Scientists find the ‘meow-tation’ that gives cats their orange fur
A small deletion in a gene on the X-chromosome lies behind the fiery coats of ginger tabbies and the splotchy orange patches of calicos and tortoiseshell cats.
Kyushu University
image:
Professor Hiroyuki Sasaki, a geneticist at Kyushu University with a soft spot for cats, makes fast friends with one of the calico cats at a local shelter while on his hunt for the gene behind orange fur.
view moreCredit: Hiroyuki Sasaki/Kyushu University
Fukuoka, Japan—From Tama, Japan’s most famous stationmaster calico cat, to the lasagna-loving, ginger Garfield, cats with orange fur are both cultural icons and beloved pets. But their distinctive color comes with a genetic twist—most orange tabbies are male, while calicos and tortoiseshells are nearly always female. This pattern points to an unknown “orange gene” on the X chromosome, but identifying this gene has eluded scientists for decades.
Now, researchers from Kyushu University, Japan, have found the X-linked mutation behind orange fur in house cats. This deletion mutation, a type of mutation where a section of DNA is missing, not only explains the peculiarity of ginger genetics, but also reveals an entirely new mechanism for promoting orange coloring in animals. The findings are confirmed by a second independent study by researchers at Stanford University, U.S., with both papers publishing simultaneously in Current Biology on May 15, 2025.
“Identifying the gene has been a longtime dream, so it’s a joy to have finally cracked it,” says Professor Hiroyuki Sasaki, lead author of the study, self-proclaimed cat-lover, and geneticist at Kyushu University’s Medical Institute of Bioregulation and the Institute for Advanced Study.
For over a century, scientists have suspected that the orange gene is located on the X chromosome. Male cats, with only one X chromosome, will have orange coats if they inherit the orange gene. Females, with two X chromosomes, need two copies of the gene to be fully orange, making them less common. If females inherit one orange and one black gene, they develop the patchy or mottled coats seen in calicos and tortoiseshells.
“These ginger and black patches form because, early in development, one X chromosome in each cell is randomly switched off,” explains Sasaki. “As cells divide, this creates areas with different active coat color genes, resulting in distinct patches. The effect is so visual that it has become the textbook example of X-chromosome inactivation, even though the responsible gene was unknown.”
Armed with funding from a successful crowdfunding campaign, Sasaki therefore set out to find the elusive gene.
His team analyzed DNA from 18 cats—10 with orange fur and 8 without—and found that all orange cats shared a specific deletion in the ARHGAP36 gene, while the non-orange cats did not. This pattern held true in 49 additional cats, including samples from an international cat genome database. They also found that in mice, cats, and humans, the ARHGAP36 gene is chemically marked for silencing during X chromosome inactivation, aligning perfectly with the long-standing hypothesis.
“This was such strong evidence that even at this stage, we were confident that ARHGAP36 was the orange gene,” says Sasaki.
Looking closer at the mutation, Sasaki found that the deletion lies in a non-coding region of ARHGAP36, so the protein itself remains unchanged.
“This is key,” he explains. “ARHGAP36 is essential for development, with many other roles in the body, so I had never imagined it could be the orange gene. Mutations to the protein structure would likely be harmful to the cat.”
Instead, Sasaki’s team suspected the mutation altered the gene’s activity. With help from local vets, they examined skin tissue from four calico cats and found that ARHGAP36 was much more active in melanocytes—the pigment-producing cells found in skin—in tissue taken from orange patches compared to tissue from black or white patches.
“This suggests that when present, this section of DNA normally suppresses ARHGAP36 activity,” says Sasaki. “When missing, ARHGAP36 stays active.”
Further analysis showed that high ARHGAP36 activity is linked to reduced activity in many genes involved in melanogenesis, the process that produces pigment in skin and hair. Through a not yet known mechanism, the team believes this shift may steer pigment production from dark eumelanin to lighter pheomelanin, creating orange fur.
Since ARHGAP36 is active in many areas of the body, including in areas of the brain and hormonal glands, it’s possible that the orange variant may cause shifts in gene activity elsewhere, influencing more than just coat color.
“For example, many cat owners swear by the idea that different coat colors and patterns are linked with different personalities,” laughs Sasaki. “There’s no scientific evidence for this yet, but it’s an intriguing idea and one I’d love to explore further.”
Sasaki has other big plans ahead, including using cat cell cultures to decipher the molecular function of ARHGAP36. Since the gene also exists in humans and is linked to conditions like skin cancer and hair loss, the findings could have surprising medical relevance.
He’s also curious about the orange gene’s origins, such as where and when the mutation happened. “One idea is to study ancient Egyptian cat paintings—or even to test DNA from mummified cats—to see if any cats back then were orange,” he says. “It’s ambitious, but I’m excited to try.”
