Chris Kaelin, a geneticist at Stanford Medicine, found himself thinking about cats. Not just any cats, but the loud, lovable, and often male ones streaked in unmistakable marmalade. These orange felines — icons of internet memes and cozy laps — have baffled scientists for over a century. Why, among all mammals that come in sunset shades, are domestic cats the only ones whose orange coloring is so tightly bound to sex?

Kaelin now believes he has the answer.

In a study published today in Current Biology, Kaelin and colleagues report they’ve pinpointed the peculiar genetic mutation behind the orange coat in cats — and it’s unlike anything seen in any other mammal.

“For more than a century, orange coat color in cats has been recognized as an exception to the genetic rules that explain coloration in most mammals. Orange male cats are uniformly colored, but female cats often have a patchwork of orange and black fur, commonly referred to as tortoiseshell or calico patterns,” Kaelin told ZME Science.

“Using a combination of approaches, we hoped to resolve the longstanding question of why this sex-linked orange color trait occurs only in domestic cats.”

Turning on a Rogue Gene

Orange coloration in domestic cats almost always shows up in males. Only about 20% of all orange cats are female. Females, with two X chromosomes, need both copies of the orange gene to appear fully orange — rare. Most end up displaying a mosaic of orange and black, a patchwork quilt of fur caused by a genetic process called random X inactivation.

“The orange mutation affects a gene on the X chromosome. In mammals, males have a single X chromosome and therefore one copy of the orange gene, whereas females have two X chromosomes and two copies,” Kaelin said.

In most mammals, orange or yellowish fur results from mutations in one of two specific pigment genes. But these genes aren’t sex-linked and show up in both males and females alike. That’s not what happens in domestic cats.

“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,” Kaelin said.

So, scientists knew they were chasing a mutation unique to the feline X chromosome. But, until now, the exact spot remained elusive.

No Ordinary Gene

To find the mutation, Kaelin’s team combed through the genomes of orange cats. Working with DNA samples from spay and neuter clinics, they relied on advanced genomic tools that weren’t available just a decade ago.

Ultimately, they found something surprising: a tiny deletion on the X chromosome that causes a gene named Arhgap36 to turn on in pigment cells.

This is no ordinary gene. In humans, Arhgap36 is linked to certain neuroendocrine tumors and plays a role in cell signaling during development. But it had never been associated with coat color in any species.

In orange cats, its unexpected activation in pigment cells throws a wrench into the cellular machinery responsible for melanin production. It blocks a late step in the pigment pathway — effectively flipping the fur’s palette from dark to bright orange.

“Certainly, this is a very unusual mechanism where you get misexpression of a gene in a specific cell type,” Kaelin noted in a press release.

More Than Just a Coat?

The mutation, it turns out, isn’t recent. It’s ancient enough that medieval paintings from the 12th century already depict calico cats lounging in the margins. That suggests the mutation emerged early in the history of feline domestication — and perhaps flourished under human influence.

“Although we discovered the mutation years ago, the challenge was understanding how it affects coat color. The mutation alters gene activity instead of disrupting the gene itself, and the affected gene codes for a protein that functions differently from what we could infer without experimentation. Insights from other groups over the course of our study guided our efforts to understand precisely how the mutation ultimately influences coat color in cats,” said Kaelin.

Still, orange cats’ vibrant coats often come with big personalities — at least, according to their owners. Are the genes behind their hue doing more than we think?

The researchers actually explored that possibility. They scanned non-skin tissues — kidney, heart, brain, adrenal gland — and found no difference in Arhgap36 expression between orange and non-orange cats.

“The expectation, based on our observations, is this is highly specific to pigment cells,” Kaelin said.

Still, he didn’t completely rule out surprises.

“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,” he added. “However, our survey of gene activity was limited to specific tissues.”

So, orange cats’ alleged mischievousness? That might be more about who gets the gene — mostly males — than what the gene does.

This was more than just solving a feline riddle. The findings offer a textbook example of how new biological traits can arise through unexpected pathways. Misexpression of a gene. A switch flipped in the wrong tissue. A molecular hiccup that gave rise to a beloved orange coat.

“Color traits in mammals are a useful scientific tool for understanding how genes function and interact,” Kaelin said. “And also a great vehicle for communicating scientific concepts to non-scientists.”

The findings appeared in the journal Current Biology.