W.With their long necks, giraffes are a showcase for evolutionary curiosities, but scientists know very little about the genetic basis of such extreme adaptation. An updated giraffe genome published March 17 in Advances in science, reveals new insights into how the species houses what Rasmus Heller, evolutionary geneticist at the University of Copenhagen and author of the new study, describes as “obviously strange body architecture”. The giraffe’s bones, for example, grow faster than any other animal, and the blood pressure required to pump blood down its six-foot-high neck would be fatal to humans. “If you’re an evolutionary biologist, it’s a piece of cake to explain what made this animal look the way it looks and the genetic changes that have become necessary.”
A few years ago, Heller and his colleagues started the Ruminant Genome Project (RGP), a team designed to work out the genomes of all mammals with straight toes and hooves. While the genomes of commercially important species such as cattle have been well studied, wild species receive far less attention. The first giraffe genome was published in 2016, with few related genomes to analyze against. In this study, the researchers matched the genome of the giraffe with the genome of a cow, a dog and a human. With the publication of three papers in 2019 by researchers associated with the RGP, the total number of ruminant genomes available for comparison increased from six to 50.
To generate a more robust giraffe genome, the team used various sequencing technologies to ultimately map nearly 98 percent of the giraffe’s DNA, compared to about two-thirds in the previous genome. The gap between the two has been closed in large part with the advent of sequencing technologies that can produce 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 assume for the time being is that. . This gene helps the giraffe grow strong bones despite having the fastest bone growth rate of any known animal.
– Rasmus Heller, University of Copenhagen
When looking for what makes giraffes unique, it helps to see what sets them apart from their closest relatives rather than distantly related species. At the chromosomal level, giraffes differ from their distant cousins from ruminants, who are 11.5 million years apart from their closest relative, the okapi. While most ruminants have 30 chromosomes, giraffes only have 15, which is the result of a series of fission and fusion events over time. While Heller says that ruminants as a group rearranged their chromosomes more often than other animals, the reason for this remains unclear. “It’s a good question that doesn’t have an easy answer,” says Heller The scientist. “We just don’t know what the functional meaning is.”
When the team examined the genome further, they identified nearly 500 genes that are either unique to giraffes or contain variants unique to giraffes.
Functional analysis of these genes showed that they are most commonly 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. For example, because of their tall stature, giraffes must maintain blood pressure about 2.5 times higher than that of humans in order to pump blood to their brains. In addition, giraffes have keen eyesight to scan the horizon, and because their strange bodies make it difficult for them to stand quickly, they sleep easily, often while standing, for only minutes at a time, probably due to changes during the evolution of genes regulate circadian rhythms.
Within those hundreds of genes FGFRL1 stood out. The seven amino acid substitutions in the giraffe are not only most different from other ruminants, but are also found only in giraffes. In humans, this gene appears to be involved in cardiovascular development and bone growth, leading the researchers to hypothesize that it may also play a role in the giraffe’s unique adaptation to a highly vertical life.
To test this idea, Heller and his team used CRISPR to create giraffe-type mice FGFRL1 Gen. The inclusion of the giraffe-specific gene didn’t dramatically change the mice’s appearance – they didn’t sprout from the giraffe’s iconic long neck, as the team originally hoped – but there was something Heller called “more subtle changes.”
The bones of prenatal mice with the giraffe genotype grew more slowly than unchanged mice. However, after birth, the CRISPR mice quickly grew to a comparable size. Upon closer inspection of the bone structure, the researchers found that the mice with the giraffe variant had a slightly higher bone mineral density, a compensation mechanism that prevents fast-growing bones from becoming structurally weak. “What we are provisionally assuming is that. . This gene helps the giraffe grow strong bones despite the fastest bone growth rate of any known animal, ”says Heller.
Douglas Cavener, a Penn State molecular biologist who was part of the team that sequenced the first giraffe genome, relates The scientist that despite the lack of an obvious morphological change, he agrees with the team’s hypothesis. “I guess FGFRL1 to be critically involved in the giraffe-specific differences in the skeleton, but there are also other genes that are necessary, “says Cavener, which were not built into the CRISPR mice. “FGFRL1. . .may be necessary, but not enough. “
To judge if FGFRL1 Heller’s team injected five mutant mice and five normal mice with a drug called angiotensin-II, which 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 began to suffer from heart and kidney damage. The giraffe-type mice, meanwhile, were largely unaffected, a finding that strongly suggests this FGFRL1 protects against lifelong high blood pressure in giraffes.
“What makes this paper really meaningful are the experiments they did with infusing angiotensin,” says Julian Lui, a staff member at the National Institute for Child Health and Human Development who was not involved in the study. These results, he says The scientist, give “Insight into part of giraffe history because the giraffe has such unique evolutionary adaptations for dealing with hypertension.”
In addition to developing a broader understanding of giraffe genetics – knowledge that can be useful in protecting these species as the species is classified as critically endangered by the International Union for Conservation of Nature – insights into FGFRL1 could help develop treatments for high blood pressure in humans.
Heller adds that there is no evidence yet FGFRL1 has been linked to heart disease in people, it’s a promising place to look. “When we find these genes that are linked to phenotypes that we’re interested in as humans, it’s natural to at least ask the questions,” says Heller The scientist. “We have identified a new variant of a gene that in some situations can have a dramatic impact on the control of high blood pressure. That makes it an interesting gene for further study. ”
C. Liu et al., “A Towering Genome: Experimentally Validated Adaptations to Hypertension and Extreme Stature in the Giraffe”. Sci Adv, doi: 10.1126 / sciadv.abe9459, 2021.
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