Calico cats have X chromosomes that have two variants of the gene ARHGAP36. In orange patches of fur, the active chromosome (red) contains a deletion mutation in ARHGAP36, which increases its expression and reduces the activity of melanogenesis genes. This leads to higher levels of pheomelanin, resulting in ginger fur. In black patches of fur, the active chromosome (red) does not contain the deletion, and ARHGAP36 is suppressed. The activity of melanogenesis genes remains high, and eumelanin is produced, resulting in black fur.
Calico cats (left) and tortoiseshell cats (right) are the classic example of X chromosome inactivation, where either an orange color or a black color variant of a gene on the X chromosome is active in skin cells, resulting in orange and black patches.
Credit
Hiroyuki Sasaki/Kyushu University
For more information about this research, see “A deletion at the X-linked ARHGAP36 gene locus is associated with the orange coloration of tortoiseshell and calico cats” Hidehiro Toh, Wan Kin Au Yeung, Motoko Unoki, Yuki Matsumoto, Yuka Miki, Yumiko Matsumura, Yoshihiro Baba, Takashi Sado, Yasukazu Nakamura, Miho Matsuda, Hiroyuki Sasaki, Current Biology, https://doi.org/10.1016/j.cub.2025.03.075
About Kyushu University
Founded in 1911, Kyushu University is one of Japan's leading research-oriented institutes of higher education, consistently ranking as one of the top ten Japanese universities in the Times Higher Education World University Rankings and the QS World Rankings. The university is one of the seven national universities in Japan, located in Fukuoka, on the island of Kyushu—the most southwestern of Japan’s four main islands with a population and land size slightly larger than Belgium. Kyushu U’s multiple campuses—home to around 19,000 students and 8000 faculty and staff—are located around Fukuoka City, a coastal metropolis that is frequently ranked among the world's most livable cities and historically known as Japan's gateway to Asia. Through its VISION 2030, Kyushu U will “drive social change with integrative knowledge.” By fusing the spectrum of knowledge, from the humanities and arts to engineering and medical sciences, Kyushu U will strengthen its research in the key areas of decarbonization, medicine and health, and environment and food, to tackle society’s most pressing issues.
Journal
Current Biology
Method of Research
Experimental study
Subject of Research
Animals
Article Title
A deletion at the X-linked ARHGAP36 gene locus is associated with the orange coloration of tortoiseshell and calico cats
Article Publication Date
15-May-2025
Scientists track down mutation that makes orange cats orange
Orange cat mutation identified
Many an orange cat-affiliated human will vouch for their cat’s, let’s say, specialness. But now scientists have confirmed that there is, in fact, something unique about ginger-hued domestic felines. In a new study, Stanford Medicine researchers have discovered the long-posited but elusive genetic mutation that makes orange cats orange — and it appears to occur in no other mammal.
The finding adds to our understanding of how subtle genetic changes give rise to new traits, the researchers said.
Lots of mammals come in shades of orange — think tigers, golden retrievers, orangutans and red-headed humans — but only in domestic cats is orange coloration linked to sex, appearing much more often in males.
“In a number of species that have yellow or orange pigment, those mutations almost exclusively occur in one of two genes, and neither of those genes are sex-linked,” said Christopher Kaelin, PhD, a senior scientist in genetics and lead author of the study to be published online May 15 in Current Biology.
Greg Barsh, MD, PhD, emeritus professor of genetics and of pediatrics, is the study’s senior author.
While scientists have pinpointed the typical mutations that induce pigment cells in the skin to produce yellow or orange pigment instead of the default brown or black, they had only a rough idea of where to find the corresponding mutation in cats.
They knew from the preponderance of male orange cats that the mutation — dubbed sex-linked orange — was somewhere on the X chromosome. (As in most mammals, females have XX while males have XY sex chromosomes.) Any male cat with sex-linked orange will be entirely orange, but a female cat needs to inherit sex-linked orange on both X chromosomes to be entirely orange — a less likely occurrence.
Female cats with one copy of sex-linked orange appear partially orange — with a mottled pattern known as tortoiseshell, or with patches of orange, black and white known as calico. That’s due to a genetic phenomenon in females, called random X inactivation, in which one X chromosome is inactivated in each cell. The result is a mosaic of pigment cells, some that express sex-linked orange and others that do not.
A genetic puzzle
Scientists have taken advantage of the wide variety of cat colors and patterns to study genetics since the turn of the 20th century, yet the molecular identity of the peculiar orange mutation remained hazy.
“It’s a genetic exception that was noticed over a hundred years ago,” Kaelin said. “It’s really that comparative genetic puzzle that motivated our interest in sex-linked orange.”
