A Tall Order: Sequencing the Giraffe Genome
Until now, one could have said the highlight of Douglas Cavener’s professional career might be when, in 2015, he was named Verne M. Willaman Dean of the Eberly College of Science and elected a fellow of the American Association for the Advancement of Science. But that was before he and his collaborators published research results on the giraffe genome.
Cavener, also a professor of biology at Penn State, headed a team that recently sequenced the giraffe genome and published results that had many members of the science community intrigued. Not only did they sequence the giraffe and okapi genomes, but they also presented compelling clues as to which part of the genome is responsible for the giraffe’s most unique characteristic: its long neck.
New Research Inspiration
Cavener had spent a career studying the developmental and physiological regulatory processes that are important in the regulation of metabolic and neurological diseases, most recently receiving a grant from the National Institutes of Health to study insulin regulation in diabetes. But atalk given by a Department of Biology colleague would help take his research in a completely new direction.
Nina Fedoroff, emeritus professor of biology, had spoken about a new organization called the Global Knowledge Initiative. The Initiative’s mission was to create collaborations between universities in the West with fledgling universities in developing countries. Cavener was inspired by her talk and he asked Fedoroff how Penn State could be involved. The Global Knowledge Initiative team paired Penn State with a university that was just starting in Arusha, Tanzania, called the Nelson Mandela African Institute of Science and Technology (NMAIST)
Cavener and Peter Hudson, a fellow Department of Biology faculty member and director of the Huck Institutes of the Life Sciences, traveled to Tanzania in 2011 to establish a collaboration with NMAIST, where now both hold adjunct faculty positions.
After his very first visit to Tanzania, Cavener knew one way he wanted to link the two universities was by teaching a class that traveled to Tanzania. Then he met Morris Agaba, a professor in NMAIST’s School of Life Sciences and Bioengineering, and the two hit it off. They discovered they had similar research interests and discussed possible ideas for research collaboration.
“We thought it would be marvelous to sequence the genome of one of the iconic African animals, and we thought this project would spark the research enterprise of this new university in Tanzania,” said Cavener.
When they started discussing ideas for which animal, they discovered that a few iconic African animals had already been sequenced. It turns out that the African lion had been sequenced, as had the African elephant.
The two kept thinking about their choice. While they were in a restaurant in Arusha, Tanzania, having lunch during one of the exchange trips, Agaba looked down at the tablecloth and saw a giraffe printed on it. He pointed to the giraffe on the tablecloth, showing Cavener, who immediately agreed that they had found their iconic African animal genome to sequence.
The choice was perfect, as the giraffe is the quintessential African iconic animal, but also because it had long baffled biologists.
“As soon as I realized the giraffe hadn’t been sequenced, I also realized that it would be far more interesting because of giraffe’s unique attributes, and we might actually learn something through the analysis of its DNA sequence,” Cavener said.
How can an animal as tall and lanky as the giraffe sprint up to 37 miles per hour? And it’s not just the giraffe’s physical appearance and behavior that have long intrigued scientists, but also its inner workings. Because of its long neck and legs, the giraffe’s cardiovascular system must work very hard to pump blood two meters straight up to its brain, and then adjust when a giraffe lowers its head to drink water.
To determine which genes might be responsible for its unique characteristics, Cavener and Agaba decided to compare the giraffe genome with its closest relative, the okapi.
“Giraffe and okapi diverged from a common ancestor only 11-to-12 million years ago,” Cavener explained. “In spite of this close evolutionary relationship, the okapi looks more like a zebra and it lacks the giraffe’s imposing height and impressive cardiovascular capabilities. For these two reasons, okapi’s genome sequence provides a powerful screen that we have used to identify some of the giraffe’s unique genetic changes.”
Using comparative tests, the research team analyzed differences in the giraffe and okapi genomes as well as to over 40 other mammals to help identify where adaptations relating to giraffe’s unique characteristics could lie. The tests allowed them to narrow down 20,000 genes to just 70 genes that showed multiple signs of adaptation.
