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| The spots displayed by a typical cheetah (standing), compared with the blotched pattern of king cheetahs. (Credit: Courtesy of the Ann van Dyk Cheetah Preserve) |
Feral cats in Northern California have enabled researchers to unlock the biological secret behind a rare, striped cheetah found only in sub-Saharan Africa, according to researchers at the Stanford University School of Medicine, the National Cancer Institute and HudsonAlpha Institute for Biotechnology in Huntsville, Alabama. The study is the first to identify a molecular basis of coat patterning in mammals.
The scientists
found that the two felines share a biological mechanism responsible for both
the elegant stripes on the tabby cat and the cheetah's normally dappled coat.
Dramatic changes to the normal patterns occur when this pathway is disrupted:
The resulting house cat has swirled patches of color rather than orderly
stripes, and the normally spotted cheetah sports thick, dark lines down its
back.
"Mutation of a
single gene causes stripes to become blotches, and spots to become
stripes," said Greg Barsh, MD, PhD, emeritus professor of genetics and of
pediatrics at Stanford and an investigator at the HudsonAlpha Institute.
The differences are
so pronounced that biologists at first thought that cheetahs with the mutated
gene belonged to an entirely different species. The rare animals became known
as "king cheetahs," while affected tabby cats received the less-regal
moniker of "blotched." (The more familiar, striped cat is known as a
mackerel tabby.)
The study will be
published Sept. 21 in Science. Christopher Kaelin, PhD, a senior scientist in
the Barsh laboratory, is the co-first author; Xiao Xu PhD, from the National
Cancer Institute-Frederick National Laboratory for Cancer Research and the
Sichuan Key Laboratory of Conservation Biology on Endangered Wildlife in
Sichuan, China, is the other co-first author. Marilyn Menotti-Raymond, PhD, of
NCI-Frederick is the senior author.
Barsh and his lab
members have spent decades investigating how traditional laboratory animals
such as mice develop specific coat colors. His previous work identified a
variety of biologically important pathways that control more than just hair or
skin color, and have been linked to brain degeneration, anemia and bone marrow
failure. But laboratory mice don't display the pattern variation seen in many
mammals.
"We were
motivated by a basic question," said Barsh of the turn to the study of big
(and little) cats. "How do periodic patterns like stripes and spots in
mammals arise? What generates them? How are they maintained? What is their
biological and evolutionary significance? It's kind of surprising how little is
known. Until now, there's been no obvious biological explanation for cheetah
spots or the stripes on tigers, zebras or even the ordinary house cat."
The research relied
primarily on DNA samples from feral cats in Northern California captured for
sterilization and release, on tissue samples provided by the City of Huntsville
Animal Services group, and on small skin biopsies and blood samples from
captive and wild South African and Namibian cheetahs. It also hinged on the
recent availability of the whole-genome sequence of the domestic cat.
(Menotti-Raymond's research focuses on the genomic analysis of the domestic cat
to better understand many human diseases.)
"The
Laboratory of Genomic Diversity at the National Cancer Institute has long
championed the cat as an animal model of human disease," said
Menotti-Raymond. "Studying color variation in cats provides the
opportunity to uncover new principles of gene action and interaction that may
have unexpected applications to understanding developmental and morphologic
variation in natural populations, including humans."
Comparing gene
sequences of feral cats with different patterns allowed Kaelin and Xu to
identify mutations in a gene they dubbed Taqpep associated with the blotched
tabby markings: 58 of 58 blotched tabbies had a mutation in each of its two
copies of Taqpep, while 51 of 51 mackerel tabbies had a least one unmutated
version.
Taqpep encodes a
protease normally found in the cell membrane, but that can also be cleaved to
allow it to diffuse outside the cell. This ability to float freely and interact
with other molecules in the extracellular soup is a key component of a
principle called reaction diffusion proposed by the famous computer scientist
Alan Turing, PhD, in 1952 as a way to explain how periodic patterns (like
stripes and spots) can arise out of randomness.
"Turing
realized that, under specific conditions, diffusible 'activator' and
'inhibitor' molecules can self-organize into a variety of periodic
patterns," said Barsh. "We are excited about the idea that Taqpep
might be an entry point to understand if, and how, reaction-diffusion
mechanisms can explain 'how the leopard got its spots.'"
After nailing down
Taqpep's role in tabby stripes (and analyzing its sequence in more than 350
other cats of 24 distinct breeds), Kaelin wondered if it might play a similar
role in generating and maintaining the spots on wild and captive cheetahs. He
obtained blood samples from a king cheetah named Kgosi, a resident of a wildcat
education and conservation program in Northern California, and found that Kgosi
also had a mutation in Taqpep.
Kaelin next
contacted Ann van Dyk, who maintains a cheetah conservation center in South
Africa from which all captive king cheetahs, including Kgosi, originate. (Van
Dyk was the first to learn, though meticulous breeding records, that the king
cheetah pattern is due to a recessive genetic mutation.) Van Dyk obtained DNA
samples from all her cheetahs, allowing confirmation that a Taqpep mutation is
responsible for the king cheetah pattern.
Mammals aren't the
only animals with patterned hair or skin, obviously. Fish, salamanders and some
invertebrates also have stripes and spots. However, there is an essential
difference. While the non-mammals simply add stripes or spots as they grow to
adulthood, mammals keep the same number and pattern by increasing the surface
area of the contrasting colors.
"Somehow,
cells in the black stripes know they are in a black stripe and remember that
fact throughout the organism's life," said Barsh. "We were curious
about what's happening at the boundary between light and dark stripes and
spots. How do these spots know to grow with an animal?"
When Kelly McGowan,
MD, PhD, a senior scientist in Barsh's group, studied fetal cat skin after
seven weeks of gestation, she found that the tabby pattern begins to arise only
when the hair begins to grow. In other words, there are no apparent differences
between the cells themselves -- only in the color of hair they produce. That
suggested that the changes in color are due to differences in the levels of
expression of certain genes within the cells.
Lewis Hong, a
former graduate student in Barsh's lab, used a technique he developed called
EDGE to identify changes in gene expression levels between black and yellow
areas of cheetah skin (obtained under anesthesia). He found several
differences, many associated with a pathway influencing the expression of a
gene called Edn3. McGowan found that Edn3 mRNA was produced at the base of the
follicles making the black hairs. To test their theory, the researchers
collaborated with a group at Florida International University to study a
yellow-colored laboratory mouse that had been engineered to express Edn3. The
coats of the resulting animals were much darker than their unmodified peers.
"This is very
strong evidence that Edn3 is a critical regulator of black versus yellow hair
in animals," said Barsh. The researchers hypothesize that expression of
Taqpep is required to establish a pattern of stripes or spots in early feline development
that is then carried out by Edn3 as the hair grows.
Clearly, not all
cats are patterned. In particular, some big adult cats like African lions and
mountain lions are distinctive for their lack of color variation even though
their cubs are striped. Furthermore, Taqpep mutations are surprisingly common
in some non-striped domestic cat breeds like the Abyssinian and the Himalayan.
"We know
there's a mutation that suppresses pattern formation in some cats," said
Barsh. "We'd like to investigate that mechanism as well."
In
addition to Kaelin, Barsh, McGowan and Hong, Stanford researcher and technician
Hermogenes Manuel also participated in the study.
The
research was funded by the National Institutes of Health, the NCI and the
HudsonAlpha Institute.
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