"Giraffe-Type" Gene-Edited Mice Are Resistant to High Blood Pressure

The giraffe's unique phenotype

The giraffe’s unique body shape has intrigued cultures and scientists alike for many centuries. "Since ancient times, and certainly since Lamarck and Darwin, it has inspired naturalists to philosophize about the forces that could have led to such an exceptional body shape," says Rasmus Heller, associate professor in computational and RNA biology at the University of Copenhagen.

Whilst impressive to look at visually, the tall stature of the giraffe is also impressive physiologically. Maintaining a stable blood supply to the head without incurring cardiovascular damage, and relaying neural signals across incredibly long nerve fibers, are just two examples. This complex phenotype makes the giraffe something of a "Holy Grail" to evolutionary biologists, according to Heller. The long-necked creatures have subsequently been the subject of genomic studies that aim to unravel the underlying genotype.

Heller is the corresponding author of a new study published in Science Advances that sought to better understand the molecular mechanisms behind the giraffe’s unique physiology. To do so, the scientists sequenced the genome of a subspecies of the Northern giraffe – Rothschild's giraffe – and compared it with okapis and bovid relatives, such as cattle and goats.

"Our methods rely on comparing giraffe genes with corresponding genes in other, closely related species. We are looking for genes in which the giraffe has unique mutations that are not found anywhere else […] especially mutations that cause changes in the protein that the gene is coding for," says Heller. These coding genes have been selected for in the course of the giraffe’s evolution, he says, and therefore it is likely that those genes carry out important functions in the giraffe's unique phenotype.

Heller and colleagues used a combination of short-read and long-read sequencing and Hi-C contact maps, a chromosome conformation capture method that enables the examination of all interacting loci across a genome, to achieve an improved assembly of the giraffe genome at the chromosome level. "This is an improvement compared to previous versions of the giraffe genome, which were more fragmented and had higher amounts of uncalled sites," Heller notes.

The researchers identified 414 giraffe genes that had unique substitutions. Within this pool, they confirmed that a fibroblast growth factor (FGF) receptor gene – FGFRL1 – contained seven amino acid substitutions that were not found in any other ruminant.

Giraffe genes confer resistance to high blood pressure in mice

Using CRISPR-Cas9 genome-editing techniques, Heller and colleagues introduced these mutations into the FGFRL1 gene of mice. "The giraffe has a blood pressure that is about twice as high as other animals. We therefore wanted to see what happens to mice carrying the giraffe-specific FGFRL1 gene when we induce high blood pressure in them," he explains.

To the researchers' surprise, they found that the genetically edited mice did not have a "normal" reaction to the compound Ang2, which typically induces high blood pressure. Additionally, they did not present with any associated cardiovascular damage that was found in wild-type mice treated with Ang2 28 days post-administration. "We know that the giraffe-specific FGFRL1 changes the affinity of certain ligands to bind to a receptor involved in the cardiovascular system, and this may be related to the changes we saw in the 'giraffe-type' mice," says Heller. The precise mechanism behind this observation is not known.

The scientists also noted genetic indications of "sensory trade off", whereby the giraffe has downgraded its sense of smell while gaining improved vision. They postulate that this might be because the economy of natural selection typically acts against resource-demanding structures that do not carry a sufficient advantage: the giraffe does not need a highly developed sense of smell to succeed in its environment. "We hypothesize this would make sense, given that giraffes rely a lot on accurate horizon-scanning vision from its tall vantage point and plausibly much less on olfaction – although this is a hypothesis. We believe that the odour landscape is very different, and possibly much impoverished, at five-meter height compared to near the ground," Heller comments.

Further exploring giraffe-specific mutations

As for next steps, Heller and colleagues are further exploring their findings on FGFRL1, aiming to understand any relevant changes to the cardiovascular system as a result of the giraffe-specific mutations.

They emphasize that it is difficult to prove the phenotypic effect of a certain gene variant by introducing it into a foreign genetic background such as their genetically-edited mice. It is possible that genes may not behave in the same way in different organisms.

"We acknowledge that there are many unknowns about the role and effect of the giraffe-type FGFRL1 before we can claim that it has significance also in a human medical setting. Yet, we believe studies such as ours give us fundamentally new insights into the wealth of diversity in function encoded in the genes found throughout the natural world," Heller concludes.

Reference: Liu C, Cui X, Chen L, et al. A towering genome: Experimentally validated adaptations to high blood pressure and extreme stature in the giraffe. Science Advances. 2021. doi: 10.1126/sciadv.abe9459.

Rasmus Heller was speaking to Molly Campbell, Science Writer for Technology Networks.