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Giraffe Genome Assembly, Functional Analyses Highlight Variants Linked to Height Adaptations

NEW YORK — The giraffe genome includes mutations that enable it to adapt to its tall height, a new analysis has found.

Giraffes, with their long necks and legs, are the tallest terrestrial animals. But their great height — between 14 and 20 feet tall — also poses physiological challenges.

By generating a new Rothschild's giraffe (Giraffa camelopardalis rothschildi) genome assembly, researchers led by Qiang Qiu from Northwestern Polytechnical University in Xi'an, China, uncovered giraffe-specific variants, including ones affecting the cardiovascular system and bone growth. Using gene-edited mice, the researchers further found that substitutions found in FGFRL1 influence both resistance to hypertension resistance and bone mineral density among giraffes, which could be serve as adaptions to their height. These findings could inform studies of cardiovascular disease and hypertension treatments among humans.

"Compared to the previous genome assemblies, this assembly has higher genome completeness," Qiu wrote in an email, adding "we could also discover many more genes in this improved giraffe genome."

The new giraffe assembly appeared Wednesday in Science Advances.

To generate it, the researchers sequenced the genome of a male Rothschild's giraffe using a combination of Oxford Nanopore and Illumina HiSeq2000 and anchored the resulting contigs to chromosomes using Hi-C sequencing data. This yielded a final assembly of 2.44Gb with nearly 98 percent of the bases anchored to 15 chromosomes.

By comparing the new giraffe genome assembly to those of other mammals, the researchers uncovered 101 genes under positive selection and 359 rapidly evolving genes in giraffes. Gene ontology and pathway-based analyses indicated that many of these genes are involved in the circulatory system and growth and development processes.

The researchers in particular homed in on the FGFRL1 gene, which includes a cluster of seven nonsynonymous mutations affecting its FGF binding domain. In humans and mice, alterations in FGFRL1 can cause cardiovascular and skeletal defects, suggesting that these mutations could account for cardiovascular and skeletal adaptions in giraffes. In order to supply their brains with blood, giraffes' cardiovascular systems can tolerate systemic blood pressure that is about two-fold higher than that of other mammals without detrimental effects.

To investigate the role of FGFRL1, the researchers used CRISPR-Cas9 to introduce these seven mutations into the FGFRL1 gene of mice. Mice with the giraffe-style FGFRL1 gene exhibited no signs of heart defects or changes in heart rate.

They additionally infused both altered mice and control mice with angiotensin II to induce high blood pressure. After 28 days of treatment, wild-type mice had significantly increased blood pressure, but mice with the giraffe-style FGFRL1 gene had blood pressure levels similar to untreated control mice. This finding suggested to the researchers that giraffe-style FGFRL1 can help avoid the damaging effects of hypertension and could represent a potential target to treat or prevent hypertension or cardiovascular disease in people.

At the same time, mice with the giraffe-style FGFRL1 genes initially exhibited smaller body sizes, but adult mice did not show skeletal differences from wildtype mice. Bone density analysis, though, found that mice with the giraffe-style FGFRL1 gene had significantly higher bone density. Typically, the researchers noted, animals with high bone growth rates have lower bone density.

This, the researchers said, indicates that the FGFRL1 mutations may affect the cardiovascular and bone — and possibly other — systems in giraffes.

"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 noted.

Qiu said they are further studying FGFRL1 to better understand at the molecular level how the giraffe version influences the cardiovascular system, and are following up on regulatory elements that may contribute to giraffes' long necks.