Building on a prior study that had begun to narrow down the region of the X chromosome containing the mutation, Kaelin and his colleagues zeroed in on sex-linked orange using a step-by-step process.
“Our ability to do this has been enabled by the development of genomic resources for the cat that have become available in just the last 5 or 10 years,” he said. That includes the complete sequenced genomes of a wide assortment of cats. The researchers also collected DNA samples from cats at spay and neuter clinics.
First, they looked for variants on the X chromosome shared by male orange cats and found 51 candidates. They eliminated 48 of these, as they were also found in some non-orange cats. Of the three remaining variants, one stood out as likely having a role in gene regulation: It was a small deletion that increased the activity of a nearby gene known as Arhgap36.
Unusual expression
“At the time we found it, the Arhgap36 gene had no connection to pigmentation,” Kaelin said.
The gene, which is highly conserved in mammalian species, was being studied by researchers in cancer and developmental biology. Arhgap36 is normally expressed in neuroendocrine tissues, where overexpression can lead to tumors. It was not known to do anything in pigment cells.
Except, Kaelin and colleagues discovered, in pumpkin-colored cats.
“Arghap36 is not expressed in mouse pigment cells, in human pigment cells or in cat pigment cells from non-orange cats,” Kaelin said. “The mutation in orange cats seems to turn on Arghap36 expression in a cell type, the pigment cell, where it’s not normally expressed.”
This rogue expression in pigment cells inhibits an intermediate step of a well-known molecular pathway that controls coat color — the same one that operates in other orange-shaded mammals. In those species, typical orange mutations disrupt an earlier step in that pathway; in cats, sex-linked orange disrupts a later step.
“Certainly, this is a very unusual mechanism where you get misexpression of a gene in a specific cell type,” Kaelin said.
Molecular evolution
These efforts to learn how domestic cats acquired different colors and patterns are an entry point to understanding the emergence of other physical traits, from cheetah spots to the streamlined bodies of dolphins. Sex-linked orange is a novel example of how evolution happens on the molecular scale.
“We think it’s an example of how genes acquire new functions that allow for adaptation,” said Kaelin, who has also studied colors and patterns in dogs, cheetahs, tigers, bears, zebras and hamsters.
In the case of orange cats, the “adaptation” could simply be to our whims. Centuries ago, the rare orange, calico or tortoiseshell cat may have caught the attention of humans, who encouraged their proliferation. Orange cats are now widely distributed throughout the world.
“This is something that arose in the domestic cat, probably early on in the domestication process,” Kaelin said. “We know that because there are paintings that date to the 12th century where you see clear images of calico cats. So, the mutation is quite old.”
Only skin deep
Besides a marmalade coat, could sex-linked orange be responsible for other qualities in orange cats? “The expectation, based on our observations, is this is highly specific to pigment cells,” Kaelin said.
To verify, the researchers also measured Arhgap36 expression in several non-skin tissues — the kidney, heart, brain and adrenal gland — and found no differences between orange and non-orange cats.
“I don’t think we can exclude the possibility that there is altered expression of the gene in some tissue we haven’t tested that might affect behavior,” Kaelin conceded. But he thinks orange cats’ reputation as friendly agents of chaos is more likely due to most of them being male.
“There are not many scientific studies of the personality of orange cats,” he added.
Researchers from Brown University, the Frederick National Laboratory for Cancer Research and Auburn University contributed to the study.
The study received funding from the National Institutes of Health (grant R01AR067925) and the HudsonAlpha Institute for Biotechnology.
# # #
About Stanford Medicine
Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.
Orange cat mutation identified
Many an orange cat-affiliated human will vouch for their cat’s, let’s say, specialness. But now scientists have confirmed that there is, in fact, something unique about ginger-hued domestic felines. In a new study, Stanford Medicine researchers have discovered the long-posited but elusive genetic mutation that makes orange cats orange — and it appears to occur in no other mammal.
The finding adds to our understanding of how subtle genetic changes give rise to new traits, the researchers said.
Lots of mammals come in shades of orange — think tigers, golden retrievers, orangutans and red-headed humans — but only in domestic cats is orange coloration linked to sex, appearing much more often in males.
“In a number of species that have yellow or orange pigment, those mutations almost exclusively occur in one of two genes, and neither of those genes are sex-linked,” said Christopher Kaelin, PhD, a senior scientist in genetics and lead author of the study to be published online May 15 in Current Biology.
Greg Barsh, MD, PhD, emeritus professor of genetics and of pediatrics, is the study’s senior author.
While scientists have pinpointed the typical mutations that induce pigment cells in the skin to produce yellow or orange pigment instead of the default brown or black, they had only a rough idea of where to find the corresponding mutation in cats.
