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Researchers Identify Genetic Mutation Responsible for Orange Coat in Domestic Cats

This mutation is located in the Rho GTPase Activating Protein 36 (Arhgap36) gene and appears to occur in no other mammal, according to a research team led by Stanford University School of Medicine scientists.

The sex-linked orange mutation in domestic cats causes variegated patches of reddish/yellow hair and is a defining signature of random X inactivation in female tortoiseshell and calico cats; unlike the situation for most coat color genes, there is no apparent homolog for sex-linked orange in other mammals; Kaelin et al. show that sex-linked orange is caused by a 5-kb deletion that leads to ectopic and melanocyte-specific expression of the Arhgap36 gene. Image credit: Kaelin et al., doi: 10.1016/j.cub.2025.04.055.

The sex-linked orange mutation in domestic cats causes variegated patches of reddish/yellow hair and is a defining signature of random X inactivation in female tortoiseshell and calico cats; unlike the situation for most coat color genes, there is no apparent homolog for sex-linked orange in other mammals; Kaelin et al. show that sex-linked orange is caused by a 5-kb deletion that leads to ectopic and melanocyte-specific expression of the Arhgap36 gene. Image credit: Kaelin et al., doi: 10.1016/j.cub.2025.04.055.

Lots of mammals come in shades of orange — think tigers, golden retrievers, orangutans and red-headed humans — but only in domestic cats (Felis silvestris catus) 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 Dr. Christopher Kaelin, a researcher at Stanford University School of Medicine and HudsonAlpha Institute for Biotechnology.

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.

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.

“It’s a genetic exception that was noticed over a hundred years ago,” Dr. 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, Dr. 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,” Dr. Kaelin 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.

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

The team’s discovery is described in a paper published this week in the journal Current Biology.

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Christopher B. Kaelin et al. Molecular and genetic characterization of sex-linked orange coat color in the domestic cat. Current Biology, published online May 15, 2025; doi: 10.1016/j.cub.2025.04.055

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