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Orange cats come with genetic twist: X-linked mutation points to new mechanism for coloring

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 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 by researchers at Stanford University, U.S., with both papers publishing simultaneously in Current Biology.

"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."

Sasaki set out to find the elusive gene.

His team analyzed DNA from 18 cats—10 with orange fur and eight 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," says 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."