They knew from the preponderance of male orange cats that the mutation — dubbed sex-linked orange — was somewhere on the X chromosome. (As in most mammals, females have XX while males have XY sex chromosomes.) Any male cat with sex-linked orange will be entirely orange, but a female cat needs to inherit sex-linked orange on both X chromosomes to be entirely orange — a less likely occurrence.
Female cats with one copy of sex-linked orange appear partially orange — with a mottled pattern known as tortoiseshell, or with patches of orange, black and white known as calico. That’s due to a genetic phenomenon in females, called random X inactivation, in which one X chromosome is inactivated in each cell. The result is a mosaic of pigment cells, some that express sex-linked orange and others that do not.
A genetic puzzle
Scientists have taken advantage of the wide variety of cat colors and patterns to study genetics since the turn of the 20th century, yet the molecular identity of the peculiar orange mutation remained hazy.
“It’s a genetic exception that was noticed over a hundred years ago,” Kaelin said. “It’s really that comparative genetic puzzle that motivated our interest in sex-linked orange.”
Building on a prior study that had begun to narrow down the region of the X chromosome containing the mutation, Kaelin and his colleagues zeroed in on sex-linked orange using a step-by-step process.
“Our ability to do this has been enabled by the development of genomic resources for the cat that have become available in just the last 5 or 10 years,” he said. That includes the complete sequenced genomes of a wide assortment of cats. The researchers also collected DNA samples from cats at spay and neuter clinics.
First, they looked for variants on the X chromosome shared by male orange cats and found 51 candidates. They eliminated 48 of these, as they were also found in some non-orange cats. Of the three remaining variants, one stood out as likely having a role in gene regulation: It was a small deletion that increased the activity of a nearby gene known as Arhgap36.
Unusual expression
“At the time we found it, the Arhgap36 gene had no connection to pigmentation,” Kaelin said.
The gene, which is highly conserved in mammalian species, was being studied by researchers in cancer and developmental biology. Arhgap36 is normally expressed in neuroendocrine tissues, where overexpression can lead to tumors. It was not known to do anything in pigment cells.
Except, Kaelin and colleagues discovered, in pumpkin-colored cats.
“Arghap36 is not expressed in mouse pigment cells, in human pigment cells or in cat pigment cells from non-orange cats,” Kaelin said. “The mutation in orange cats seems to turn on Arghap36 expression in a cell type, the pigment cell, where it’s not normally expressed.”
This rogue expression in pigment cells inhibits an intermediate step of a well-known molecular pathway that controls coat color — the same one that operates in other orange-shaded mammals. In those species, typical orange mutations disrupt an earlier step in that pathway; in cats, sex-linked orange disrupts a later step.
“Certainly, this is a very unusual mechanism where you get misexpression of a gene in a specific cell type,” Kaelin said.
Molecular evolution
These efforts to learn how domestic cats acquired different colors and patterns are an entry point to understanding the emergence of other physical traits, from cheetah spots to the streamlined bodies of dolphins. Sex-linked orange is a novel example of how evolution happens on the molecular scale.
“We think it’s an example of how genes acquire new functions that allow for adaptation,” said Kaelin, who has also studied colors and patterns in dogs, cheetahs, tigers, bears, zebras and hamsters.
In the case of orange cats, the “adaptation” could simply be to our whims. Centuries ago, the rare orange, calico or tortoiseshell cat may have caught the attention of humans, who encouraged their proliferation. Orange cats are now widely distributed throughout the world.
“This is something that arose in the domestic cat, probably early on in the domestication process,” Kaelin said. “We know that because there are paintings that date to the 12th century where you see clear images of calico cats. So, the mutation is quite old.”
Only skin deep
Besides a marmalade coat, could sex-linked orange be responsible for other qualities in orange cats? “The expectation, based on our observations, is this is highly specific to pigment cells,” Kaelin said.
To verify, the researchers also measured Arhgap36 expression in several non-skin tissues — the kidney, heart, brain and adrenal gland — and found no differences between orange and non-orange cats.
“I don’t think we can exclude the possibility that there is altered expression of the gene in some tissue we haven’t tested that might affect behavior,” Kaelin conceded. But he thinks orange cats’ reputation as friendly agents of chaos is more likely due to most of them being male.
“There are not many scientific studies of the personality of orange cats,” he added.
Researchers from Brown University, the Frederick National Laboratory for Cancer Research and Auburn University contributed to the study.
The study received funding from the National Institutes of Health (grant R01AR067925) and the HudsonAlpha Institute for Biotechnology.
# # #
About Stanford Medicine
Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.
Journal
Current Biology
Current Biology
Method of Research
Experimental study
Experimental study
Subject of Research
Animals
Animals
Article Publication Date
15-May-2025
15-May-2025
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