Feline Genetics and Why Orange Cats Are the Most Special

Recently, butlers to orange-colored cats got a bit of a shock when reading the news, as headlines began to call out their fuzzy feline friends as ‘freaks of nature’ and …read more

Jun 10, 2025 - 01:10

Feline Genetics and Why Orange Cats Are the Most Special

Recently, butlers to orange-colored cats got a bit of a shock when reading the news, as headlines began to call out their fuzzy feline friends as ‘freaks of nature’ and using similarly uncouth terms. Despite the name-calling, the actual reason for this flurry of feline fascination was more benign — with two teams of scientists independently figuring out the reason why some cats have fur that is orange. Tracking down the reason for this turned out to be far more complicated than assumed, with the fact that about 80% of orange cats are male being only the tip of the cat-shaped iceberg.

It was known to be an X chromosome-linked mutation, but rather than the fur coloring being affected directly, instead the mechanism was deduced to be a suppression of the black-brownish pigmentation (eumelanin) in favor of the orange coloration (pheomelanin). Finding the exact locus of the responsible ‘O gene’ (for orange) in the cat genome has been the challenge for years, which turned out to be a mutation related to the X-linked ARHGAP36 gene, whose altered expression results in the suppression of many melanogenesis genes.

Interestingly, this particular mutation appears to be of a singular origin that apparently persisted over millennia courtesy of the domestication of humans (H. sapiens) by Felis catus.

Furry Patterns

Although F. catus doesn’t have the wide variety of phenotypes that everyone’s favorite canid companions (Canis familiaris) got subjected to after the first grey wolves got cozy with H. sapiens, there is still significant variety among cats. Most of this variety is seen in the fur, with characteristics including coloration, curliness and length varying quite significantly.

European wildcat (F. silvestris). (Credit: Alena Houšková, Wikimedia) — European wildcat (*F. silvestris*). (Credit: Alena Houšková, Wikimedia)

The underlying genetics are relatively straightforward despite the pretty wild number of possible phenotypes. Here we should mind the cautionary note that some phenotypes are the result of inbreeding of recessive genetic defects, such as the hr mutation in the KRT71 (keratin) gene that prevents hair follicles from forming, as found in the so-called Sphynx cats. Due to the amount of inbreeding required to maintain these recessive mutations, such breeds suffer many health issues and a shortened lifespan. Here we will thus only look at healthy F. catus genetics without such inbreeding baggage.

F. catus has the African wildcat (F. lybica) as its direct ancestor, with the European wildcat (F. silvestris) being the other divergent branch. Interestingly, F. silvestris seems to resist domestication more than F. lybica, with the latter being the cat species that the Ancient Egyptians would have kept around. All of these have similar genetics, and thus the wildcats give a good idea of what a ‘wild’ phenotype range looks like. Of note is that these wildcats are generally not orange, unlike many of their brethren in the Pantherinae sub-family of Felidae, like tigers and lions, which is another kettle of genetic fish.

Hair length is determined by the FGF5 gene, which much like in H. sapiens determines for how long a hair grows before it enters the catagen (regression) phase. In e.g. Norwegian Forest Cats as well as Maine Coons the growth cycle is much longer, which gets these breeds a thicker coat, which normally consists out of the typical down, awn and guard hairs.

Fur color is solely determined by melanin, specially the dark & brown eumelanin along with the yellow-reddish pheomelanin, with the amount or absence of each determining the final color. As far as patterns go, it’s likely that the ‘tabby’ coat pattern originates in wildcats, with naturally bred F. catus (‘non-pedigree’) often displaying this pattern.

In order for an orange, generally called ‘red’ or ‘ginger’, coat color to appear, there would thus have be a severe decrease in eumelanin production, with pheomelanin being primarily present. This is effectively the same as in H. sapiens and the ‘ginger’ phenotype with reddish hair and lack of eumelanin pigmentation in the skin.

The problem for genetic scientists was that they did not know exactly why the eumelanin production was being suppressed in favor of pheomelanin, with researchers finally sufficiently narrowing down the location on the X-chromosome through comparative analysis between F. catus DNA to pin-point the location and from there understand the mechanics.

Deleted

Summary of study findings by Hidehiro Toh et al., Current Biology, 2025

Both the study by Hidehiro Toh et al. and the study by C.B. Kaelin et al. (BioRxiv) came to the same conclusion, namely that a 5 – 5.1 kilobase (kb) section had been deleted which resulted in a significantly higher expression of ARHGAP36 (Rho GTPase Activating Protein 36). This is likely because the deleted section that normally precedes ARHGAP36 inhibits the expression of this gene.

Normally the production of eumelanin is activated via the following pathway in melanocytes:

Melanocortin 1 receptor (Mc1r)
cyclic adenosine monophosphate (cAMP)
protein kinase A (PKA)

In the case of eumelanin suppression, the affected cats still have this pathway intact, but the increased expression of ARHGAP36 leads to reduced levels of the PKA catalytic subunit (PKA_c), thus interrupting this pathway at the final step and preventing the production of eumelanin.

Impact of increased ARHGAP36 expression on melanocyte gene expression. (Credit: Hidehiro Toh et al., Current Biology, 2025)

Although melanin is commonly associated with hair and skin coloring, these neural crest-derived melanocytes have more roles and are considered part of the body’s immune system. Neuromelanin, for example, is a form of melanin that is produced in the brain, though with an unknown function. The ARHGAP36 gene is strongly expressed in neuro-endocrinological tissues, which conceivably may imply a significant role for the normal functioning of melanocytes in this context.

In the case of hair & skin pigmentation, the effect is as we can observe rather striking, with mixed negative and positive health effects based on the effective change in gene expression. Fortunately a drop in IQ is not among the negative outcomes, despite the slander often hurled at orange-coated cats.

Randomly Tortoise

A cat with calico coat pattern. (Credit: Ksmith4f, Wikimedia)

The two coat patterns most commonly associated with this orange mutation without being purely orange are the tortoiseshell and calico patterns, which are effectively the same except with white (no pigment, courtesy of the KIT gene) present with the latter. This kind of coat pattern is caused by the random inactivation of either of the two X chromosomes in female cats (X-inactivation), where just one of the X chromosomes has the ARHGAP36 mutation.

A female cat can have this mutation on both X chromosomes, but this is far less likely, thus explaining why most orange cats are male, and why calico and tortoiseshell cats are overwhelmingly female.

Although male cats can have a calico or tortoiseshell pattern, this is because they have a genetic (intersex) condition like Klinefelter syndrome (XXY), or chimerism (merged cell lines from two distinct embryos). This rare confluence of factors makes such coat patterns with male cats very rare, at less than one percent.

Most Special of All

From what we can determine based on historical writings and art, and on the similarity of these deletions near the ARHGAP36 gene, this is a mutation that occurred likely once thousands of years ago, and has persisted in F. catus populations ever since. Even if similar mutations were to have occurred in wildcat populations, they are likely to have been heavily selected against. European wildcats are however known to interbreed with feral F. catus, which may introduce such mutations in those populations.

Ultimately these findings mean that orange cats as well as calicos and tortoiseshells are the result of a very special moment in history, when H. sapiens and F. lybica met up and the former saw fit to preserve one of the most unique phenotypes that truly define F. catus as the wildcat who came to conquer our homes and our hearts.