Why a Mutation in Ginger Cats Might Explain Both Color (and Chaos)

Orange cats tend to have a reputation. People call them quirky, affectionate, chaotic or just a bit odd.

But while their behavior might be up for debate, their color has always raised a clear genetic question.

Now, a new study conducted at Stanford University has identified a deletion on the X chromosome that switches on a normally silent gene in pigment cells, causing orange fur.

The results were published in Current Biology.

A genetic mystery with a long history

Orange fur in domestic cats shows a strong link to sex, with most orange cats being male. This pattern has been noticed since the early 1900s, informing scientists that the gene responsible most likely sits on the X chromosome. Any male cat that inherits it turns orange, whereas female cats, with two X chromosomes, need two copies of the gene to do the same. Female cats can be orange, but it’s rare – usually they’re a patchwork of orange and black (tortoiseshell or calico).

Unlike other mammals with orange shades – tigers, golden retrievers and red-haired humans – cat orange isn't linked to the usual pigment genes (like MC1R or ASIP).

“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 lead author Dr. Christopher Kaelin, a life science research professional in the Department of Genetics at Stanford University.

Scientists had a rough idea where the mutation in cats might be, but nothing was confirmed – it was a genetic outlier.

In cats, the color comes with a mystery: a trait that’s inherited, clearly tied to sex, but missing the usual genetic suspects.

“It’s a genetic exception that was noticed over a hundred years ago,” said Kaelin. “It’s that comparative genetic puzzle that motivated our interest in sex-linked orange.”

Using previous work, Kaelin and his colleagues set out to find the exact mutation responsible for orange fur in domestic cats and to understand why this trait behaves so differently from similar colors in other mammals.

Identifying the mutation behind ginger fur

The team used novel genomic resources, including full genome sequences from many cat breeds and DNA samples collected at spay and neuter clinics across the US.

“Our ability to do this has been enabled by the development of genomic resources for the cat that has become available in just the last 5 or 10 years,” said Kaelin.

They focused on male orange cats since males have only one X chromosome, any mutation on it would show up clearly. Comparing their DNA, the researchers found 51 variants shared by orange males. They then ruled out most by checking non-orange cats, leaving only three variants remaining.

One of them, a small 5,000-base-pair deletion, stood out. It was linked to higher activity in a nearby gene called Arhgap36.

The team confirmed the deletion was present in all 145 orange cats and absent from 37 non-orange cats, strengthening its link to coat color.

“At the time we found it, the Arhgap36 gene had no connection to pigmentation,” said Kaelin.

Using single-cell RNA sequencing of fetal cat skin, the team found that in orange cats, Arhgap36 was switched on in pigment cells; however, in non-orange cats and other mammals, it wasn’t.

“Arghap36 is not expressed in mouse pigment cells, human pigment cells or cat pigment cells from non-orange cats. The mutation in orange cats seems to turn on Arghap36 expression in a cell type, the pigment cell, where it’s not normally expressed,” Kaelin added.

This misexpression appears to block part of the MC1R signaling pathway, which usually drives the production of black or brown pigment. Instead, pigment cells default to producing orange.

Unlike other species where orange coloration disrupts early steps in pigment production, the cat mutation acts later in the pathway, blocking the function of a key signaling molecule downstream of MC1R.

The team confirmed that Arhgap36 is only activated in the skin of orange cats. Other organs showed no changes, suggesting the effect is specific to pigment cells.

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

To test the effect of Arhgap36, the researchers introduced the gene into human pigment cells, where it reduced levels of PKAC – a protein essential for activating pigment genes.

The evolutionary story behind the ginger cat gene

The findings show how a gene with no known link to color can take on a new role. This switch in location, not function, creates a visible trait.

“We think it’s an example of how genes acquire new functions that allow for adaptation,” said Kaelin.

This kind of regulatory rewiring – sometimes called molecular tinkering – is a common theme in evolution. The orange cat mutation shows how changes in gene regulation, rather than gene structure, can drive traits.

The team found that all orange cats in their study carried the same chunk of DNA around the mutation, pointing to a single origin for the trait at least 900 years ago.

“This is something that arose in the domestic cat, probably early in the domestication process,” said Kaelin. “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.”

Could this unusual genetic discovery also play a part in ginger cats' questionable behavior?

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

“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.

Still, he suspects the ginger cat stereotype is more about gender than genetics – most orange cats are male.

“There are not many scientific studies of the personality of orange cats,” he noted.

 

Reference: Kaelin CB, McGowan KA, Trotman JC, et al. Molecular and genetic characterization of sex-linked orange coat color in the domestic cat. Curr Biol. 2025. doi: 10.1016/j.cub.2025.04.055

 

This article is a rework of a press release issued by Stanford Medicine. Material has been edited for length and content.