, the okapi. While most ruminants have 30 chromosomes, giraffes have only 15, the result of a series of fission and fusion events over time. While Heller says that ruminants as a group have rearranged their chromosomes more frequently than other animals, the reason for this remains unclear. “It’s a good question that doesn’t have a simple answer,” Heller tells The Scientist. “We simply don’t know what the functional significance is.”

Unlocking giraffeness 

When the team probed the genome further, they identified almost 500 genes that are either unique to giraffes or contain variants found only in giraffes. 

A functional analysis of these genes showed that they are most often associated with growth and development, nervous and visual systems, circadian rhythms, and blood pressure regulation, all areas in which the giraffe differs from other ruminants. As a consequence of their tall stature, for example, giraffes must maintain a blood pressure that is roughly 2.5 times higher than that of humans in order to pump blood up to their brain. In addition, giraffes have sharp eyesight for scanning the horizon, and because their strange bodies make it difficult for them to stand quickly, they sleep lightly, often standing up and for only minutes at a time, likely a result of changes during evolution to genes that regulate circadian rhythms.

Within those hundreds of genes, FGFRL1 stood out. In addition to being the giraffe’s most divergent gene from other ruminants’, its seven amino acid substitutions are unique to giraffes. In humans, this gene appears to be involved in cardiovascular development and bone growth, leading the researchers to hypothesize that it might also play a role in the giraffe’s unique adaptations to a highly vertical life. 

To test this idea, Heller and his team used CRISPR to create mice with the giraffe-type FGFRL1 gene. Inserting the giraffe-specific gene didn’t cause any drastic changes to how the mice looked—they didn’t, as the team initially hoped, sprout the giraffe’s iconic long neck—but there were what Heller calls “more subtle changes.” 

The bones of prenatal mice with the giraffe genotype grew more slowly compared to unaltered mice. Once born, however, the CRISPR mice quickly grew to a comparable size. When the researchers looked more closely at the bones’ structure, they saw that the mice with the giraffe variant had a slightly higher bone mineral density, a compensatory mechanism that keeps fast-growing bones from becoming structurally weak. “What we tentatively hypothesize is that . . . this gene is doing something to help the giraffe grow strong bones despite having the fastest growth rate of bones of any known animal,” Heller says.

Douglas Cavener, a molecular biologist at Penn State who was part of the team that sequenced the first giraffe genome, tells The Scientist that, despite the lack of an obvious morphological change, he agrees with the team’s hypothesis. “I suspect FGFRL1 of being critically involved in the giraffe-specific differences in the skeleton, but there are other genes that are necessary as well” that haven’t been built into the CRISPR mice, Cavener says. “FGFRL1 . . .may be necessary, but it’s not sufficient.”

To assess whether FGFRL1 helps giraffes cope with the hypertension necessary to push blood throughout their long bodies, Heller’s team next injected five mutant mice and five normal mice with a drug called angiotensin-II that induces high blood pressure. They also included five mutant mice that did not receive the drug as a control. After 28 days, the normal mice had developed hypertension and were beginning to suffer from heart and kidney damage. The giraffe-type mice, meanwhile, were largely unaffected, a finding that strongly suggests FGFRL1 is protective against lifelong high blood pressure in giraffes.

“What really makes this paper significant is the experiments that they did with the infusion of angiotensin,” says Julian Lui, a staff scientist at the National Institute of Child Health and Human Development who was not involved in the study. These results, he tells The Scientist, give “insight into one part of the giraffe story because the giraffe has such unique evolutionary adaptations for dealing with hypertension.” 

In addition to cultivating a more complete understanding of giraffe genetics—knowledge that may be useful in protecting them, as the species is listed as vulnerable to extinction by the International Union for Conservation of Nature—insight into FGFRL1 could help efforts to develop treatments for high blood pressure in humans.

Heller adds that while there’s no evidence yet that FGFRL1 is associated with heart disease in people, it’s a promising place to start looking. “When we find these genes that are linked to phenotypes that we are interested in as humans, it’s natural to at least ask the questions,” Heller tells The Scientist. “What we have done here is identify a new variant of a gene that may have a dramatic impact on controlling hypertension in some settings. That makes it an interesting gene for further study.” 

C. Liu et al., “A towering genome: Experimentally validated adaptations to high blood pressure and extreme stature in the giraffe,” Sci Adv, doi:10.1126/sciadv.abe9459, 2021.

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giraffe, genetics & genomics, CRISPR, gene editing, genome, physiology, hypertension, bone growth, techniques, mouse model

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