“These adaptations include unique amino-acid-sequence substitutions that are predicted to alter protein function, protein-sequence divergence, and positive natural selection,” Cavener said. “Over half of these 70 genes code for proteins that are known to regulate development and physiology of the skeletal, cardiovascular, and nervous system—just the type of genes predicted to be necessary for driving the development of the giraffe’s unique characteristics.”
Of these genes, several that are known to regulate the development of the cardiovascular system or control blood pressure are showing multiple signs of adaptation—a sign that they have isolated the right cluster of genes to explain those specific unique characteristics. Some of those genes work double duty, also playing a big role in skeletal development, suggesting that the giraffe’s stature and cardiovascular system evolved together from the same set of genes.
As for its long neck and legs, the team also may have discovered the genes responsible for that.
“To achieve their extraordinary length, giraffe cervical vertebrae and leg bones have evolved to be greatly extended,” Cavener explained. “At least two genes are required—one gene to specify the region of the skeleton to grow more and another gene to stimulate increased growth.”
The team found a gene called FGFRL1 to be the most interesting of these genes. FGFRL1 has a cluster of amino acid substitutions unique to giraffe that are located in the part of the protein that binds fibroblast growth factors, which are important for controlling development. In addition, the team discovered four homeobox genes—genes involved in body structure development—which are commonly known to specify the regions of the spine and legs. Together with FGFRL1, these genes could explain the giraffe’s interesting skeletal structure.
“The combination of changes in these homeobox genes and the FGFRL1 gene might provide two of the required ingredients for the evolution of the giraffe’s long neck and legs,” said Cavener.
While the findings were monumental, the path there was not without its challenges.
“An easily overlooked challenge was sample acquisition,” said Agaba. Luckily, they were able to build relationships with zoos that could provide tissue samples for the research.
A Productive Partnership
There is no doubt that this research collaboration has achieved the original goal set forth by the Global Knowledge Initiative. The response to the team’s research results has been great for both researchers at Penn State and at NMAIST.
“There’s no comparison. I’ve never had anything like this in my career. Not even close,” said Cavener. “It’s gotten a huge amount of attention.”
The paper is currently resting at the top of the research publication world, sitting comfort- ably in the top 0.1% of research published in any field to date according to the research publication analytics site Altmetrics. Cavener estimates that members of national and international media have interviewed him more than 25 times about this project.
Agaba and NMAIST have felt the enormous success as well. “The international, global coverage of the publication was a huge point for NMAIST,” said Agaba. “It cast a bright light on our young institute.”
Cavener attributes much of their press to the topic they covered: “In terms of being able to identify clues to a major developmental change in mammals, there’s nothing that comes close to giraffe—it is so awe-inspiring. The fact that we identified the most likely genes and genetic changes behind giraffe’s unique adaptations was the major reason for all of the attention.”
Agaba hopes to channel the attention to showcase the importance of basic research: “I guess my challenge is to translate the attention into more interest and need by policy makers to invest in basic research,” he said. “When you have a generation of people that have been raised on a menu of battling poverty, disease, and hunger, it can be daunting to sell them a story of the origins of the giraffe’s long neck. The reflex or gut response is more like, ‘where is the food, or how does this cure a disease?’”
Challenges like this are why the Global Knowledge Initiative exists, and why they facilitate partnerships like the one between Penn State and NMAIST.
Agaba looks forward to working on it. “It is a challenge that I hope we can tackle together.”
Did you Know?
- Although a giraffe’s neck is 1.5–1.8 meters, it contains the same number of
vertebrae as a human neck. - The giraffe is the tallest mammal in the world, with even its newborn babies being taller than most humans.
- Even giraffe tongues are huge. They are up to 45cm long.
- A giraffe’s heart weighs about 25 pounds—it has to be that big to pump blood all the way to its brain.
- Giraffes only spend between 10 minutes and two hours asleep per day. They have
one of the shortest sleep requirements of any mammal. - Just like human fingerprints, no two giraffes have the same spot pattern and the 9 subspecies are distinguished by their coat patterns.
- A group of giraffes is called a tower.
- Giraffes can go longer without drinking water than camels can.
- Giraffes are ruminants. This means that they have more than one stomach. In fact, giraffes have four stomachs, the extra stomachs assisting with digesting food.